Funapide TV 45070,  XEN-402,  Funapide, (+)-

• Molecular FormulaC₂₂H₁₄F₃NO₅
• Average mass429.345 Da

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one

Spiro(furo(2,3-F)-1,3-benzodioxole-7(6H),3′-(3H)indol)-2′(1’H)-one, 1′-((5-(trifluoromethyl)-2-furanyl)methyl)-, (3’S)-

(3’S)-1′-((5-(Trifluoromethyl)furan-2-yl)methyl)-2H,6H-spiro(furo(2,3-F)(1,3)benzodioxole-7,3′-indol)-2′(1’H)-one

Phase II clinical trials for Postherpetic neuralgia (PHN)

Treatment of Neuropathic Pain

• Originator Xenon Pharmaceuticals
• Developer Teva Pharmaceutical Industries; Xenon Pharmaceuticals
• Class Benzodioxoles; Fluorobenzenes; Furans; Indoles; Non-opioid analgesics; Small molecules; Spiro compounds
• Mechanism of Action Nav1.7-voltage-gated-sodium-channel-inhibitors; Nav1.8 voltage-gated sodium channel inhibitors

• Orphan Drug Status Yes – Erythromelalgia

Highest Development Phases

• Phase II Erythromelalgia; Postherpetic neuralgia
• No development reported Dental pain; Pain
• Discontinued Musculoskeletal pain

Most Recent Events

• 09 May 2017 Teva Pharmaceutical Industries completes a phase IIb trial for Postherpetic neuralgia in USA (Topical) (NCT02365636)
• 26 Sep 2016 Adverse events data from a phase II trial in Musculoskeletal pain presented at the 16^th World Congress on Pain (PAN – 2016)
• 19 Aug 2015 No recent reports of development identified – Phase-I for Pain (In volunteers) in Canada (PO)

MP 100 – 102 DEG CENT EP2538919

S ROT  ALPHA 0.99 g/100ml, dimethyl sulfoxide, 14.04, US 20110087027

Funapide (INN) (former developmental code names TV-45070 and XEN402) is a novel analgesic under development by Xenon Pharmaceuticals in partnership with Teva Pharmaceutical Industries for the treatment of a variety of chronic pain conditions, including osteoarthritis, neuropathic pain, postherpetic neuralgia, and erythromelalgia, as well as dental pain.^[1][2][3][4] It acts as a small-moleculeNa_v1.7 and Na_v1.8 voltage-gated sodium channel blocker.^[1][2][4] Funapide is being evaluated in humans in both oral and topicalformulations, and as of July 2014, has reached phase IIb clinical trials.^[1][3]

Sodium channels play a diverse set of roles in maintaining normal and pathological states, including the long recognized role that voltage gated sodium channels play in the generation of abnormal neuronal activity and neuropathic or pathological pain. Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors. These changes can produce long-lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia. Examples of neuropathic pain include, but are not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.

There have been some advances in treating neuropathic pain symptoms by using medications, such as gabapentin, and more recently pregabalin, as short-term, first-line treatments. However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates. Consequently, there is still a considerable need to explore novel treatment modalities.

There remain a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic. There is also an unmet medical need to treat neuropathic pain and other sodium channel associated pathological states effectively and without adverse side effects. PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708 discloses certain spiro-oxindole compounds. These compounds are disclosed therein as being useful for the treatment of sodium channel-mediated diseases, preferably diseases related to pain, central nervous conditions such as epilepsy, anxiety, depression and bipolar disease;

cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome.

Methods of preparing these compounds and pharmaceutical compositions containing them are also disclosed in PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT

Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708.

Column: Chiralcel® OJ-RH; 20 mm I.D.×250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical Industries, Ltd)

Eluent: Acetonitrile/Water (60/40, v/v, isocratic)

Flow rate: 10 mL/min

Run time: 60 min

Loading: 100 mg of compound of formula (I) in 1 mL of acetonitrileTemperature: Ambient

Under the above chiral HPLC conditions, the (R)-enantiomer of the compound of formula (I), i.e., (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)>99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.2 Hz, 2H), 5.13, 5.02 (ABq, J_AB=16.4 Hz, 2H), 4.82, 4.72 (ABq, J_AB=9.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]_D−17.46° (c 0.99, DMSO).

The (S)-enantiomer of the compound of formula (I), i.e., (S)-1′-{[5-(trifluoromethypfuran-2-yl]methyl}spiro-[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was isolated as the second fraction as a white solid; ee >99% (analytical OJ-RH, 55% acetonitrile in water); mp 100-102° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.3 Hz, 2H), 5.12, 5.02 (ABq, J_AB=16.4 Hz, 2H), 4.82, 4.72 (ABq, J_AB=9.4 Hz, 2H); ¹³C NMR (75MHz, CDCl₃) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]_D+14.04° (c 0.99, DMSO)

Synthetic Example 3Resolution of Compound of Formula (I) by SMB Chromatography

The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by SMB chromatography under the following conditions:

Extract: 147.05 mL/min, Raffinate: 76.13 mL/min Eluent: 183.18 mL/min Feed: 40 mL/min Recycling: 407.88 mL/min Run Time: 0.57 min Temperature: 25° C. Pressure: 46 bar

The feed solution (25 g of compound of formula (I) in 1.0 L of mobile phase (25:75:0.1 (v:v:v) mixture of acetonitrile/methanol/trifluoroacetic acid)) was injected continuously into the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm I.D.) of ChiralPAK-AD as stationary phase. The first eluting enantiomer (the (R)-enantiomer of the compound of formula (I)) was contained in the raffinate stream and the second eluting enantiomer (the (S)-enantiomer of the compound of formula (I)) was contained in the extract stream. The characterization data of the (S)-enantiomer and the (R)-enantiomer obtained from the SMB resolution were identical to those obtained above utilizing chiral HPLC.

The compound of formula (I) was resolved into its constituent enantiomers on a Waters preparative LCMS autopurification system. The first-eluting enantiomer from the chiral column was brominated (at a site well-removed from the stereogenic centre) to give the corresponding 5′-bromo derivative, which was subsequently crystallized to generate a single crystal suitable for X-ray crystallography. The crystal structure of this brominated derivative of the first-eluting enantiomer was obtained and its absolute configuration was found to be the same as the (R)-enantiomer of the invention. Hence, the second-eluting enantiomer from the chiral column is the (S)-enantiomer of the invention. Moreover, the material obtained from the extract stream of the SMB resolution had a specific optical rotation of the same sign (positive, i.e. dextrorotatory) as that of the material obtained from the aforementioned LC resolution.

Patent

WO 2013154712

EXAMPLE 8

Synthesis of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yllmethylJspirotfurop.S-flll .Sl enzoclioxole-y.S’-indoll-Zil ‘Wi-one

Compound of formula (ia1 )

To a cooled (0 °C) solution of (3S)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 7 (16.4 mmol) and 2- (diphenylphosphino)pyridine (5.2 g, 20 mmol) in anhydrous tetrahydrofuran (170 mL) was added di-ferf-butylazodicarboxylate (4.5 g, 20 mmol). The mixture was stirred for 2 h at 0 °C, then the reaction was diluted with ethyl acetate (170 mL), washed with 3 N hydrochloric acid (7 x 50 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (80 mL), decolorizing charcoal (15 g) was added and the mixture was heated at reflux for 1 h. The mixture was filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated in a mixture of diethyl ether/hexanes to afford (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3-/][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (1.30 g) as a colorless solid in 18% yield. The mother liquor from the trituration was concentrated in vacuo, trifluoroacetic acid (20 mL) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride (100 mL), 3 N hydrochloric acid (4 x 60 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate in hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (2.6 g) as a colorless solid (37% yield, overall yield 55% over 2 steps): H NMR (300 MHz, CDCI₃) £7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert- butyl ether).

EXAMPLE 9

Synthesis of 1-(diphenylmethyl)-1 H-indole-2,3-dione

Compound of formula (15a)

A. To a suspension of hexanes-washed sodium hydride (34.0 g, 849 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) at 0 °C was added a solution of isatin (99.8 g, 678 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) dropwise over 30 minutes. The reaction mixture was stirred for 1 h at 0 °C and a solution of benzhydryl bromide (185 g, 745 mmol) in anhydrous N-dimethylformamide (100 mL) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 h and heated at 60 °C for 2 h. The mixture was cooled to 0 °C and water (500 mL) was added. The mixture was poured into water (2 L), causing a precipitate to be deposited. The solid was collected by suction filtration and washed with water (2000 mL) to afford 1-(diphenylmethyl)-1H-indole-2,3- dione (164 g) as an orange solid in 77% yield.

B. Alternatively, to a mixture of isatin (40.0 g, 272 mmol), cesium carbonate (177 g, 543 mmol) and A/./V-dimethylformamide (270 mL) at 80 °C was added dropwise a solution of benzhydryl bromide (149 g, 544 mmol) in N,N- dimethyiformamide (200 mL) over 30 minutes. The reaction mixture was heated at 80 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was rinsed with ethyl acetate (1000 mL). The filtrate was washed with saturated aqueous ammonium chloride (4 x 200 mL), 1 N

hydrochloric acid (200 mL) and brine (4 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1 -(diphenylmethyl)-1 H-indole-2,3-dione (59.1 g) as an orange solid in 69% yield. The mother liquor from the trituration was concentrated in vacuo and the residue triturated in diethyl ether to afford a further portion of 1-(diphenylmethyl)-1 H- indole-2,3-dione (8.2 g) in 10% yield: ¹H NMR (300 MHz, CDCI₃) £7.60 (d, J = 7.4 Hz, 1 H), 7.34-7.24 (m, 1 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

C. Alternatively, a mixture of isatin (500 g, 3.4 mol) and anhydrous N,N- dimethylformamide (3.5 L) was stirred at 15-35 °C for 0.5 h. Cesium carbonate (2.2 kg, 6.8 mol) was added and the mixture stirred at 55-60 °C for 1 h. A solution of benzhydryl bromide (1.26 kg, 5.1 mol) in anhydrous N, A/-dimethylformamide (1.5 L) was added and the resultant mixture stirred at 80-85 °C for 1 h, allowed to cool to ambient temperature and filtered. The filter cake was washed with ethyl acetate (12.5 L). To the combined filtrate and washes was added 1 N hydrochloric acid (5 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with 1 N hydrochloric acid (2 * 2.5 L) and brine (3 ^χ 2.5 L) and concentrated in vacuo to a volume of approximately 750 mL. Methyl ferf-butyl ether (2 L) was added and the mixture was cooled to 5-15 °C, causing a solid to be deposited. The solid was collected by filtration, washed with methyl ferf- butyl ether (250 mL) and dried in vacuo at 50-55 °C for 16 h to afford 1- (diphenylmethyl)-1 H-indole-2,3-dione (715 g) as an orange solid in 67% yield: ¹H NMR (300 MHz, CDCI₃) 7.60 (d, J = 7.4 Hz, H), 7.34-7.24 (m, 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

EXAMPLE 10

Synthesis of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3- dihydro-2H-indol-2-one

Compound of formula (16a1 )

A. To a solution of sesamol (33.1 g, 239 mmol) in anhydrous

tetrahydrofuran (500 mL) at 0 °C was added dropwise a 2 M solution of

isopropylmagnesium chloride in tetrahydrofuran (104 mL, 208 mmol), followed by 1 – (diphenylmethyl)-1H-indole-2,3-dione (50.0 g, 160 mmol) and tetrahydrofuran (100 mL). The reaction mixture was stirred at ambient temperature for 5 h, diluted with ethyl acetate (1500 mL), washed with saturated aqueous ammonium chloride (400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford 1- (diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-in

2- one (70.7 g) as a colorless solid in 98% yield: ¹H NMR (300 MHz, CDCI₃) <59.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56- 6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

B. Alternatviely, a mixture of sesamol (0.99 kg, 7.2 mol) and anhydrous tetrahydrofuran (18 L) was stirred at 15-35 °C for 0.5 h and cooled to -5-0 °C.

Isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 3.1 L, 6.2 mol) was added, followed by 1-(diphenylmethyl)-1 H-indole-2,3-dione (1.50 kg, 4.8 mol) and further anhydrous tetrahydrofuran (3 L). The mixture was stirred at 15-25 °C for 5 h. Ethyl acetate (45 L) and saturated aqueous ammonium chloride (15 L) were added. The mixture was stirred at 15-25 °C for 0.5 h and was allowed to settle for 0.5 h. The phases were separated and the organic phase was washed with brine (2.3 L) and concentrated in vacuo to a volume of approximately 4 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 4 L. Heptane (6 L) was added and the mixture was stirred at 15-25 °C for 2 h, causing a solid to be deposited. The solid was collected by filtration, washed with methyl tert- butyl ether (0.3 L) and dried in vacuo at 50-55 °C for 7 h to afford 1-(diphenylmethyl)-3- hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.12 kg) as an off-white solid in 98% yield: ¹H NMR (300 MHz, CDCI₃) 9.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56-6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

EXAMPLE 1 1

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one

Compound of formula (17a1)

A. A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (30.0 g, 66.5 mmol), benzyl bromide (8.3 mL, 70 mmol), and potassium carbonate (18.4 g, 133 mmol) in anhydrous N,N- dimeihylformamide (100 mL) was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the solid was washed with /V,A/-dimethylformamide (100 mL). The filtrate was poured into water (1000 mL) and the resulting precipitate was collected by suction filtration and washed with water to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol- 5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g) as a beige solid in 83% yield: ¹H NMR (300 MHz, CDCI₃) 7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10- 6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1), 523.9 (M – 17).

B. Alternatively, to a solution of 1-(diphenylmethyl)-3-hydroxy-3-(6- hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.1 kg, 4.6 mol) in anhydrous A/,A/-dimethylformamide (8.4 L) at 20-30 °C was added potassium carbonate (1.3 kg, 9.2 mol), followed by benzyl bromide (0.58 L, 4.8 mol). The mixture was stirred at 20-30 °C for 80 h and filtered. The filter cake was washed with

A/,/V-dimethylformamide (0.4 L) and the filtrate was poured into water (75 L), causing a solid to be deposited. The mixture was stirred at 15-25 °C for 7 h. The solid was collected by filtration, washed with water (2 L) and dried in vacuo at 50-60 °C for 48 h to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one (2.1 1 kg) as an off-white solid in 84% yield; ¹H NMR (300

MHz, CDCI₃) £7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1 ).

EXAMPLE 12

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H- indol-2-one

Compound of formula (18a1 )

A. To a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g, 57.7 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL) followed by triethylsilane (50 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyi acetate (250 mL), washed with saturated aqueous ammonium chloride (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5- yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (19.0 g) as a colorless solid in 61 % yield: ¹H NMR (300 MHz, CDCI₃) 7.31 -7.23 (m, 15H), 7.10-6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

B. Alternatively, to a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (2.0 kg, 3.7 mol) in

dichloromethane (7 L) at 20-30 °C was added trifluoracetic acid (2.5 L), followed by triethylsilane (3.1 L). The mixture was stirred at 15-35 °C for 4 h and concentrated in vacuo to dryness. To the residue was added ethyl acetate (16 L) and the mixture was stirred at 15-35 °C for 0.5 h, washed with saturated aqueous ammonium chloride (3 x 7 L) and brine (3 ^χ 7 L) and concentrated in vacuo to a volume of approximately 7 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 9 L and stirred at 10-20 °C for 2.5 h, during which time a solid was deposited. The solid was collected by filtration, washed with methyl te/t-butyl ether (0.4 L) and dried in vacuo at 50-55 °C for 7 h to afford 3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1 .26 kg) as an off-white solid in 65% yield: ¹H NMR (300 MHz, CDCI₃) £7.31 -7.23 (m, 15H), 7.10- 6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

EXAMPLE 13

Synthesis of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 –

(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one

Compound of formula (19a1 )

A. To a nitrogen-degassed mixture of 50% w/w aqueous potassium hydroxide (69.6 mL, 619 mmol), toluene (100 mL), and (9S)-1 -(anthracen-9- ylmethyl)cinchonan-1 -ium-9-ol chloride (0.50 g, 0.95 mmol) cooled in an ice/salt bath to an internal temperature of -18 °C was added a nitrogen-degassed solution of 3-[6- (benzyloxy)-l ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H-indol-2-one (10.0 g, 19.0 mmol) and benzyl chloromethyl ether (2.9 mL, 21 mmol) in

toluene/tetrahydrofuran (1 :1 v/v, 80 mL) dropwise over 1 h. The reaction mixture was stirred for 3.5 h and diluted with ethyl acetate (80 mL). The organic phase was washed with 1 N hydrochloric acid (3 x 150 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (3S)-3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (12.6 g) as a colorless solid in quantitative yield: ¹H NMR (300 MHz, CDCI₃) 7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83- 5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, a mixture of 50% w/v aqueous potassium hydroxide (4.2 kg), toluene (12 L) and (9S)-1 -(anthracen-9-ylmethyl)cinchonan-1 -ium-9-ol chloride (0.06 kg, 0.1 mol) was degassed with dry nitrogen and cooled to -18 to -22 °C. To this mixture was added a cold (-18 to -22 °C), nitrogen-degassed solution of 3-[6-

(benzyloxy)-l ,3-benzodioxol-5-yl]-1 ~(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.2 kg, 2.3 mol) and benzyl chloromethyl ether (0.43 kg, 2.8 mol) in toluene (10 L) and tetrahydrofuran (10 L) at -18 to 22 °C over 3 h. The mixture was stirred at -18 to -22 °C for 5 h, allowed to warm to ambient temperature and diluted with ethyl acetate (10 L). The phases were separated and the organic layer was washed with 1 N

hydrochloric acid (3 ^χ 8 L) and brine (2 ^χ 12 L) and concentrated in vacuo to dryness to afford (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1- (diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.5 kg) as a colorless solid in quantitative yield: ¹H NMR (300 MHz, CDCI₃) £7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83-5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17- 4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, ChiralPak IA). EXAMPLE 14

Synthesis of (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1 ,3-dihydro-2/-/-indol-2-one

Compound of formula (20a1)

A. A mixture of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3- [(benzyloxy)methyl]-1 -(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (8.8 g, 14 mmol), 10% w/w palladium on carbon (50% wetted powder, 3.5 g, 1.6 mmol), and acetic acid (3.9 ml_, 68 mmol) in a nitrogen-degassed mixture of ethanol/tetrahydrofuran (1 : 1 v/v, 140 mL) was stirred under hydrogen gas (1 atm) at ambient temperature for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to afford (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3- dihydro-2H-indol-2-one as a colorless solid that was carried forward without further purification: H NMR (300 MHz, CDCI₃) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15- 7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 93% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl ie t-butyl ether).

B. Alternatively, a glass-lined hydrogenation reactor was charged with (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 -(diphenylmethyl)- 1 ,3-dihydro-2H-indol-2-one (0.1 kg, 0.15 mol), tetrahydrofuran (0.8 L), ethanol (0.4 L), acetic acid (0.02 L) and 20% w/w palladium (li) hydroxide on carbon (0.04 kg). The reactor was purged three times with nitrogen. The reactor was then purged three times with hydrogen and was then pressurized to 50-55 lb/in² with hydrogen. The mixture was stirred at 20-30 °C for 5 h under a 50-55 lb/in² atmosphere of hydrogen. The reactor was purged and the mixture was filtered. The filtrate was concentrated in vacuo to a volume of approximately 0.2 L and methyl te/t-butyl ether (0.4 L) was added. The mixture was concentrated in vacuo to a volume of approximately 0.2 L and methyl ie/t-butyl ether (0.2 L) was added, followed by heptane (0.25 L). The mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.05 L) and dried in vacuo at a temperature below 50 °C for 8 h to afford (3S)-1 -(diphenylmethyl)-3-(6-hydroxy- 1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one (0.09 kg) as a colorless solid in 95% yield: ¹H NMR (300 MHz, CDCI₃) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15-7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 91% (HPLC, ChiralPak IA).

EXAMPLE 15

Synthesis of (7S)-1′-(diphenylmethyl)spiro[furo[2,3-/][1 ,3]benzodioxole-7,3′-indol]-

2′(1 ‘tf)-one

Compound of formula (21 a1 )

A. To a cooled (0 °C) solution of (3S)-1 -(diphenylmethyl)-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 14 (13.6 mmol) and 2-

(diphenylphosphino)pyridine (4.3 g, 16 mmol) in anhydrous tetrahydrofuran (140 mL) was added di-tert-butylazodicarboxylate (3.8 g, 17 mmol). The reaction mixture was stirred at 0 °C for 3 h, diluted with ethyl acetate (140 mL), washed with 3 N

hydrochloric acid (6 * 50 mL) and brine (2 ^χ 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (4.55 g) as a colorless solid in a 75% yield over 2 steps: ¹H NMR (300 MHz, CDCI₃) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99-6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1); ee

(enantiomeric excess) 93% (HPLC, Chiraipak IA, 2.5% acetonitrile in methyl te/f-butyl ether).

B. Alternativel, to a cooled (0-5 °C) solution of (3S)-1-(diphenylmethyl)-3- (6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2 -/-indol-2-one (1 .0 kg, 2.1 mol) and 2-(diphenylphosphino)pyridine (0.66 kg, 2.5 mol) in anhydrous tetrahydrofuran (20 L) was added over 2 h a solution of di-terf-butylazodicarboxylate (0.62 kg, 2.7 mmol) in anhydrous tetrahydrofuran (5 L). The mixture was stirred for 4 h at 0-5 °C and was allowed to warm to ambient temperature. The mixture was diluted with ethyl acetate (20 L), washed with 3 N hydrochloric acid (6 * 8 L) and brine (2 x 12 L) and concentrated in vacuo to a volume of approximately 1.5 L. Methyl rert-butyl ether (4 L) was added and the mixture concentrated in vacuo to a volume of

approximately 1.5 L. Methyl terf-butyl ether (2 L) and heptane (2 L) were added and the mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.5 L) and dried in vacuo below 50 °C for 8 h to afford (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (0.76 kg) as a colorless solid in 79% yield: ¹H NMR (300 MHz, CDCI₃) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99- 6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1 ); ee (enantiomeric excess) 92% (HPLC, ChiralPak IA).

EXAMPLE 16

Synthesis of (7S)-spiro[furo[2,3-f][1 ,3]benzodioxole-7,3′-indol]-2′(1 ‘H)-one

Compound of formula (22a1)

A. To a solution of (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (4.55 g, 10.2 mmol) in trifluoroacetic acid (80 ml_) was added triethylsilane (7 ml_). The reaction mixture was heated at reflux for 2.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford

(7S)-spiro[furo[2,3-/][1 ,3]benzodioxole-7,3^,-indol]-2′(1’W)-one (2.30 g) as a colorless solid in 80% yield: ¹H NMR (300 MHz, CDCI₃) £8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1 ); ee (enantiomeric excess) 99% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl fert-butyl ether). B. Alternatively, a mixture of (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- /Kl^benzodioxole^-indol^ r^-one (0.70 kg, 1.6 mol), trifluoroacetic acid (12 L) and triethylsilane (1.1 L) was heated at reflux under nitrogen atmosphere for 3 h, allowed to cool to ambient temperature and concentrated in vacuo to dryness. To the residue was added ethyl acetate (0.3 L), methyl fert-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration, taken up in dichloromethane (3 L), stirred at ambient temperature for 1 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was taken up in ethyl acetate (0.3 L), methyl ferf-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration and dried in vacuo below 50 °C for 8 h to afford (7S)-spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘ -/)-one (0.40 kg) as a colorless solid in 91 % yield: ¹H NMR (300 MHz, CDCI₃) 8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1); ee (enantiomeric excess) 98.6% (HPLC, ChiralPak IA).

EXAMPLE 17

Synthesis of of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yl]methyl}spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(rH)-one

Compound of formula (Ia1)

A. To a mixture of (7S)-6H-spiro[[1 ,3]dioxolo[4,5-f]benzofuran-7,3′-indolin]- 2′-one (1.80 g, 6.41 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan (1.47 g, 6.41 mmol) in acetone (200 mL) was added cesium carbonate (3.13 g, 9.61 mmol). The reaction mixture was heated at reflux for 2 h and filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford (7S)-1′-{[5- (trifluoromethyOfuran^-yllmethy^spiroIfurop.S- ltl .Slbenzodioxole^.S’-indol^ rH)- one (2.71 g) as a colorless solid in quantitative yield (97% purity by HPLC). The product was crystallized from a mixture of methanol and hexanes to afford (7S)-1 ‘-{[5- (trifluoromethy furan^-yllmethylJspirotfuro^.S- lfl .Slbenzodioxole^.S’-indoll^ rH)- one (1.46 g) as colorless needles in 53% yield. The mother liquor was concentrated in vacuo and subjected to a second crystallization in methanol and hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-/][1 ,3]benzodioxole- 7,3’-indol]-2′(1 ‘H)-one (0.469 g) as a colorless solid in 17% yield (total yield 70%): ¹H NMR (300 MHz, CDCI₃) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, to a solution of (7S)-spiro[furoI2,3-f][1 ,3]benzodioxole-7,3′- indol]-2′(1’H)-one (0.40 kg, 1.4 mol) in anhydrous N, W-dimethylformamide (5 L) was added cesium carbonate (1.2 kg, 3.4 mol), followed by 2-(bromomethyl)-5- (trifluromethyl)furan (0.24 L, 1.7 mol). The mixture was heated at 80-85 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate (8 L). The combined filtrate and washes were washed with water (4 L), saturated aqueous ammonium chloride (2 * 4 L) and brine (2 * 4 L) and concentrated in vacuo to dryness. The residue was purified by recrystallization from te/t-butyl methyl ether (0.4 L) and heptane (0.8 L), followed by drying of the resultant solid in vacuo at 40-50 °C for 8 h to afford (7S)-1 ‘-{[5- (trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)- one (0.37 kg) as a colorless solid in 61% yield: ¹H NMR (300 MHz, CDCI₃) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz,1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) > 99% (HPLC, Chiralpak IA).

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Na_v1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

The First Asymmetric Pilot-Scale Synthesis of TV-45070

Joseph A. Sclafani^*†§ , Jian Chen†∥, Daniel V. Levy†§, Harlan Reese†⊥, Mina Dimitri†, Partha Mudipalli†, Michael Christie†, Christopher J. Neville‡, Mark Olsen‡, and Roger P. Bakale†#

^†Chemical Process Research and Development, ^‡Analytical Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00237

Publication Date (Web): September 8, 2017

Copyright © 2017 American Chemical Society

*E-mail: jasclafan@yahoo.com.

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one (1)

¹H NMR (DMSO, 400 MHz) δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H), 6.77 (d, J= 3.3 Hz, 1H), 6.72 (s, 1H), 6.10 (s, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H).

¹³C NMR (100 MHz, DMSO-d₆): 176.48, 155.28, 153.02, 148.40, 141.80, 141.51, 139.54 (q, J_CF = 41.9 Hz), 131.63, 128.79, 123.64, 123.29, 119.69, 118.92 (q, J_CF = 266.4 Hz), 114.01 (q, J_CF = 2.9 Hz) 109.86, 109.21, 102.55, 101.44, 93.31, 79.52, 57.41, 36.44.

Funapide

Clinical data
Routes of administration	By mouth, topical
ATC code	None
Identifiers
IUPAC name[show]
CAS Number	1259933-16-8
PubChem CID	49836093
ChemSpider	34500834
UNII	E3COJ2T10W
Chemical and physical data
Formula	C22H14F3NO5
Molar mass	429.34547 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] C1C2(C3=CC=CC=C3N(C2=O)CC4=CC=C(O4)C(F)(F)F)C5=CC6=C(C=C5O1)OCO6

CARMUSTINE

Molecular Formula: C5H9Cl2N3O2
Molecular Weight: 214.046 g/mol

CAS 154-93-8

Brain tumor; Hodgkins disease; Multiple myeloma; Non-Hodgkin lymphoma

1,3-bis(2-chloroethyl)-3-nitrosourea

• Urea, 1,3-bis(2-chloroethyl)-1-nitroso- (8CI)
• N,N’-Bis(2-chloroethyl)-N-nitrosourea
• 1,3-Bis(2-chlorethyl)-1-nitrosourea
• 1,3-Bis(2-chloroethyl)-1-nitrosourea
• 1,3-Bis(2-chloroethyl)nitrosourea

• 1,3-Bis(β-chloroethyl)-1-nitrosourea
• BCNU
• Becenun
• BiCNU
• Carmubris
• Carmustin
• Carmustine
• DTI 015
• FDA 0345
• Gliadel
• Gliadel Wafer
• NSC 409962
• Nitrumon
• SK 27702
• SRI 1720

A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)
It has the appearance of an orange-yellow solid.Carmustine (bis-chloroethylnitrosourea, BCNU, BiCNU) is a medication used mainly for chemotherapy and sometimes for immunosuppression before organ transplantation. It is a nitrogen mustard β-chloro-nitrosourea compound used as an alkylating agent. As a dialkylating agent, BCNU is able to form interstrand crosslinks in DNA, which prevents DNA replication and DNA transcription.

Carmustine for injection was earlier marketed under the name BiCNU by Bristol-Myers Squibb^[2] and now by Emcure Pharmaceuticals.^[3] In India it is sold under various brand names, including Consium.

It is disclosed that carmustine is useful for treating brain tumor, multiple myolema, Hodgkin’s disease and non-Hodgkin’s lymphomas. In September 2017, Newport Premium™ reports that MSN laboratories is potentially interested in carmustine and holds an active US DMF for the drug. Represents new area of patenting to be seen from MSN lab on Carmustine . Supratek was investigating SP-1009C , carmustine formulated in the company’s Biotransport carrier technology, for the potential treatment of glioblastoma. However, no further development has been reported since 2000 , and as of February 2004, SP-1009C was no longer listed on Supratek’s pipeline.

Uses

It is used in the treatment of several types of brain cancer (including glioma, glioblastoma multiforme, medulloblastoma and astrocytoma), multiple myeloma and lymphoma (Hodgkin’s and non-Hodgkin). BCNU is sometimes used in conjunction with alkyl guanine transferase (AGT) inhibitors, such as O⁶-benzylguanine. The AGT-inhibitors increase the efficacy of BCNU by inhibiting the direct reversal pathway of DNA repair, which will prevent formation of the interstrand crosslinkbetween the N¹ of guanine and the N³ of cytosine.

It is also used as part of a chemotherapeutic protocol in preparation for hematological stem cell transplantation, a type of bone marrow transplant, in order to reduce the white blood cell count in the recipient (patient). Use under this protocol, usually with Fludarabine and Melphalan, was coined by oncologists at the University of Texas MD Anderson Cancer Center.

Implants

In the treatment of brain tumours, the U.S. Food and Drug Administration (FDA) approved biodegradable discs infused with carmustine (Gliadel).^[4] They are implanted under the skull during a surgery called a craniotomy. The disc allows for controlled release of carmustine in the extracellular fluid of the brain, thus eliminating the need for the encapsulated drug to cross the blood-brain barrier.^[5]

Reference:

Synthesis, , # 11 p. 1027 – 1029

Celaries, Benoit; Parkanyi, Cyril Synthesis, 2006 , # 14 p. 2371 – 2375

PAPER

Pharmaceutical Chemistry Journal, 2001, vol. 35, vol 2, pg. 108 – 111

10.1023/A:1010485224267

PATENT

EP 3214075

EP 902015

CA1082223

US 523334

SYNTHESIS

PATENT

http://www.google.co.in/patents/US4028410

The Urea. This material is used in good grades, preferably CP, and the amount of urea utilized is the base on which the amounts of nitrosating agent are calculated. The starting material 1,3-bis(2-chloroethyl)urea is commercially available and also may be prepared readily from phosgene and ethyleneimine.

Dinitrogen trioxide (N₂ O₃). Efficacy of reaction has been observed where this nitrosation agent was utilized in preference to the prior use of aqueous NaNO₂. It has also been found for stoichiometric reasons that an excess of the nitrosating agent ranging from 10-200% and preferably 10-20% based on urea is necessary to force the reaction to the right and obtain satisfactory completion. Furthermore, it is known from the literature art, Cotton, Advanced Inorganic Chemistry, Interscience, 1972, page 357, that this oxide exists in a pure state only at low temperatures and, therefore, reaction is conducted at nitrosation temperatures of about 0° C. to -20° C.

The Solvent. In contrast to prior art methods, the present reaction is conducted in an organic milieu. The preferred non-aqueous solvent is of the chlorinated variety; i.e., methylene dichloride. Other preferred compounds include related halogenated compounds such as ethylene dichloride, nitro-compounds such as nitromethane, acetonitrile, and simple ethers such as ethyl ether. Other less preferred but operable compounds include esters such as ethyl acetate, simple ketones such as acetone, and chloroform. Solvents to be avoided are olefins, unsaturated ethers and other unsaturated compounds, amines, malonate esters, acid anhydrides, and solvents which would interact with the reactant N₂ O₃ and the urea as well as the product nitrosourea. In general, the solvent should be low boiling (b.p. less than 120° C. and preferably less than 100° C.).

BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea is one of a group of relatively recent drugs used against cancer and since 1972 has been charted by the National Cancer Institute for utilization against brain tumors, colon cancer, Hodgkins disease, lung cancer, and multiple myeloma. The modus of action of BCNU (NSC 409962) is as an alkylating agent. Such an alkylating agent is injurious to rapidly proliferating cells such as are present in many tumors and this action is known as antineoplastic activity.

EXAMPLE 1 1,3-Bis(2-chloroethyl)-1-nitrosourea

A suspension of 1.11 mmole (0.205 g) of 1,3-bis(2-chloroethyl)urea in 8 ml methylene dichloride at -10° C. was saturated with dinitrogen trioxide in 20% excess of theoretical. The heterogeneous mixture gradually changed to a green homogeneous solution. The methylene dichloride was evaporated, and the residue was extracted with 3× 10 ml hexane. Evaporation of the hexane gave 0.1773 g of oil which was the crude BCNU (NSC 409962). The hexane insoluble portion, 0.0649 g, when treated with benzene, gave 0.020 g of 1,3-bis(2-chloroethyl)urea which was benzene insoluble. The benzene solubles were processed through a silica column (1× 10 cm) and 0.0245 g of crude BCNU was obtained. The combined fractions of crude product amounted to 0.2018 g (85.1%).

In order to evaluate the product, the above crude was recrystallized from hexane to yield a first crop and from this first crop the ir spectrum was identical to that of known BCNU. A tlc (benzene on sillica) gave a single spot R_f 0.35 (blue, 254 mμ).

EXAMPLE 2 Comparative

A cold solution of 0.2346 g (3.4 mmole) sodium nitrite in 2 ml water was slowly added to a stirred solution of 0.2727 g (1.47 mmole) 1,3-bis(2-chloroethyl)urea in 2 ml 88% formic acid at 0°. After 2 hours at 0°, 0.1449 g (46.0%) of an oil solid phase was removed. The ir spectrum of this fraction failed to agree with that of BCNU. After 2 days a small amount of crystalline BCNU slowly formed in this oil phase. A methylene dichloride extract of the aqueous phase yielded 0.0943 g (30.0%) of an amber oil whose ir spectrum agreed with that of a known sample of BCNU. Treatment of this oil with 5 ml hexane and cooling to 0° gave crystalline BCNU which formed an oil on warming to ambient temperature.

EXAMPLE 3

A cold slurry at -15° C. of the 1,3-bis(2-chloroethyl)urea (2.0 mmole) in 8 ml methylene dichloride was treated with a small excess of N₂ O₃. The 1,3-bis(2-chloroethyl)urea is almost insoluble in the cold methylene dichloride, whereas the BCNU product is quite soluble. Thus, treatment of the urea with the N₂ O₃ changed the slurry to a homogeneous solution. Evaporation of the methylene dichloride gave a quantitative yield of crude BCNU. Purification by silica column chromatography gave 93.4% yield and recrystallization from benzene-heptane gave 85.2% yield of pure BCNU.

PAPER

Journal of Medicinal Chemistry (1963), 6(6), 669-81.

SPECTROSCOPY

Chloroform-d, Nitrogen-15 NMR Spectrum,  Lown, J. William; Journal of Organic Chemistry 1981, V46(26), P5309-21

1H NMR

WO-2017154019

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=103D413664C194D84095110F1084E521.wapp2nA?docId=WO2017154019&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for preparing 1,3-bis(2-chloroethyl)-1- nitrosourea (also known as carmustine) and its intermediate 1,3-bis(2-chloroethyl)urea is claimed. Also claimed are composition comprising them and novel crystalline polymorphic form of carmustine.

,3-bis(2-chloroethyl)-l -nitrosourea is known as Carmustine and is approved in USA under the brand names of BICNU for the treatment of chemotherapy of certain neoplastic diseases such as brain tumor, multiple myolema, Hodgkin’s disease and non-Hodgkin’s lymphomas & Gliadel for the treatment of newly-diagnosed high-grade-malignant glioma as an adjunct to surgery and radiation, recurrent glioblastoma multiforme as an adjunct to surgery.

Journal of Medicinal Chemistry 1963, 6, 669-681 firstly disclosed process for the preparation of l,3-bis(2-chloroethyl)-l-nitrosourea.

US2288178 patent disclosed the process for the preparation of the compound of formula-2 from aziridine and phosgene. J. Med. Chem., 1979, 22 (10), pp 1193-1198 disclosed the process for the preparation of the compound of formula-2 using 2-chloroethanamine and 2-chloroisocyanoethane.

Prior disclosed processes for the preparation of the compound of formula-2 are used hazardous reagents which were difficult to handle in the laboratory. The present inventors have developed an improved process for the preparation of the compound of formula-2 by using easily available raw materials and usage of that compound in the preparation of the compound of formula- 1 to get good yield and having high purity.

he present invention is schematically represented in the scheme- 1.

Scheme-1

Examples:

Example-1: Preparation of l,3-bis(2-chloroethyl)urea compound of formula-2

2-chloroethanamine hydrochloride (429.19 gm) was added to the mixture of carbonyldiimidazole (200 gm) and tetrahydrofuran (1000 ml) at 25-30°C and stirred the reaction mixture for 5 minutes. Heated the reaction mixture to 65-70°C and stirred for 14 hours at the same temperature. Cooled the reaction mixture to 25-30°C and water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with isopropanol. Isopropanol (100 ml) was added to the obtained compound and stirred the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred the reaction mixture for 10 minutes at the same temperature.

Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 1 10 gm; M.P: 121-125°C.

Example-2: Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (50 gm) was added to the mixture of dilute hydrochloric acid (16 ml) and acetic acid (205 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Sodium nitrite (46.6 gm) was added to the reaction mixture in lot-wise over the period of 3 hours at 0-5 °C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched into pre-cooled water at 0-5°C and stirred it for 30 minutes at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (100 ml) at 0-5°C. The reaction mixture was added to pre-cooled n-heptane (250 ml) at 0-5°C and stirred for 1 ½ hour at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 28 gm.

Example-3: Preparation of l,3-bis(2-chloroethyl)urea compound of formuIa-2

Carbonyldiimidazole (8 kg) was slowly added to the pre-cooled mixture of 2-chloroethanamine hydrochloride (14.31 kg) and tetrahydrofuran (40 lit) at 0-5°C in lot-wise under nitrogen atmosphere and stirred the reaction mixture for 5 minutes. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 36 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water was added to the obtained compound at 25-30°C and stirred it for I hour at the same temperature. Filtered the precipitated solid and washed with water. The obtained compound was slurried in water at 25-30°C, filtered and washed with water. Methanol was added to the obtained compound at 25-30°C and stirred it for 1 hour at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 6 kg; PXRD of the obtained compound is shown in figure-3.

Example-4: Preparation of l,3-bis(2-ch!oroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (6 kg) was added to the mixture of dilute hydrochloric acid (1.9 lit) and acetic acid (24.5 lit) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (5.59 kg) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (24 lit) at 5-10°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Silicagel (3 kg) was added to the organic layer at 5-10°C and stirred for 25 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tertiary butyl ether. Pre-cooled Methyl tertiary butyl ether (12 lit) was added to the obtained compound and stirred it for at 0-5°C. This reaction mixture was added to pre-cooled n-heptane (60 lit) at -15 to -10°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the precipitated solid and washed with chilled n-heptane. Dried the compound at 0-10°C under reduced pressure.

Yield: 4.5 kg; MR: 30-32°C;

Purity by HPLC: 99.97%; Impurity at RRT -0.08: 0.01%, Impurity at RRT -0.13: Not detected; l,3-bis(2-chloroethyl)urea: 0.02%

PXRD of the obtained compound is shown in figure- 1 and IR shown in figure-2.

Example-5: Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (150 gm) was added to the mixture of dilute hydrochloric acid (48 ml) and acetic acid (612 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (139.8 gm) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water.

Purity by HPLC: 95.1 1%, Impurity at RRT -0.08: 4.17%, Impurity at RRT -0.13: 0.63%.

Example 6: Purification of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1

Dissolved the compound of formula 1 obtained in example-5 in dichloromethane (600 ml) at 5-10°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Silicagel (75 gm) was added to the organic layer at 5-10°C and stirred for 25 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tertiary butyl ether. Pre-cooled Methyl tertiary butyl ether (300 ml) was added to the obtained compound and stirred it for 10-15 min at 0-5°C. This reaction mixture was added to pre-cooled n-heptane (1500 ml) at -15 to -10°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the precipitated solid and washed with chilled n-heptane. Dried the compound at 0-10°C under reduced pressure. Yield: HO gm; MR: 30-32°C;

Purity by HPLC: 99.96%, Impurity at RRT -0.08: 0.02%, Impurity at RRT -0.13: Not detected; l,3-bis(2-chloroethyl)urea: 0.02%

References

External links

• MedlinePlus DrugInfo medmaster-a682060
• BiCNU package insert, U.S.
• Idis press release for EU

1.  Lown, J. William; Journal of Organic Chemistry 1981, V46(26), P5309-21 
2.  Barcelo, Gerard; Synthesis 1987, (11), P1027-9 
3.  Barcelo, Gerard; FR 2589860 A1 1987 
4.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
5.  Xu, Longji; International Journal of Pharmaceutics 2008, V355(1-2), P249-258 
6.  Xu, Xiuling; Journal of Controlled Release 2006, V114(3), P307-316 
7.  Lown, J. William; Journal of Organic Chemistry 1982, V47(5), P851-6 
8. “PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)

Carmustine

Names
IUPAC name 1,3-Bis(2-chloroethyl)-1-nitrosourea[1]
Other names N,N’-Bis(2-chloroethyl)-N-nitrosourea
Identifiers
CAS Number	154-93-8
3D model (JSmol)	Interactive image
ChEBI	CHEBI:3423
ChemSpider	2480
DrugBank	DB00262
ECHA InfoCard	100.005.309
EC Number	205-838-2
KEGG	D00254
MeSH	Carmustine
PubChem CID	2578
RTECS number	YS2625000
UNII	U68WG3173Y
UN number	2811
InChI[show]
SMILES[show]
Properties
Chemical formula	C5H9Cl2N3O2
Molar mass	214.05 g·mol−1
Appearance	Orange crystals
Odor	Odourless
Melting point	30 °C (86 °F; 303 K)
log P	1.375
Acidity (pKa)	10.194
Basicity (pKb)	3.803
Pharmacology
ATC code	L01AD01 (WHO)
Hazards
GHS pictograms
GHS signal word	DANGER
GHS hazard statements	H300, H350, H360
GHS precautionary statements	P301+310, P308+313
Lethal dose or concentration (LD, LC):
LD50 (median dose)	20 mg kg−1 (oral, rat)
Related compounds
Related ureas	Dimethylurea
Related compounds	Noxytiolin 1,1,3,3-Tetramethylguanidine Metformin Allantoic acid Buformin
Except where otherwise noted, data are given for materials in their standa

/////////////

ClCCNC(=O)N(CCCl)N=O

Xanomeline (LY-246,708; Lumeron, Memcor)

CAS 131986-45-3

• Molecular FormulaC₁₄H₂₃N₃OS
• Average mass281.417 Da

SYNTHESIS WILL BE UPDATED

EP 0384288; US 5260311; US 5264444; US 5328925, US 5834495; WO 9429303, EP 0687265; JP 1996507298; WO 9420495

The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

PAPER

http://www.mdpi.com/1420-3049/6/3/142/htm

Xanomeline (39) has emerged as one of the most potent unbridged arecoline derivatives. It has higher potency and efficacy for m₁ and m₄ than for m₂, m₃ and m₅ receptor subtypes [73], binds to the m₁receptor subtype uniquely tightly [74,75] and stimulates phosphoinositide hydrolysis in the brain. In cells containing human m₁ receptors which are stably expressing amyloid precursor protein (APP), xanomeline (39) stimulates APP release with a potency 1000 greater than carbachol and reduces the secretion of Aβ by 46% [76] (cf 2.6 Central nervous system). In patients with Alzheimer’s disease, it halted cognitive decline and reduced behavioural symptoms such as hallucinations, delusions and vocal outbursts [77,78]. As might be expected there have been numerous attempts to prepare analogues with comparable potency and efficacy. Transplanting the thiadiazole ring of xanomeline to a range of bicyclic amines reduced selectivity [79,80] as did the use of pyrazine analogues (40) [81].

Paper

J Med Chem 1992,35(12),2274-83

see http://pubs.acs.org/doi/pdf/10.1021/jm00090a019

PAPER

Classics in Chemical Neuroscience: Xanomeline

Aaron M. Bender^†, Carrie K. Jones^†‡, and Craig W. Lindsley^*†‡§ 

^† Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States

^‡ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States

^§ Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States

ACS Chem. Neurosci., 2017, 8 (3), pp 435–443

DOI: 10.1021/acschemneuro.7b00001

Publication Date (Web): January 31, 2017

Copyright © 2017 American Chemical Society

*E-mail: craig.lindsley@vanderbilt.edu.

Abstract

Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M₁/M₄-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer’s disease (AD) patients. Despite the compound’s promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound’s unique M₁/M₄-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M₁ or M₄. This Review will address xanomeline’s overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.

PAPER

References

Xanomeline

Clinical data
ATC code	None
Identifiers
IUPAC name[show]
CAS Number	131986-45-3
PubChem CID	60809
IUPHAR/BPS	57
ChemSpider	54797
UNII	9ORI6L73CJ
KEGG	D06330
ChEMBL	CHEMBL21536
ECHA InfoCard	100.208.938
Chemical and physical data
Formula	C14H23N3OS
Molar mass	281.42 g/mol
3D model (JSmol)	Interactive image
SMILES[show

///////Xanomeline, LY 246708, Lumeron, Memcor, ксаномелин , كسانوميلين , 诺美林 , allosteric modulation, Alzheimer’s disease, antipsychotic,  muscarinic acetylcholine receptors, schizophrenia, 

FDA approves new treatment for certain advanced or metastatic breast cancers

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm

//////////Verzenio, abemaciclib, fda 2017, metastatic breast cancers, Eli Lilly ,  Priority Review,  Breakthrough Therapy designations, antibodies

WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED

WO2017163257) PROCESS FOR PREPARING PURE LH-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVE

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017163257&recNum=1&maxRec=145&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28IND+SWIFT%29&tab=PCTDescription

IND-SWIFT LABORATORIES LIMITED

ARUL, Ramakrishnan; (IN).
SARIN, Gurdeep Singh; (IN).
WAS, Sandeep; (IN).
KUMAR, Vishal; (IN)

The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib. Particularly, the present invention provides a process for the preparation of 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, wherein none of the intermediates have been isolated, an important precursor for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine.

The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib, wherein none of the intermediates have been isolated to prepare 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, an important precursor.

Ibrutinib (IMBRUVICA), chemically known as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1 -yl] prop-2-en- 1 -one is an orally administered drug that targets Bruton’s tyrosine kinase (BTK). Ibrutinib may be used for treating both B cell-related hematological cancers/ B cell chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis, Sjogrens syndrome, lupus and asthma and is represented by following chemical formula:

Ibrutinib and its pharmaceutically acceptable salts were first disclosed in US patent US7,514,444. This patent discloses a process for the preparation of Ibrutinib by involving use of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, as intermediate as shown below:

4-Amino-3-(4-phenoxyphenyl)- l H-pyrazolo[3,4-d]pyrimidine, a key intermediate of ibrutinib, and its preparation from 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole was first disclosed in a PCT patent publication WO2001/019829 A2 as shown in below scheme.

Various other publications like US patents US7,514,444; US7.718,662; US8,883,803 and PCT publications WO2012/158843 A2; WO2013/010136A2 follow the same process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine as described above.

The process comprises the conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, which is then taken up in mixture of toluene and tetrahydrofuran and further reacted with malononitrile in the presence of diisopropylethylethylamine in toluene. The reaction mixture is stirred overnight and after completion of reaction, followed by work up 1 , 1 -dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is isolated as a residue and which is further purified.

The resulting l, l-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is reacted with trimethylsilyldiazomethane in a mixture of acetonitrile and methanol in the presence of diisopropylethylamine as a base. The resulting reaction mixture is stirred for 2 days to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product) as an oil, which is purified by flash chromatography.

The O-methylated product is treated with hydrazine hydrate to give 3-amino-4-cyano- 5-(4-phenoxyphenyl)pyrazole, which is further reacted with formamide at a temperature of 180°C to give 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4- d]pyrimidine as pale brown-grey solid.

Since, the above process involves the isolation of intermediates and takes long time during reaction completion. Therefore, it is lengthy, not efficient. Further publication is silent about the purity of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine. Acetonitrile solvent has been used in methylation reaction, which is carcinogenic.

The cyclization reaction has been carried out at 180°C and it is observed that the cyclization reaction at high temperature of 180°C, results in grey brown solid colour of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, may be due to presence of inorganic impurities.

The said process also requires the use of expensive (trimethylsilyl)diazomethane to obtain O-methylated product, which is sensitive to air and water, and hence, the methylation reaction has to be carried out in the absence of water, under anaerobic conditions; silica and flash chromatography are also used for purifying O-methylated product. Since the above process involves complicated operation processes, which leads to high production cost and therefore is not an attractive option at industrially scale.

PCT publication WO2014/173289A1 discloses a process for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as shown below and its conversion into 4- amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine has not been disclosed.

The process involves conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, followed by reaction with malononitrile in the presence of diisopropylethylethylamine in tetrahydrofuran. The reaction mixture has been stirred for 16 hours and thereafter l, l -dicyano-2-hydroxy-2-(4-phenoxyphenyl) ethene is isolated from reaction mixture. A solution of l, l-dicyano-2-hydroxy-2-(4- phenoxyphenyl)ethene in trimethoxymethane has been heated for 16 hours to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product), which is then reacted with hydrazine hydrate to give 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole.

The above process is inefficient, since it involves isolation of intermediates and takes long time to complete the reactions and purity of 3-amino-4-cyano-5-(4- phenoxypheny pyrazole has not been disclosed.

A similar approach has been described in a PCT publication WO2014/082598 A 1 for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole and is presented as below:

The process involves conversion of 4-phenoxybenzoic acid to the corresponding acyl chloride by using sulfurous dichloride, followed by reaction with malononitrile in the presence of sodium hydride to obtain l, l-dicyano-2-hydroxy-2-(4-phenoxy phenyl)ethene, which is recrystallized from 1,4-dioxane. The hydroxy moiety is then methylated using dimethyl sulphate to give l, l-dicyano-2-methoxy-2-(4-phenoxy phenyl)ethene (O-methylated product) which is recrystallized from a mixture of hexane and ethylactetate. The solution of resulting O-methylated product in ethanol was treated with hydrazine hydrate at reflux temperature to give 3-amino-4-cyano-5- (4-phenoxy phenyl)pyrazole, followed by its recrystallization in hexane and further, its conversion into 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine was not disclosed.

The above process also involves isolation of intermediates; their purification which leads to longer time in reaction completion, and it does not disclose the purity of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole. Further the above process involves use of sodium hydride, which is a hazardous reagent and can ignite in air during scale up. Several alternative methods have been reported in literature, wherein process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has been disclosed and are discussed herein.

A Chinese patent application CN103121999A discloses a process of preparation of 4- amino-3 -(4-phenoxy phenyl)- 1 H-pyrazolo[3 ,4-d] pyrimidine, as below :

The process involves reaction of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine with (4-phenoxyphenyl)boronic acid in the presence of alkali agents and aprotic solvents to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine.

The said Chinese application is also silent about the purity of target compound and even starts with the advance intermediates, which are expensive and make the process unattractive from industrial point of view.

A similar approach has been described in US patent US8,940,893; PCT publication WO2013/1 13097A1 and WO2015/018333 A 1 for preparing 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine .

In US patent US8,940,893 and PCT publication WO2013/1 13097A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by using Combi-flash chromatography on silica gel. In PCT publication WO2015/018333A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by recrystallization in ethyl acetate.

The purity of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has not been reported in above publications too. Further two of the above processes involve tedious step of chromatographic purification, which is not industrial viable.

Another Chinese patent application CN 103965201 A discloses a process for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, wherein 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine was reacted with trimethyl tin (4- phenoxy phenyl) to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidine and followed by its recrystallization in isopropanol, as shown below:

The said Chinese application is also silent about the purity of 4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine and is not cost-effective because it starts with advance intermediates, which are expensive. Therefore, said route of synthesis is not industrially applicable.

Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. The impurities that can be present in pharmaceutical compounds are starting materials, by-products of the reaction, products of side reactions, or degradation products.

According to ICH guidelines, process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction etc., in the manufacturing process. Typically, these limits should less than about 0.15 % by weight of each identified impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.10 % by weight. The limits for genotoxic impurities could be much lower depending upon the daily dose of the drug and duration of the treatment. Therefore, in the manufacture of a drug substance, the purity of the starting materials is also important, as impurities may carry forward to the active pharmaceutical ingredient such as ibrutinib.

In view of the above, most of the prior art processes involve isolation of intermediates, additional purification steps and silent about the purity or the assay of 4-amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine.

Thus, there is an urgent need for the development of a synthetic process which produces pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine or its acid addition salts.

The present invention fulfills the need in the art and provides an improved, industrially advantageous process for the synthesis of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate in the preparation of ibrutinib, through preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole from 4-phenoxy benzoic acid using same organic solvent and none of the intermediates have been isolated.

Examples:

Example 1: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

4-Phenoxybenzoic acid (200g) was slowly added to thionyl chloride (400ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 60-65°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 60°C. Toluene (2x400ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 60°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (2000ml). Malononitile (80g) and diisopropylethylamine (320ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature 50-55°C. The reaction mass was further stirred for 30 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid ( 1.25 M) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride ( 10%) and the resulting organic layer was used directly in next reaction.

Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30°C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes. The solution was filtered through hyflo bed and to the resulting organic layer hydrazine hydrate ( 120ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-50°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1 -2 hours. The resulting precipitated solid was filtered, slurry washed with dichloromethane (400ml) and finally, dried to obtain title compound of formula V ( 140g) purity 93.28% measured by HPLC.

Example 2: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

4-Phenoxybenzoic acid (lOOg) was slowly added to thionyl chloride (200ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 50-55°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 50°C. Toluene (250ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 50°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (500ml). Malononitile (35.58ml) and diisopropylethylamine (160ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature around 50-55°C. The reaction mass was further stirred for 10 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid (70 ml in 1000 ml water) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride (10%) and the resulting organic layer was used directly in next reaction.

Dimethyl sulfate (95.1 1ml) and sodium bicarbonate (96.16g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 55- 60°C, demineralized water ( 1000ml) was added. The reaction mass was cooled to a temperature of 25-30°C and stirred for 10- 15 minutes. The layers were separated and the aqueous layer was extracted with toluene (500ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). To the resulting organic layer hydrazine hydrate (50ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-45°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1-2 hours. The resulting precipitated solid was filtered, suck dried to obtain 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V ( 123g) purity 86.96% measured by HPLC.

Example 3: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised and allowed to reflux to dissolve the solid completely to provide a clear solution. Then, solvent was distilled off under vacuum to obtain a residue and isopropanol (50ml) was added and after stirring for hours the solid was filtered and dried to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (26g) and having purity of 97.54 % by HPLC .

Example 4: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised upto reflux to dissolve the solid completely upto clear solution. Water (1050ml) was added to the solution and the reaction mixture was gradually cooled to crystallize the product. The resulting solid was filtered, washed with two volumes of isopropanol, dried in vacuum oven at a temperature of 40-45 °C to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (20g) and having a HPLC purity of 97.23% .

Example 5: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (20g) was suspended in formamide (100 ml) and heated at a temperature of 130°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (500ml) was added and the reaction mixture was stirred at a temperature of 25-30°C for 45 minutes. The resulting solid was filtered and acetone (200ml) was added stirred the reaction mixture for 30-45 minutes. The resulting solid was filtered, washed, dried to afford pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine compound of formula 1 (12g) having purity 99.6% measured by HPLC.

Example 6: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (lOOg) was suspended in formamide (500ml) and heated at a temperature of 135-140°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (1000ml) was added and the reaction mixture was stirred at a temperature of 20-25°C for 1 hour. The resulting solid was filtered, washed with water (500ml) then successively slurry washed with toluene (2 x 500ml) and dried to afford pure 4- amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine compound of formula I

(70g) having purity 99.8% measured by HPLC; assay > 98%; residue on ignition 0.05%; heavy metals < 20ppm.

Example 7: Preparation of (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7-tetraza-lH-inden-4-ylamine

Diisopropyl diazodicarboxylate (DAID, 1.2 ml,) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( l .Og,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-l ,2,5,7-tetraza- lH-inden-4-ylamine (l .Og). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-( l S)- l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)- l,2,5,7-tetraza- lH-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.

Example 8: Preparation of l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4- d]pyrimidin-l-yl)piperidin-l-yI)prop-2-en-l-one (Ibrutinib)

To a solution of acryloyl chloride (0.06g) in tetrahydrofuran (15.0 ml), a mixture of triethylamine (O. lg) and (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7- tetraza- lH-inden-4-ylamine (0.2g) in tetrahydrofuran (7.8 ml) was added. The reaction mixture was stirred at 25-30°C for 18 hous and filtered. The solvent was removed under vacuum to obtain crude ibrutinib, which was further purified by column chromatography on silica gel to obtain pure ibrutinib as crystalline solid.

Formula VI

Formula VII

Formula I

Formula II

Formula III

Formula IV

Formula V

///////WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED

//////////pirfenidone, CD3 version, SD-560,

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Elamipretide

H-D-Arg-Tyr(2,6-diMe)-Lys-Phe-NH2

D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide

(2S)-6-amino-2-[[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]hexanamide

CAS 736992-21-5

Chemical Formula: C32H49N9O5

Molecular Weight: 639.8

1. Elamipretide
2. bendavia
3. UNII-87GWG91S09
4. 736992-21-5
5. MTP 131
6. RX 31
7. SS 31
8. 87GWG91S09
9. L-Phenylalaninamide, D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-
10. SS-31 peptide
11. Arg-Dmt-Lys-Phe-NH2
12. D-Arg-Dmt-Lys-Phe-NH2
13. SS31 peptide
14. Elamipretide [USAN:INN]
15. MTP-131
16. Elamipretide (USAN/INN)
17. arginyl-2,’6′-dimethyltyrosyl-lysyl-phenylalaninamide
18. CHEMBL3833370
19. SCHEMBL15028020
20. CTK2H1007

Elamipretide is a cardiolipin peroxidase inhibitor and mitochondria-targeting peptide, Improves Left Ventricular and Mitochondrial Function. In vitro: Elamipretide significantly increases enzymatic activities of both complexes to near normal levels.

Background Information

Elamipretide (also known as SS-31 and Bendavia)^[1][2] is a small mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that appears to reduce the production of toxic reactive oxygen species and stabilize cardiolipin.^[3]

Stealth Peptides, a privately held company, was founded in 2006 to develop intellectual property licensed from several universities including elamipretide; it subsequently changed its name to Stealth BioTherapeutics.^[4][5]

Acute coronary syndrome; Age related macular degeneration; Cardiac failure; Corneal dystrophy; Diabetic macular edema; Lebers hereditary optic atrophy

• Originator Stealth Peptides
• Developer Stealth BioTherapeutics
• Class Eye disorder therapies; Ischaemic heart disorder therapies; Oligopeptides; Peptides; Small molecules
• Mechanism of Action Free radical scavengers; Mitochondrial permeability transition pore inhibitors
• Phase II/III Barth syndrome
• • Phase II Acute kidney injury; Corneal disorders; Heart failure; Leber’s hereditary optic atrophy; Mitochondrial disorders; Reperfusion injury
  • Phase I/II Diabetic macular oedema; Dry age-related macular degeneration; Mitochondrial myopathies
  • Phase I Age-related macular degeneration
  • No development reported Chronic heart failure; Diabetes mellitus; Eye disorders; Neurodegenerative disorders

  Most Recent Events

  • 29 Jun 2017 Initial efficacy and adverse events data from phase II MMPOWER-2 trial in Mitochondrial-myopathies released by Stealth
  • 02 Jun 2017 Stealth BioTherapeutics completes a phase II trial in Heart failure in Germany and Serbia (SC) (NCT02814097)
  • 01 May 2017 Phase-II/III clinical trials in Barth syndrome (In children, In adolescents, In adults, In the elderly) in USA (SC) (NCT03098797)

Novel crystalline salt (eg hydrochloride, mesylate and tosylate salts) forms of D-Arg-Dmt-Lys-Phe-NH2 (referred to as MTP-131 or elamipretide ) and composition comprising them are claimed. See WO2016190852 , claiming therapeutic compositions including chromanyl compounds, variants and analogues and uses thereof. Stealth BioTherapeutics (formerly known as Stealth Peptides) is developing elamipretide, which targets mitochondria, for the potential iv/sc treatment of cardiac reperfusion injury, acute coronary syndrome, acute kidney injury, mitochondrial myopathy, skeletal muscle disorders and congestive heart failure.

Also, the company is developing an oral formulation of elamipretide , which targets mitochondria and reduces the production of excess reactive oxygen species, for treating chronic heart failure. In January 2015, a phase II trial was ongoing . In July 2016, a phase II trial was initiated in Latvia, Spain and Hungary .

Further, the company is developing an ophthalmic formulation of elamipretide , a mitochondria targeting peptide, for treating ocular diseases including diabetic macular edema, age-related macular degeneration and fuchs’ corneal endothelial dystrophy and Leber’s hereditary optic neuropathy.

In April 2016, a phase II trial was initiated for LHON . Family members of the product case of elamipretide ( WO2007035640 ) hold protection in the EU until 2026 and expires in the US in 2027 with US154 extension.

Acute coronary syndrome; Age related macular degeneration; Cardiac failure; Corneal dystrophy; Diabetic macular edema; Lebers hereditary optic atrophy

SYNTHESIS

NEXT………………………

PATENT 2

ELAMIPRETIDE BY STEALTH

WO-2017156403

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017156403&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

; MTP-131; D-Arg-Dmt-Lys-Phe-Nth). Compound

1 has been shown to affect the mitochondrial disease process by helping to protect organs from oxidative damage caused by excess ROS production and to restore normal ATP production.

PATENT

US 20110082084

WO 2011091357

WO 2012129427

WO 2013059071

WO 2013126775

US 20140378396

US 20140093897

WO 2015134096

WO 2015100376

WO 2015060462

US 20150010588

PATENNT

WO 2015197723

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015197723

PROCESS FOR PREPARING

D-ARGINYL-2,6-DIMETHYL-L-TYROSYL-L-LYSYL-L-PHENYLALANINAMIDE

TECHNICAL FIELD

The invention relates to a process for solution-phase synthesis of D- Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide (abbreviated H-D-Arg-(2,6-Dimethyl)Tyr-L-Lys-L-Phe-NH₂, development code SS-31 , MTP-131 , X-31) of Formula (I), an active ingredient developed by Stealth BioTherapeutics under the investigational drug brand names Bendavia® and Ocuvia®, for both common and rare diseases including a mitochondrial targeted therapy for ischemia reperfusion injury.

Formula (I)

BACKGROUND

The product belongs to the class of so-called “Szeto-Schiller peptides”. Szeto-Sciller peptides or “SS peptides” are small, aromatic-cationic, water soluble, highly polar peptides, such as disclosed in US 6703483 and US 7576061 , which can readily penetrate cell membranes. The aromatic-cationic peptides include a minimum of two amino acids, and preferably include a minimum of four amino acids, covalently joined by peptide bonds. The maximum number of amino acids is about twenty amino acids covalently joined by peptide bonds. As described by EP 2012/2436390, optimally, the number of amino acids present in the SS peptides is four.

Bendavia® is being tested for the treatment of ischemia reperfusion injury in patients with acute myocardial infarction (AMI), for the treatment of acute kidney injury (AKI) and renal microvascular dysfunction in hypertension, for the treatment of skeletal muscle dysfunction, for the treatment of mitochondrial myopathy and for the treatment of chronic heart failure. Trials are ongoing to assess the Ocuvia’s potential to treat Leber’s Hereditary Optic Neuropathy (LHON) a devastating inherited disease that causes sudden blindness, often in young adults.

Mitochondria are the cell’s powerhouse, responsible for more than 90% of the energy our bodies need to sustain life and support growth. The energetics from mitochondria maintains healthy physiology and prevents disease. In many common and rare diseases, dysfunctional mitochondria are a key component of disease progression.

D-Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide is a cell-permeable and mitochondria-targeted peptide that showed antioxidant activity and was concentrated in the inner mitochondrial membrane. Compound (< 1 nM) significantly reduced intracellular reactive oxygen species, increased mitochondrial potential and prevented tBHP-induced apoptosis in both N2A and SH-SY5Y neuronal cell lines. In rats, intraperitoneal treatment (1 and 3 mg/kg) 1 day prior to unilateral ureteral obstruction and every day thereafter for 14 days significantly decreased tubular damage, macrophage infiltration and interstitial fibrosis. Compound (3 mg/kg i.p. qd for 2 weeks) also prevented apoptosis and insulin reduction in mouse pancreatic islets caused by streptozotocin.

Further studies performed in a G93A mouse model of amyotrophic lateral sclerosis (ALS) demonstrated that the compound (5 mg/kg/day i.p. starting at 30 days of age) led to a significant delay in disease onset.

Potentially useful for the treatment of ALS and may be beneficial in the treatment of aging and diseases associated with oxidative stress.

In the last few years the peptide H-D-Arg-(2,6-Dimethyl)Tyr-L-Lys-L-Phe-NH2, shown in Fig 1 , and its therapeutic activity have been disclosed and

claimed by in several patent applications.

EP 2436390, US 201 10245182 and US 201 10245183 claim topical anesthetic compositions for application to the skin for pain management or anti-skin aging agents, respectively, comprising Szeto-Schiller peptides; SS-31 is specifically claimed as active ingredient. Sequence of solid-phase synthesis is indicated as the preferred preparation process.

US 7718620 claims a process of treating or preventing ischemia-reperfusion injury of the kidney in a mammal by administrating an effective amount of an aromatic-cationic peptide. SS-31 is specifically claimed as active ingredient.

WO2005/001023 discloses a generical process and carrier complexes for delivering molecules to cells comprising a molecule and an aromatic cationic peptide of type D-Arg-Dmt-Lys-Phe-NH2. The tetrapeptide SS-31 is

specifically claimed as product useful for the process at claim 18.

WO2012/1741 17 and WO2014/210056 claim therapeutic compositions based on SS peptides and the aromatic-cationic peptide D-Arg-Dmt-Lys-Phe-NH2 as active agent.

WO 2013/086020, WO 2004/070054 and WO 2005/072295 provide processes for preventing mithochondrial permeability transition and reducing oxidative damage in a mammal, a removed organ, or a cell in need thereof and specifically claims the process wherein the peptide does not have mu-opioid receptor agonist activity, i.e., D-Arg-Dmt-Lys-Phe-NH2.

WO 2009/108695 discloses a process for protecting a kidney from renal injury which may be associated with decreased or blocked blood flow in the subject’s kidney or exposure to a nephrotoxic agent, such as a radiocontrast dye. The processes include administering to the subject an effective amount of an aromatic-cationic peptide to a subject in need thereof and one of the selected peptide is D-Arg-Dmt-Lys-Phe-NH2.

US 6703483 discloses a detailed procedure for the preparation of novel analogs of DALDA [H-Tyr-D-Arg-Phe-Lys-NH2], namely H-Dmt-D-Arg-Phe-Lys-NH2 using the solid-phase techniques and /?-methylbenzhydrylamine

resin and protocols that have been extensively used by inventor’s laboratory.

Most prior art processes for preparing the compound typically comprise conventionally performed peptide solid-phase synthesis with further purification by chromatography in order to obtain the requested purity for therapeutic use.

It is well known that solid-phase synthesis followed by chromatographic purification is time consuming, very expensive and very difficult to be scaled up on industrial scale, so the need of developing a process for large scale production is obvious. The compound is isolated as organic acid salt, as acetate or trifluoro acetate.

eddy et al., Adv. Exp. Med. Biol, 2009, 61 1 , 473 generally describes the liquid-phase synthesis of antioxidant peptides of Figure 1 and similar others (SS-02, SS-20), involving routinely used side chain protecting groups for amino acid building blocks. The guanidine group was protected with NO₂ and the ε-ΝΗ2 of Lys was protected by Cbz or 2-Cl-Cbz. These peptides were

synthesized using Boc/Cbz chemistry and BOP reagent coupling. Starting with the C-terminal Lys residue protected as H-Lys(2-Cl-Cbz)-NH2, (prepared

from the commercially available Boc-Lys(2-Cl-Cbz)-OH in two steps by amidation with NH₄HCO3 in the presence of DCC/HOBt following a literature procedure [Ueyama et all, Biopolymers, 1992, 32, 1535, PubMed: 1457730], followed by exposure to TFA). Selective removal of the 2-Cl-Cbz in the

presence of the NO₂ group was accomplished using catalytic transfer hydrogenolysis (CTH) [Gowda et al., Lett. Pept. Sci., 2002, 9, 153].

A stepwise procedure by standard solution peptide synthesis for preparation of potent μ agonist [DmtJDALDA and its conversion into a potent δ antagonist H-Dmt-Tic-Phe-Lys(Z)-OH by substitution of D-Arg with Tic to enhance the δ opioid agonist activity is described by Balboni et al., J. Med.

Chem., 2005, 48, 5608. A general synthetic procedure for a similar tetrapeptide ([Dmt-D-Arg-Phe-Lys-NH2 is described by Ballet et al., J. Med.

Chem. 2011, 54, 2467.

Similar DALDA analog tetrapeptides were prepared by the manual solid-phase technique using Boc protection for the a-amino group and DIC/HOBt or HBTU/DIEA as coupling agent [Berezowska et al., J. Med. Chem., 2009, 52, 6941 ; Olma et al., Acta Biochim. Polonica, 2001, 48, 4, 1 121 ; Schiller at al., Eur. J. Med. Chem., 2000, 35, 895].

Despite the high overall yield in the solid-phase approach, it has several drawbacks for the scale-up process such as:

a. the application of the highly toxic and corrosive hydrogen fluoride for cleavage of the peptide from the resin,

b. low loading (0.3-0.35 mmol/g of resin) proved necessary for successful end-step, and

c. use of excess amounts of reagents (3-fold of DIC, 2.4-fold of HOBt, etc.) on each step [ yakhovsky et al., Beilstein J. Org. Chem., 2008, 4(39), 1 , doi: 10.376/bjoc.4.39]

SUMMARY

The invention relates to a more efficient process avoiding either solid-phase synthesis or chromatographic purification, more suitable for large scale production. The process of the invention is described in Scheme A.

The following abbreviations are used:

Dmt = 2,6-dimethyl tyrosine; Z= benzyloxycarbonyl; MeSO3H = methane sulphonic acid; Boc = Tert-butyloxycarbonyl; NMM = N-methyl morpholine; TBTU= N,N,N’,N’-Tetramethyl-O-(benzotriazol- l-yl)uronium tetrafluoroborate; DMF = dimethyl formamide; TFA = trifluoroacetic acid

Scheme A shows the process for the solution phase synthesis of peptide

1 for assembly of the tetrapeptide backbone using O-Benzyl (Bzl) group and benzyloxycarbonyl (Z) group respectively, as the temporary protection for amino acids’ N-termini (Scheme Figure 2), followed by a final catalytic hydrogenolysis. The final product is isolated as organic acid salt, for example, acetic acid salt.

H-Phe-NH ₂ + Boc-Lys(Z)-OH

Boc-Lys(Z)-Phe-NH ₂

(IV)

(V) I MeS0₃H/CH₂CI₂

Boc-DMTyr(Bzl)-OH + MeS0₃H.H-Lys(Z)-Phe-NH ₂

(

Boc-DMTyr(Bzl)-Lys(Z)-Phe-NH ₂

(VIII)

I MeS0₃H/CH₂CI₂

Z-D-Arg-ONa + H-DMTyr(Bzl)-Lys(Z)-Phe-NH ₂.MeS0₃H

(X) (IX)

TBTU/NMM/DMF

Z-D-Arg-DMTyr(Bzl)-Lys(Z)-Phe-NH

(XI)

I H₂, Pd/C

X ACOH

H-D-Arg-DMTyr-Lys-Phe-NH

(I)

Scheme A

This process is a notable improvement with respect to the prior art and its advantages can be summarized as follows:

• The synthesis is performed in liquid phase allowing the scale up on industrial scale without need of special equipment; · The selection of the protecting group in the building blocks allows a straightforward synthesis with very simple deprotection at each step and minimize the formation of undesired by-product;

• Each intermediate can be crystallized allowing removal of impurities which are not transferred to the following step;

· The purity of each intermediate is very high and usually close to

99%.

EXAMPLES

Example 1: Preparation of Boc-Lys(Z)-Phe-NH2

Charge 200 mL of DMF, 44 g of Boc-Lys(Z)-OH and 15.6 g of H-Phe-NH2 in a flask. Stir the mixture at room temperature for 10 min. Add 19.2 g of

N-methylmorpholine and 32.1 g of TBTU successively at room temperature. Stir the mixture at room temperature for 1 h. Add 500 mL of water into the reaction mixture to precipitate the product at room temperature. Filter the mixture to isolate the solid product and wash the filter cake with water.

Transfer the filter cake into a flask containing 360 mL of ethyl acetate and heat the mixture at 50°C till all the solid is dissolved. Separate the organic phase of product and discard the small aqueous phase. Concentrate the organic phase at 40~45°C and under vacuum to remove the solvent till lots of solid is formed. Filter the residue to isolate the solid product. Transfer the filter cake into a flask containing 2000 mL of MTBE and heat the mixture at refluxing for 20 min. Then, cool down the mixture to room temperature. Filter the mixture to isolate the solid product. Dry the filter cake at 30 °C and under vacuum to give 35 g of solid product.

Example 2: Preparation of H-Lys(Z)-Phe-NH2.MeSC>3H

Charge 26.3 g of Boc-Lys(Z)-Phe-NH2, 200 mL of methylene chloride

and 9.6 g of methanesulfonic acid. Stir the mixture at 15-20 °C for 18 h. Add 100 mL of MTBE into the mixture and stir at 15-20 °C for 1 h. Filter the mixture to isolate the solid product. Dry the wet cake in air at room temperature to give 26.4 g of white solid product.

Example 3: Preparation of Boc-DMeTyr(Bzl)-Lys(Z)-Phe-NH2

Charge 8.4 g of Boc-DMeTyr(Bzl)-OH, 1 1 g of H-Lys(Z)-Phe-NH2.MeSO3H, 7.4 g of TBTU and 80 mL of THF in a flask. Stir the mixture

at room temperature for 15 min, and then cool down to 10°C. Add 6.36 g of N-methylmorpholine and stir the mixture at 20-25°C for 3 h. Add the reaction mixture into a flask containing 240 mL of water. Add 32 mL of methylene chloride into the mixture obtained in the previous operation of. Stir the resultant mixture at room temperature for 20 min. Filter the mixture to isolate the solid product and wash the filter cake with acetone (300 mL X 2). Dry the filter cake in air at room temperature to give 14.3 g of white solid product.

Example 4: Preparation of H-DMeTyr(Bzl)-Lys(Z)-Phe-NH₂.MeS0₃H

Charge 14 g of Boc-BMeTyr(Bzl)-Lys(Z)-Phe-NH₂, 280 mL of methylene chloride and 3.3 g of methanesulfonic acid in a flask. Stir the mixture at 18 ~ 22 °C for 10 h. Add 560 mL of heptanes into the mixture and stir the mixture at room temperature for 30 min. Filter the mixture to isolate the solid product. Dry the wet cake in air at room temperature to give 14 g of white solid product.

Example 5: Preparation of Z-D-Arg-DMeTyr(Bzl)-Lys(Z)-Phe-NH2

Charge 6.34 g of Z-D-Arg-ONa, 100 mL of DMF and 2.0 g of methanesulfonic acid in a flask. Stir the mixture at room temperature till a clear solution was formed. Add 14 g of H-DMeTyr(Bzl)-Lys(Z)-Phe-NH₂.MeSO3H and cool down the mixture to 10°C. Add 6.15 g of TBTU and

9.67 g of N-methylmorpholine successively. Stir the mixture at room temperature for 4 h. Add aqueous solution of LiOH prepared by dissolving 2.9 g of LiOH.L O in 8 mL of water. Stir the mixture for 30 min. Add the resultant mixture slowly into a flask containing 420 mL of water under stirring. Add 56 mL of methylene chloride into the mixture. Filter the mixture to isolate the solid product. Transfer the filter cake into a flask containing 150 mL of acetic acid, and heat the mixture at 35-40 °C till most of the solid was dissolved. Add 450 mL of MTBE into the mixture and cool down the mixture under stirring to room temperature. Filter the mixture to isolate the solid product. Dry the filter cake in air at room temperature to give 17.3 g of the white solid product.

Example 6 Preparation of H-D-Arg-DMeTyr-Lys-Phe-NH2.3AcOH

Charge 2.0 g of Z-D-Arg-DMeTyr(Bzl)-Lys(Z)-Phe-NH₂, 20 mL of acetic acid and 5% Pd/C catalyst (which is obtained by washing 5.0 g of 5% Pd/C containing 60% of water with 30 mL of acetic acid) in a flask. Change the atmosphere of the flask with hydrogen. Stir the mixture at room temperature and pressure of 1 atm of hydrogen for 2 h. Filter the mixture to remove the Pd/C catalyst and wash the filter cake with 10 mL of acetic acid. Combine the filtrate and washing solution and concentrate the solution at 20°C and under vacuum to remove most the solvent. Add 100 mL of acetonitrile into the residue and stir the mixture at room temperature for 20 min. Filter the mixture to isolate the solid product. Dry the filter cake at room temperature and under vacuum to give 0.7 g of the white product.

PATENT

WO 2016001042

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016001042&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

References

REFERENCES

1: Alam NM, Mills WC 4th, Wong AA, Douglas RM, Szeto HH, Prusky GT. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis Model Mech. 2015 Jul 1;8(7):701-10. doi: 10.1242/dmm.020248. Epub 2015 Apr 23. PubMed PMID: 26035391; PubMed Central PMCID: PMC4486862.

2: Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014 Dec;96(6):672-83. doi: 10.1038/clpt.2014.174. Epub 2014 Sep 4. Review. PubMed PMID: 25188726; PubMed Central PMCID: PMC4267688.

3: Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. J Cardiovasc Pharmacol. 2014 Dec;64(6):543-53. PubMed PMID: 25165999.

4: Eirin A, Ebrahimi B, Zhang X, Zhu XY, Woollard JR, He Q, Textor SC, Lerman A, Lerman LO. Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. Cardiovasc Res. 2014 Sep 1;103(4):461-72. doi: 10.1093/cvr/cvu157. Epub 2014 Jun 19. PubMed PMID: 24947415; PubMed Central PMCID: PMC4155472.

5: Liu S, Soong Y, Seshan SV, Szeto HH. Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis. Am J Physiol Renal Physiol. 2014 May 1;306(9):F970-80. doi: 10.1152/ajprenal.00697.2013. Epub 2014 Feb 19. PubMed PMID: 24553434.

6: Brown DA, Hale SL, Baines CP, del Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Moukdar F, Shaikh SR, Fisher-Wellman KH, Neufer PD, Kloner RA. Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. J Cardiovasc Pharmacol Ther. 2014 Jan;19(1):121-32. doi: 10.1177/1074248413508003. Epub 2013 Nov 28. PubMed PMID: 24288396; PubMed Central PMCID: PMC4103197.

7: Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014 Apr;171(8):2017-28. doi: 10.1111/bph.12468. PubMed PMID: 24134698; PubMed Central PMCID: PMC3976619.

8: Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014 Apr;171(8):2029-50. doi: 10.1111/bph.12461. Review. PubMed PMID: 24117165; PubMed Central PMCID: PMC3976620.

9: Zhao WY, Han S, Zhang L, Zhu YH, Wang LM, Zeng L. Mitochondria-targeted antioxidant peptide SS31 prevents hypoxia/reoxygenation-induced apoptosis by down-regulating p66Shc in renal tubular epithelial cells. Cell Physiol Biochem. 2013;32(3):591-600. doi: 10.1159/000354463. Epub 2013 Sep 6. PubMed PMID: 24021885.

10: Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. doi: 10.1161/CIRCHEARTFAILURE.113.000406. Epub 2013 Aug 9. PubMed PMID: 23935006; PubMed Central PMCID: PMC3856238.

/////////////////////Elamipretide,  SS-31,  Bendavia, PEPTIDE

CC1=CC(=CC(=C1CC(C(=O)NC(CCCCN)C(=O)NC(CC2=CC=CC=C2)C(=O)N)NC(=O)C(CCCN=C(N)N)N)C)O

Phytomenadione,

PHYTONADIONE, Phylloquinone

13C NMR

1. Murahashi, Shun-ichi; European Journal of Organic Chemistry 2011, VOL2011(27), P5355-5365 
2. Huang, Zhihong; Advanced Synthesis & Catalysis 2007, VOL349(4+5), PG539-545 

IR LIQ FILM

Phytomenadione, also known as vitamin K₁ or phylloquinone, is a vitamin found in food and used as a dietary supplement.^[1][2] As a supplement it is used to treat certain bleeding disorders.^[2] This includes in warfarin overdose, vitamin K deficiency, and obstructive jaundice.^[2] It is also recommended to prevent and treat hemorrhagic disease of the newborn.^[2] Use is typically recommended by mouth or injection under the skin.^[2] Use by injection into a vein or muscle is recommended only when other routes are not possible.^[2] When given by injection benefits are seen within two hours.^[2]

Common side effects when given by injection include pain at the site of injection and altered taste.^[2] Severe allergic reactions may occur with injected into a vein or muscle.^[2] It is unclear if use during pregnancy is safe; however, use is likely okay during breastfeeding.^[3] It works by supplying a required component for making a number of blood clotting factors.^[2] Found sources include green vegetables, vegetable oil, and some fruit.^[4]

Phytomenadione was first isolated in 1939.^[5] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[6] The wholesale cost in the developing world is about 0.11 to 1.27 USD for a 10 mg vial.^[7]In the United States a course of treatment costs less than 25 USD.^[8] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prizefor its discovery.^[5]

Terminology

Phytomenadione is often called phylloquinone or vitamin K,^[9] phytomenadione or phytonadione. Sometimes a distinction is made between phylloquinone, which is considered to be a natural substance, and phytonadione, which is considered to be a synthetic substance.^[10]

A stereoisomer of phylloquinone is called vitamin k₁ (note the difference in capitalization).

Chemistry

Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight. It is a polycyclic aromatic ketone, based on 2-methyl–1,4-naphthoquinone, with a 3-phytyl substituent. It is found naturally in a wide variety of green plants, particularly in leaves, since it functions as an electron acceptor during photosynthesis, forming part of the electron transport chain of photosystem I.

Phylloquinone is an electron acceptor during photosynthesis, forming part of the electron transport chain of Photosystem I.

The best-known function of vitamin K in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver. It is also required for the formation of anticoagulant factors protein C and S. It is commonly used to treat warfarin toxicity, and as an antidote for coumatetralyl.

Vitamin K is required for bone protein formation.

SYN

e-EROS Encyclopedia of Reagents for Organic Synthesis, 1-2; 2001

WO2016060670

PAPERS

Helvetica Chimica Acta (1944), 27, 317-19.

PATENT

US 2683176

CN 105399615

WO 2016060670

References

Phytomenadione

Clinical data
Trade names	Mephyton, others
Synonyms	Vitamin K1, phytonadione, phylloquinone
AHFS/Drugs.com	Monograph
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	by mouth, subQ, IM, IV
ATC code	B02BA01 (WHO)
Identifiers
IUPAC name[show]
CAS Number	84-80-0
PubChem CID	4812
DrugBank	DB01022
ChemSpider	4447652
UNII	A034SE7857
ChEBI	CHEBI:18067
ChEMBL	CHEMBL1550
ECHA InfoCard	100.001.422
Chemical and physical data
Formula	C31H46O2
Molar mass	450.70 g/mol
3D model (JSmol)	Interactive image

/////////////PHYTONADIONE, фитоменадион ,فيتوميناديون , PHYTONADIONE, Phylloquinone

MELTING POINT	:	Yellow viscous oil (Ref. 0001)
REFRACTIVE INDEX	:	n20D=1.5263(Ref. 0010)
OPTICAL ROTATION	:	[a]25D=-28(Ref. 0001)Optical rotation [Table ] (Ref. 0010)
SOLUBILITY	:	Insol in water. Sparingly sol in methanol; sol in ethanol, acetone, benzene, petr ether, hexane, dioxane, chloroform, ether, other fat solvents and in vegetable oils(Ref. 0001)

UV SPECTRA	:	Uv max (petr ether) 242, 248, 260, 269, 325 nm (E1%1cm396, 419, 383, 387, 68) (Ref. 0001). Uv max (ethanol) 243, 248, 262, 270, 330 nm (Ref. 0002). (UV Ref. 0010)Em at 248 nm (EtOH) =18,900 (Ref. 0002/0006).
IR SPECTRA	:	(liquid) : 6.05m (CO), 6.21, 6.28m (aromatic nucleus) (Ref. 0008) (IR Ref. 0010) [Table 0002] (Ref. 0010)
NMR SPECTRA	:	at 60 MHz in CDCl3, i nternal standard Si(CH3)4: multiplet at 453-486 Hz (4 aromatic H), triplet at 302 Hz (J=7 Hz) (olefinic H at C2. , doublet at 201 Hz ) (J=7 Hz) (CH2.-1), singlet at 130 Hz (CH3-2), signal at 107 Hz (trans-methyl group at C3. .(Ref. 0008) ( NMR Ref. 0010) Proton magnetic resonance data
MASS SPECTRA	:	[Spectrum  (Ref. 0005)

//////////////

JTV-519

• Molecular FormulaC₂₅H₃₂N₂O₂S
• Average mass424.599 Da
• 145903-06-6 CAS

JTV-519 hydrochloride salt

• Molecular FormulaC₂₅H₃₃ClN₂O₂S
• Average mass461.060 Da

JTV-519 (K201) is a 1,4-benzothiazepine derivative that interacts with many cellular targets.^[1] It has many structural similarities to diltiazem, a Ca²⁺ channel blocker used for treatment of hypertension, angina pectoris and some types of arrhythmias.^[2] JTV-519 acts in the sarcoplasmic reticulum (SR) of cardiac myocytes by binding to and stabilizing the ryanodine receptor (RyR2) in its closed state.^[3][4]It can be used in the treatment of cardiac arrhythmias, heart failure, catecholaminergic polymorphic ventricular tachycardia (CPVT) and store overload-induced Ca²⁺ release (SOICR).^[2][3][4] Currently, this drug has only been tested on animals and its side effects are still unknown.^[5] As research continues, some studies have also found a dose-dependent response; where there is no improvement seen in failing hearts at 0.3 μM and a decline in response at 1 μM.^[4]

K-201 (JTV-519; 1,4-benzothiazepine derivative) is an antiarrhythmic drug, had been in phase II clinical development at Japan Tobacco and Sequel Pharmaceuticals for the intravenous treatment of atrial fibrillation; however no recent developments have been reported and Sequel Pharmaceuticals has ceased operations.

In 2006, NovaCardia acquired rights from Aetas to develop the product in Europe and US for cardiovascular disorders. Sequel acquired the compound, which has a unique multi-ion channel profile, from NovaCardia following its acquisition by Merck & Co.

Treatment with JTV-519 involves stabilization of RyR2 in its closed state, decreasing its open probability during diastole and inhibiting a Ca²⁺ leak into the cell’s cytosol.^[3][4] By decreasing the intracellular Ca²⁺ leak, it is able to prevent Ca²⁺ sparks or increases in the resting membrane potential, which can lead to spontaneous depolarization (cardiac arrhythmias), and eventually heart failure, due to the unsynchronized contraction of the atrial and ventricular compartments of the heart.^[2][3][4] When Ca²⁺ sparks occur from the SR, the increase in intracellular Ca²⁺ contributes to the rising membrane potential which leads to the irregular heart beat associated to cardiac arrhythmias.^[3] It can also prevent SOICR in the same manner; preventing opening of the channel due to the increase of Ca²⁺ inside the SR levels beyond its threshold.^[2]

Molecular problem

In the closed state, N-terminal and central domains come into close contact interacting to cause a “zipping” of domains. This leads to conformational constraints that stabilize the channel and maintain the closed state.^[1] Most RyR2 mutations are clustered into three regions of the channel, all affecting the same domains that interact to stabilize the channel.^[1] Any of these mutations can lead to “unzipping” of the domains and a decrease in the energy barrier required for opening the channel (increasing its open probability).^[1]This channel “unzipping” allows for an increase in protein kinase A phosphorylation and calstabin2 dissociation. Phosphorylation of RyR2 increases the channel’s response to Ca²⁺, which usually binds the RyR2 to open it.^[1] If the channel become phosphorylated, this can lead to an increase in Ca²⁺ sparks due to an increase in Ca²⁺ sensitivity.

Some researchers believe that the depletion of calstabin2 from the RyR2 causes the calcium leak.^[3] The depletion of calstabin2 can occur in both heart failure and CPVT.^[3]Calstabin2 is a protein that stabilizes RyR2 in its closed state, preventing Ca²⁺ leakage during diastole. When calstabin2 is lost, the interdomain interactions of RyR2 become loose, allowing the Ca²⁺ leak.^[3] However, the role of calstabin2 has been controversial, as some studies have found it necessary for the effect of JTV-519,^[3] whereas others have found the drug functions without the stabilizing protein.^[2]

Molecular mechanism

JTV-519 seems to restore the stable conformation of RyR2 during the closed state.^[1][4] It is still controversial whether or not calstabin2 is necessary for this process, however, many studies believe that JTV-519 can act directly on the channel and by binding, prevents conformational changes.^[2] This stabilization of the channel decreases its open probability resulting in fewer leaks of Ca²⁺ into the cytosol and fewer Ca²⁺ sparks to occur.^[3][4] Researchers who believe that calstabin2 is necessary for JTV-519 effect, found that this drug may function by inducing the binding of calstabin2 back to the channel or increasing calstabin2’s affinity for the RyR2 and thus increasing its stability.^[2][3]

SYNTHESIS

PATENT

US 20050186640

https://www.google.com/patents/US20050186640

PATENT

WO 9212148

https://www.google.co.in/patents/WO1992012148A1?cl=en

PATENT

US 2014121368

2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines are important compounds because of their biological activities, as disclosed, for example, in U.S. Pat. Nos. 5,416,066 and 5,580,866 and published US Patent Applications Nos. 2005/0215540, 2007/0049572 and 2007/0173482.

Synthetic procedures exist for the preparation of 2-oxo-, 3-oxo-, 5-oxo- and 3,5-dioxo-1,4-benzothiazepines and for 2,3-dihydro-1,4-benzothiazepines. However, relatively few publications describe the preparation of 2,3,4,5-tetrahydrobenzo-1,4-thiazepines that contain no carbonyl groups, and most of these involve reduction of a carbonyl group or an imine. Many of the routes described in the literature proceed from an ortho-substituted arene and use the ortho substituents as “anchors” for the attachment of the seven-membered ring. Essentially all the preparatively useful syntheses in the literature that do not begin with an ortho-substituted arene employ a modification of the Bischler-Napieralski reaction in which the carbon of the acyl group on the γ-amide becomes the carbon adjacent the bridgehead and the acyl substituent becomes the 5-substituent. Like earlier mentioned syntheses, the Bischler-Napieralski synthesis requires reduction of an iminium intermediate.

It would be useful to have an intramolecular reaction for the direct construction of 2,3,4,5-tetrahydrobenzo[1,4]thiazepines that would allow more flexibility in the 4- and 5-substituents and that would avoid a separate reduction step. The Pictet Spengler reaction, in which a β-arylethylamine such as tryptamine undergoes 6-membered ring closure after condensation (cyclization) with an aldehyde, has been widely used in the synthesis of 6-membered ring systems over the past century and might be contemplated for this purpose. The Pictet Spengler reaction, however, has not been generally useful for 7-membered ring systems such as 1,4-benzothiazepines. A plausible explanation is that the failure of the reaction for typical arenes was due to the unfavorable conformation of the 7-membered ring. There are two isolated examples of an intramolecular Pictet-Spengler-type reaction producing a good yield of a benzothiazepine from the addition of formaldehyde. In one case, the starting material was a highly unusual activated arene (a catechol derivative) [Manini et al. J. Org. Chem. (2000), 65, 4269-4273]. In the other case, the starting material is a bis(benzotriazolylmethyl)amine that cyclizes to a mono(benzotriazolyl)benzothiazole [Katritzky et al. J. Chem. Soc. Pl (2002), 592-598].

PATENT

US 20050186640

WO 2015031914

US 20040229781

US 20090292119

US 7704990

PAPER

Journal of Medicinal Chemistry (2013), 56(21), 8626-8655

http://pubs.acs.org/doi/full/10.1021/jm401090a

PAPER

Synthesis of 2,3,4,5-Tetrahydrobenzo[1,4]thiazepines via N-Acyliminium Cyclization

Shixian Deng^†‡, Zhenzhuang Cheng^†, Charles Ingalls^†, Ferenc Kontes^†, Jiaming Yan^†, and Sandro Belvedere^*† 

^† ARMGO Pharma, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, United States

^‡ Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00260

Publication Date (Web): September 28, 2017

Copyright © 2017 American Chemical Society

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00260

*Phone: (914)-425-0000. E-mail: sbelvedere@armgo.com.

Abstract

We report an efficient and scalable synthesis of 7-methoxy-2,3,4,5-tetrahydrobenzo[1,4]thiazepine, the core structure of biologically active molecules like JTV-519 and S107. This synthetic route, starting with 4-methoxythiophenol and proceeding via acyliminum cyclization, gives the target product in four steps and 68% overall yield and is a substantial improvement over previously published processes. Nine additional examples of tetrahydrobenzo[1,4]thiazepine synthesis via acyliminium ring closure are also presented.

References

1. ^ Jump up to:^{a b c d e f} Oda, T; Yano, M; Yamamoto, T; Tokuhisa, T; Okuda, S; Doi, M; Ohkusa, T; Ikeda, Y; et al. (2005). “Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure”. Circulation. 111 (25): 3400–10. PMID 15967847. doi:10.1161/CIRCULATIONAHA.104.507921.
2. ^ Jump up to:^{a b c d e f g} Hunt, DJ; Jones, PP; Wang, R; Chen, W; Bolstad, J; Chen, K; Shimoni, Y; Chen, SR (2007). “K201 (JTV519) suppresses spontaneous Ca2+ release and 3Hryanodine binding to RyR2 irrespective of FKBP12.6 association”. The Biochemical Journal. 404 (3): 431–8. PMC 1896290 . PMID 17313373. doi:10.1042/BJ20070135.
3. ^ Jump up to:^{a b c d e f g h i j k} Wehrens, XH; Lehnart, SE; Reiken, SR; Deng, SX; Vest, JA; Cervantes, D; Coromilas, J; Landry, DW; Marks, AR (2004). “Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2”. Science. 304 (5668): 292–6. PMID 15073377. doi:10.1126/science.1094301.
4. ^ Jump up to:^{a b c d e f g} Toischer, K; Lehnart, SE; Tenderich, G; Milting, H; Körfer, R; Schmitto, JD; Schöndube, FA; Kaneko, N; et al. (2010). “K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum”. Basic research in cardiology. 105 (2): 279–87. PMC 2807967 . PMID 19718543. doi:10.1007/s00395-009-0057-8.
5. Jump up^ Viswanathan, MN; Page, RL (2009). “Pharmacological therapy for atrial fibrillation: Current options and new agents”. Expert Opinion on Investigational Drugs. 18 (4): 417–31. PMID 19278302. doi:10.1517/13543780902773410.

JTV-519

Names
IUPAC name 3-(4-Benzyl-1-piperidinyl)-1-(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1-propanone
Other names K201
Identifiers
CAS Number	1038410-88-6
3D model (JSmol)	Interactive image
ChemSpider	8044593 (HCl)
PubChem CID	9868902
UNII	0I621Y6R4Q
SMILES[show]
Properties
Chemical formula	C25H32N2O2S
Molar mass	424.60 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////JTV-519, K201, JTV 519, K 201, 

FDA clears first 7T magnetic resonance imaging device

Today, the U.S. Food and Drug Administration cleared the first seven tesla (7T) magnetic resonance imaging (MRI) device, more than doubling the static magnetic field strength available for use in the United States. The Magentom Terra is the first 7T MRI system cleared for clinical use in the United States. Continue reading.

Conclusions

Isosorbide is a versatile platform molecule that shows key features to make it a credible alternative to petro-based products. The molecule is already available on large industrial scale (tens of thousands tons per years), which allows its development in commercial products such as active pharma ingredient, additive for cosmetic, speciality chemicals and polymers (ex: polycarbonates – polyesters). The development of more selective and higher yields syntheses of isosorbide are greatly needed to consolidate isosorbide production in view of a large expansion of its uses. Sorbitol conversion to isosorbide, relying on a starch route, is already a tough challenge. In a farther future, development of a credible path to isosorbide relying on cellulose source could even be thought of, provided that very versatile innovative catalysts will be developed in the next years. In all cases, a key issue is to develop catalysts that will avoid the massive production of “oligomeric/polymeric” by-products in order to access more sustainable processes by limiting the amounts of wastes produced during the synthesis. For this purpose, more selective homogeneous catalysts than the conventional Brønsted acids or alternative reaction conditions would be of strong interest. Selective and recyclable heterogeneous catalysts would be even more profitable as they would allow the continuous production of catalyst free isosorbide. This latter approach faces strong limitations due to the need of high reaction temperatures that often result in high amounts of side-products and the need of frequent and often tedious catalyst regeneration. Innovation concerning isosorbide synthesis is still an open field on which the design of efficient and robust catalysts, either homogeneous or heterogeneous, is a key issue. Such developments would pave the way to high scale effective processes considering altogether synthesis and purification of isosorbide.

////////////////

Isosorbide is a heterocyclic compound that is derived from glucose. Isosorbide and its two isomers, namely isoidide and isomannide, are 1,4:3,6-dianhydrohexitols. It is a white solid that is prepared from the double dehydration of sorbitol. Isosorbide is a non-toxic diolproduced from biobased feedstocks, that is biodegradable and thermally stable. It is used in medicine and has been touted as a potential biofeedstock.

Production

Hydrogenation of glucose gives sorbitol. Isosorbide is obtained by double dehydration of sorbitol:

(CHOH)₄(CH₂OH)₂ → C₆H₁₀O₂(OH)₂ + 2 H₂O

An intermediate in the dehydration is the monocycle sorbitan.^[1]

Application

Isosorbide is used as a diuretic, mainly to treat hydrocephalus, and is also used to treat glaucoma.^[2] Other medications are derived from isosorbide, including isosorbide dinitrate and isosorbide mononitrate, are used to treat angina pectoris. Other isosorbide-based medicines are used as osmotic diuretics and for treatment of esophageal varices. Like other nitric oxide donors (see biological functions of nitric oxide), these drugs lower portal pressure by vasodilation and decreasing cardiac output. Isosorbide dinitrate and hydralazineare the two components of the anti-hypertensive drug isosorbide dinitrate/hydralazine (Bidil).

Isosorbide is also used as a building block for bio based polymers such as polyesters.^[3]

References

Isosorbide

Names
Other names D-Isosorbide; 1,4:3,6-Dianhydro-D-sorbitol; 1,4-Dianhydrosorbitol
Identifiers
CAS Number	652-67-5
3D model (JSmol)	Interactive image
ChemSpider	12077
ECHA InfoCard	100.010.449
KEGG	D00347
PubChem CID	12597
UNII	WXR179L51S
InChI[show]
SMILES[show]
Properties
Chemical formula	C6H10O4
Molar mass	146.14 g·mol−1
Appearance	Highly hygroscopic white flakes
Density	1.30 at 25 °C
Melting point	62.5 to 63 °C (144.5 to 145.4 °F; 335.6 to 336.1 K)
Boiling point	160 °C (320 °F; 433 K) at 10 mmHg
Solubility in water	in water (>850 g/L), alcoholsand ketones
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

From the net

1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

REF

http://www.rsc.org/suppdata/gc/c4/c4gc01822b/c4gc01822b1.pdf

Synthesis of five- and six-membered heterocycles by dimethyl carbonate with catalytic amount of nitrogen bicyclic bases

http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01822b#!divAbstract

F. Aricò, a,*S. Evaristoa and P. Tundoa,*

Catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU and TBD is effective for the one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases, that previously showed to enhance the reactivity of DMC in methoxycarbonylation reaction by BAc2 mechanism, are herein used for the first time as efficient catalysts for cyclization reaction encompassing both BAc2 and BAl2 pathways. This synthetic procedure was also applied to a large scale synthesis of cyclic sugars isosorbide and isomannide starting from D-sorbitol and D-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure crystalline compounds that did not require any further purification or crystallization.

Larger scale synthesis of isosorbide: In a round bottom flask equipped with a reflux condenser, D-sorbitol (0.05 mol, 1.00 mol. eq.), DMC (0.44 mol, 8.00 mol. eq.), DBU (2.70 mmol, 0.05 mol. eq.) and MeOH (20.00 mL) were heated at reflux while stirring. The progress of the reaction was monitored by NMR. After 48 hours the reaction was stopped, cooled at room temperature and the mixture was filtered over Gooch n°4. Finally, DMC was evaporated under vacuum and the product was obtained as pure in 98% yield (7.90 g, 0.05 mol). Characterization data were consistent with those obtained for the commercially available compound.

File:Isosorbide dinitrate synthesis.png

Amantadine

• Molecular Formula C₁₀H₁₇N
• Average mass 151.249 Da

Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a drug that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian drug. It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadineis a closely related derivative of adamantane with similar biological properties.

Apart from medical uses, this compound is useful as a building block in organic synthesis, allowing the insertion of an adamantyl group.

According to the U.S. Centers for Disease Control and Prevention (CDC) 100% of seasonal H3N2 and 2009 pandemic flu samples tested showed resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support of or against its efficacy and safety.^[2]

Medical uses

Parkinson’s disease

Amantadine is used to treat Parkinsons disease, as well as parkinsonism syndromes.^[3] A 2003 Cochrane review concluded evidence was inadequate to support the use of amantadine for Parkinson’s disease.^[2]

An extended release formulation is used to treat dyskinesia, a side effect of levodopa which is taken by people who have Parkinsons.^[4]

Influenza

Amantadine is no longer recommended for treatment of influenza A infection. For the 2008/2009 flu season, the CDC found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes.^[5] The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for treatment of flu.^[6][7] A 2014 Cochrane review did not find benefit for the prevention or treatment of influenza A.^[8]

Fatigue in multiple sclerosis

Amantadine also seems to have moderate effects on multiple sclerosis (MS) related fatigue.^[9]

Adverse effects

Amantadine has been associated with several central nervous system (CNS) side effects, likely due to amantadine’s dopaminergic and adrenergic activity, and to a lesser extent, its activity as an anticholinergic. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson’s disease. The usefulness of amantadine as an anti-parkinsonian drug is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.

Rare cases of severe skin rashes, such as Stevens-Johnson syndrome,^[10] and of suicidal ideation have also been reported in patients treated with amantadine.^[11][12]

Livedo reticularis is a possible side effect of amantadine use for Parkinson’s disease.^[13]

Influenza

The mechanisms for amantadine’s antiviral and antiparkinsonian effects are unrelated. The mechanism of amantadine’s antiviral activity involves interference with the viral protein, M2, a proton channel.^[14][15] After entry of the virus into cells via endocytosis, it is localized in acidic vacuoles; the M2 channel functions in transporting protons with the gradient from the vacuolar space into the interior of the virion. Acidification of the interior results in disassociation of ribonucleoproteins, and the initiation of viral replication. Amantadine and rimantadine function in a mechanistically identical fashion in entering the barrel of the tetrameric M2 channel, and blocking pore function (i.e., proton translocation). Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, leading to the inability of the sterically bulky adamantane ring that both amantadine and rimantadine share, in entering in their usual way, into the channel.^{[citation needed]}

Influenza B strains possess a structurally distinct M2 channels with channel-facing side chains that fully obstruct the channel vis-a-vis binding of adamantine-class channel inhibitors, while still allowing proton flow and channel function to occur; this constriction in the channels is responsible for the ineffectiveness of this drug and rimantadine towards all circulating Influenza B strains.

Parkinson’s disease

Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.^[16] Amantadine probably does not inhibit MAO enzyme.^[17] Moreover, the mechanism of its antiparkinsonian effect is poorly understood.^{[citation needed]} The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist^[18][19] as well as an anticholinergic, specifically a nicotinic alpha-7 antagonist like the similar pharmaceutical memantine.

In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the σ₁ receptor (K_i = 7.44 µM and 2.60 µM, respectively), and that activation of the σ₁receptor is involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations.^[20] These findings may also extend to the other adamantanes such as adapromine, rimantadine, and bromantane, and could explain the psychostimulant-like effects of this family of compounds.^[20]

History

Amantadine was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza, and eventually received approval for the treatment of influenzavirus A^{[21][22][23][24]} in adults. In 1969, the drug was also discovered by accident upon trying to help reduce symptoms of Parkinson’s disease, drug-induced extrapyramidal syndromes, and akathisia.

In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation developed by Adamas Pharma for the treatment of dyskinesia, an adverse effect of levodopa, that people with Parkinson’s experience.^[25]

Veterinary misuse

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.^[26] In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine.^[26] Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to the scarcer and costlier oseltamivir and zanamivir, which work by a different mechanism and are less likely to trigger resistance.

On September 23, 2015, the US Food and Drug Administration announced the recall of Dingo Chip Twists “Chicken in the Middle” dog treats because the product has the potential to be contaminated with amantadine.^[27]

PAPER

An Improved Synthesis of Amantadine Hydrochloride

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00242

Duong Binh Vu^†, Thinh Van Nguyen^†, Son Trung Le^†, and Chau Dinh Phan^*‡ 

^† Vietnam Military Medical University, No. 160, Phung Hung str., Phuc La ward, Ha Dong district, Hanoi, Vietnam

^‡ School of Chemical Engineering, Hanoi University of Science and Technology, No.1, Dai Co Viet str., Bach Khoa ward, Hai Ba Trung district, Hanoi, Vietnam

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00242

*E-mail: chau.phandinh@hust.edu.vn.

Amantadine hydrochloride 1 is an antiviral drug used in the prevention and treatment of influenza A infections. It has also been used for alleviating early symptoms of Parkinson’s disease. Several methods for the preparation of 1 have been reported. These procedures started with adamantane 2 using as many as four reaction steps to produce amantadine hydrochloride with overall yields ranging from 45% to 58%. In this article, we describe a two-step procedure for the synthesis of 1from 2 via N-(1-adamantyl)acetamide 4 with an improved overall yield of 67%. The procedure was also optimized to reduce the use of toxic solvents and reagents, rendering it more environment-friendly. The procedure can be considered as suitable for large-scale production of amantadine hydrochloride. The structure of amantadine hydrochloride was confirmed by ¹H NMR, ¹³C NMR, IR, and MS.

Amantadine Hydrochloride (1)

Title: Amantadine CAS Registry Number: 768-94-5 CAS Name: Tricyclo[3.3.1.13,7]decan-1-amine Additional Names: 1-adamantanamine; 1-aminoadamantane; 1-aminodiamantane (obsolete); 1-aminotricyclo[3.3.1.13,7]decane Molecular Formula: C10H17N Molecular Weight: 151.25 Percent Composition: C 79.41%, H 11.33%, N 9.26% Literature References: NMDA-receptor antagonist; also active vs influenza A virus. Prepn: H. Stetter et al., Ber. 93, 226 (1960); W. Haaf, ibid. 97, 3234 (1964); P. Kovacic, P. D. Roskos, Tetrahedron Lett. 1968, 5833. Antiviral activity: W. L. Davies et al.,Science 144, 862 (1964). GC determn in biological samples and pharmacodynamics: W. E. Bleidner et al., J. Pharmacol. Exp. Ther. 150, 484 (1965). Pharmacology and toxicology: V. G. Vernier et al., Toxicol. Appl. Pharmacol. 15, 642 (1969). Comprehensive description: J. Kirschbaum, Anal. Profiles Drug Subs. 12, 1-36 (1983). Review of use vs influenza A: R. L. Tominack, F. G. Hayden, Infect. Dis. Clin. North Am. 1, 459-478 (1987); of pharmacokinetics: F. Y. Aoki, D. S. Sitar, Clin. Pharmacokinet. 14, 35-51 (1988). Review of NMDA receptor binding and neuroprotective properties: J. Kornhuber et al., J. Neural Transm. 43, Suppl., 91-104 (1994). Series of articles on clinical experience in Parkinson’s disease: ibid. 46, Suppl., 399-421 (1995). Properties: Crystals by sublimation, mp 160-190° (closed tube) (Stetter). Also reported as mp 180-192° (Haaf). pKa: 10.1. Sparingly sol in water. Melting point: mp 160-190° (closed tube) (Stetter); mp 180-192° (Haaf) pKa: pKa: 10.1 Derivative Type: Hydrochloride CAS Registry Number: 665-66-7 Manufacturers’ Codes: EXP-105-1; NSC-83653 Trademarks: Adekin (Desitin); Lysovir (Alliance); Mantadan (Boehringer, Ing.); Mantadine (Endo); Mantadix (BMS); Symmetrel (Endo); Virofral (Novo) Molecular Formula: C10H17N.HCl Molecular Weight: 187.71 Percent Composition: C 63.99%, H 9.67%, N 7.46%, Cl 18.89% Properties: Crystals from abs ethanol + anhydr ether, mp >360° (dec). Freely sol in water (at least 1:20); sol in alcohol, chloroform. Practically insol in ether. LD50 orally in mice, rats: 700, 1275 mg/kg (Vernier). Melting point: mp >360° (dec) Toxicity data: LD50 orally in mice, rats: 700, 1275 mg/kg (Vernier) Derivative Type: Sulfate CAS Registry Number: 31377-23-8 Trademarks: PK-Merz (Merz) Molecular Formula: C10H17N.½H2SO4 Molecular Weight: 200.29 Percent Composition: C 59.97%, H 9.06%, N 6.99%, S 8.00%, O 15.98% Therap-Cat: Antiviral; antiparkinsonian. Keywords: Antidyskinetic; Antiparkinsonian; Antiviral.

Amantadine

Clinical data
Trade names	Symmetrel
Synonyms	1-Adamantylamine
AHFS/Drugs.com	Monograph
MedlinePlus	a682064
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral
ATC code	N04BB01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	86–90%[1]
Protein binding	67%[1]
Metabolism	Minimal (mostly to acetyl metabolites)[1]
Biological half-life	10–31 hours[1]
Excretion	Urine[1]
Identifiers
IUPAC name[show]
CAS Number	768-94-5
PubChem CID	2130
IUPHAR/BPS	4128
DrugBank	DB00915
ChemSpider	2045
UNII	BF4C9Z1J53
KEGG	D07441
ChEBI	CHEBI:2618
ChEMBL	CHEMBL660
ECHA InfoCard	100.011.092
Chemical and physical data
Formula	C10H17N
Molar mass	151.249 g/mol
3D model (JSmol)	Interactive image

References

/////////////

Escitalopram

(+)-Citalopram

(1S)-1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile [ACD/IUPAC Name]

(S)-citalopram

128196-01-0 [RN]

5-Isobenzofurancarbonitrile, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-, (1S)- [ACD/Index Name]

• Molecular FormulaC₂₀H₂₁FN₂O
• Average mass324.392 Da
• S-(+)-Citalopram
  эсциталопрам [Russian] [INN]
  إيسكيتالوبرام [Arabic] [INN]
  艾司西酞普兰 [Chinese] [INN]

Lexapro^® (escitalopram oxalate) is an orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure Senantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1-[3(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:

The molecular formula is C₂₀H₂₁FN₂O • C₂H₂O₄ and the molecular weight is 414.40.

Escitalopram oxalate occurs as a fine, white to slightly-yellow powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.

Lexapro (escitalopram oxalate) is available as tablets or as an oral solution.

Lexapro tablets are film-coated, round tablets containing escitalopram oxalate in strengths equivalent to 5 mg, 10 mg, and 20 mg escitalopram base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: talc, croscarmellose sodium, microcrystalline cellulose/colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and polyethylene glycol.

Lexapro oral solution contains escitalopram oxalate equivalent to 1 mg/mL escitalopram base. It also contains the following inactive ingredients: sorbitol, purified water, citric acid, sodium citrate, malic acid, glycerin, propylene glycol, methylparaben, propylparaben, and natural peppermint flavor.

Escitalopram, also known by the brand names Lexapro and Cipralex among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder (MDD) or generalized anxiety disorder (GAD). Escitalopram is the (S)-stereoisomer(Left-enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Whether escitalopram exhibits superior therapeutic properties to citalopram or merely represents an example of “evergreening” is controversial.^[2]

Medical uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults.^[3] In European countries and Australia, it is approved for depression (MDD) and certain anxiety disorders: general anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.^[4]

Controversy exists regarding the effectiveness of escitalopram compared to its predecessor citalopram. The importance of this issue follows from the greater cost of escitalopram relative to the generic mixture of isomers citalopram prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. The most recent of these have concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.^[5][6][7][8]

In contrast to these findings, a 2011 review concluded that all second-generation antidepressants are equally effective,^[9] and treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.^[10][11]

Anxiety disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram (20%) less than placebo (50%).^[12]

Other

Escitalopram as well as other SSRIs are effective in reducing the symptoms of premenstrual syndrome, whether taken in the luteal phase only or continuously.^[13] There is no good data available for escitalopram for seasonal affective disorder as of 2011.^[14] SSRIs do not appear to be useful for preventing tension headaches or migraines.^[15][16]

Adverse effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, genital anesthesia,^[17] and anorgasmia.^[18][19]

An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications.^[20][21][22] The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.^[23]

Escitalopram is not associated with significant weight gain. For example, 0.6 kg mean weight change after 6 months of treatment with escitalopram for depression was insignificant and similar to that with placebo (0.2 kg).^[24] 1.4–1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,^[25] and generalized anxiety disorder.^[26] A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.^[27] Escitalopram may help reduce weight in those treated for binge eating associated obesity.^[28]

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation^[29] and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses.^[30][31] The U.S. Food and Drug Administration and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.^[32]

Escitalopram should be taken with caution when using Saint John’s wort.^[33] Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern.^[34] Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome, liver damage, and other negative side effects have been reported.

Discontinuation symptoms

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as “electric shock” sensations^[35] (also known as “brain shivers” or “brain zaps”), dizziness, acute depressions and irritability, as well as heightened senses of akathisia.^[36]

Pregnancy

There is a tentative association of SSRI use during pregnancy with heart problems in the baby.^[37] Their use during pregnancy should thus be balanced against that of depression.^[37]

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Plasma escitalopram concentrations are usually in a range of 20–80 μg/L in therapeutic situations and may reach 80–200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolizers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.^[38][39][40] Escitalopram seems to be less dangerous than citalopram in overdose and comparable to other SSRIs.^[41]

Pharmacology

Mechanism of action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.^[43] The opposite enantiomer, (R)-citalopram, counteracts to a certain degree the serotonin-enhancing action of escitalopram.^{[citation needed]} As a result, escitalopram has been claimed to be a more potent antidepressant than the racemic mixture, citalopram, of the two enantiomers. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.^[44] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,^[45] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that (R)-citalopram decreases binding of escitalopram to the transporter.^[46] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood-brain penetrability.^[47] In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor enhanced its antidepressant-like effects.^[47]

Interactions

Escitalopram, similarly to other SSRIs (with the exception of fluvoxamine), inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As much of the effect of codeine is attributable to its conversion (10%) to morphine its effectiveness will be reduced by this inhibition, not enhanced.^[48] As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected.^[49] Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that have the ability to prolong the QT interval. Being a SSRI, escitalopram should not be given concurrently with MAOIs or other serotonergic medications.^[43]

History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.^[50] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.^[51] On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.^[52]

In 2006 Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram.^[53] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

Society and culture

Allegations of illegal marketing

In 2004, two separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers, one by a practicing physician named Joseph Piacentile, and the other by a Forest salesman named Christopher Gobble.^[54] In February 2009, these two suits received support from the US Attorney for Massachusetts and were combined into one. Eleven states and the District of Columbia have also filed notices of intention to intervene as plaintiffs in the action. The suits allege that Forest illegally engaged in off-label promoting of Lexapro for use in children, that the company hid the results of a study showing lack of effectiveness in children, and that the company paid kickbacks to doctors to induce them to prescribe Lexapro to children. It was also alleged that the company conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors.^[55][56] Forest responded to these allegations that it “is committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy.”^[57] In 2010 Forest Pharmaceuticals Inc., agreed to pay more than $313 million to settle the charges over Lexapro and two other drugs, Levothroid and Celexa.^[58]

Brand names

Escitalopram is sold under many brand names worldwide such as Cipralex.^[1]

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.

A new method for the preparation of citalopram has been developed: The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (I) with refluxing SOCl2 gives the acyl chloride (II), which is condensed with 2-amino-2-methyl-1-propanol (III) in THF yielding the corresponding amide (IV). The cyclization of (IV) by means of SOCl2 affords the oxazoline (V), which is treated with 4-fluorophenylmagnesium bromide (VI) in THF giving the benzophenone (VII). This compound (VII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (VIII) in the same solvent, providing the cabinol (IX), which is cyclized by means of methanesulfonyl chloride and Et3N in CH2Cl2 yielding the isobenzofuran (X). Finally, this compound is treated with POCl3 in refluxing pyridine to generate the 5-cyano substituent of citalopram.

The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (XII) with refluxing SOCl2 gives the acyl chloride (XIII), which is condensed with 2-amino-2-methyl-1-propanol (XIV) in THF to yield the corresponding amide (XV). The cyclization of (XV) by means of SOCl2 affords the oxazoline (XVI), which is treated with 4-fluorophenylmagnesium bromide (XVII) in THF to give the benzophenone (XVIII). This compound (XVIII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (XIX) in the same solvent to provide the carbinol (XX), which is submitted to optical resolution with (+)- or (-)-tartaric acid, or (+)- or (-)-camphor-10-sulfonic acid (CSA) to give the desired (S)-enantiomer (XXI). Cyclization of (XXI) by means of methanesulfonyl chloride and TEA in dichloromethane yields the chiral isobenzofuran (XXII), which is finally treated with POCl3 in refluxing pyridine.

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.

Racemic 5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (I) is submitted to optical resolution by chiral chromatography to give the corresponding (S)-isomer (II), which is treated with Zn(CN)2 and Pd(PPh3)4 to afford the target Escitalopram.

The esterification of racemic 1-[4-bromo-2-(hydroxymethyl)phenyl]-4-(dimethylamino)-1-(4-fluorophenyl)-1-butanol (I) with (S)-2-(6-methoxynaphth-2-yl)propionyl chloride (II) by means of TEA and DMAP in THF gives the corresponding ester (III) as a diastereomeric mixture that is separated by chiral chromatography over Daicel AD, the desired diastereomer (IV) is easily isolated. Finally, this ester is hydrolyzed and simultaneously cyclized by means of NaH in DMF to provide the target intermediate (V). Other acyl chlorides such as (S)-2-(4-isobutylphenyl)propionyl chloride, (S)-O-acetylmandeloyl chloride, (S)-benzyloxycarbonylprolyl chloride, (S)-2-phenylbutyryl chloride, (S)-2-methoxy-2-phenylacetyl chloride or (S)-N-acetylalanine can also be used in the preceding sequence.

Title: Citalopram CAS Registry Number: 59729-33-8 CAS Name: 1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile Additional Names: 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-phthalancarbonitrile; nitalapram Manufacturers’ Codes: Lu-10-171 Molecular Formula: C20H21FN2O Molecular Weight: 324.39 Percent Composition: C 74.05%, H 6.53%, F 5.86%, N 8.64%, O 4.93% Literature References: Selective serotonin reuptake inhibitor (SSRI). Prepn: K. P. Boegesoe, A. S. Toft, DE 2657013; eidem, US4136193 (1977, 1979 both to Kefalas); A. J. Bigler et al., Eur. J. Med. Chem. – Chim. Ther. 12, 289 (1977). Prepn of enantiomers: K. P. Boegesoe, J. Perregaard, EP 347066; eidem, US 4943590, reissued as US RE 34712 (1989, 1990, 1994 all to Lundbeck). Pharmacology: A. V. Christensen et al., Eur. J. Pharmacol. 41, 153 (1977). HPLC determn in plasma and urine: E. Oyehaug et al.,J. Chromatogr. 308, 199 (1984). Comparative biotransformation of enantiomers: L. L. Von Moltke et al., Drug Metab. Dispos. 29, 1102 (2001). Review of clinical pharmacokinetics: K. Brosen, C. A. Naranjo, Eur. Neuropsychopharmacol. 11, 275-283 (2001). Review of clinical experience in depression: M. B. Keller, J. Clin. Psychiatry 61, 896-908 (2000). Clinical trial of S-form in depression: W. J. Burke et al, ibid. 63, 331 (2002). Properties: bp0.03 175-181°. Boiling point: bp0.03 175-181° Derivative Type: Hydrobromide CAS Registry Number: 59729-32-7 Trademarks: Celexa (Forest); Cipramil (Lundbeck); Elopram (Recordati); Seropram (Lundbeck) Molecular Formula: C20H21FN2O.HBr Molecular Weight: 405.30 Percent Composition: C 59.27%, H 5.47%, F 4.69%, N 6.91%, O 3.95%, Br 19.71% Properties: Crystals from isopropanol, mp 182-183°. Melting point: mp 182-183° Derivative Type: S-(+)-Form CAS Registry Number: 128196-01-0 Additional Names: Escitalopram Properties: [a]D +12.33° (c = 1 in methanol). Optical Rotation: [a]D +12.33° (c = 1 in methanol) Derivative Type: Escitalopram oxalate CAS Registry Number: 219861-08-2 Manufacturers’ Codes: Lu-26-054-0 Trademarks: Cipralex (Lundbeck); Gaudium (Recordati); Lexapro (Forest) Molecular Formula: C20H21FN2O.C2H2O4 Molecular Weight: 414.43 Percent Composition: C 63.76%, H 5.59%, F 4.58%, N 6.76%, O 19.30% Properties: Fine white to slightly yellow powder. Crystals from acetone, mp 147-148°. [a]D +12.31° (c = 1 in methanol). Freely sol in methanol, DMSO; sol in isotonic saline; sparingly sol in water, ethanol; slightly sol in ethyl acetate. Insol in heptane. Melting point: mp 147-148° Optical Rotation: [a]D +12.31° (c = 1 in methanol) Therap-Cat: Antidepressant. Keywords: Antidepressant; Bicyclics; Serotonin Uptake Inhibitor.

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