Poziotinib for the treatment of Adenocarcinoma of Lung Stage IIIB or Adenocarcinoma of Lung Stage IV

Poziotinib

l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazol in-6- yloxy)piperidin-l-yl)prop-2-en-l-one

: 1 – [4 – [[4 – [(3, 4 - dichloro - 2 - phenyl) amino] – 7 – methoxy – 6 – base] quinazoline oxygen radicals] – 1 – piperidine base] – 2 – acrylic – 1 – ketone

UNII-OEI6OOU6IK;

cas 1092364-38-9

HM781-36B

NOV120101

Erbb2 tyrosine kinase receptor inhibitor; EGFR family tyrosine kinase receptor inhibitor

Non-small-cell lung cancer; Stomach tumor

for the treatment of Adenocarcinoma of Lung Stage IIIB or Adenocarcinoma of Lung Stage IV

http://www.centerwatch.com/clinical-trials/listings/external-studydetails.aspx?StudyID=NCT01819428

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation…….http://clinicaltrials.gov/show/NCT01819428

KR 1013319

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WO2013051883

http://www.google.com/patents/WO2013051883A2?cl=en

1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidin-l-yl)-prop-2-en-l-one hydrochloride of formula (I) below is an important drug having antiproliferative activities such as anti-tumor activity, which can be used for selectively and effectively treating drug resistance caused by tyrosine kinase mutation. Its free base form, i.e., l-(4-(4-(3,4-dichloro-2- fluoropheny lamino)-7-methoxyquinazolin-6-y loxy)piperidin- 1 -y l)-prop-2-en- 1 – one having formula (II) below is identified as CAS Registry Number 1092364-38-

9.

The compound of formula (II) may be prepared by, e.g., the method disclosed in Korean Patent No. 1013319, the reaction mechanism thereof being shown in Reaction Scheme 1 below. The compound of formula (II) prepared according to Reaction Scheme 1 may then be reacted with hydrochloric acid to produce the compound of formula (I).

wherein R is halogen.

formula (I):

In accordance with another aspect of the present invention, there are provided N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride of formula (III), tert-butyl 4-(4-(3,4- dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l- carboxylate of formula (IV) and 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol of formula (V), which can be used as intermediates for preparing the compound of formula (I).

Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenyIamino)-7- methoxyquinazolin-6-yl acetate the compound of formula (VI))

7-methoxy-4-oxo-3,4-dihydroquinazolin-yl acetate (100 g) was added to toluene (850 ml) and NN-diisopropylethylamine (82.5 ml). Phosphorusoxy chloride (100 ml) was added thereto over 20 minutes at 75°C, followed by stirring for 3 hours. Toluene (450 ml) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. Upon completion of the reaction, the resulting mixture was cooled to 25°C. The solid thus obtained was filtered under a reduced pressure and washed with toluene (400 ml). Isopropanol (1,000 ml) was added to the solid, which was then stirred for 2 hours. The resulting solid was filtered and washed with isopropanol (400 ml). The solid was dried at 40°C in an oven to produce the compound of formula (VI) (143 g, yield: 83%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69- 7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

Example 2: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol (the com ound of formula (V))

4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate (100 g) was admixed with methanol (1,000 ml). The mixture was cooled to 10 to 15°C, added with an ammonia solution (460 g), and stirred for 3 hours at 25°C. The solid thus obtained was filtered and washed with a mixed solvent of methanol (200 ml) and water (200 ml). The resulting solid was dried at 40°C in an oven to produce the compound of formula (V) (74 g, yield: 83%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 6 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s, 1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

Example 3: Preparation of /er/-but l-4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l-carboxylate (the compound of formu

4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (60 g) was admixed with N-dimethylformamide (360 ml) under stirring, followed by addition of tert-butyl 4-(tosyloxy)piperidin-l-carboxylate (120 g) and potassium carbonate (72 g) to the mixture. The reaction temperature was raised to 70°C, and the mixture was stirred for 14 hours. The temperature of the resulting solution was cooled to 25°C, and water (480 ml) was slowly added thereto. The solid thus obtained was filtered and dried. The solid was dissolved in a mixed solvent (600 ml) of dichloromethane and methanol. Active carbon (6 g) was then added thereto, followed by stirring for 30 minutes. The resulting mixture was filtered through a Celite pad, distilled under a reduced pressure, added with acetone (300 ml), and stirred for 2 hours. The resulting solid was filtered and washed with acetone (100 ml). The solid was dried at 40°C in an oven to produce the compound of formula (IV) (75 g, yield: 83%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 6 8.69 (s, 1H), 8.47 (t, 1H), 7.34- 7.29 (m, 2H), 7.20 (s, 1H), 4.63-4.60 (m, 1H), 3.82 (s, 3H), 3.83-3.76 (m, 2H), 3.37-3.29 (m, 2H), 1.99-1.96 (m, 2H), 1.90-1.84 (m, 2H), 1.48 (s, 9H).

Example 4: Preparation of N-(3,4-dichIoro-2-fluorophenyi)-7- methoxy-6-(piperidin-4-yloxy)quinazoIin-4-amine dihydrochloride (the compound of formula (III))

Acetone (740 ml) was added to ter/-butyl 4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l-carboxylate (75 g), which was then stirred. The mixture was added with hydrochloric acid (145 ml) for 10 minutes and stirred for 5 hours. Upon completion of the reaction, the resulting mixture was filtered, and the solid thus obtained was washed with acetone (73 ml). The solid was dried at 30°C in an oven to produce the compound of formula (III) (71 g, yield: 99%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 512.95 (bs, 1H), 9.42 (bs, 1H), 9.18 (bs, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 7.69-7.56 (m, 2H), 7.45 (s, 1H), 5.11- 5.08 (m, 1H), 4.03 (s, 3H), 3.29-3.20 (m, 4H), 2.33-2.30 (m, 2H), 1.96-1.93 (m, 2H).

Example 5: Preparation of l-(4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazoIin-6-yloxy)piperidin-l-yl)prop-2-en- 1-one (the compound of formula II))

N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride (100 g) and sodium hydrogen carbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0°C with iced water. Acryloyol chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0°C for 30 minutes. Upon completion of the reaction, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidin-l-yl)prop-2-en-l-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), added with ethyl acetate (1.2 L), and stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried at 40°C in an oven to produce the compound of formula (II) (55 g, yield: 76%, total yield = 57%).

Ή-NMR (CDC1₃, 300 MHz, ppm) 68.68(s, 1H), 8.39(t, 3H), 7.3 l(m, 3H), 6.61(m, 1H), 6.29(m, 1H), 5.72(m, 1H), 4.75(m, 1H), 4.02(s, 3H), 3.89(m, 2H), 3.60(m, 2H), 1.86(m, 4H). Example 6: Preparation of l-(4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yIoxy)piperidin-l-yl)prop-2-en- 1-one hydrochloride (the com ound of formula (I))

1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidine-l-yl)prop-2-en-l-one (150 g) was added to methanol (700 ml). Hydrochloric acid (38.2 ml) diluted with methanol (300 ml) was added thereto, followed by stirring for 24 hours. The solid thus obtained was filtered and washed with acetone (100 ml). The resulting solid was dried at 40°C in an oven for 24 hours to produce the compound of formula (I) (131 g, yield: 81%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 512.31 (bs, 1H), 8.83 (s, 1H), 8.67 (s, 1H), 7.64-7.55 (m, 2H), 7.39 (s, 1H), 6.87-6.78 (m, 1H), 6.12-6.06 (m, 1H), 5.68-5.64 (m, IH), 5.07-5.01 (m, IH), 4.06-3.88 (m, 5H), 3.51 (t, IH), 3.32 (t, IH), 2.10 (t, IH), 1.60 (t, IH).

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WO-2014116070

http://www.sumobrain.com/patents/wipo/Method-preparing-1-4-34/WO2014116070.html

Process for preparing poziotinib – comprising the reaction of a 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol compound with an N-acyl piperidine derivative.

A process for preparing poziotinib comprising the reaction of a 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol compound with an N-acyl piperidine derivative in the presence of an inert polar protic solvent (eg N,N-dimethylformamide), and a base (eg sodium bicarbonate) is claimed. Also claimed are processes for preparing intermediates of poziotinib. Poziotinib is known to be an inhibitor of EGFR family, and Erbb2 tyrosine kinase receptors, useful for the treatment of stomach tumor and non-small-cell lung cancer.  Novel method for preparing poziotinib. Follows on from WO2013051883 claiming method for preparing poziotinib and its intermediates. Hanmi, in collaboration with National Oncoventure, is developing poziotinib for the oral treatment of non small cell lung cancer and gastric cancer. As of August 2014, the drug is in phase 2 trials for both indications.

Compound of formula (II) is (I) and compound of formula (I) (poziotinib) is (II) (claim 1, page 13).The synthesis of (II) via intermediate (I) is described (example 1, pages 8-11).

Preparation Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)- 7-methoxyquinazolin-6-ol, the compound of formula (II)

Step (i): Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-yl acetate, the compound of formula (V)

7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (100 g) was added to toluene (850 mL) and NN-diisopropylethylamine (82.5 mL). Phosphorus oxychloride (100 mL) was added thereto over 20 minutes at 75°C, followed by stirring for 3 hours. Toluene (450 mL) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. Upon completion of the reaction, the resulting mixture was cooled to 25°C, and the solid thus obtained was filtered under a reduced pressure and washed with toluene (400 mL). Isopropanol (1,000 mL) was added to the solid, and the resulting mixture was stirred for 2 hours. The solid thus obtained was filtered and washed with isopropanol (400 mL), and then was dried at 40°C in an oven to obtain the target compound (143 g, yield: 83%).

1H-NMR (DMSO-d ₆ , 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69- 7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

Step (ii): Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol, the compound of formula (II)

4-(3,4-dichloro-2-fluorophenyIamino)-7-methoxyquinazolin-6-y l acetate (100 g) prepared in step (i) was admixed with methanol (1,000 mL). The mixture was cooled to 10 to 1 °C, added with an ammonia solution (460 g), and stirred for 3 hours at 25°C. The solid thus obtained was filtered and washed with a mixed solvent of methanol (200 mL) and water (200 mL). The resulting solid was dried at 40°C in an oven to obtain the target compound (74 g, yield: 83%). 1H-NMR (DMSO-d ₆ , 300 MHz, ppm) 5 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s,

1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

Example 1: Preparation of l-(4-(4-(3,4-dichIoro-2-fluorophenylamino)-7- methoxyquinazolin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I) Step (1-1 : Preparation of l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate. the compound of formula (HI)

Piperidin-4-yl 4-methylbenzenesulfonate hydrochloride (200 g, 685 mmol), tetrahydrofuran (THF, 1.6 L) and NaHCO ₃ (172 g, 2047 mmol) were added to water (2 L), and the mixture was cooled to 0°C. A solution prepared by adding acryloyl chloride (56 mL, 519 mmol) to THF (0.4 L) was added thereto over 30 minutes, followed by stirring for 1 hour. Upon completion of the reaction, MeOH (0.4 L) was added thereto for quenching. The solution was extracted with ethyl ester (2 L), and washed with water (2 L). The organic layer was separated, distilled under a reduced pressure, and the residue thus obtained was recrystallized from dichloromethane-hexane to obtain the target compound (174 g, yield: 82%). 1H-NMR (300 MHz, DMSO-d ₆ ) δ 7.82 (d, 2H), 7.48 (d, 2H), 6.80-6.71 (m,

1H), 6.10-6.03 (m, 1H), 5.67-5.62 (m, 1H), 4.76-4.71 (m, 1H), 3.70-3.68 (m, 2H), 3.43-3.31 (m, 2H), 2.42 (s, 3H), 1.73 (m, 2H), 1.52 (m, 2H).

Step (1-2): Preparation of l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I)

4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-o l (12 g, 34 mmol) prepared in Preparation Example 1, l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), K ₂ CO ₃ (9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 mL) were admixed. The reaction temperature was raised to 70°C, and the mixture was stirred for 24 hours. Upon completion of the reaction, the mixture was cooled down to room temperature, extracted with ethyl ester (300 mL), and then washed with water (300 mL). The organic layer was separated, and distilled under a reduced pressure. The residue thus obtained was solidified by adding ethyl ester, filtered, and dried to obtain the target compound (12.8 g, yield: 77%). 1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H),

7.64-7.56 (m, 2H), 7.24 (s, 1H), 6.89-6.80 (m, 1H), 6.15-6.08 (m, 1H), 5.70-5.66 (m, 1H), 4.78 (m, 1H), 3.94 (s, 3H), 3.87 (m, 2H), 3.48 (m, 2H), 2.03 (m, 2H), 1.70 (m, 1H). Example 2: Preparation of l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazoIin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I)

SEE

http://www.yuaigongwu.com/thread-8891-1-1.html