Regulators in Europe have given the green light to Pierre Fabre’s Hemangiol for the treatment of proliferating infantile haemangioma.

The European Commission has granted the French company authorisation to market Hemangiol, an oral solution of the beta-blocker propranolol specially developed for paediatric use. The thumbs-up follows an approval in the USA in March; it will be launched across the Atlantic as Hemangeol next month.

read at

http://www.pharmatimes.com/Article/14-05-06/Europe_approves_Pierre_Fabre_s_Hemangiol.aspx

by

Kevin Grogan

Follow @PTkevingrogan

Kevin Grogan is the World News Online Editor for PharmaTimes and has been writing about the industry since 1997, having previously worked as a journalist on rock/pop music publications, while contributing articles to the likes of The Independent and the Manchester Evening News on football. He specialises in the business developments of the pharmaceutical industry – financial results, mergers and acquisitions, alliances, legal tussles – and has a particular interest in emerging markets and the prospects for biotech.

FDA Approves Epanova (omega-3-carboxylic acids) for the Treatment of Severe Hypertriglyceridemia

Tuesday, 6 May 2014 — AstraZeneca today announced that the US Food and Drug Administration (FDA) has approved Epanova (omega-3-carboxylic acids) as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia (triglyceride levels greater than or equal to 500 mg/dL).
Epanova is the first FDA approved prescription omega-3 in free fatty acid form. The dosage of Epanova is 2 grams (2 capsules) or 4 grams (4 capsules), making it the first prescription omega-3 to have a dosing option as few as two capsules once a day, with or without food.http://www.drugs.com/newdrugs/fda-approves-epanova-omega-3-carboxylic-acids-severe-hypertriglyceridemia-4038.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+May+6%2C+2014  AT DRUGS.COM

old cut paste

LONDON, Sept. 18, 2013 – AstraZeneca today announced that the US Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for EpanovaTM, an investigational compound for the treatment for patients with severe hypertriglyceridaemia (triglyceride levels greater than or equal to 500mg/dL). The NDA submission for Epanova was filed by Omthera Pharmaceuticals, now a wholly-owned subsidiary of AstraZeneca, as a 505(b)(1) application in July 2013. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA is 5 May 2014.http://www.pharmalive.com/fda-accepts-astrazeneca-nda-for-epanova

COMPOUND 80 ABOVE

IN

http://www.google.com/patents/WO2014056953A1?cl=en

(3S)-3-[[2-Amino-5-(2-methoxybenzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino]heptan-1-ol

TLR7 Receptor Agonists , Signal Transduction Modulators

Janssen R&D Ireland (INNOVATOR)

Janssen R&D Ireland

383.4873

C21 H29 N5 O2

(4aS,7aR)-1-[5-[(3-Fluorophenyl)ethynyl]pyridin-2-yl]hexahydrocyclopenta[d][1,3]oxazin-2(1H)-one

(4aS,7aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d] [l,3]oxazin-2-one

336.35

C20 H17 F N2 O2

F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc.

mgluR5 Positive Allosteric Modulators

Signal Transduction Modulators

http://www.google.com/patents/WO2014056710A1?cl=en

Example 1

(4aS,7aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d] [l,3]oxazin-2-one

Ste 1 : ((lR,2S)-2-Hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester

To a well stirred suspension of 0.94 g (24.7 mmol, 2 equiv.) of L1AIH₄ in 30ml of THF at 0°C was added dropwise at 0°C a solution of (lS,2R)-methyl 2-(tert-butoxycarbonylamino)- cyclopentanecarboxylate (CAS: 592503-55-4) (3.0 g, 12.3 mmol) (gas evolution, lightly exo therm). After 15 minutes at 0°C the reaction mixture was allowed to warm up to room temperature and was stirred for 2h. The mixture was cooled to 0°C and water was added dropwise. The precipitated inorganic salts were filtered through Celite and were washed with ethyl acetate. The filtrate was evaporated and the residue was purified by column

chromatography on silica gel eluting with a 0% to 50% ethyl acetate in heptane gradient to yield 1.99 g (75%) of the title compound as a crystalline white solid which was directly used in the next step. Ste 2: (4aS,7aR)-Hexahydro-cyclopenta[d][l,3]oxazin-2-one

To a solution of ((lR,2S)-2-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (1.6 g, 7.43 mmol) in THF (40 ml) was added potassium tert-butoxide (3.34 g, 29.7 mmol, 4.0 equiv.) at room temperature. After stirring for lh at 60°C the reaction was allowed to warm up to room temperature and after workup with Ethyl acetate/water, drying and concentration in vaccuo, the crude material mixture was adsorbed on silica and chromatographed over a prepacked silica column (50g, 50% to 100% EtOAc in Heptane gradient) to yield 950 mg (91%) of the title compound as a white solid, which was directly used in the next step. -Fluoro-5-phenylethynyl-pyridine

In an 100ml 2-necked round bottomed flask under Argon were dissolved 2-fluoro-5-iodopyridine (5.0 g, 22.4 mmol, 1.0 equiv.) in THF (30 ml). After 5 minutes at room temperature were added bis(triphenylphosphin)palladium(II)chloride (944 mg, 1.35 mmol, 0.06 equiv.), triethylamine (6.81 g, 9.32 ml, 67.3 mmol, 3.0 equiv.), phenyl acetylene (2.75 g, 2.95 ml, 26.9 mmol, 1.2 equiv.) and copper(I)iodide (128 mg, 0.67 mmol, 0.03 equiv.). The brown suspension was cooled with water (exothermic) to room temperature and stirred overnight. Then 200ml of diethylether were added, the mixture was filtered, washed with ether and concentrated in vacuum to yield 5.7g of a brown solid which was adsorbed on silica and was chromatographed in 2 portions over a lOOg prepacked silica column eluting with a 0-10% ethyl acetate in heptane gradient to yield 3.99g (91%) of the title compound as a light brown solid, MS: m/e = 198.1 (M+H⁺). Step 4: (4aS aR)-l-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[d][l,3]oxazin-2-one In a 10ml Round bottomed flask were dissolved (4aS,7aR)-hexahydro-cyclopenta[d]- [l,3]oxazin-2-one (80 mg, 0.57 mmol, 1.0 equiv.) and 2-fluoro-5-(phenylethynyl)pyridine (112 mg, 0.57 mmol, 1.0 equiv.) in 2ml of DMF. Sodium hydride (60%> suspension) (29.5 mg, 0.74 mmol, 1.3 equiv.) were added and the brown suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic phases were dried, filtered and concentrated. The crude material was purified by flash chromatography over a prepacked silica column eluting with 0-50% ethyl acetae in heptane gradient to yield 42.5mg of the title compound as colorless amorphous solid, MS: m/e = 319.1 (M+H⁺).

Example 2

(4aS,7aR)- 1- [5-(3-Fluorophenylethynyl)-py ridin-2-yl] -hexahydro- cyclopenta[d] [l,3]oxazin-2-one

Step 1 : 2-Fluoro-5-(3-fluoro-phenylethynyl)-pyridine

The title compound was prepared in accordance with the general method of Example 1, step 3 using 3-flurorophenylacetylene instead of phenylacetylene to yield the title compound as a crystalline white solid, MS: m/e = 216.2 (M+H⁺).

Step 2 : (4aS ,7aR)- 1 – [5 -(3 -Fluorophenylethynyl)-pyridin-2-yl] -hexahydro- cyclopenta[d] [ 1 ,3]oxazin-2-one

The title compound was prepared in accordance with the general method of Example 1, step 4 using (4aS,7aR)-hexahydro-cyclopenta[d]-[l,3]oxazin-2-one (66 mg, 0.47 mmol) (Example 1, step 2) and 2-fluoro-5-((3-fluorophenyl)ethynyl)pyridine (100 mg, 0.47 mmol) to yield 48 mg (31%) of the title compound as a light yellow amorphous solid; MS: m/e = 337.3 (M+H⁺).

DASABUVIR, ABT 333

1132935-63-7

Non-nucleoside NS5B polymerase inhibitor

• Methanesulfonamide, N-(6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl)-
• N-(6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide
• Methanesulfonamide, N-(6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl)-
• 
  N-(6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Dasabuir (ABT-333), an oral non-nucleoside NS5B polymerase inhibitor, is a component of an all-oral hepatitis C treatment regimen under FDA review for the chronic Hepatitis C treatment.
On April 22, 2014, AbbVie submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection.

…………………………..

http://www.google.com/patents/WO2009039127A1?cl=en

 Example 4A. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00768] Part A. Preparation of N-(6-bromonaphthalen-2-yl)methanesulfonamide. [00769] A solution of the product from Example 3, Part B (4.48g, 20.17mmol) in pyridine (10OmL) was treated drop wise with methanesulfonyl chloride (1.97mL, 2.89 g, 25.2mmol) followed by stirring at room temperature for Ih. Diluted with toluene and concentrated under vacuum twice. The residue was extracted with EtOAc and washed with water, IM citric acid and brine. Treated with Darco G-60, dried over Na₂SO₄, filtered through celite and concentrated under vacuum. Solid was triturated with ether- hexane, collected by filtration and dried under vacuum to give the title compound as a faint pink solid (3.32g, 55 %).

[00770] Part B. Preparation of N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl) methanesulfonamide .

[00771] A mixture of the product from Part A (1.0Og, 3.33mmol), bis(pincolato)diboron (1.27g,

5.00mmol), potassium acetate (0.98 g, 9.99mmol) and Combiphos Pd6 (84mg, 0.17mmol) in toluene

(22mL) was heated at reflux for 3h. Cooled and diluted with ethyl acetate and water. The mixture was treated with Darco G-60 and filtered through celite. The filtrate was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Oil was dissolved in ether and precipitated by addition of hexanes. The product was collected by filtration and washed with hexanes. Evaporation of the filtrate and purification by silica gel column chromatography eluting with EtOAc/hexanes. The title compound from crystallization and chromatography was obtained as a white solid (927mg, 80%).

[00772] Part C. Preparation of tert-butyl 3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido) naphthalen-

2-yl)phenylcarbamate.

[00773] Combined the product from Example 3, Part H (87mg, 0.243mmol), the product from Part B

(169mg, 0.486mmol), toluene (1.0ml), ethanol (1.0ml) and sodium carbonate (0.243ml, 0.243mmol) in a sealed tube and de-gassed with N₂ gas for 20min. Tetrakis(triphenylphosphine)palladium(0) (5.61mg,

4.86μmol) was added and de-gassing was continued another 5-10 min. Heated at 90-95⁰C for 16h.

Cooled and concentrated under vacuum. Purification by silica gel column chromatography eluting with

EtOAc/hexanes gave the title compound (92.2mg, 76 %).

[00774] Part D. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00775] A solution of the product from Part C (90mg, 0.180mmol) in CH₂Cl₂ (2.0ml) was treated with trifluoroacetic acid (1.0ml, 12.98mmol) at room temperature for Ih. Concentrated under vacuum, dissolved residue in EtOAc, washed with 10% NaHCO₃, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Dissolved in DMF (1.4ml) and cooled to -25⁰C and added (E)-3-methoxy- acryloyl isocyanate (0.633ml, 0.361mmol) drop wise while maintaining the temperature below -1O⁰C. Warmed to room temperature and stirred for 2h. Poured into ether, washed with water, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Added a mixture OfH₂SO₄ (0.1ml, 1.876mmol), water (1.0ml) and EtOH (1.0ml) and stirred at 100⁰C 16h. Cooled and concentrated under vacuum. Poured into water, extracted with EtOAc, combined extracts and washed with brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel column chromatography eluting with MeOH/CHCl₃ gave the title compound (53mg, 59%). ¹H NMR (300 MHz DMSO-J6) δ 1.42 (s, 9 H) 3.08 (s, 3 H) 3.25 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H) 7.34 (dd, J=15.81, 2.57 Hz, 2 H) 7.42 (dd, J=8.82, 1.84 Hz, 1 H) 7.65 – 7.76 (m, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.96 (t, J= 8.27 Hz, 2 H) 8.02 (s, 1 H) 10.04 (s, 1 H) 11.41 (s, 1 H); MS (ESI+) m/z 494 (M+H)⁺; (ESI-) m/z 492 (M-H)^“.

[00776] Example 4B. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00777] Part A. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

[00778] To the product from Example 3, Part E (4.5g, 23.05mmol) dissolved in MeOH (120ml) and water (3OmL) was added iodine monochloride (1.155ml, 23.05mmol) drop wise over a period of lOmin.

The mixture was stirred for 2h and diluted into IL of water and allowed to stand overnight. The solid material was collected by filtration and washed 3 x 5OmL with water and dried under vacuum overnight to give a tan solid (7.14g, 96%).

[00779] Part B. Preparation of l-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

[0078O]To an ice bath cooled solution of the product from Part A (5.5g, 17.13mmol) in MTBE (15ml) in a 5OmL pressure vessel was added 2.0M trimethylsilyl diazomethane (12.85ml, 25.7mmol) followed by drop-wise addition of methanol (1.OmL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 16h, cooled and the pressure was released. The solution was partitioned between

EtOAc and water. The organic layer was washed with 1.0M HCl, saturated potassium carbonate solution, and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to give a red oil that was used without purification (5.4g, 84%).

[00781] Part C. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

[00782] A mixture of the product from Part B (5.80g, 17.31mmol), ammonium chloride (1.389g,

26.0mmol), and iron (4.83g, 87mmol) in THF/MeOH/water (20OmL total, 2/2/1) was refluxed for 2h, cooled and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated brine, dried with sodium sulfate, filtered and evaporated to give a brown oil (5.28g, 100% yield).

[00783] Part D. Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.

[00784] To a solution of the product from Part C (3.05g, lOmmol) in DMF (50ml) at -20 ⁰C under N₂ was added at a fast drip a 0.4M solution in benzene of (E)-3-methoxyacryloyl isocyanate (50.0ml,

20.00mmol, prepared by the method of Santana et al., J. Heterocyclic. Chem. 36:293 (1999). The solution was stirred for 15min at -20 ⁰C, warmed to room temperature for 45min and diluted with EtOAc. The organic was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated to a brown solid. The residue was triturated in Et₂θ/hexane to give a fine powder that was collected by filtration and dried under vacuum to give the title compound as a tan powder (2.46g, 57%).

[00785] Part E. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione.

[00786] To a suspension of the product from Part D (2.46g, 5.69mmol) in ethanol (50ml) was added a solution of 5.5mL OfH₂SO₄ in 5OmL water and the mixture was heated at 110⁰C for 2.5h to give a clear solution. Cooled and diluted with 5OmL of water while stirring to give an off-white solid that was collected by filtration, washed with water and dried under vacuum to give the title compound (2.06g,

90%).

[00787]Part F. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00788] In a microwave tube, the product from Part E (104mg, 0.26mmol), the product from Example

4A, Part B (108mg, 0.31mmol), and 1.0M sodium carbonate solution (312μL, 0.31mmol) in 1: 1 ethanol- toluene (1.7mL) was degassed by nitrogen sparge for 15min. l,l’-Bis(diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (9mg, 0.01 lmmol) was added, and degassing was continued for another 5min. The tube was sealed and heated in the microwave at 100⁰C for Ih. Diluted with dichloromethane and washed with IM citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel for Ih. Filtered through celite and concentrated under vacuum.

Triturated with ether, methanol, and then again with ether to give the title compound as a nearly white solid (32mg, 25 %). ¹H NMR (300 MHz, DMSO-J₆): δ 11.41 (d, J=I.84 Hz, 1 H) 10.04 (s, 1 H) 8.03 (s,

1 H) 7.96 (t, J=8.09 Hz, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.63 – 7.79 (m, 2 H) 7.35 – 7.45 (m, 1 H) 7.37 (d,

J=2.57 Hz, 1 H) 7.32 (d, J=2.57 Hz, 1 H) 5.65 (dd, J=8.09, 2.21 Hz, 1 H) 3.25 (s, 3 H) 3.09 (s, 3 H) 1.43

(s, 9 H). MS (+ESI)m/z (rel abundance): 494 (100,M+H), 511 (90, M+NH4), 987 (20, 2M+H), 1009

(8, 2M+Na).

…………………….

http://www.google.com/patents/WO2009039134A1?cl=en

Example 2A. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00511] Part A. Preparation of N-(6-bromonaphthalen-2-yl)methanesulfonamide. [00512] A solution of the product from Example 1, Part B (4.48g, 20.17mmol) in pyridine (10OmL) was treated drop wise with methanesulfonyl chloride (1.97mL, 2.89 g, 25.2mmol) followed by stirring at room temperature for Ih. Diluted with toluene and concentrated under vacuum twice. The residue was extracted with EtOAc and washed with water, IM citric acid and brine. Treated with Darco G-60, dried over Na₂SO₄, filtered through celite and concentrated under vacuum. Solid was triturated with ether- hexane, collected by filtration and dried under vacuum to give the title compound as a faint pink solid (3.32g, 55 %).

[00513] Part B. Preparation of N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl) methanesulfonamide .

[00514] A mixture of the product from Part A (1.0Og, 3.33mmol), bis(pincolato)diboron (1.27g,

5.00mmol), potassium acetate (0.98 g, 9.99mmol) and Combiphos Pd6 (84mg, 0.17mmol) in toluene

(22mL) was heated at reflux for 3h. Cooled and diluted with ethyl acetate and water. The mixture was treated with Darco G-60 and filtered through celite. The filtrate was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Oil was dissolved in ether and precipitated by addition of hexanes. The product was collected by filtration and washed with hexanes. Evaporation of the filtrate and purification by silica gel column chromatography eluting with EtOAc/hexanes. The title compound from crystallization and chromatography was obtained as a white solid (927mg, 80%).

[00515] Part C. Preparation of tert-butyl 3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido) naphthalen-

2-yl)phenylcarbamate.

[00516] Combined the product from Example 1, Part H (87mg, 0.243mmol), the product from Part B

(169mg, 0.486mmol), toluene (1.0ml), ethanol (1.0ml) and sodium carbonate (0.243ml, 0.243mmol) in a sealed tube and de-gassed with N₂ gas for 20min. Tetrakis(triphenylphosphine)palladium(0) (5.61mg,

4.86μmol) was added and de-gassing was continued another 5-10 min. Heated at 90-95⁰C for 16h.

Cooled and concentrated under vacuum. Purification by silica gel column chromatography eluting with

EtOAc/hexanes gave the title compound (92.2mg, 76 %).

[00517]Part D. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00518] A solution of the product from Part C (90mg, 0.180mmol) in CH₂Cl₂ (2.0ml) was treated with trifluoroacetic acid (1.0ml, 12.98mmol) at room temperature for Ih. Concentrated under vacuum, dissolved residue in EtOAc, washed with 10% NaHCO₃, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Dissolved in DMF (1.4ml) and cooled to -25⁰C and added (E)-3-methoxy- acryloyl isocyanate (0.633ml, 0.361mmol) drop wise while maintaining the temperature below -1O⁰C. Warmed to room temperature and stirred for 2h. Poured into ether, washed with water, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Added a mixture Of H₂SO₄ (0.1ml, 1.876mmol), water (1.0ml) and EtOH (1.0ml) and stirred at 100⁰C 16h. Cooled and concentrated under vacuum. Poured into water, extracted with EtOAc, combined extracts and washed with brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel column chromatography eluting with MeOH/CHCl₃ gave the title compound (53mg, 59%). ¹H NMR (300 MHz OMSO-d6) δ 1.42 (s, 9 H) 3.08 (s, 3 H) 3.25 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H) 7.34 (dd, J=15.81, 2.57 Hz, 2 H) 7.42 (dd, J=8.82, 1.84 Hz, 1 H) 7.65 – 7.76 (m, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.96 (t, J= 8.27 Hz, 2 H) 8.02 (s, 1 H) 10.04 (s, 1 H) 11.41 (s, 1 H); MS (ESI+) m/z 494 (M+H)⁺; (ESI-) m/z 492 (M-H)^“.

[00519] Example 2B. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00520] Part A. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

[00521] To the product from Example 1, Part E (4.5g, 23.05mmol) dissolved in MeOH (120ml) and water (3OmL) was added iodine monochloride (1.155ml, 23.05mmol) drop wise over a period of lOmin.

The mixture was stirred for 2h and diluted into IL of water and allowed to stand overnight. The solid material was collected by filtration and washed 3 x 5OmL with water and dried under vacuum overnight to give a tan solid (7.14g, 96%).

[00522]Part B. Preparation of l-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

[00523] To an ice bath cooled solution of the product from Part A (5.5g, 17.13mmol) in MTBE (15ml) in a 5OmL pressure vessel was added 2.0M trimethylsilyl diazomethane (12.85ml, 25.7mmol) followed by drop-wise addition of methanol (1.OmL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 16h, cooled and the pressure was released. The solution was partitioned between

EtOAc and water. The organic layer was washed with 1.0M HCl, saturated potassium carbonate solution, and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to give a red oil that was used without purification (5.4g, 84%).

[00524] Part C. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

[00525] A mixture of the product from Part B (5.8Og, 17.31mmol), ammonium chloride (1.389g,

26.0mmol), and iron (4.83g, 87mmol) in THF/MeOH/water (20OmL total, 2/2/1) was refluxed for 2h, cooled and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated brine, dried with sodium sulfate, filtered and evaporated to give a brown oil (5.28g, 100% yield).

[00526] Part D. Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.

[00527] To a solution of the product from Part C (3.05g, lOmmol) in DMF (50ml) at -20 ⁰C under N₂ was added at a fast drip a 0.4M solution in benzene of (E)-3-methoxyacryloyl isocyanate (50.0ml,

20.00mmol, prepared by the method of Santana et al., J. Heterocyclic. Chem. 36:293 (1999). The solution was stirred for 15min at -20 ⁰C, warmed to room temperature for 45min and diluted with EtOAc. The organic was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated to a brown solid. The residue was triturated in Et₂O/hexane to give a fine powder that was collected by filtration and dried under vacuum to give the title compound as a tan powder (2.46g, 57%).

[00528] Part E. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione.

[00529] To a suspension of the product from Part D (2.46g, 5.69mmol) in ethanol (50ml) was added a solution of 5.5mL OfH₂SO₄ in 5OmL water and the mixture was heated at 110°C for 2.5h to give a clear solution. Cooled and diluted with 5OmL of water while stirring to give an off-white solid that was collected by filtration, washed with water and dried under vacuum to give the title compound (2.06g,

[00530] Part F. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[0053I]In a microwave tube, the product from Part E (104mg, 0.26mmol), the product from Example 2A, Part B (108mg, OJ lmmol), and 1.0M sodium carbonate solution (312μL, 0.31mmol) in 1:1 ethanol- toluene ( 1.7mL) was degassed by nitrogen sparge for 15min. 1 , 1 ‘-Bis(diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (9mg, O.Ol lmmol) was added, and degassing was continued for another 5min. The tube was sealed and heated in the microwave at 100⁰C for Ih. Diluted with dichloromethane and washed with IM citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel for Ih. Filtered through celite and concentrated under vacuum. Triturated with ether, methanol, and then again with ether to give the title compound as a nearly white solid (32mg, 25 %). ¹H NMR (300 MHz, OMSO-d₆): δ 11.41 (d, J=1.84 Hz, 1 H) 10.04 (s, 1 H) 8.03 (s, 1 H) 7.96 (t, J=8.09 Hz, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.63 – 7.79 (m, 2 H) 7.35 – 7.45 (m, 1 H) 7.37 (d, J=2.57 Hz, 1 H) 7.32 (d, J=2.57 Hz, 1 H) 5.65 (dd, J=8.09, 2.21 Hz, 1 H) 3.25 (s, 3 H) 3.09 (s, 3 H) 1.43 (s, 9 H). MS (+ESI) m/z (rel abundance): 494 (100, M+H), 511 (90, M+NH4), 987 (20, 2M+H), 1009 (8, 2M+Na).

…………………….

http://www.google.com/patents/EP2593439A2?cl=en

 Example 2. Preparation of l -(3-teri-butyl-5-(6-hydroxynaphthalen-2-yl)-4- methoxyphenyl)pyrimidine-2,4(l f,3H)-dione (compound (4)).

[00165] This reaction is sensitive to oxygen, and so all vessels were sealed with rubber septa. All solution transfers were accomplished by cannula technique using nitrogen as the inert gas. Anhydrous tetrahydrofuran was sparged with nitrogen gas for 2 hours prior to use to render it anaerobic. Hereafter this is referred to as degassed tetrahydrofuran. [00166] A 100-mL round-bottom flask was charged with 12.9 g of potassium phosphate tribasic (60.8 mmol, 2.0 equivalents), a magnetic stir bar, and 60 mL of water. The mixture was stirred to dissolve the solids, and the aqueous solution was sparged with nitrogen gas for 2 hours prior to use. Hereafter this is referred to as the phosphate solution.

[00167] A 100-mL round-bottom flask was purged with nitrogen gas and charged with 282 mg of tris(dibenzylideneacetone)dipalladium(0) (0.31 mmol, 0.02 equivalents Pd), 413 mg ofphosphine ligand, l ,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1 '⁷]decane (1.4 mmol, 2.3 equivalents relative to Pd) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere. This solution was sparged for 15 minutes prior to use and is hereafter referred to as the catalyst solution.

[00168] A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 12.1 g of l -(3-?er?-butyl-5-iodo- 4-methoxyphenyl)pyrimidine-2,4(l f,3 /)-dione, (30.3 mmol, 1.0 equivalent) and 5.98 g of 6- hydroxynaphthalen-2-ylboronic acid (31.8 mmol, 1.05 equivalents). The atmosphere was purged with nitrogen gas with stirring of the solid reagents for 20 minutes. The reactor was charged with 120 mL of degassed tetrahydrofuran, and the mixture was stirred to dissolve the solids. The solution was sparged with nitrogen gas for 10 minutes. The phosphate solution was added to the reactor by cannula, followed by the catalyst solution. The resulting biphasic mixture was stirred aggressively to ensure adequate phase mixing, and the jacket was warmed to 65 °C. The reaction jacket was cooled to room temperature prior to quench.

[00169] After 2.5 hours, the reaction jacket was cooled to room temperature prior to quench.

[00170] The workup of the reaction was also conducted under anaerobic conditions. Fifty-seven grams of sodium chloride and 4.2 g of cysteine (15 weight equivalents relative to palladium catalyst) were dissolved in 300 mL of water, and the resulting solution was sparged for 2 hours prior to use. To quench the reaction, approximately 1/3 of this solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 2 hours. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Approximately 1/3 of the quench solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. The final portion of the quench solution was transferred to the reaction mixture by cannula, the resulting biphasic mixture was stirred vigorously for 45 minutes and the aqueous solution was drained out of the reactor through the bottom valve. [00171] The remainder of the workup was not conducted under anaerobic conditions. The pale yellow organic solution was drained from the reactor through the bottom valve and filtered over a pad of grade 4 Filtrol® (1 cm deep by 4.5 cm diameter). The reactor and filter cake were rinsed with 70 mL of tetrahydrofuran. The bulk of the solvent was distilled in vacuo (ca 90-130 torr) at ca 40 °C with good agitation from an overhead stirrer. The solution was concentrated to approximately 50 mL volume, during which time the product began to precipitate out. Ethyl acetate (100 mL, 8 volume/weight relative to product) was added to the mixture, and the resultant slurry was stirred overnight at room temperature. The crystalline material was isolated by filtration and the filter cake was washed twice with 20 mL portions of ethyl acetate. The wet-cake was air-dried on the filter and dried in a vacuum oven at 50 °C at approximately 250 torr with a gentle nitrogen sweep overnight.

[00172] The desired product was isolated as a white solid (11.6 g, 96.4% potency vs. standard, 88% potency-adjusted yield).^!H NMR (400 MHz, DMSO-4) δ ppm δ 1 1.39 (d, J = 2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.80 (d, J= 8.9 Hz, 1H), 7.77 – 7.74 (m, 2H), 7.58 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.27 (d, J= 2.7 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 5.64 (dd, J = 7.9, 2.2 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 9H).

Example 3. Preparation of 6-(3-?eri-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)-2- methoxyphenyl)naphthalen-2-yl 1 ,1 ,2,2,3,3,4,4,4-nonafluorobutane-l -sulfonate (compound (5a)).

[00174] A reactor was equipped with an overhead stirrer in the central neck and charged with 45.0 g of 1- (3-?eri-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(l f,3H)-dione (97.8 weight%>, 106 mmol, 1.0 equivalent) and 21.9 g of 325 mesh potassium carbonate (159 mmol, 1.5 equivalents). The atmosphere was purged with nitrogen gas while the solids were stirred. The flask was charged with 445 mL of Λ^Λ^-dimethylformamide, and the slurry was stirred to dissolve the l-(3-?eri- butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(l f,3H)-dione. The purge was stopped and the reaction was conducted under a slight positive pressure of nitrogen gas.

Perfluorobutanesulfonyl fluoride (35.2 g, 117 mmol, 1.1 equivalents) was added in one portion, and the mixture was stirred vigorously to mix the immiscible liquids overnight.

[00175] The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with approximately 30 mL of Λ^,Λ^-dimethylformamide. The Λ^,Λ^-dimethylformamide solution was filtered directly into a second flask with an overhead stirrer. With stirring, 1 12 g of water (25 weight% of total Λ^,Λ^-dimethylformamide employed) was added to the Λ^,Λ^-dimethylformamide solution of product over approximately 0.5 hour to induce precipitation of the desired product, and the mixture was allowed to stir for 5 hours. The wet-cake was isolated by filtration with recirculation of the liquors to recover all the solids. The wet-cake was washed with 60 mL of 25% (v/v) water yV-dimethylformamide, then 85 mL water.

[00176] The solids were dissolved in 760 mL of isopropyl acetate. The resultant organic solution was washed once with 200 mL of water, twice with 270 mL portions of water and once with 200 mL of water to remove residual AyV-dimethylformamide. Solvent was removed by distillation at approximately 130 torr with heating to 55 °C until the total volume was approximately 200 mL. With efficient stirring, heptane (450 mL) was added to the warm (55 °C) slurry. The slurry was allowed to cool to room temperature overnight with stirring. The desired product was isolated by filtration, with recycling of the liquors to isolate all of the solids material. The wet-cake was washed twice with 100 mL portions of 20% (v/v) isopropyl acetate/heptane. The wet-cake was air-dried on the filter and dried in a vacuum oven at 50 °C at approximately 250 torr with a gentle nitrogen sweep overnight. The title compound was isolated as a white solid (64.0 g, 100% potency vs. standard, 87% yield). ^!H NMR (600 MHz, DMSO- d₆) δ ppm 1 1.42 (s, 1H), 8.21 – 8.15 (m, 4H), 7.84 (dd, J = 8.6, 1.7 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 9.0, 2.5 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H), 3.21 (s, 3H), 1.41 (s, 9H).

[00177] Example 3-1. Alternative Preparation of 6-(3-teri-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2//)-yl)-2-methoxyphenyl)naphthalen-2-yl 1 , 1 ,2,2,3 ,3 ,4,4,4-nonafluorobutane- 1 -sulfonate (compound (5a)).

[00178] A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer was charged with 10 g of 1 -(3-ier?-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4( l//,3//)-dione (98 wt%>, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate (325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 volumes with respect to naphthol) and dimethylformamide (dimethylformide, 40 mL, 4 volumes with respect to naphthol) was charged to the reactor and the slurry was stirred. Perfluorobutanesulfonyl fluoride (96 wt%>, 8.3 g, 26 mmol, 1.1 equiv) was charged to the well-stirred mixture over 60 minutes by syringe pump. A trace (<0.1 area%) of starting material was detected by HPLC analysis of an aliquot at 20 minutes reaction time. The

acetonitrile/dimethylformamide solution was filtered over a coarse fritted funnel to separate the inorganic solids, and the flask and filter was rinsed with 15 mL of 3 :2 (v/v)

acetonitrile/dimethylformamide. The total mass of solvents employed was approximately 92 g.

[00179] First crystallization: The acetonitrile/dimethylformamide solution was transferred to a 3- neck flask equipped with an overhead stirrer. Water (50 g, 54 wt%> with respect to total solution charged) was added to the well-stirred solution over 100 minutes. This adjusts the solvent

composition to 35 wt% water. During the addition of water the mixture self-seeded, and the solution was held for approximately 1 hour after complete addition of water. The solids were isolated by filtration, and the wetcake was washed with two 30 mL portions of a rinse solution of 40 wt%

water/27 wt% dimethylformamide/33 wt% acetonitrile and then once with 40 mL of water.

[00180] Aqueous washing: A 500-L jacketed cylindrical reactor equipped with an overhead stirrer and Teflon baffle to aid in vertical mixing was charged with the wetcake and 133 g of ethyl acetate (8^X theoretical mass of product, 150 mL). The mixture was stirred to dissolve the substrate and the solution was washed twice with 40 mL portions of water.

[00181] Concentration and crystallization: A constant-volume distillation was conducted with heptanes, in vacuo (ca 100 mmHg, jacket temperature of 50 °C), to adjust the solvent composition to approximately 12 wt% ethyl acetate/88 wt% heptanes. During the distillation, solids begin to crystallize out of the solution. Once the distillation was complete, the solution was cooled to ambient temperature (23 °C). The solids were isolated by filtration and the wet cake was washed with a 50-mL portions heptane. The wet cake was dried to give the final product (14.0 g). The solids were 98.1% pure by HPLC analysis and 100% potent vs. reference standard, for an isolated yield of 85%o.

[00182] Example 4. Preparation of ^-(6-(3-ier?-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A)).

[00183] A 3-L, 3-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a Claisen condenser and a reflux condenser. Tris(dibenzylideneacetone)dipalladium(0) (0.330 g, 0.360 mmol), di-ier?-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.416 g, 0.864 mmol) and milled potassium phosphate tribasic (21.0 g, 99.0 mmol) were charged to the 3-L flask. The flask was purged with argon for not less than 90 minutes with constant stirring of the solids. i-Amyl alcohol (250 ml) was purged with argon for not less than 30 minutes and was transferred to the 3-L flask using a cannula under argon atmosphere. The contents of the 3-L flask were heated to 80 °C and stirred at this temperature for 30 minutes. A 1-L round bottom flask equipped with a magnetic stir bar was charged with 6-(3-ier?-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (62.9 g, 90 mmol), methanesulfonamide (12.85 g, 135 mmol) and i-amyl alcohol (505 mL), purged with argon and heated to 60 °C. The reaction mixture was stirred under argon for not less than 30 minutes. A clear yellow solution was observed. This solution was transferred to the 3-L flask using a cannula under argon atmosphere. The temperature of the 3-L flask was raised to 85 °C and the contents were stirred for 14 hours under a positive pressure of argon. The temperature was then raised to 95 °C and the contents were stirred for an additional 4 hours under a positive pressure of argon. The reaction mixture was allowed to cool down to room temperature, diluted with tetrahydrofuran (2200 mL) and water (800 mL) and was transferred to a 6-L separatory funnel. The organic layer was washed thrice with water (2000 mL) containing L-cysteine (17.3 g) and NaCl (235 g). The organic layer was collected, filtered through a pad of diatomaceous earth and was concentrated in vacuo to approximately 250 mL. Ethyl acetate (775 mL) was added over 7 hours with stirring, and the mixture was allowed to stir for an additional 14 hours. White solid was isolated by filtration, and the solid was washed with ethyl acetate (1000 mL). The solid was dissolved in tetrahydrofuran (1500 mL) and filtered through a pad of diatomaceous earth to obtain a clear solution. The diatomaceous earth was washed with tetrahydrofuran (300 mL). The combined tetrahydrofuran solution was concentrated in vacuo to approximately 250 mL, and then ethyl acetate (775 mL) was added over 7 hours with stirring. The product solution was allowed to stir for an additional 14 hours. White solid was isolated by filtration. The solid was washed with ethyl acetate (1000 mL) and dried in a vacuum oven at 60 °C for 24 hours. The solid was slurried in 308 mL of 200 proof ethanol for 1.5 hours, then isolated by filtration. The solid was washed with 132 mL of 200 proof ethanol and dried in a vacuum oven at 50 °C for 18 hours. The title compound was isolated as a white solid (32.6 g, 100% potency vs. standard, 73% yield). ^!H NMR (400 MHz, DMSO-i/₆) δ ppm 11.41 (d, J = 2.1 Hz, 1H), 10.04 (s, 1H), 8.02 (d, J = 0.9 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.41 (dd, J = 8.8, 2.2 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 5.65 (dd, J = 7.9, 2.2 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 3H), 1.42 (s, 9H).

[00184] Other ligands such as 2,2,7,7-tetramethyl-l-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepane; 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-l,4-dioxa-8- phosphaspiro[4.5]decane; and 8-(2-(2-methoxynaphthalen- 1 -yl)phenyl)-7,7,9,9-tetramethyl- 1 ,4-dioxa-8- phosphaspiro[4.5]decane were tested under the conditions described above and produced favorable yields of greater than 50% of the sulfonamidated product.

PREPN OF SODIUM SALT

Example 5. Preparation of the sodium salt of V-(6-(3-teri-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (As)).

[00192] A solution of 2-propanol and water was prepared by combining 18.5 g of water and 512 g of 2- propanol. Hereafter, this solution is referred to as the “antisolvent solution.”

[00193] A solution of 2-propanol and water was prepared by combining 23.94 g of water and 564 g of 2- propanol. This solution was cooled in a refrigerator prior to use. Hereafter, this solution is referred to as the “chilled wash solution.”

[00194] A jacketed reactor was equipped with an overhead stirrer and charged with 32.0 g (64.8 mmol) of A^-(6-(3-?er^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxyphenyl)naphthalen-2- yl)methanesulfonamide and 105.9 g of dimethyl sulfoxide. With stirring the mixture was heated to an internal temperature of 68 °C. A solution of 2.66 g of sodium hydroxide (66.5 mmol, 1.026 equiv) in 16 g of water was added to the reactor over several minutes, followed by 12.4 g of 2-propanol while maintaining the internal temperature at 68 °C. Antisolvent solution (24.5 g) was added to the reactor while maintaining the internal temperature at 68 °C. A slurry of 0.32 g of seed crystals of the final product in 22.8 g of antisolvent solution was added to the reactor, followed by a 2.6 g rinse of the flask with antisolvent solution. The reaction mixture was stirred for 1.5 hours while maintaining the internal temperature at 68 °C. Antisolvent solution (354 g) was added to the reactor over 7 hours while maintaining the internal temperature at 68 °C. The contents of the reactor were cooled to an internal temperature of 0 °C over 7 hours and then mixed at 0 °C for 7 hours. The solids were isolated by filtration and washed with 252 g of the chilled wash solution. The isolated solids were dried in a vacuum oven at 50 °C for 19 hours. The title compound was isolated as a white solid (30.7 g, 92% potency vs. free acid standard, 57.2 mmol free acid equivalent, 88% yield). ^!H NMR (400 MHz, DMSO-i¾) δ ppm 7.75 (s, 1H), 7.72 (d, J= 7.8 Hz, 1H), 7.59 (dd, J= 8.8, 2.2 Hz, 2H), 7.45 (dd, J= 8.5, 1.8 Hz, 1H), 7.27 (d, J = 2.6 Hz, 2H), 7.21 (d, J= 2.7 Hz, 1H), 7.06 (dd, J= 8.8, 2.2 Hz, 1H), 5.62 (d, J= 7.8 Hz, 1H), 3.24 (s, 3H), 2.68 (s, 3H), 1.40 (s, 9H).

………………………………..

http://www.google.com/patents/US20130224149

Example 2 Preparation of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a))

This reaction is sensitive to oxygen, and care was taken to establish and maintain an inert atmosphere in the handling and use of air-sensitive materials or mixtures. All solution transfers were accomplished by cannula technique using nitrogen as the inert gas. Anhydrous tetrahydrofuran was sparged with nitrogen gas for 2 hours prior to use to render it anaerobic. Hereafter this is referred to as degassed tetrahydrofuran.

A 100-mL round-bottom flask was charged with 12.9 g of potassium phosphate tribasic (60.8 mmol, 2.0 equivalents), a magnetic stir bar, and 60 mL of water. The mixture was stirred to dissolve the solids, and the aqueous solution was sparged with nitrogen gas for 2 hours prior to use. Hereafter this is referred to as the phosphate solution.

A 100-mL round-bottom flask was purged with nitrogen gas and charged with 282 mg of tris(dibenzylideneacetone)dipalladium(0) (0.31 mmol, 0.02 equivalents Pd), 413 mg of phosphine ligand, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^3,7]decane (1.4 mmol, 2.3 equivalents relative to Pd) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere. This solution was sparged with nitrogen for 15 minutes prior to use and is hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 12.1 g of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione, (30.3 mmol, 1.0 equivalent) and 5.98 g of 6-hydroxynaphthalen-2-ylboronic acid (31.8 mmol, 1.05 equivalents). The atmosphere was purged with nitrogen gas with stirring of the solid reagents for 20 minutes. The reactor was charged with 120 mL of degassed tetrahydrofuran, and the mixture was stirred to dissolve the solids. The solution was sparged with nitrogen gas for 10 minutes. The phosphate solution was added to the reactor by cannula, followed by the catalyst solution. The resulting biphasic mixture was stirred aggressively to ensure adequate phase mixing, and the jacket was warmed to 65° C. The reaction jacket was cooled to room temperature prior to quench.

After 2.5 hours, the reaction jacket was cooled to room temperature prior to quench.

The workup of the reaction was also conducted under anaerobic conditions. Fifty-seven grams of sodium chloride and 4.2 g of cysteine (15 weight equivalents relative to palladium catalyst) were dissolved in 300 mL of water, and the resulting solution was sparged with inert gas for 2 hours prior to use. To quench the reaction, approximately ⅓ of this solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 2 hours. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Approximately ⅓ of the quench solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. The final portion of the quench solution was transferred to the reaction mixture by cannula, the resulting biphasic mixture was stirred vigorously for 45 minutes and the aqueous solution was drained out of the reactor through the bottom valve.

The remainder of the workup was not conducted under anaerobic conditions. The pale yellow organic solution was drained from the reactor through the bottom valve and filtered over a pad of grade 4 Filtrol® (1 cm deep by 4.5 cm diameter). The reactor and filter cake were rinsed with 70 mL of tetrahydrofuran. The bulk of the solvent was distilled in vacuo (ca 90-130 torr) at ca 40° C. with good agitation from an overhead stirrer. The solution was concentrated to approximately 50 mL volume, during which time the product began to precipitate out. Ethyl acetate (100 mL, about 8 mL of solvent per gram of the product) was added to the mixture, and the resultant slurry was stirred overnight at room temperature. The crystalline material was isolated by filtration and the filter cake was washed twice with 20 mL portions of ethyl acetate. The wet cake was air-dried on the filter and dried in a vacuum oven at 50° C. at approximately 250 torr with a gentle nitrogen sweep overnight.

The desired product was isolated as a white solid (11.6 g, 96.4% potency vs. standard, 88% potency-adjusted yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.39 (d, J=2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 2.2 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 9H).

Example 2-1 Alternative preparation of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a))

This reaction is air-sensitive and the reaction was conducted under anaerobic conditions. A 100-mL round-bottom flask was purged with nitrogen gas and charged with 229 mg of tris(dibenzylideneacetone)dipalladium(0) (0.25 mmol, 0.02 equivalents Pd), 323 mg of 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^3,7]decane (1.13 mmol, 0.045 equivalents) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere for 20 minutes. This solution is hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 10.0 g of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione, (25.1 mmol, 1.0 equivalent), 4.98 g of 6-hydroxynaphthalen-2-ylboronic acid (26.6 mmol, 1.06 equivalents) and 10.3 g of potassium phosphate tribasic (48.7 mmol, 2.0 equivalents). The atmosphere was purged with nitrogen gas with stirring of the solid reagents for 20 minutes. The reactor was charged with 100 mL of tetrahydrofuran, 50 mL of water, and the mixture was stirred to dissolve the solids. The biphasic mixture was sparged with nitrogen gas for 30 minutes. The catalyst solution was transferred to the main reactor by positive nitrogen pressure through a cannula. The resulting biphasic mixture was stirred aggressively and warmed to an internal temperature between 60 and 65° C. under nitrogen for 2 hours. The reaction mixture was cooled to an internal temperature between 50 and 55° C. before quench.

The workup of the reaction was conducted under anaerobic conditions at an internal temperature between 50 and 55° C. Fifteen grams of sodium chloride and 1.0 g of cysteine were dissolved in 80 mL of water, and the resulting solution was sparged for 1 hour. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Fifteen grams of sodium chloride and 1.0 g of cysteine were dissolved in 80 mL of water, and the resulting solution was sparged for 1 hour. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve.

The pale yellow organic solution was drained from the reactor through the bottom valve and filtered over a polypropylene filter to remove palladium black. The reactor and filter cake were rinsed with 22 mL of tetrahydrofuran and 50 mL of ethyl acetate was added to the organic solution. The solution was distilled at atmospheric pressure (approximately 66° C. internal temperature) with continuous addition of 110 mL of ethyl acetate, keeping the volume of the solution roughly constant during the distillation. During the constant-volume distillation, solids began to precipitate in the reactor. After the ethyl acetate was charged, the distillation was continued at atmospheric pressure, concentrating the slurry to approximately 60 mL total volume. The solution was cooled to an internal temperature of approximately 30° C. and held for 3 hours with stirring. The crystalline material was isolated by filtration and the filter cake was washed twice with 20 mL portions of ethyl acetate. The wet cake was dried in a vacuum oven at 50° C. with a gentle nitrogen sweep overnight. The desired product was isolated as an off-white solid (8.33 g, 80% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm δ 11.39 (d, J=2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 2.2 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 9H).

Example 2-2 Alternative preparation of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a))

This reaction is air-sensitive and the reaction was conducted under nitrogen atmosphere. A 100-mL round-bottom flask was purged with nitrogen gas and charged with 303 mg of tris(dibenzylideneacetone)dipalladium(0) (0.33 mmol, 0.02 equivalents Pd), 411 mg of 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^3,7]decane (1.40 mmol, 0.045 equivalents) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Seventy-five (75) mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere for 25 minutes. This solution is hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 12.5 g of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione, (31.2 mmol, 1.0 equivalent), 6.20 g of 6-hydroxynaphthalen-2-ylboronic acid (33.0 mmol, 1.06 equivalents) and 13.0 g of potassium phosphate tribasic (61.2 mmol, 2.0 equivalents). The reactor was charged with 130 mL of tetrahydrofuran, 65 mL of water, and the mixture was stirred to dissolve the solids. The biphasic mixture was sparged with nitrogen gas for 30 minutes. The catalyst solution was transferred to the main reactor by positive nitrogen pressure through a cannula. The resulting biphasic mixture was stirred aggressively and warmed to an internal temperature between 60 and 65° C. under nitrogen for 2.5 hours. The reaction mixture was cooled to an internal temperature between 50 and 55° C. before quench.

The workup of the reaction was conducted under anaerobic conditions at an internal temperature between 50 and 55° C. Sodium chloride (18.8 g) and cysteine (1.25 g) were dissolved in 100 mL of water, and the resulting solution was sparged with nitrogen for 40 minutes. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Sixty-three (63) mL of degassed tetrahydrofuran were added to the reactor by cannula with positive nitrogen pressure. Sodium chloride (18.9 g) and cysteine (1.333 g) were dissolved in 100 mL of water, and the resulting solution was sparged with nitrogen for 40 minutes. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve.

The pale yellow organic solution was drained from the reactor through the bottom valve and filtered through a thin pad of filter aid on a polyethylene filter while warm. The reactor and filter cake were rinsed with 32 mL of tetrahydrofuran, and 65 mL of ethyl acetate was added to the organic solution. The solution was distilled at atmospheric pressure (approximately 66° C. internal temperature) with continuous addition of 190 mL of ethyl acetate, keeping the volume of the solution roughly constant during the distillation. During the constant-volume distillation, solids began to precipitate in the reactor. After the ethyl acetate was charged, the distillation was continued at atmospheric pressure, concentrating the slurry to approximately 90 mL total volume. The slurry was cooled to an internal temperature of approximately 40° C. and was concentrated further in vacuo to a total volume of approximately 50 mL. The slurry was cooled to an internal temperature of 30° C. and held for 16 hours with stirring. The crystalline material was isolated by filtration, and the filter cake was washed twice with 25 mL portions of ethyl acetate. The wet cake was dried in a vacuum oven at 50° C. with a gentle nitrogen sweep overnight. The desired product was isolated as an off-white solid (11.4 g, 99.5% potent vs. standard, 87% potency-adjusted yield).

Example 4 Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 3-L, 3-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a Claisen condenser and a reflux condenser. Tris(dibenzylideneacetone)dipalladium(0) (0.330 g, 0.360 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.416 g, 0.864 mmol) and milled potassium phosphate tribasic (21.0 g, 99.0 mmol) were charged to the 3-L flask. The flask was purged with argon for not less than 90 minutes with constant stirring of the solids. t-Amyl alcohol (250 ml) was charged to a separate 500-mL round-bottom flask and was purged with argon for not less than 30 minutes and was transferred to the 3-L flask using a cannula under argon atmosphere. The contents of the 3-L flask were heated to 80° C. and stirred at this temperature for 30 minutes. A 1-L round-bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (62.9 g, 90 mmol), methanesulfonamide (12.85 g, 135 mmol) and t-amyl alcohol (505 mL), purged with argon and heated to 60° C. The reagent mixture was stirred under argon for not less than 30 minutes. A clear yellow solution was observed. This solution was transferred to the 3-L flask using a cannula under argon atmosphere. The temperature of the 3-L flask was raised to 85° C. and the contents were stirred for 14 hours under a positive pressure of argon. The temperature was then raised to 95° C. and the contents were stirred for an additional 4 hours under a positive pressure of argon. The reaction mixture was allowed to cool down to room temperature, diluted with tetrahydrofuran (2200 mL) and water (800 mL) and was transferred to a 6-L separatory funnel. The organic layer was washed thrice with water (2000 mL) containing L-cysteine (17.3 g) and NaCl (235 g). The organic layer was collected, filtered through a pad of diatomaceous earth and was concentrated in vacuo to approximately 250 mL. Ethyl acetate (775 mL) was added over 7 hours with stirring, and the mixture was allowed to stir for an additional 14 hours. White solid was isolated by filtration, and the solid was washed with ethyl acetate (1000 mL). The solid was then dissolved in tetrahydrofuran (1500 mL) and filtered through a pad of diatomaceous earth to obtain a clear solution. The diatomaceous earth was washed with tetrahydrofuran (300 mL). The combined tetrahydrofuran solution was concentrated in vacuo to approximately 250 mL, and then ethyl acetate (775 mL) was added over 7 hours with stirring. The product solution was allowed to stir for an additional 14 hours. White solid was isolated by filtration. The solid was washed with ethyl acetate (1000 mL) and dried in a vacuum oven at 60° C. for 24 hours. The solid was slurried in 308 mL of 200 proof ethanol for 1.5 hours, then isolated by filtration. The solid was washed with 132 mL of 200 proof ethanol and dried in a vacuum oven at 50° C. for 18 hours. The title compound was isolated as a white solid (32.6 g, 100% potency vs. standard, 73% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.41 (d, J=2.1 Hz, 1H), 10.04 (s, 1H), 8.02 (d, J=0.9 Hz, 1H), 7.98-7.91 (m, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.69 (dd, J=8.5, 1.7 Hz, 1H), 7.41 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 5.65 (dd, J=7.9, 2.2 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 3H), 1.42 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 163.1 (C), 156.0 (C), 150.0 (C), 145.3 (CH), 142.9 (C), 136.0 (C), 134.3 (C), 134.2 CO, 133.5 (C), 132.2 (C), 129.5 (C), 129.0 (CH), 127.6 (CH), 127.1 (CH), 127.0 (CH), 126.5 (CH), 124.3 (CH), 120.2 (CH), 114.5 (CH), 101.1 (CH), 60.3 (CH₃), 39.4 (CH₃), 35.1 (C), 30.5 (CH₃).

Other ligands such as 2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepane; 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane; and 8-(2-(2-methoxynaphthalen-1-yl)phenyl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane were tested under the conditions described above and produced favorable yields of greater than 50% of the sulfonamidated product.

Example 4-1 Alternative Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 450-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.167 g, 0.344 mmol) and milled potassium phosphate tribasic (6.69 g, 31.5 mmol). The flask was purged with argon for not less than 90 minutes. Tetrahydrofuran (90 mL) was taken in a 100-mL round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL, round-bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (20.0 g, 28.6 mmol), methanesulfonamide (3.27 g, 34.4 mmol) and tetrahydrofuran (160 mL), purged with argon for not less than 45 minutes. A clear yellow solution was observed. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL reactor was raised to 90° C. and the contents were stirred for 20 hours. The reaction mixture was allowed to cool down to 50° C., diluted with tetrahydrofuran (70 mL) and water (70 mL) containing L-cysteine (0.875 g) and sodium chloride (7.7 g). The contents were stirred for 2 hours at 50° C. The aqueous layer was discarded and the organic layer was filtered through an approximately 2-inch pad of diatomaceous earth and rinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellow solution. The total weight of reaction mixture was 363.43 g. HPLC analysis of the reaction mixture revealed 13.71 g (97%) of the title compound was present in the reaction mixture. A portion of the reaction mixture (50 g) was concentrated to a final volume of 12-14 mL under vacuum. Ethyl acetate (45 mL) was added slowly and the reaction mixture was stirred over night at room temperature to obtain white slurry. Product was collected by filtration, washed with ethyl acetate (7 mL) and dried overnight in a vacuum oven at 50-60° C. to obtain 2.02 g of white solid. Ethanol (14 mL) was added to the solid and stirred overnight at the room temperature. The product was collected by filtration, washed with ethanol (4 mL) and dried overnight in a vacuum oven at 50-60° C. to obtain the title compound (1.79 g, 95.4%).

Example 4-2 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 450-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.105 g, 0.115 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.133 g, 0.275 mmol) and milled potassium phosphate tribasic (5.35 g, 25.2 mmol). The flask was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL, round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (16.0 g, 22.9 mmol), methanesulfonamide (2.61 g, 27.5 mmol) and 2-methyltetrahydrofuran (155 mL), purged with argon for not less than 60 minutes. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL flask was raised to 90° C. and the contents were stirred for 14 hours. The reaction mixture was allowed to cool down to 70° C., diluted with ethyl acetate (190 mL) and stirred for 3 hours at 70° C., cooled to the room temperature, stirred for an additional 4 hours, filtered through a fine frit filter funnel and rinsed with ethyl acetate (90 mL) to obtain 29.4 g of light brown solid. A portion of this solid (13.04 g) was transferred to a 500-mL, 3-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Tetrahydrofuran (175 mL) was added, followed by the addition of water 50 mL containing L-cysteine (0.63 g) and sodium chloride (5.5 g). The reaction mixture was stirred for 2 hours at 50° C. under a slight positive pressure of argon. The reaction mixture was transferred to a 500-mL separatory funnel and the aqueous layer was discarded. The organic layer was filtered through an approximately 2-inch pad of diatomaceous earth and rinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellow solution. The organic layer was concentrated to a total weight of 45.59 g. A portion of this organic solution (41.58 g) was charged to a 250-mL, 3-neck round bottom flask fitted with an overhead stirrer. Ethyl acetate (80 mL) was added over 6 hours by a pump with constant stirring at room temperature. The product was collected by filtration, rinsed with ethyl acetate (20 mL) and dried in a vacuum oven for 2 hours to obtain 3.17 g of the title compound (>99.8 pure and 94.6% potent vs. standard).

Example 4-3 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 600-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.229 g, 0.251 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.291 g, 0.601 mmol) and milled potassium phosphate tribasic (11.70 g, 55.1 mmol). The flask was purged with argon for not less than 90 minutes. Ethyl acetate (140 mL) was taken in a 250-mL, round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The contents of the 600-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (35.0 g, 50.1 mmol), methanesulfonamide (5.72 g, 60.1 mmol) and ethyl acetate (280 mL), purged with argon for not less than 60 minutes while stirring at 50° C. This solution was transferred to the 600-mL reactor that had been cooled to room temperature using a cannula under argon atmosphere. The temperature of the 600-mL flask was raised to 90° C., and the contents were stirred for 18 hours. The reaction mixture was allowed to cool down to 40° C., filtered and rinsed with ethyl acetate (140 mL). Solid (41.50 g) was obtained after drying for 2 hours on high vacuum. This solid contained the titled product (23.06 g, 93%).

Example 4-4 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0066 g, 7.16 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0083 g, 17 μmol) and milled potassium phosphate tribasic (0.334 g, 1.58 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. t-Amyl alcohol (4 mL) was added, the vial was capped, and the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to the room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 1.43 mmol), methanesulfonamide (0.163 g, 1.72 mmol) and t-amyl alcohol (8 mL) were added to the 40-mL reaction vial, and the vial was capped. The reaction temperature was raised to 90° C. and the contents were stirred for 5 hours. HPLC analysis of the reaction mixture showed that the product was formed in 94 area % at 210 nm.

Example 4-5 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 600-mL, stainless steel, Parr® reactor was equipped with an overhead stirrer, thermocouple and a heating mantle. Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.208 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g, 39.4 mmol) were charged to the 600-mL reactor. The reactor was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol), methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL), purged with argon for not less than 30 minutes with stirring and heated to 60° C. A clear solution was observed. This solution was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 90° C. and stirred at this temperature for 14 hours. The reaction mixture was cooled to 35° C., solids were collected by filtration, washed with ethyl acetate (300 mL) and dried under high vacuum for 2-4 hours. The solids were then transferred to a 1-L, three-neck, round-bottom flask equipped with an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58 g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid (0.85 g) were charged to the 1-L flask; the contents were heated to 60° C. and mixed for 1 hour. The mixture was filtered through approximately 2-inch pad of diatomaceous earth and washed with DMF (50 mL). The dark-brown/black-colored solid collected on diatomaceous earth was discarded and the light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask equipped with an overhead stirrer, a thermocouple and a syringe pump. The DMF solution was mixed and methanol (300 mL) was added over 8 hours, while maintaining the internal temperature at 25±5° C. The white solid was collected by filtration washed with methanol (150 mL) and dried in a vacuum oven at 50° C. for not less than 8 hours. The title compound was isolated as a white solid (15.8 g, 89% yield).

Example 4-6 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 600-mL, stainless steel, Parr® reactor was equipped with an overhead stirrer, thermocouple and a heating mantle. Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol), 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (0.238 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g, 39.4 mmol) were charged to the 600-mL reactor. The reactor was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol), methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL), purged with argon for not less than 30 minutes with stirring and heated to 60° C. A clear solution was observed. This solution was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 90° C. and stirred at this temperature for 14 hours. The reaction mixture was cooled to 35° C., 5% aqueous N-acetyl-L-cysteine solution (100 mL) was added and the contents were mixed for 1 hour at 35° C. Solids were collected by filtration, washed with water (2×25 mL) and ethyl acetate (3×80 mL) and were dried under high vacuum for 2-4 hours. The solids were then transferred to a 1-L, three-neck, round-bottom flask equipped with an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58 g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid (0.85 g) were charged to the 1-L flask; the contents were heated to 60° C. and mixed for 1 hour. The mixture was filtered through an approximately 2-inch pad of diatomaceous earth and washed with DMF (50 mL). The dark-brown/black-colored solid collected on the diatomaceous earth was discarded and the light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask equipped with an overhead stirrer, a thermocouple and a syringe pump. The DMF solution was mixed and methanol (300 mL) was added over 8 hours, while maintaining the internal temperature at 25±5° C. The white solid was collected by filtration washed with methanol (150 mL) and dried in a vacuum oven at 50° C. for not less than 8 hours. The title compound was isolated as a white solid (15.6 g, 88% yield).

Example 4-7 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0026 g, 2.80 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0033 g, 6.72 μmol) and milled potassium phosphate tribasic (0.131 g, 0.616 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.5 mL) was added, the vial was capped, and the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (0.4 g, 0.560 mmol, Example 3-7, compound (5f)), methanesulfonamide (0.064 g, 0.672 mmol) and ethyl acetate (3 mL) were added to the 40-mL reaction vial. The temperature of the closed vial was raised to 90° C. and the contents were magnetically stirred for 16 hours. HPLC analysis of the reaction mixture showed that the product was formed in 97 area % at 210 nm.

Example 4-8 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0071 g, 7.71 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0089 g, 19.0 μmol) and milled potassium phosphate tribasic (0.360 g, 1.696 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (4 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (1.0 g, 1.542 mmol, Example 3-4, compound (5c)), methanesulfonamide (0.176 g, 1.850 mmol) and ethyl acetate (8 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 20 hours. HPLC analysis of the reaction mixture showed that the product was formed in 95 area % at 210 nm.

Example 4-9 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0055 g, 6.02 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0070 g, 14.0 μmol) and milled potassium phosphate tribasic (0.281 g, 1.324 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (3.4 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl sulfofluoridate (0.6 g, 1.204 mmol, Example 3-8, compound (5g)), methanesulfonamide (0.137 g, 1.444 mmol) and ethyl acetate (6.7 mL) were added to the 40-mL reaction vial. The temperature of the closed reaction vial and its contents was raised to 90° C. and the contents were stirred for 20 hours. HPLC analysis of the reaction mixture showed that the product was formed in 79 area % at 210 nm.

Example 4-10 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0042 g, 4.56 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0053 g, 12.0 μmol) and milled potassium phosphate tribasic (0.213 g, 1.003 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.9 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl trifluoromethanesulfonate (0.5 g, 0.912 mmol, Example 3-6, compound (5e)), methanesulfonamide (0.104 g, 1.094 mmol) and ethyl acetate (5.7 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 14 hours. HPLC analysis of the reaction mixture showed that the product was formed in 91 area % at 210 nm.

Example 4-11 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0037 g, 4.04 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0047 g, 9.7 μmol) and milled potassium phosphate tribasic (0.094 g, 0.445 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to a 40-mL reaction vial. The reaction temperature was raised to 110° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 7 area % at 210 nm.

Example 4-12 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Palladium acetate (0.0018 g, 8.09 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0086 g, 0.018 mmol) and water (0.6 μL, 0.032 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, and the contents were heated to 80° C. and stirred at this temperature for 15 minutes. The reaction mixture was cooled down to room temperature. Potassium phosphate tribasic (0.094 g, 0.445 mmol), 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to the 40-mL reaction vial. The reaction temperature was raised to 110° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 5 area % at 210 nm.

…………………….

REF…

Wagner, Rolf et al, Uracil or thymine derivative for treating hepatitis C and their preparation, PCT Int. Appl., WO2009039127, 26 Mar 2009

Flentge, Charles A. et al, Preparation of anti-infective pyrimidines for treating hepatitis C,PCT Int. Appl., WO2009039134, 26 Mar 2009

Shekhar, Shashank et al,N-(6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide as HCV polymerase inhibitor and its preparation, pharmaceutical compositions and use in the treatment of hepatitis C,PCT Int. Appl., WO2012009699, 19 Jan 2012

Shekhar, Shashank et al,Process for preparing antiviral pyrimidinylphenylnaphthalenyl sulfonamide compounds,PCT Int. Appl.,US20130224149, 29 Aug 2013

Shekhar, Shashank et al,Preparation and use of phosphine ligands for catalytic reactions,U.S. Pat. Appl. Publ., US20130217876, 22 Aug 2013

May 8, 2014 — The U.S. Food and Drug Administration today approved Zontivity (vorapaxar) tablets to reduce the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore the blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs.

 
Zontivity is the first in a new class of drug, called a protease-activated receptor-1 (PAR-1) antagonist. It is an anti-platelet agent, designed to decrease the tendency of platelets to clump together to form a blood clot. By decreasing the formation of blood clots, Zontivity decreases the risk of heart attack and stroke.

Like other drugs that inhibit blood clotting, Zontivity increases the risk of bleeding, including life-threatening and fatal bleeding. Bleeding is the most commonly reported adverse reaction in people taking Zontivity. The drug’s prescribing information (label) includes a Boxed Warning to alert health care professionals about this risk.

Zontivity must not be used in people who have had a stroke, transient ischemic attack (TIA), or bleeding in the head, because the risk of bleeding in the head is too great.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death. In the study that supported the drug’s approval, Zontivity lowered this risk from 9.5 percent to 7.9 percent over a 3-year period – about 0.5 percent per year,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research.

Health care professionals should inform patients that they may bleed and bruise more easily when taking Zontivity. Patients should report to their health care professional any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine. Zontivity will be dispensed with an FDA-approved patient Medication Guide that provides instructions for its use and important safety information.

In a clinical trial with over 25,000 participants, Zontivity, added to other anti-platelet agents (generally aspirin and clopidogrel), reduced the rate of a combined endpoint of heart attack, stroke, cardiovascular death, and urgent procedures to improve blood flow to the heart (coronary revascularization) when compared to an inactive pill (placebo).

Zontivity is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. of Whitehouse Station, N.J.

Source: FDA

synthesis

http://newdrugapprovals.org/2014/01/17/vorapaxar-fda-advisory-panel-votes-to-approve-merck-cos-vorapaxar/

my earlier post

http://newdrugapprovals.org/2014/01/17/vorapaxar-fda-advisory-panel-votes-to-approve-merck-cos-vorapaxar/

GSK-1292263

1032823-75-8

3-isopropyl-5-(4-(((6-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole

5-[1-(3-Isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ylmethoxy]-2-[4-(methylsulfonyl)phenyl]pyridine

C23H28N4O4S

Mass: 456.18313

1292263
GSK-1292263
GSK-1292263A
GSK-263A

Smithkine Beecham Corp,

GSK-1292263 is a novel GPR119 receptor agonist that is currently under development for the treatment of type 2 diabetes. Treatment of male Sprague-Dawley rats with a single dose of GSK-1292263 (3-30 mg/kg) in the absence of nutrients correlated with increased levels of circulating gastrointestinal peptides; glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY) and glucagon.

GSK-1292263 had been evaluated in phase II clinical studies at GlaxoSmithKline for the oral treatment of type 2 diabetes and as monotherapy or in combination with sitagliptin for the treatment of dyslipidemia; however no recent development has been reported for this research.

Following administration of glucose in the oral glucose tolerance test (OGTT), greater increases in total GLP-1, GIP and PYY were seen in GSK-1292263-treated rats than in control animals. Despite significant decreases in the glucose AUC, no statistically significant differences in insulin responses and insulin AUC were observed between rats administered GSK-1292263 and those receiving vehicle control.

In the intravenous glucose tolerance test, significant increases in the peak insulin response and insulin AUC(0-15 min) of 30-60% were reported in the GSK-1292263 treatment group, compared with values in the vehicle control cohort. This insulin upregulation correlated with a significant increase in the glucose disposal rate (Brown, K.K. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 407).

The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of GSK-1292263 were evaluated in a recently completed randomized, placebo-controlled clinical trial in healthy volunteers (ClinicalTrials.gov Identifier NCT00783549).

A total of 69 subjects received single escalating doses of GSK-1292263 (10-400 mg) prior to administration of a 250-mg dose given once daily for 2 and 5 days, which was also evaluated in combination with sitagliptin (100 mg). Treatment with GSK-1292263 at all doses was described as well tolerated, with the most common drug-related effects being mild headache, dizziness, hyperhidrosis, flushing and post-OGTT hypoglycemia.

Hypoglycemia was not reported with the 5-day dosing schedule. Pharmacokinetic profiling revealed dose-proportional AUC and Cmax at single lower doses, but not at single higher ones. Following repeated once-daily dosing (5 days), drug accumulation was observed consistent with a mean half-life of 12-18 hours. A dose-dependent increase in glucose AUC(0-3 h) during OGTT was seen in GSK-1292263-treated subjects. The treatment was also associated with an increase in PYY during the prandial periods.

Coadministration with sitagliptin led to increases in the plasma concentrations of active GLP-1 but reduced the levels of total GLP-1, GIP and PYY. Sitagliptin affected the exposure to GSK-1292263 (50% increase) but GSK-1292263 did not affect sitagliptin exposure. The data support further evaluation of GSK-1292263 for the treatment of type 2 diabetes (Source: Nunez, D.J. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 80-OR).

WO 2008070692

http://www.google.com.au/patents/WO2008070692A2?cl=en

Example 169: 5-[({1 -[3-(1 -Methylethyl)-1,2,4-oxadiazol-5-yl]-4- piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine hydrochloride

Step 1 : A mixture of 6-bromo-3-pyridinol (7 g, 40 mmol), [4-(methylsulfonyl)phenyl]boronic acid (8 g, 40 mmol), 2M Na₂CO₃ (30 ml_), PdCI₂(PPh₃)₂ (1 g) and DME (60 ml.) under N₂ was heated at 80 ⁰C overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water. The resulting precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The aqueous phase was also concentrated. Each of the residues was recrystallized from MeOH. The solid material from the organic phase recrystallization and the mother liquors from both aqueous and organic recrystallizations were combined, concentrated and purified by chromatography on a silica gel column using 0 to 10% MeOH/CH₂CI₂ to give 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (2.9 g, 29%) as a tan solid. Step 2: Diisopropyl azodicarboxylate (0.175 ml_, 0.89 mmol) was added dropwise to a solution of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (150 mg, 0.59 mmol), {1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 200 mg, 0.89 mmol), PPh₃ (233 mg, 0.89 mmol), and THF (10 ml.) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was concentrated, and the resulting crude was purified by reverse-phase preparative HPLC using a CH₃CN:H₂O gradient (10:90 to 100:0) with 0.05% TFA as a modifier, then taken up in CH₂CI₂ and free-based with saturated NaHCO₃ (aq) to give 5-[({1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine (220 mg) as a white solid. Step 3: A mixture of the resulting white solid (50 mg, 0.1 1 mmol) in THF (3 ml.) was stirred at ambient temperature as 4Λ/ HCI in dioxane (28 μl_) was added dropwise. The resulting white precipitate was filtered, air-dried, then triturated with diethyl ether to give 35 mg (65%) of the title compound as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 8.46 (d, 1 H, J = 0.7 Hz), 8.18 (bs, 2H), 8.05 (bs, 2H), 7.83 (bs, 1 H), 7.61- 7.45 (m, 1 H), 4.24 (d, 2H, J = 10.4 Hz), 4.00 (d, 2H, J = 0.6 Hz), 3.21-3.03 (m, 5H), 2.89 (m, 1 H), 2.15 (d, 1 H, J = 1.1 Hz), 1.96 (bs, 2H), 1.50 (bs, 2H), 1.28 (d, 6H, J = 6.9 Hz); LRMS (ESI), m/z 457 (M+H).

MK-0822; Odanacatib.

603139-19-1

 Formula: C25H27F4N3O3S

 Mass: 525.17093

Merck Frosst Canada Ltd. phase 3

(S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pentanamide

N1-(1-Cyanocyclopropyl)-4-fluoro-N2-[2,2,2-trifluoro-1(S)-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl]-L-leucinamide

Odanacatib (pINN; codenamed MK-0822) is an investigational treatment for osteoporosis and bone metastasis. It is an inhibitor of cathepsin K,  an enzyme involved in bone resorption. It is being developed by Merck & Co. As of November 2009, Merck is conducting phase III clinical trials.

  Odanacatib, also known as MK-0822,  is an inhibitor of cathepsin K with potential anti-osteoporotic activity. Odanacatib selectively binds to and inhibits the activity of cathepsin K, which may result in a reduction in bone resorption, improvement of bone mineral density, and a reversal in osteoporotic changes. Cathepsin K, a tissue-specific cysteine protease that catalyzes degradation of bone matrix proteins such as collagen I/II, elastin, and osteonectin plays an important role in osteoclast function and bone resorption

……………….

The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
Bioorg Med Chem Lett 2008, 18(3): 923

http://www.sciencedirect.com/science/article/pii/S0960894X07015065

………………

WO 2003075836  or http://www.google.com/patents/EP1482924A2?cl=en

EXAMPLE 10

Synthesis of N l-cyanocyclopropyl)-N²{(lS)-2,2,2-trifluoro-l-[4'-(m^

1 , 1 -biphenyl-4-yl]ethyl ) -L-leucinamide

To a mixture of Ν-{(lS)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)-l,l'- biphenyl-4-yl]ethyl} -L-leucine from Example 8 (0.83 g), O-(7-azabenzotriazol-l-yl)- N, N, N\ N’-tetramethyluronium hexafluorophosphate (0.78 g), cyclopropylamine hydrochloride (0.466 g) in DMF (18 mL) at 0 °C was added triethylamine (0.9 mL). The mixture was kept at room temperature for 48 hours and then poured into dilute aqueous ammonium cholride and diethyl ether. The ether layer was separated and the aqueous further extracted with diethylether. The combined ether extracts were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo. The residue was purified in SiO₂ using ethyl acetate and hexanes (1:1) as eluant, followed by a swish in diethyl ether to yield the title compound.

H NMR (CD₃COCD₃) δ 8.15(1H, bs), 8.05(2H, d), 8.0(2H, d), 7.8(2H, d), 7.65(2H, d), 4.35-4.45(lH, m), 3.35-3.45(lH, m), 3.2(3H, s), 2.65-2.7(lH, m), 1.85-1.95(1H, m), 1.3-1.6(5H, m), 1.05-1.15(1H, m), 0.85-0.95(6H, m).

……….

WO 2008119176

http://www.google.com/patents/WO2008119176A1?cl=en

EXAMPLE 1

4-FLUORO-iV- {(1 S)-2,2,2-TRIFLUORO- 1 -[4'-(METHYLSULFONYL)BIPHENYL^- YL]ETHYL}-L-LEUCINE DICYCLOHEXYLAMINE SALT

Biphenyl acid (20.74 g) was dissolved in 2-propanol (186 mL) / water (20.7 mL). A solution of iV,jV-dicyclohexylamine (9.82 mL) in 2-propanol (21 mL) / water (2 mL) was added (-10% of volume) and the solution was seeded with DCHA salt (10 mg). A heavy seed bed formed and the slurry was let stir at rt for 30 min. Addition of DCHA was continued over 20-30 min. The slurry was let stir at rt overnight and filtered. The filter cake was washed with 2-propanol / water (2 x 30 mL, 10:1) and MTBE (2 x 30 mL). DCHA salt was obtained as a white solid, 24.4 g, 84% yield. ¹H NMR (CD₃OD) δ 8.07 (d, 2H, J- 8.0), 7.94 (d, 2H, J= 8.0), 7.75 (d, 2H, J= 8.0), 7.61 (d, 2H, J= 8.0), 4.31 (m, IH), 3.46 (bq, IH, J= 4), 3.22 (m, 2H), 3.19 (s, 3H), 2.11 (bm, 5H), 1.91 (bm, 5H), 1.75 (bm, 2H), 1.49 (d, 3H, J= 21.6), 1.48 (d, 3H, J= 21.6), 1.35 (m, 9H); ¹⁹F NMR (CD₃OD) δ – 72.9, – 129.4; mp 209-211°C, [α]_D ²⁰ + 18.7 (c = 0.29, MeOH).

EXAMPLE 2

N-(I -CYANOCYCLOPROPYL)-4-FLUORO-N²- {(1 S)-2,2,2-TRIFLUORO- 1 -[4'- (METHYLSULFOΝYL)BIPHEΝYL-4- YL]ETHYL}-L-LEUCINAMIDE

Acid (1.9 g) was dissolved in DMAc (10 mL) and cooled to 0°C. 1 -

Aminocyclopropane carbonitrile hydrochloride (0.57 g) and HATU (1.85 g) were added. The resulting slurry was stirred for 15 min and DIEA (2.12 mL) was added over 1.5 h. The reaction was aged for 1 h. Water (11.2 mL) was added via dropping funnel over 70 min and the slurry was aged for Ih at 2O⁰C. The mixture was filtered and the filter cake was washed with a solution of DMAc:water (9.4 mL, 1 : 1.2), water (18.7 mL), 2-propanol (9.3 mL) The batch was dried to yield 1.67 g, 79% yield of the corresponding amide.

Amide (2.56 g), was dissolved in THF (30.7 mL) at 30°C. Water (19 mL) was added via dropping funnel. The batch was seeded and aged for Ih at 2O⁰C. Additional water (40.9 mL) was added over 1.5 h and the batch was aged for 16 h. The batch was filtered and washed with water (15 mL). The solids were dried to a constant weight to yield 2.50 g, 97% yield of pure amide. ¹H NMR (CD₃OD) δ 8.17 (bs, IH), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J= 8.5), 7.80 (d, 2H, J= 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, IH), 3.55 (ddd, IH, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, IH), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J= 22.0), 1.36 (m, 2H), 1.07 (m, IH), 0.94 (m, IH); ¹³C NMR (CD₃OD) δ; ¹⁹F NMR (CD₃OD) δ -73.2, -136.8; IR (cm^“1) 3331, 2244, 1687, 1304, 1152; mp 223-224 ⁰C, [α]_D ²⁰ + 23.3 (c = 0.53, MeOH).

EXAMPLE 3

N-(l-CYANOCYCLOPROPYL)-4-FLUORO-iV²-{(l₁S)-2,2,2-TRrFLUORO-l-[4'- (METHYLSULFONYL)BIPHENYL^-YL]ETHYL) -L-LEUCINAMIDE

A round-bottom flask was charged with biphenyl acid’DCHA salt (76.6 g, 99.2% ee, diastereomeric ratio 342:1) and DMF (590 g). Solid aminocyclopropane carbonitrile-HCl (15.2 g), HOBt-H₂O (17.9 g), and EDCΗC1 (29.1 g) were all charged forming a white slurry. The batch was then heated to 38-42°C and aged for 5 hours. The batch was then cooled to 20- 25⁰C and held overnight. HPLC analysis showed 99.4% conversion. The batch was heated to 38-42°C and water (375 g) was charged to batch over 2 hours. The batch remained as a slurry throughout the water addition. The batch was then heated to 58-62⁰C and aged for 1 hour. Following age, water (375 g) was charged over 3 hours, at a rate of 2.1 g/min. The batch was then cooled to 15-25°C and aged overnight. The batch was filtered and washed with 39% DMF in water (2 x 300 g) and 2-propanol (180 g). The solids were dried in the filter at 40-60⁰C for 24 hours. The desired crude product was isolated as a white solid (57g, 92% yield, 99.4 wt%). A round-bottom flask was charged with crude solid (57 g) and acetone/water solution (324 g, 88/12). The slurry was then heated to 40⁰C, at which point the batch was in solution, and aged for an hour. Water (46 g) was then charged over 30 minutes. The batch was then seeded (1.7 g, 3.0 wt%), and the batch was aged at 40°C for an hour prior to proceeding with the crystallization. Water (255 g) was charged over 4.5 h. The batch was then cooled to 23⁰C over 1.5 h, aged for 4 h and filtered. The solids were washed with acetone/water (158 g, 45/55) and water (176 g). The filter cake was dried with nitrogen sweep / vacuum at 55°C. The desired product (57.2 g , 99.9wt%, 99.8A% (enantiomer ND), was obtained in 94.9% yield. ¹H NMR (CD₃OD) δ 8.17 (bs, IH), 8.05 (d, 2H, J= 8.5), 7.96 (d, 2H, J= 8.5), 7.80 (d, 2H, J= 8.0), 7.64 (d, 2H, J= 8.0), 4.43 (m, IH), 3.55 (ddd, IH, J= 5.0, 8.5, 8.0), 3.18 (s, 3H), 2.84 (bm, IH), 2.02 (m, 2H), 1.46 (d, 3H, J= 21.5), 1.43 (d, 3H, J= 22.0), 1.36 (m, 2H), 1.07 (m, IH), 0.94 (m, IH); ¹³C NMR

(CD₃OD) δ; ¹⁹F NMR (CD₃OD) δ -73.2, -136.8; IR (cm^“1) 3331, 2244, 1687, 1304, 1152; mp 223-224 ⁰C, [α]_D ²⁰ + 23.3 (c = 0.53, MeOH).

……………..

JOC 2009 74(4): 1605-1610

http://pubs.acs.org/doi/abs/10.1021/jo8020314

An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S_N2 triflate displacement of a chiral α-trifluoromethylbenzyl triflate 9a with (S)-γ-fluoroleucine ethyl ester 3 to generate the required α-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.

…………..

in Ovariectomized Rabbits. Calcif Tissue Int. 2013 Oct 2. [Epub ahead of print]Clinical study:Int J Clin Pharmacol Ther. 2013 Aug;51(8):688-92.J Clin Endocrinol Metab. 2013 Feb;98(2):571-80.

Br J Clin Pharmacol. 2013 May;75(5):1240-54.

J Bone Miner Res. 2010 May;25(5):937-47.

Clin Pharmacol Ther. 2009 Aug;86(2):175-82.Review papers:Clin Interv Aging. 2012;7:235-47.Clin Calcium. 2011 Jan;21(1):59-62.

IDrugs. 2009 Dec;12(12):799-809.

Ther Adv Musculoskelet Dis. 2013 Aug;5(4):199-209.

1: Chapurlat RD. Treatment of postmenopausal osteoporosis with odanacatib. Expert Opin Pharmacother. 2014 Jan 24. [Epub ahead of print] PubMed PMID: 24456412.

2: Odanacatib, a cathepsin K inhibitor, superior to alendronate. Bonekey Rep. 2013 Sep 4;2:426. doi: 10.1038/bonekey.2013.160. eCollection 2013. PubMed PMID: 24422127; PubMed Central PMCID: PMC3789222.

3: Retraction notice: Odanacatib for the treatment of postmenopausal osteoporosis. Expert Opin Pharmacother. 2014 Jan;15(1):151. doi: 10.1517/14656566.2014.868399. Epub 2013 Nov 30. PubMed PMID: 24289716.

4: Anderson MS, Gendrano IN, Liu C, Jeffers S, Mahon C, Mehta A, Mostoller K, Zajic S, Morris D, Lee J, Stoch SA. Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women. J Clin Endocrinol Metab. 2013 Dec 20:jc20131688. [Epub ahead of print] PubMed PMID: 24276460.

5: Chapurlat RD. Odanacatib for the treatment of postmenopausal osteoporosis. Expert Opin Pharmacother. 2014 Jan;15(1):97-102. doi: 10.1517/14656566.2014.853038. Epub 2013 Oct 25. Retraction in: Expert Opin Pharmacother. 2014 Jan;15(1):151. PubMed PMID: 24156249.

6: Stoch SA, Witter R, Hrenuik D, Liu C, Zajic S, Mehta A, Chandler P, Morris D, Xue H, Denker A, Wagner JA. Odanacatib does not influence the single dose pharmacokinetics and pharmacodynamics of warfarin. J Popul Ther Clin Pharmacol. 2013;20(3):e312-20. Epub 2013 Oct 2. PubMed PMID: 24142206.

7: Jensen PR, Andersen TL, Pennypacker BL, Duong le T, Delaissé JM. The bone resorption inhibitors odanacatib and alendronate affect post-osteoclastic events differently in ovariectomized rabbits. Calcif Tissue Int. 2014 Feb;94(2):212-22. doi: 10.1007/s00223-013-9800-0. Epub 2013 Oct 2. PubMed PMID: 24085265.

8: Bonnick S, De Villiers T, Odio A, Palacios S, Chapurlat R, Dasilva C, Scott BB, Le Bailly De Tilleghem C, Leung AT, Gurner D. Effects of Odanacatib on BMD and Safety in the Treatment of Osteoporosis in Postmenopausal Women Previously Treated With Alendronate: A Randomized Placebo-Controlled Trial. J Clin Endocrinol Metab. 2013 Dec;98(12):4727-35. doi: 10.1210/jc.2013-2020. Epub 2013 Sep 24. PubMed PMID: 24064689.

9: Zerbini CA, McClung MR. Odanacatib in postmenopausal women with low bone mineral density: a review of current clinical evidence. Ther Adv Musculoskelet Dis. 2013 Aug;5(4):199-209. doi: 10.1177/1759720X13490860. PubMed PMID: 23904864; PubMed Central PMCID: PMC3728981.

10: Williams DS, McCracken PJ, Purcell M, Pickarski M, Mathers PD, Savitz AT, Szumiloski J, Jayakar RY, Somayajula S, Krause S, Brown K, Winkelmann CT, Scott BB, Cook L, Motzel SL, Hargreaves R, Evelhoch JL, Cabal A, Dardzinski BJ, Hangartner TN, Duong le T. Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate. Bone. 2013 Oct;56(2):489-96. doi: 10.1016/j.bone.2013.06.008. Epub 2013 Jun 24. PubMed PMID: 23806798.

11: Cabal A, Jayakar RY, Sardesai S, Phillips EA, Szumiloski J, Posavec DJ, Mathers PD, Savitz AT, Scott BB, Winkelmann CT, Motzel S, Cook L, Hargreaves R, Evelhoch JL, Dardzinski BJ, Hangartner TN, McCracken PJ, Duong le T, Williams DS. High-resolution peripheral quantitative computed tomography and finite element analysis of bone strength at the distal radius in ovariectomized adult rhesus monkey demonstrate efficacy of odanacatib and differentiation from alendronate. Bone. 2013 Oct;56(2):497-505. doi: 10.1016/j.bone.2013.06.011. Epub 2013 Jun 20. PubMed PMID: 23791777.

12: Stoch SA, Witter R, Hreniuk D, Liu C, Zajic S, Mehta A, Brandquist C, Dempsey C, Degroot B, Stypinski D, Denker A, Wagner JA. Absence of clinically relevant drug-drug interaction between odanacatib and digoxin after concomitant administration. Int J Clin Pharmacol Ther. 2013 Aug;51(8):688-92. doi: 10.5414/CP201864. PubMed PMID: 23782582.

13: Nakamura T, Shiraki M, Fukunaga M, Tomomitsu T, Santora AC, Tsai R, Fujimoto G, Nakagomi M, Tsubouchi H, Rosenberg E, Uchida S. Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis-a double-blind, randomized, dose-finding study. Osteoporos Int. 2014 Jan;25(1):367-76. doi: 10.1007/s00198-013-2398-2. Epub 2013 May 29. PubMed PMID: 23716037.

14: Brixen K, Chapurlat R, Cheung AM, Keaveny TM, Fuerst T, Engelke K, Recker R, Dardzinski B, Verbruggen N, Ather S, Rosenberg E, de Papp AE. Bone density, turnover, and estimated strength in postmenopausal women treated with odanacatib: a randomized trial. J Clin Endocrinol Metab. 2013 Feb;98(2):571-80. doi: 10.1210/jc.2012-2972. Epub 2013 Jan 21. PubMed PMID: 23337728.

15: Fratzl-Zelman N, Roschger P, Fisher JE, Duong le T, Klaushofer K. Effects of Odanacatib on bone mineralization density distribution in thoracic spine and femora of ovariectomized adult rhesus monkeys: a quantitative backscattered electron imaging study. Calcif Tissue Int. 2013 Mar;92(3):261-9. doi: 10.1007/s00223-012-9673-7. Epub 2012 Nov 23. PubMed PMID: 23179105.

16: Stoch SA, Zajic S, Stone JA, Miller DL, van Bortel L, Lasseter KC, Pramanik B, Cilissen C, Liu Q, Liu L, Scott BB, Panebianco D, Ding Y, Gottesdiener K, Wagner JA. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics–results from single oral dose studies in healthy volunteers. Br J Clin Pharmacol. 2013 May;75(5):1240-54. doi: 10.1111/j.1365-2125.2012.04471.x. PubMed PMID: 23013236; PubMed Central PMCID: PMC3635595.

17: Ng KW. Potential role of odanacatib in the treatment of osteoporosis. Clin Interv Aging. 2012;7:235-47. doi: 10.2147/CIA.S26729. Epub 2012 Jul 12. Review. PubMed PMID: 22866001; PubMed Central PMCID: PMC3410681.

18: Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, Denker A, Lombardi A, Le Bailly De Tilleghem C, Dasilva C, Rosenberg E, Leung A. Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res. 2012 Nov;27(11):2251-8. doi: 10.1002/jbmr.1695. PubMed PMID: 22777865.

19: Jayakar RY, Cabal A, Szumiloski J, Sardesai S, Phillips EA, Laib A, Scott BB, Pickarski M, Duong le T, Winkelmann CT, McCracken PJ, Hargreaves R, Hangartner TN, Williams DS. Evaluation of high-resolution peripheral quantitative computed tomography, finite element analysis and biomechanical testing in a pre-clinical model of osteoporosis: a study with odanacatib treatment in the ovariectomized adult rhesus monkey. Bone. 2012 Jun;50(6):1379-88. doi: 10.1016/j.bone.2012.03.017. Epub 2012 Mar 24. PubMed PMID: 22469953.

20: Khosla S. Odanacatib: location and timing are everything. J Bone Miner Res. 2012 Mar;27(3):506-8. doi: 10.1002/jbmr.1541. PubMed PMID: 22354850.

21      nmr……..http://www.medkoo.com/Product-Data/Odanacatib/Odanacatib-QC-BBC20130906Web.pdf

http://www.medkoo.com/Product-Data/Odanacatib/JOC2009p1605-NMR-Data.pdf

4-amino-1-[(2R,3E,4S,5R)-3-(fluoromethylidene)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one

130306-02-4 

Tezacitabine is a ribonucleotide reductase inhibitor. It is a synthetic purine nucleoside analogue with potential antineoplastic activity. It is used for DNA synthetic.^[1]

EP 0372268; JP 1990178272; US 5378693 The acetylation of uridine (I) with acetic anhydride gives the 2′,3′,5′-triacetyl derivative (II), which is treated with SOCl2 and sodium ethoxide yielding the 4-ethoxypyrimidinone (III). The partial protection of (III) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (IV) yields the silylated compound (V), which is oxidized with oxalyl chloride to the silylated furanone (VI). The reaction of (VI) with fluoromethyl phenyl sulfone (A) by means of diethyl chlorophosphate (B) and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (VII) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (VII) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VIII), which is finally treated with CsF and NH3 in refluxing methanol to afford the target compound.

US 5607925

http://www.drugfuture.com/synth/syndata.aspx?ID=165222

………………..

http://www.google.com/patents/WO2005049563A2?cl=en  

References

4-[6-Amino-5-bromo-2- [(4-cyanophenyl)amino] pyrimidin-4-yl]oxy-3,5-dimethylbenzonitrile

EMA:Link, US FDA:link

269055-15-4

It was originally developed and launched by Johnson & Johnson, for the treatment of HIV-1 infection. Family members of the product case, WO0027825, hold SPC protection in the EU until 2023 and expire in the US in 2020.

Etravirine (ETR,^[1] brand name Intelence, formerly known as TMC125) is a drug used for the treatment of HIV. Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Etravirine works by reducing the amount of HIV and increasing the number of CD4 or T cells in the blood. Unlike the currently available agents in the class, resistance to other NNRTIs does not seem to confer resistance to etravirine.^[2] Etravirine is marketed by Tibotec, a subsidiary of Johnson & Johnson. In January 2008, the Food and Drug Administration approved its use for patients with established resistance to other drugs, making it the 30th anti-HIV drug approved in the United States and the first to be approved in 2008.^[3] It was also approved for use in Canada on April 1, 2008.^[4]

Etravirine is licensed in the United States, Canada, Israel, Russia and the European Union,^[5] and is under regulatory review in Switzerland and Australia.^[6]

Indications and dosage

Etravirine, in combination with other anti-retrovirals, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

The recommended dose of etravirine is 200 mg (2 x 100 mg tablets, or 1 x 200 mg tablet as of 03/18/2011) taken twice daily following a meal. The type of food does not affect the exposure to etravirine.^[7]

Contraindication

Each 100 mg etravirine tablet contains 160 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.^[8]

Mechanism of action

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), designed to be active against HIV with mutations that confer resistance to the two most commonly prescribed first-generation NNRTIs, mutation K103N for efavirenz and Y181C for nevirapine.^[9] This potency appears to be related to etravirine’s flexibility as a molecule. Etravirine is a diarylpyrimidine (DAPY), a type of organic molecule with some conformational isomerism that can bind the enzyme reverse transcriptase in multiple conformations, allowing for a more robust interaction between etravirine and the enzyme, even in the presence of mutations.^[10] Other diarylpyrimidine-analogues are currently being developed as potential anti-HIV agents, notably rilpivirine.

Warnings and risks

In 2009, the prescribing information for etravirine was modified to include “postmarketing reports of cases of Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Intelence therapy should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.”^[11]

Etravirine (I), formerly TMC 125 and chemically known as 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, is an NNRTI approved in 2008 for use in combination with other antiretroviral agents in treatment- experienced adult patients with multidrug-resistant HIV infections. Etravirine is marketed worldwide as an oral tablet and was first disclosed by De Corte et al in US 7,037,917.

Etravirine (I)

De Corte et al in US 7,037,917 provides a method for manufacturing of diarylpyrimidine compounds wherein a compound of formula (II) is heated with ammonia in presence of a inert solvent such as 1,4-dioxane in a pressure vessel at 150⁰C for 4 days.

(H) (I) X – halogen

Davies et al in Drugs of the Future 2005, 30(5): 462-468 discloses that the intermediate compound (II) can be prepared in two different routes. The first route discloses that 5-bromo-2,4,6-trichloropyrimidine is reacted with 4- aminobenzonitrile by means of diisopropylethylamine in refluxing dioxane giving a diarylamine which is then reacted with 4-hydroxy-3,5- dimethylbenzonitrile to give intermediate of formula (II) (Scheme – 1).

Scheme – 1 ^lll)

The second method for synthesis of compound of formula (II) discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)- benzonitrile, which upon treatment with POCI₃ yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin- 2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives intermediate of formula (II) (Scheme – II).

However, the abovementioned procedure for synthesis of diarylpyrimidine NNRTIs suffers from the disadvantage that the conversion of compound of formula II to the final compound is very slow. The reaction of compound of formula (II) with ammonia, even in refluxing dioxane requires four days for completion and the yields obtained are not very satisfactory.

Recently, De Kock et al, in US 2008/0194602 has reported that diarylpyrimidine oxide derivatives possesses HIV replication inhibiting properties. The diarylpyrimidine oxide derivatives are prepared from corresponding diarylpyrimidine derivatives of formula III by N-oxidation of the tertiary nitrogen of pyrimidine ring.

(III)

There are various method reported for synthesis of diarylpyrimidine derivatives of formula III, as summarized in Scheme – 3.

One of the most preferred processes reported for synthesis of diarylpyrimidine derivatives of formula (III), is by halogenating a compound of formula (IV). Further, the compound of formula (IV) is reported to be prepared from 4-aminobenzonitrile and cyanamide. This reaction is conducted in water in the presence of a strong acid, to yield 4-cyanophenyl guanidine, which is then reacted with an alkyl malonic ester, in the presence of a strong base and at increased temperature. The obtained 4,6- dihydroxypyrimidine is then treated with a halogenating agent. The pyrimidine derivative is then reacted with a 4-substituted benzonitrile and then further with ammonia to yield the intermediates (IV).

Although, the process disclosed herein relates to synthesis of N-oxide derivatives and not particularly etravirine, the same method could be used for synthesis of etravirine. However, the said process again suffers from the limitation that it utilizes cyanamide, which is a highly toxic compound. Thus, from the above, it would be evident, that though NNRTIs, such as etravirine, are the main-stay therapy for treatment of HIV infections,

……………………………….

http://www.google.com/patents/EP2342186A2?cl=en

Scheme – 4.

aq. ammonia

Halogenation

(I) (IV)

EXAMPLES:

Example 1

Synthesis of 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5 dimethylbenzonitrile (Compound-V):

2,4,6-Trichloropyrimidine (100 g, 0.545 m) was dissolved in 1,4-dioxane (300 ml) and 3,5,-dimethyl-4-hydroxybenzonitrile (80.1 g, 0.545m) was added under stirring. Addition of N,N-diisopropylethylamine (141.0Og, 1.09m) was carried to this solution over a period of 30 minutes. Reaction mass was heated at 70⁰C and stirred for 2.0 hours. The reaction mass was cooled slowly to 15°C and obtained product was filtered at 12-15°C followed by washing the cake with 50 ml of 1,4-dioxane. Finally the cake was washed with water (200ml) to get the desired product. Melting point: 208-210⁰C.

Yield: 128 g, %Yield=80%;

Example 2

Synthesis of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]- 3,5-dimethylbenzonitrile (Compound-VT) Compound-V (100 g, 0.34 m) was dissolved in N-methylpyrrolidone (500 ml) and 4-Aminobenzonitrile (40.12 g, 0.34m) was added under stirring. The reaction mass was cooled to 0⁰C. To this solution, addition of potassium t- butoxide was carried out (76.3g, 0.68m) in lots over a period of 1.0 hour at 0 to 10⁰C. The reaction mass was allowed to come at room temperature gradually over 1 to 2 hours. Then slowly the reaction mass was added in chilled water (2.0L) by maintaining the reaction mass temperature below 2O⁰C. The reaction mass was filtered and washed the cake with 200 ml water. Wet cake was again dissolved in 1.0L water below 20⁰C and filtered. The obtained product was purified by using ethyl acetate (2×300 ml) at 60- 7O⁰C followed by filtration at 10-15⁰C. Yield: 50 g.

Example 3

Synthesis of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]- 3,5-dimethylbenzonitriIe (Compound – IV)

Aqueous ammonia (25%) (600 ml) was added to a solution of Compound- VI (100 g, 0.266 m) in 1,4-Dioxane (1000 ml) and the reaction mass was heated in pressure autoclave at 12O⁰C and maintain at 120-125⁰C forlO-12 hours. The reaction mass was allowed to cool to 50⁰C, and again heated to 70-80⁰C, at which water (200 ml) was added slowly. The reaction mass gradually cooled to 10⁰C and filtered to obtain wet cake, which was dried to get desired product.

Yield: 75 g, %Yield= 80%. Example 4

Synthesis of Etravirine

Compound-IV (100 g, 0.28 m) was taken in methylene dichloride (800 ml) and cooled to a temperature of 0 to 5°C. Slowly liquid bromine (47.2 g, 0.294 m) was added at 0 to 5⁰C by dissolving in 200 ml of methylene dichloride. The reaction mass was stirred at 0 to 5⁰C for 2 to 4 hrs. Chilled water (800 ml) was added in to the reaction mass and pH was adjusted at 9 to 10 by slow addition of sodium hydroxide solution at 0 to 5°C. Sodium metabisulphite solution was added at 0 to 5⁰C and the reaction mass was stirred at 0-10⁰C for 1 hour by maintaining the reaction mass pH at 8 to 9. The reaction mass was filtered and washed the cake with 200 ml water. Dry the wet product at 50-60⁰C & recrystallize from acetone. Yield: 100 g, Melting point: 252 to 254°C.

………………………………………..

http://www.google.com/patents/EP2212298B1?cl=en

• The synthesis of compounds of Formula I can be readily achieved by synthetic chemists of ordinary skill. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant procedures and intermediates are disclosed, for instance in PCT patent publication WO2000/27825 ; European Patent 1 002 795 ; United State patent 7,241,458 ; and Ludovici, DW et al, Biorg Med Chem Lett 2001, 11:2235. The compounds may be prepared as illustrated in the schemes shown below.

Exemplary Synthesis

• [0043]
• [0044]
  Scheme 1 shows a general route for preparing compounds of Formula I. An appropriately deuterated benzonitrile 10 is converted to the corresponding aryl guanidine compound 11 by refluxing in ethanol with cyanamide and nitric acid. Reaction with diethylmalonate and sodium ethoxide in ethanol produces the cyanophenylamino-4-dihyroxypyrimidine 12, which is then chlorinated by treatment with POCl₃, and brominated by treatment with bromine gas and aqueous sodium bicarbonate in methanol to yield compound 13. Compound 13 is combined with appropriately deuterated 4-cyanophenol 14 in the presence of N-methylpyrrolidone (“NMP”) and dioxane to form tricyclic compound 15. Compound 15 is then treated with ammonia in isopropyl alcohol (“IPA”) to form a compound of Formula I.
• [0045]
  Scheme 2 shows how various deuterated benzonitriles 10, useful in Scheme 1, may be prepared. Reaction A, starting with compound 20, illustrates the preparation of the 4-amino-2,3,5,6-d₄-benzonitrile reagent 10a. Treatment of commercially available 4-chloro-2,3,5,6-d ₄-aniline (20) with palladium(II) trifluoroacetate, 2-di-tert-butylphosphino-1,1 ‘-binaphthyl, zinc flakes, and zinc cyanide according to the procedure described by Littke, A et al., Org Lett, 2007, 9:1711-1714 affords 10a.
• [0046]
  Scheme 2B shows the preparation of an alternative benzonitrile intermediate 4-amino-2,6-d₂-benzonitrile 10b, starting with commercially available 4-nitroaniline (21). Treatment of 21 with commercially available deuterium chloride in deuterated water according to the procedure described by Suehiro, T et al., Bull Chem Soc Jap, 1987, 60:3321-3330 affords the 2,6-d₂-4-nitroaniline 22, which can be elaborated through nitrochloro intermediate 23 and chloroaniline intermediate 24 to the necessary d₂-benzonitrile building block 10b using the procedures described in Suehiro, T et al., Bull Chem Soc Jap, 1987, 60:3321-3330.
• [0047]
  Scheme 3 shows the synthesis of appropriately deuterated.cyanophenols 14 useful in Scheme 1. Sequence A, starting with commercially available ortho-cresol-d ₇ 30, shows the preparation of the 2,6-d₂-4-hydroxy-3,5-bis(methyl-d₃)benzonitrile intermediate 14a (R¹, R² = CD₃; Y¹, Y² = D). Treatment of 30 with commercially available d ₂-diiodomethane and diethylzinc according to the procedure described by Macdonald, TL et al., Tet Lett, 1989, 39:5215-5218 affords the 2,6-bis(methyl-d₃)phenol 31. Subsequent bromination of the phenol with N-bromosuccinimde (NBS) in carbon tetrachloride using the protocol described by Srinivasan, KV et al., TetLett, 1994, 35:7055-7056 affords the 4-bromo-substituted phenol 32 Treatment of the bromophenol 32 with copper(I) cyanide in refluxing DMF according to the procedure described in Chinese patent publication 1687060 affords the requisite benzonitrile 14a.
• [0048]
  Scheme 3B, starting with commercially available 1-(methoxymethoxy)benzene (33), illustrates the preparation of 4-hydroxy-3,5-bis(methyl-d₃)benzonitrile 14b (R¹, R² = CD₃; Y¹ Y² = H). Treatment of 33 with n-butyllithium followed by treatment of the in situ generated organolithium with commercially available d₃-iodomethane according to the procedure described by Hayes, RN et al., Aus J Chem, 1989, 42:865-874 affords the 2-(methyl-d₃)phenol 34, which can then be processed as shown to afford the desired bis(methyl-d₃)benzonitrile (14b: R¹, R² = CD₃; Y¹, Y² = H).

Examples

• [0102]
  Example 1. Synthesis of 2,6-d₂-4-hydroxy-3,5-bis(methyl-d₃)benzonitrile (14b). Intermediate 14b was prepared as outlined in Scheme 4 below. Details of the synthesis follow.
• [0103]
  Synthesis of 3,4,5-d₃-2,6-bis(methyl-d₃)phenol (31). To a sealed tube containing a suspension of 2,6-dimethylphenol 40 (2.0 g, 16.4 mmol) in D₂O (25 mL), was added 5% Pt/C (20 wt%, 0.40 g). The mixture was purged with nitrogen then placed under an H₂ atmosphere and stirred at ambient temperature for 15 minutes (min). The tube was then sealed and the mixture heated to 180 °C for a period of 24 hours (h). After cooling to ambient temperature, the mixture was diluted with. Et₂O and filtered through Celite. The aqueous phase was extracted with Et₂O (3 x 25 mL) and the organic extracts were dried, (MgSO₄), filtered, and concentrated in vacuo to afford 1.8 g (84%) of pure 31 as a white solid; 98% D incorporation by ¹H NMR.
• [0104]
  Synthesis of 4-bromo-3,5-d₂2,6-bis(methyl-d₃)phenol (32). To a solution of 31 (1.6 g, 12.2 mmol) in AcOH (12 mL) at ambient temperature, was added 4,4-dibromo-3-methyl-pyrazol-5-one (3.1 g, 12.2 mmol, 1.0 equiv). The mixture was stirred at ambient temperature for period of 20 h then filtered through Celite and washed with cold AcOH (5 mL). The mixture was then concentrated in vacuo and the residue obtained was diluted with H₂O (15 mL) and neutralized with a saturated aqueous NaHCO₃ solution. The aqueous mixture was then extracted with hexane/Et₂O (1:1, 3 x 15 mL) and the organic extracts were dried, (MgSO₄), filtered, and concentrated in vacuo. Purification of the crude mixture on SiO₂ (10%-20% EtOAc/Hex) afforded 1.4 g (79 %) of pure 32 as a white solid;
• [0105]
  Synthesis of 2,6-di-4-hydroxy-3,5-bis(methyl-d₃)benzonitrile (14b). To a sealed vessel containing a solution of phenol 32 (1.45 g, 6.93 mmol) in DMF (15 mL), was added zinc cyanide (0.98 g, 8.32 mmol, 1.2 equiv), Pd₂(dba)₃ (0.36 g, 0.35 mmol, 5 mol%), dppf (0.19 g, 0.35 mmol, 5 mol%), polymethylhydrosiloxane (PMHS, 0.15 g, 10 wt%) and water (0.35 mL). The vessel was sealed and heated to 120 °C for a period of 18 h. After cool ing to ambient temperature, the mixture was diluted with H₂O (20 mL) and Et₂O (20 mL). The aqueous phase was further extracted with Et₂O (3 x 20 mL) and the organic extracts were dried, (MgSO₄) filtered, and concentrated in vacuo. Purification of the crude mixture on SiO₂ (10%-20% EtOAc/Hex) afforded 1.0 g (92%) of pure 14b as an off-white solid.
• [0106]
  Example 2. Synthesis of 104. Compound 104 was prepared as outlined in Scheme 5 below. Details of the synthesis follow. Pyrimidine 42 was prepared as set forth in Ludovici, DW et al., Biorg. Med. Chem. Lett. 2001, 11:2235-2239.
• [0107]
  Synthesis of 4-(5-bromo-6-cbloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-2,6-d₂ -3,5-bis(methyl-d₃)benzonitrile (43). To a sealed tube containing a solution of nitrile 41 (100 mg, 0.64 mmol, 1.1 equiv) in 1,4-dioxane (0.6 mL), was added NaH (26 mg, 0.64 mmol, 1,1 equiv). The mixture was stirred at ambient temperature for a period of 2 min, NMP (0.6 mL) was added, and the resulting mixture was stirred for an additional 10 min at ambient temperature. Pyrimidine 42 (0.20 g, 0.58 mmol, 1.0 equiv) was added to the mixture, and the vessel was sealed and heated to 155 °C for a period of 16 h. After cooling to ambient temperature, the mixture was diluted with H₂O (4 mL) and the crude product was filtered off and washed with additional water. Purification of the crude solid on SiO₂ (70% CH₂Cl₂/Hexanes) afforded 72 mg (27%) of pure 43 as a white solid.
• [0108]
  Synthesis of 4-(6-amino-5-bromo-2-(4-cyanopheaylamino)pyrimidin-4-yloxy)-2,6-dideutero-3,5-bis(trideuteromethyl)benzonitrile (104) Pyrimidine 43 (72 mg, 0.16 mmol) was dissolved in a 0.5 M solution of 1,4-dioxane (4 mL) in a sealed tube. The vessel was heated to 130 °C for a period of 24 h. After cooling to ambient temperature, the mixture was concentrated in vacuo. Purification of the crude mixture on SiO₂ (0.25%-0.5% MeOH*/ CH₂Cl₂) (*2.0 M NH₃ in MeOH) afforded 12.1 mg (17%) of pure 104 as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (d, J=8.8, 2H), 7.30 (d, J=8.8, 2H), 6.82 (br s, 1H), 5.33 (br s, 2H). HPLC (method: 150 mm C18-RP column-gradient method 5-95% ACN; Wavelength: 254 nm): retention time: 5.39 min; purity: 97.8%. MS (M+H): 443.0, 445.1.

http://www.google.com/patents/EP2212298B1?cl=en

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http://www.google.com/patents/WO2012001695A1?cl=en

Etravirine can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

Etravirine and its salts were described in US patent nos. 7,037,917. According to the patent also described a process for the preparation of etravirine which comprises treating 4-[[6-chloro-5-bromo-2[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile with ammonia.

Process for the preparation of etravirine was described in Drugs of the Future 2005, 30(5): 462-468. According to the process of etravirine which comprises treating 4- [[6-chloro-5 -bromo-2 [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 ,5 -dimethylbenzonitrile with ammonia.

Process for the preparation of 4-[[6-^'chloro-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile was described in Organic process research & development., 2010, 14(3); 657-660. According to the process of 4-[[6-chloro-2-[(4- cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile which comprises reacting 4-aminobenzonitrile in N-methylpyrrolidone with 4-[(2,6-dichloro)-4- pyrimidinyloxy]-3,5-dimethylbenzonitrile in the presence of potassium tert-butoxide. Process for the preparation of etravirine was described in Organic process research & development., 2010, 14(3); 657-660. According to the publication, crystalline solid of etravirine was obtained by dissolving crude etravirine in acetone at 50 to 55°C and was treated with activated charcoal, and isolating. The crystalline etravirine obtained by the process of the prior art is herein after designated as etravirine crystalline form I. The powdered x-ray diffractogram (PXRD) of etravirine crystalline Form I is shown in figure 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 8.7, 9.1, 13.0, 19.4, 19.6, 23.5, 26.5, 26.8 and 28.5 ± 0.2 degrees.

preparation of 4- [[6-chloro-2- [(4-cyanophenyl)amino] -4-pyrimidinyl] oxy] -3 ,5 -dimethylbenzonitrile of formula I:

which comprises reacting the 4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile of formula II:

with 4-hydroxy-3,5-dimethylbenzonitrile of formula III:

in the presence of a base to obtain a compound of formula I.

Examples

Preparation of l-(4-cvanophenyl)guanidine

Preparative example 1 :

A solution of P-aminobenzonitrile (100 gm), ethanol (500 ml), concentrated nitric acid (36 ml) and aqueous cyanamide (50%, 54 ml) was heated at reflux. The solution was maintained for 16 hours at reflux. The reaction mass was further cooled to 0°C and then added methyl tert-butyl ether (500 ml) at 0 to 5°C. The reaction mass was maintained for 5 hours at 0 to 5°C and separated solid obtained was collected by filtration to obtain 59 gm of guanidine nitrate.

Guanidine nitrate (59 gm) was dissolved in water (590 ml) and then added sodium hydroxide solution (1M, 325 ml). The separated solid obtained was filtered and dried to obtain 33 gm of l-(4-cyanophenyl)guanidine. Preparation of 4-(4,6-dihvdroxypyrimidine-2-yl-amino)benzonitrile

Preparative example 2: Diethyl malonate (30 gm) was added to l-(4-cyanophenyl)guanidine (30 gm) at room temperature. A solution of sodium (17.2 gm) in ethanol (450 ml) was added to the above reaction mass. The contents were heated to reflux and maintained for 12 hours. Distilled off the solvent completely under vacuum and then added water (500 ml). The reaction mass was stirred for 30 minutes and filtered. The solid obtained was dried to obtain 40 gm of 4-(4,6-dihydroxypyrimidine-2-yl-amino)benzonitrile.

Preparation of 4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile

Preparative example 3 :

Phosphoryl chloride (159 ml), Ν,Ν-dimethyl aniline (1 18 ml) and 4-(4,6- dihydroxypyrimidine-2-yl-amino)benzonitrile (40 gm) are added and heated to reflux. The reaction mass was maintained for 6 hours at reflux and then poured into ice water (1000 ml). The reaction mass stirred for 2 hours at room temperature and filtered. The solid obtained was dried to obtain 35 gm of 4-(4,6-dichloropyrimidine-2-yl- amino)benzonitrile.

Preparation of 4- [ [6-chloro-2- [(4-cyanophenyl)aminol -4-pyrimidinyl] oxyl -3,5- dimethylbenzonitrile

Example 1 :

4-(4,6-Dichloropyrimidine-2-yl-amino)benzonitrile (35 gm) as obtained in preparative example 3 was added to 4-hydroxy-3,5-dimethylbenzonitrile (22 gm) and then added a mixture of N-methylpyrrolidone and potassium carbonate (22 gm ) at 45°C. The reaction mass was stirred for 12 hours at 45°C and then added water (1000 ml). The reaction mass was cooled to 25°C and stirred for 2 hours at 25°C, filtered. The wet solid obtained was dissolved in acetone (140 ml) under stirring and the separated solid was filtered, and then dried at 50°C to obtain 24 gm of 4-[[6-chloro-2-[(4- cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile.

Preparation of 4-ff6-amino-2-[(4-cvanophenyl)aminol-4-pyrimidinylloxyl-3,5- dimethylbenzonitrile

Example 2: 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrin idinyl]oxy]-3,5-dimethyl- benzonitrile (24 gm) was dissolved in aqueous ammonia (240 ml) and 1,4-dioxane (274 ml) at room temperature. The contents were heated to 120°C and maintained for 12 hours at 120°C. To the reaction mass was added water (360 ml) and the reaction mass was slowly cooled to 50 to 60°C. The reaction mass was further cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The wet solid obtained was dissolved in toluene (150 ml) under stirring. The separated solid was filtered and dried at 50°C to obtain 10 gm of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5- dimethylbenzonitrile.

Preparation of etravirine

Example 3 :

4- [ [6-amino-2- [(4-cyanophenyl)amino] -4-pyrimidinyl]oxy] -3 ,5 -dimethyl – benzonitrile (10 gm) was dissolved in dichloromethane (100 ml) at 0 to 5°C and then added bromine solution (4.7 gm in 50 ml of dichloromethane). The reaction mass was stirred for 4 hours at 0 to 5°C and then added water (100 ml). The pH of the reaction mass was adjusted to 9 to 10 with sodium hydroxide solution (4N, 10 ml). Sodium metabisulphite solution (0.5 gm in 2 ml of water) was added to the reaction mass and pH of the reaction mass was maintained between 7.5 to 8.5 with sodium hydroxide solution (4N, 10 ml). The separated solid was filtered and dried at 50 to 55°C to obtain crude etravirine.

Crude etravirine obtained above was dissolved in acetone (200 ml) at 50 to 55°C and then treated with activated charcoal (1.5 gm). The reaction mass was filtered through celite and the filtrate was distilled off acetone completely to obtain residue. The residue was cooled to 5 to 10°C and filtered. The solid obtained was dried at 60°C to obtain 5.2 gm of pure etravirine.

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http://www.google.com/patents/WO2013159286A1?cl=en

Etravirine (Etravirine, -165335, TMC-125) under the trade name British Terai (Intelence), chemical name 4 – [6 - amino-5 - bromo-2 - (4 - cyanide Diaminodiphenol) pyrimidine-4 - oxy] -3, 5 – dimethyl-benzonitrile, the following structural formula:

Etravirine is a Johnson & Johnson subsidiary Tibotec has developed a next-generation non-nucleoside reverse transcriptase inhibitors (NN-RTI), with anti-HIV-infection. Clinical studies have shown that patients with the first use of NN-RTI drug therapy, etravirine showed strong antiviral activity; patients previously used antiviral drugs, this product also has the characteristics of rapid and long-lasting effect. In addition, HIV-1-infected patients with oral ribavirin according to the song has a good distribution of drug metabolism and is well tolerated. January 18, 2008 the FDA approved Tibotec Therapeutics’s priority review program by etravirine tablets combined with other anti-HIV drugs for the treatment of other antiretroviral drugs ineffective in adult HIV-infected patients.

Currently on the synthesis of etravirine have the following main categories:

One, WO0027825A1 etravirine first disclosed the following synthetic route:

The above line is not easy to get raw materials, and the last step amination exist for a long time, conversion rate of defects, is not suitable for industrial production.

.. Second, Bioorg Med Chem Lett, 2001,11 (17) ,2235-9 etravirine reported the following methods:

This method not only synthetic route length (total of 5-step reaction), starting 4 – cyanophenyl guanidine expensive and difficult to obtain, and the condensation reaction selectivity in step 4, ammonolysis step 5 incomplete conversion, resulting in The total yield of less than 10%, is not suitable for industrial production.

Three, WO2010150279A2 reported the following synthetic methods:

This method, although only four steps, each step is also more readily available raw materials, the reaction rate is improved amination, etravirine total crude yield of 40%. However, with the second reaction step up to nearly 12% of the byproduct [i.e. a compound of formula (3)], can be purified after the amination reaction of the next step, the compound (3) with a compound of formula (2) and the same formula isomers, very similar structures and physicochemical properties, and therefore, the formula (2) the difficulty of purification of the compounds higher.

This method yields a condensation reaction of step 4 is only 48% ammoniated reaction yield of step 5 is also only 44%, the yield is low this two-step reaction, the product purity is not high, leading to the final step of bromine on behalf of the reaction yield is also low, as low as 43%, only 9% of the total yield of these three steps, not suitable for industrial production. Therefore, an urgent need to develop a simple, low cost of production etravirine preparation.

Preparation methods according to Qu Wei Lin

Qu Wei Lin preparation method according to the present invention is shown in the formula (V), preferably based preparation steps according to Qu Wei Lin intermediates of the present invention (il), (i2) and (ii), the step ( ii) to obtain a compound of formula IV, the following bromination step further:

(Iii) at room temperature (eg 25 – 28 ° C) in an inert solvent, in the presence of bromide reagents, step (ii) of the resulting compound of formula IV).

In another preferred embodiment, the reagent or the solvent in step (iii) of the bromination reaction can be used by those of ordinary skill in the reagents or solvents used, preferably bromination reagent bromosuccinimide (NBS ) or Br _2, the inert solvent used for the bromination reaction solvent, preferably acetone.

Compounds of formula II is calculated by the method according to Qu Wei obtained a 50% yield of the forest of the present invention, preferably 55%; better to 60%; optimally 65%. The main advantages of the present invention are:

1 provides a method for preparing formula IV as shown by curved intermediate Wei Lin, the method using the same or substantially the same solvent system, can be performed continuously multistep reaction without separation and purification between steps, the operation is very simple, compound The yield is much higher than existing methods, and high-purity compounds obtained can be directly used in the preparation according to Qu Wei Lin.

2 provides a method for preparing formula V according to Qu Wei Lin, the method based on production method according to Qu Wei Lin intermediates in the present invention provides a significantly improved yield according to Qu Wei Lin, thereby significantly reducing its production cost, high value industrial applications. Below with reference to specific embodiments, further illustrate the present invention. It should be understood that these embodiments are merely illustrative of the invention and are not intended to limit the scope of the invention. Example experimental method does not indicate the specific conditions of the following examples, usually in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. Example 1

4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (1 1.8g, 0.080mol) was dissolved in lOOmL N-methylpyrrole embankment ketone (ΝΜΡ) was then added K ₂ CO ₃ (ll Og, 0.080mol.). Warmed to 90 ° C, incubated for 2 hours.

The above reaction mixture was cooled to 25 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile (21.3g, 0.081mol), incubated for 3 hours. Heated to 50 ° C, and then continue to heat for 10 hours. Filtered and the solid rinsed two times with 30mL NMP.

The combined filtrates were saturated with ammonia gas was heated to 120 ° C, the reaction was kept for 10 hours.

Thereto was added water 500mL. Crystallization, filtration, the filter cake was rinsed with 50 mL of water.

The obtained wet cake was added to a mixed solvent of 90 mL of acetone and 15 mL of water was heated at reflux for 30 minutes. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 25.0g yield of 87.8%.

HPLC purity 98.7%. MS (ESI) m / z: (M + H) 357.4, (M + Na) 379.4. Example 2

4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (6.0g, 0.041mol) was dissolved in 75mL N, N-dimethylformamide (DMF) was then added Na ₂ CO ₃ (5.2g, 0.049mol). Heated to 80 ° C, incubated for 2 hours.

The above reaction mixture was cooled to 25 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile

(13.0g, 0.049mol), incubated for 4 hours. Heated to 55 ° C, and then continue to heat for 8 hours. Filtered and the solid rinsed two times with 20mL DMF.

The combined filtrate was slowly added 25% aqueous ammonia 30ml. Heated to 110 ° C, the reaction was kept for 15 hours. Water was added to the system 300mL. Crystallization, filtration, the filter cake was rinsed with 30 mL of water.

The obtained wet cake was added into a 50 mL of acetone was heated at reflux for 1 hour. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 12.3 g yield of 84.3%.

HPLC purity 98.2%. An example of mass spectral data consistent with the implementation. Example 3

4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (6.0g, 0.041mol) was dissolved in 60mL of tetrahydrofuran (THF), and then sodium acetate (13.5 g, 0.16mol). Warmed to reflux, the reaction was kept for 3 hours.

The above reaction mixture was cooled to 30 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile (21.6g, 0.082mol), incubated for 3 hours. Heated to 60 ° C, and then continue to heat for 12 hours.

Then, the reaction mixture up one step, the ammonia gas until saturation. Heated to 120 ° C, the reaction was kept for 12 hours.

Water was added to the system 300mL. Crystallization, filtration, the filter cake was rinsed with 30 mL of water.

The obtained wet cake was added to a mixed solvent of 40 mL of acetone and 20 mL of water was heated at reflux for 30 minutes. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 11.3 g yield of 77.2%.

HPLC purity 97.7%. An example of mass spectral data consistent with the implementation. Example 4

4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile A mixture of 3,5 – dimethyl – 4 – hydroxybenzonitrile (6.0g, 0.041mol) was dissolved in 60mLl, 4 – dioxane, and then added sodium ethoxide (2.8g, 0.041mol). Heated to 75 ° C, the reaction was kept for 1 hour.

The above reaction mixture was cooled to 20 ° C, the solution of 4 – (4,6 – dichloro-pyrimidin-2 – amino) benzonitrile

(Ll. Og, 0.042mol), incubated for 3 hours. Warmed to 45 ° C, and then incubation was continued for 10 hours.

Then, a step up of the reaction mixture was slowly added 25% aqueous ammonia 30ml. Warming up to

120 ° C, the reaction was kept for 15 hours.

Water was added to the system 300mL. Crystallization, filtration.

The obtained wet cake was added to a mixed solvent of acetone and 15mL 35mL of water, heated at reflux for 30 minutes. Cooling to room temperature, filtered and dried in vacuo to give 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile 11.8g The yield was 80.8%.

HPLC purity 98.1%. An example of mass spectral data consistent with the implementation. Example 5

Preparation according to Qu Wei Lin

Obtained in Example 1 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile (35.6g, O.lOmol) was dissolved in 300ml of acetone at room temperature, was added portionwise N-bromosuccinimide (NBS) (17.8g, O.lOmol). After the addition was complete, stirring was continued at room temperature for 2 hours.

Then, stirring was added 0.5M sodium hydroxide solution 140mL, stirring was continued for 30 minutes, filtered, and the filter cake was dried under vacuum, the crude product may, in accordance etravirine.

The crude product is recrystallized from acetone, may, in accordance etravirine 35.0g, yield 80.4%.

HPLC purity 99.3%. MS (ESI) m / z: (M + H) 436.3, (M + Na) 458.3. Comparative

Different solvent systems Preparation of 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethylbenzonitrile

3,5 – dimethyl-4 – hydroxybenzonitrile as starting material a compound of formula II, the preparation of compounds of formula via a two-step IV, the preparation methods, see WO2012001695 Example specification of a page 11-12 and Example 2, calculated by the compound of formula II, in the present Comparative Example 4 – [[6 - amino-2 - [(4 - cyanophenyl) amino] -4 – pyrimidinyl] oxy] -3,5 – dimethyl benzene carbonitrile yield of approximately 21%. Conclusion:

1 The present invention is a method for preparing the compound of formula IV, although the reaction of a compound prepared by a plurality of formula IV, however, use the same or substantially the same throughout the solvent system, multi-step continuous reaction without separation and purification between steps, operation is very simple, and the resulting compound of formula IV is very high yield (yield not less than 77%), far exceeding the prior art, 21% yield and high purity, used directly without purification step Preparation according to Qu Wei Lin.

(2) Preparation method according to Qu Wei Lin of the present invention is a system of law based on the compound of formula IV, is a compound of formula IV further bromination. The method significantly improves the yield according to Qu Wei Lin: A compound of formula II according to the calculation of the starting material, the method according to the present invention, Qu Wei Lin yield up to 60-70%, much higher than the existing technology By Qu Wei Lin in yield, as Bioorg. Med. Chem. Lett., 2001, 11 (17), revealed 2235-9 method through a three-step system may, in accordance yield about Qu Wei Lin 14%, WO2012001695A1 disclosed method, three-step total yield of only 9%, thereby significantly reducing the cost of production, high industrial value. All documents mentioned in the present invention are incorporated by reference as if each reference was individually incorporated by reference, as cited in the present application. It should also be understood that, after reading the foregoing teachings of the present invention, those skilled in the art that various modifications of the present invention or modifications, and these equivalents falling as defined by the appended claims scope of claims of the present application.

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Organic process research & development., 2010, 14(3); 657-660

http://pubs.acs.org/doi/abs/10.1021/op9003289

Etravirine (1) is a novel diarylpyrimidine non-nucleoside reverse transcriptase inhibitor and has recently been approved by the U.S. Federal Drug Administsration for the treatment of AIDS. Its reported synthesis is fraught with many difficulties, the foremost being the poor yield and long reaction time required at the aminolysis stage. We attributed this problem to the presence of a bromide group adjacent to the reaction site of the advance intermediate (6). In order to circumvent this issue, we proposed to defer the installation of the bromide group at a later stage, preferably after aminolysis. Indeed, this protocol has worked well. However, in the process of installation of diarylether and diarylamine functionalities at appropriate positions, we had to reverse the sequence of displacement reactions of the dichloride intermediate (9) with 3,5-dimethyl-4-hydroxybenzonitrile (5) and 4-aminobenzonitrile (3). The classical bromination led to the completion of etravirine synthesis.

References

NEW PATENT

WO-2014068588

Biophore India Pharmaceuticals Pvt Ltd

Process for preparing etravirine by reacting 4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile with 4-hydroxy-3,5-dimethyl benzonitrile in presence of a base such as N-methylpyrrolidone. Also claims the preparation of intermediates involved in synthesis of etravirine. Useful for treating HIV infection.