WO2019186429A1 - A process for the preparation of bosutinib - Google Patents

A process for the preparation of bosutinib Download PDF

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Publication number
WO2019186429A1
WO2019186429A1 PCT/IB2019/052506 IB2019052506W WO2019186429A1 WO 2019186429 A1 WO2019186429 A1 WO 2019186429A1 IB 2019052506 W IB2019052506 W IB 2019052506W WO 2019186429 A1 WO2019186429 A1 WO 2019186429A1
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Prior art keywords
dichloro
methoxyphenyl
cyano
acetamide
reaction mixture
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PCT/IB2019/052506
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French (fr)
Inventor
Sourav HANDIQUE
Ashok Kumar
Narender GOTTIPAMULA
Amit Kumar Jain
Mohan Prasad
Kaptan Singh
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Sun Pharmaceutical Industries Limited
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Publication of WO2019186429A1 publication Critical patent/WO2019186429A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Definitions

  • the present invention provides an improved process for the preparation of bosutinib and its intermediate 2-cyano-/V-(2, 4-dichloro-5-methoxyphenyl)acetamide.
  • Bosutinib is chemically designated as 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, as depicted by Formula I.
  • the present invention provides an efficient and commercially useful process for the preparation of bosutinib via 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide intermediate.
  • the present invention provides an improved process for the preparation of bosutinib and its intermediate 2-cyano-/V-(2, 4-dichloro-5-methoxyphenyl) acetamide. Detailed Description of the Invention
  • treating includes adding, dissolving, suspending, slurring, stirring, reacting, heating, cooling, condensing, or combinations thereof.
  • a first aspect of the present invention provides a process for the preparation of 2- cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide of Formula II:
  • the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide of Formula II is further converted to bosutinib.
  • a second aspect of the present invention provides a process for the preparation of 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide of Formula II:
  • step ii) reacting the reaction mixture of step i) with 2,4-dichloro-5-methoxyaniline to obtain 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide.
  • the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide of Formula II is further converted to bosutinib.
  • 2,4-dichloro-5-methoxyaniline can be prepared by following the process described herein or the process disclosed in Synthesis 2015, 47, 3133-3138.
  • Cyanoacetic acid is treated with oxalyl chloride in the presence of a solvent at a temperature of about 0°C to about lO°C.
  • the solvent is selected from tetrahydrofuran, dimethylformamide,
  • the solvent is preferably selected from ethyl acetate and dimethylformamide or mixture thereof.
  • the solvent is most preferably a mixture of ethyl acetate and catalytic amount of dimethylformamide.
  • the reaction of cyanoacetic acid and oxalyl chloride is carried out at a temperature of about 0°C to about lO°C, for example, at about 0°C to about 6°C.
  • the reaction of cyanoacetic acid and oxalyl chloride is carried out for about 90 minutes to about 150 minutes, for example, for about 120 minutes to about 130 minutes.
  • reaction mixture obtained after treating cyanoacetic acid and oxalyl chloride is reacted with 2,4-dichloro-5-methoxyaniline under stirring.
  • the reaction with 2,4-dichloro-5-methoxyaniline is carried out at a temperature of about 20°C to about 70°C, for example, at about 23°C to about 65°C.
  • the reaction mixture is stirred for about 1 hour to about 4 hours, for example, for about 2 hours.
  • 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide can be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization, and dried under reduced pressure, by air drying, or vacuum tray drying.
  • 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide can be converted to bosutinib by following the process disclosed in U.S. Patent No. 7,297,795 or Journal of Medicinal Chemistry , 2001, 44 (23), 3965-3977.
  • the present invention provides 2-cyano-N-(2,4-dichloro-5- methoxyphenyl)acetamide with chromatographic (HPLC) purity of more than 99.6%. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
  • Step-l Preparation of 2.4-dichloro acetamidophenol:
  • Step-2 Preparation of 2.4-dichloro-5-methoxy acetamidophenol:
  • Potassium carbonate (285 g) was added to deionized water (750 mL) and mixture was stirred at 20°C to 25°C for about 10 minutes.
  • 2,4-dichloro acetamidophenol (entire batch obtained from Step-l) was charged into acetone (450 mL) and stirred at 20°C to 25°C to get clear solution.
  • Dimethyl sulphate (260 g) was added to the obtained solution at 20°C to 25 °C drop wise over a period of about 60 minutes.
  • the reaction mixture was stirred at 20°C to 25 °C for about 3 hours.
  • Deionized water (1000 mL) was added to the reaction mixture at 20°C to 25 °C slowly over a period of about 30 minutes.
  • the reaction mixture was stirred at 20°C to 25 °C for 2 hours.
  • the obtained solid was filtered and washed with deionized water (1000 mL).
  • the wet solid was dried at 40°C to 45°C in air oven for approximately 12 hours to obtain the title product.
  • Step-3 Preparation of 2.4-dichloro-5-methoxy aniline:
  • Deionized water 200 mL was added to the reaction mixture at 20°C to 30°C followed by stirring for 1 hour.
  • the product obtained was filtered and washed with ethyl acetate (50 mL) followed by deionized water (500 mL) and ethyl acetate (200 mL) respectively.
  • the wet product was dried in air oven to provide the title product.
  • Deionized water 100 mL was added to the reaction mixture at 20°C to 3 l°C followed by stirring for 45 minutes.
  • the product obtained was filtered and washed with deionized water (250 mL) followed by ethyl acetate (50 mL). The wet product was dried under vacuum to provide the title product.

Abstract

The present invention provides an improved process for the preparation of bosutinib and its intermediate 2-cyano-N-(2, 4-dichloro-5-methoxyphenyl)acetamide.

Description

A PROCESS FOR THE PREPARATION OF BOSUTINIB
Field of the Invention
The present invention provides an improved process for the preparation of bosutinib and its intermediate 2-cyano-/V-(2, 4-dichloro-5-methoxyphenyl)acetamide.
Background of the Invention
Bosutinib is chemically designated as 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, as depicted by Formula I.
Figure imgf000002_0001
Formula I
U.S. Patent No. 6,002,008 and RE 42,376 disclose substituted 3-cyanoquinolines derivatives and preparation thereof.
U.S. Patent No. 7,297,795; Chinese Publication No. 102952037, and Indian Patent Application No. 3287/MUM/2014 disclose processes for the preparation of bosutinib and its intermediate 2-cyano-/V-(2,4-dichloro-5 -methoxyphenyl)acetamide .
There is a need for an alternate and improved process for the preparation of bosutinib and its intermediate 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide. The present invention provides an efficient and commercially useful process for the preparation of bosutinib via 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide intermediate.
Summary of the Invention
The present invention provides an improved process for the preparation of bosutinib and its intermediate 2-cyano-/V-(2, 4-dichloro-5-methoxyphenyl) acetamide. Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term“about,” as used herein, refers to any value which lies within the range defined by a variation of up to ± 10% of the value .
The term“treating,” as used herein, includes adding, dissolving, suspending, slurring, stirring, reacting, heating, cooling, condensing, or combinations thereof.
A first aspect of the present invention provides a process for the preparation of 2- cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide of Formula II:
Figure imgf000003_0001
Formula II
comprising reacting cyanoacetic acid with 2,4-dichloro-5-methoxyaniline in the presence of oxalyl chloride.
In an embodiment of this aspect, the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide of Formula II is further converted to bosutinib.
A second aspect of the present invention provides a process for the preparation of 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide of Formula II:
Figure imgf000003_0002
Formula II
comprising
i) treating cyanoacetic acid with oxalyl chloride;
ii) reacting the reaction mixture of step i) with 2,4-dichloro-5-methoxyaniline to obtain 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide.
In an embodiment of this aspect, the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide of Formula II is further converted to bosutinib. 2,4-dichloro-5-methoxyaniline can be prepared by following the process described herein or the process disclosed in Synthesis 2015, 47, 3133-3138.
Cyanoacetic acid is treated with oxalyl chloride in the presence of a solvent at a temperature of about 0°C to about lO°C.
The solvent is selected from tetrahydrofuran, dimethylformamide,
dichloromethane, ethyl acetate, diethyl ether, diisopropyl ether, methyl ter-butyl ether, 1,4- dioxane or mixture thereof. The solvent is preferably selected from ethyl acetate and dimethylformamide or mixture thereof. The solvent is most preferably a mixture of ethyl acetate and catalytic amount of dimethylformamide.
The reaction of cyanoacetic acid and oxalyl chloride is carried out at a temperature of about 0°C to about lO°C, for example, at about 0°C to about 6°C.
The reaction of cyanoacetic acid and oxalyl chloride is carried out for about 90 minutes to about 150 minutes, for example, for about 120 minutes to about 130 minutes.
The reaction mixture obtained after treating cyanoacetic acid and oxalyl chloride is reacted with 2,4-dichloro-5-methoxyaniline under stirring.
The reaction with 2,4-dichloro-5-methoxyaniline is carried out at a temperature of about 20°C to about 70°C, for example, at about 23°C to about 65°C.
The reaction mixture is stirred for about 1 hour to about 4 hours, for example, for about 2 hours.
2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide obtained is isolated.
2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide can be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization, and dried under reduced pressure, by air drying, or vacuum tray drying.
2-cyano-/V-(2,4-dichloro-5-methoxyphenyl)acetamide can be converted to bosutinib by following the process disclosed in U.S. Patent No. 7,297,795 or Journal of Medicinal Chemistry , 2001, 44 (23), 3965-3977.
The present invention provides 2-cyano-N-(2,4-dichloro-5- methoxyphenyl)acetamide with chromatographic (HPLC) purity of more than 99.6%. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
The following example is for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.
Method:
Chromatographic purity of the sample was determined by HPLC instrument using “Agilent HPLC with Non PDA detector and HPLC column Kromasil® C18 (150 x 4.6) mm, 5 pm.
The following example is for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES:
Example 1 : Preparation of 2-CYano-N-(2.4-dichloro-5-methoxYphenyl)acetamide
Step-l : Preparation of 2.4-dichloro acetamidophenol:
Acetic acid (600 mL) and 3 -amino phenol (100 g) were charged into a flask at 20°C to 25 °C followed by addition of ammonium acetate (106 g) to obtain a reaction mixture. The reaction mixture was refluxed and stirred for 3 hours sulfuryl chloride (310 g) was added to the reaction mixture at 20°C to 25 °C slowly over a period of about 60 minutes and stirred at 20°C to 25°C for 3 hours. Deionized water (1000 mL) was added to the reaction mixture at 20°C to 25 °C drop wise over a period of about 30 minutes. The reaction mixture was stirred at 20°C to 25 °C for 2 hours. The solid was filtered and washed with deionized water (2500 mL). The wet solid was used as such in the next step.
Step-2: Preparation of 2.4-dichloro-5-methoxy acetamidophenol:
Potassium carbonate (285 g) was added to deionized water (750 mL) and mixture was stirred at 20°C to 25°C for about 10 minutes. 2,4-dichloro acetamidophenol (entire batch obtained from Step-l) was charged into acetone (450 mL) and stirred at 20°C to 25°C to get clear solution. Dimethyl sulphate (260 g) was added to the obtained solution at 20°C to 25 °C drop wise over a period of about 60 minutes. The reaction mixture was stirred at 20°C to 25 °C for about 3 hours. Deionized water (1000 mL) was added to the reaction mixture at 20°C to 25 °C slowly over a period of about 30 minutes. The reaction mixture was stirred at 20°C to 25 °C for 2 hours. The obtained solid was filtered and washed with deionized water (1000 mL). The wet solid was dried at 40°C to 45°C in air oven for approximately 12 hours to obtain the title product.
Yield: 145 g
Step-3: Preparation of 2.4-dichloro-5-methoxy aniline:
Methanolic hydrochloric acid (400 mL) was added into 2,4-dichloro-5-methoxy acetamidophenol (100 g, obtained from Step-2) at 25°C. The reaction mixture was heated to 50°C to 55°C and stirred for 3 hours. The reaction mixture was cooled to 25 °C and acetone (200 mL) was added. The reaction mixture was further cooled to -l0°C and stirred at -l0°C to 0°C for 2 hours. The solid obtained was filtered and washed with pre-cooled (0°C) acetone (100 mL). The wet solid was dried at 35°C to 40°C in air oven for approximately 12 hours to obtain the title product.
Yield: 80 g
Step-4: Preparation of 2-cvano-N-(2.4-dichloro-5-methoxyphenyl)acetamide:
Method A:
Cyanoacetic acid (50 g) was added to ethyl acetate (400 mL) at 25 °C followed by addition of dimethylformamide (2 mL). The obtained reaction mixture was cooled to 0°C and oxalyl chloride (82.6 g) was slowly added at 0°C to 5°C over a period of about 60 minutes. The temperature of the reaction mixture was raised up to 25°C to 28°C and stirred for 2 hours. 2,4-dichloro-5-methoxyaniline (100 g, obtained from Step-3) was added to the reaction mixture and heated up to 55°C to 60°C under stirring for about 2 hours. Deionized water (200 mL) was added to the reaction mixture at 20°C to 30°C followed by stirring for 1 hour. The product obtained was filtered and washed with ethyl acetate (50 mL) followed by deionized water (500 mL) and ethyl acetate (200 mL) respectively. The wet product was dried in air oven to provide the title product.
Yield: 97 g
Chromatographic Purity: 99.67% Method B:
Cyanoacetic acid (20 g) was added to ethyl acetate (200 mL) at 25 °C followed by addition of dimethylformamide (2.5 mL). The obtained reaction mixture was cooled to 2°C and oxalyl chloride (41.1 g) was slowly added at 2°C to 6°C over a period of 30 minutes. The temperature of reaction mixture was raised up to 23°C to 28°C and stirred for 2 hours. 2,4- dichloro-5-methoxyaniline (50.8 g, obtained from Step-3) was added to the reaction mixture and heated up to 62°C to 64°C under stirring for 2 hours. Deionized water (100 mL) was added to the reaction mixture at 20°C to 3 l°C followed by stirring for 45 minutes. The product obtained was filtered and washed with deionized water (250 mL) followed by ethyl acetate (50 mL). The wet product was dried under vacuum to provide the title product.
Yield: 93 g
Chromatographic Purity: 99.77 %

Claims

Claims
1. A process for the preparation of 2-cyano-/V-(2.4-dichloro-5- methoxyphenyl)acetamide of Formula II:
Figure imgf000008_0001
Formula II
comprising reacting cyanoacetic acid with 2,4-dichloro-5-methoxyaniline in the presence of oxalyl chloride.
2. A process for the preparation of 2-cyano-/V-(2.4-dichloro-5- methoxyphenyl)acetamide of Formula II:
Figure imgf000008_0002
Formula II
comprising
i) treating cyanoacetic acid with oxalyl chloride;
ii) reacting the reaction mixture of step i) with 2,4-dichloro-5-methoxyaniline to obtain 2-cyano-/V-(2.4-dichloro-5 -methoxyphenyl)acetamide .
3. The process of claim 2 wherein the cyanoacetic acid is treated with oxalyl chloride in the presence of a solvent.
4. The process of claim 3 wherein the solvent is selected from the group consisting of tetrahydrof iran, dimethylformamide, dichloromethane, ethyl acetate, diethyl ether, diisopropyl ether, methyl ter.-butyl ether, l,4-dioxane, or mixture thereof.
5. The process of claim 2, wherein the cyanoacetic acid is treated with oxalyl chloride at a temperature of about 0°C to about lO°C.
6. The process of claim 2 wherein the reaction mixture of step i) is reacted with 2,4- dichloro-5-methoxyaniline at a temperature of about 20°C to about 70°C.
7. The process of claim 1 wherein the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide is further converted to bosutinib.
8. The process of claim 2 wherein the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide is further converted to bosutinib.
9. The process of claim 1 wherein the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide obtained is having HPLC purity of more than 99.6%.
10. The process of claim 2 wherein the 2-cyano-/V-(2,4-dichloro-5-methoxyphenyl) acetamide obtained is having HPLC purity of more than 99.6%.
PCT/IB2019/052506 2018-03-30 2019-03-27 A process for the preparation of bosutinib WO2019186429A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116396A (en) * 2019-12-18 2020-05-08 江苏远大仙乐药业有限公司 Preparation method of bosutinib raw material
CN111116397A (en) * 2019-12-18 2020-05-08 江苏远大仙乐药业有限公司 Synthesis method of bosutinib intermediate
WO2022127327A1 (en) * 2020-12-16 2022-06-23 南京华威医药科技集团有限公司 Bosutinib 1,3-propanediether dimer impurity and preparation method therefor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080033175A1 (en) * 2003-08-19 2008-02-07 Wyeth Holdings Corporation Process for preparation of 4-amino-3-quinolinecarbonitriles
US20140012007A1 (en) * 2008-01-23 2014-01-09 Bristol-Myers Squibb Company 4-pyridinone compounds and their use for cancer
WO2014177978A2 (en) * 2013-05-02 2014-11-06 Alembic Pharmaceuticals Limited An improved process for the preparation of teriflunomide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080033175A1 (en) * 2003-08-19 2008-02-07 Wyeth Holdings Corporation Process for preparation of 4-amino-3-quinolinecarbonitriles
US20140012007A1 (en) * 2008-01-23 2014-01-09 Bristol-Myers Squibb Company 4-pyridinone compounds and their use for cancer
WO2014177978A2 (en) * 2013-05-02 2014-11-06 Alembic Pharmaceuticals Limited An improved process for the preparation of teriflunomide

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116396A (en) * 2019-12-18 2020-05-08 江苏远大仙乐药业有限公司 Preparation method of bosutinib raw material
CN111116397A (en) * 2019-12-18 2020-05-08 江苏远大仙乐药业有限公司 Synthesis method of bosutinib intermediate
CN111116396B (en) * 2019-12-18 2022-04-15 江苏远大仙乐药业有限公司 Preparation method of bosutinib raw material
CN111116397B (en) * 2019-12-18 2022-04-15 江苏远大仙乐药业有限公司 Synthesis method of bosutinib intermediate
WO2022127327A1 (en) * 2020-12-16 2022-06-23 南京华威医药科技集团有限公司 Bosutinib 1,3-propanediether dimer impurity and preparation method therefor

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