WO2019155486A1 - Process for the preparation of sorafenib tosylate polymorph iii - Google Patents

Process for the preparation of sorafenib tosylate polymorph iii Download PDF

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Publication number
WO2019155486A1
WO2019155486A1 PCT/IN2019/050084 IN2019050084W WO2019155486A1 WO 2019155486 A1 WO2019155486 A1 WO 2019155486A1 IN 2019050084 W IN2019050084 W IN 2019050084W WO 2019155486 A1 WO2019155486 A1 WO 2019155486A1
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Prior art keywords
sorafenib tosylate
methanol
sorafenib
form iii
preparation
Prior art date
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PCT/IN2019/050084
Other languages
French (fr)
Inventor
Muddasani Pulla Reddy
Budideti SHANKAR REDDY
Talasila Sambasiva Rao
Chintalapati SRINIVASACHARY
Kotte TIRUPATHI
Arabinda Sahu
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Publication of WO2019155486A1 publication Critical patent/WO2019155486A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to an improved process for the preparation of Sorafenib tosylate form III with high purity and high yield.
  • the present process controls the genotoxic impurities content in final API.
  • Sorafenib tosylate is chemically known as 4-(4- ⁇ 3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido ⁇ phenoxy)N2methylpyridine-2-carboxamide 4-methylbenzenesulfonate and structurally represented as below.
  • Sorafenib tosylate is marketed as Nexavar® by Bayer for treatment of advanced renal cell carcinoma (primary kidney cancer).
  • Sorafenib and its salts such as the tosylate salt and a process for preparation thereof are disclosed in US7351834.
  • sorafenib tosylate polymorph III can be prepared by suspending sorafenib tosylate form II in methanol at room temperature, maintained for one week and then filtered to obtain a residual solid. The residual solid was heat-treated at 150° C, for 30 minutes to obtain sorafenib tosylate polymorph III.
  • sorafenib tosylate polymorph III can be prepared by providing a suspension comprising sorafenib tosylate and a solvent selected from methanol, a mixture of methanol and N-methyl-2-pyrrolidone, a mixture of methanol and dimethyl sulfoxide to obtain sorafenib tosylate methanol solvate and then drying the sorafenib tosylate methanol solvate at 80 to 90° C.
  • WO2014118807A1 describes sorafenib tosylate form III preparation from sorafenib tosylate ethanol solvate.
  • the present inventors have found a novel process for the preparation of Sorafenib tosylate form III with high purity.
  • the present process is cost effective and feasible in large scale production also.
  • the present process controls the genotoxic impurities content in final API.
  • the main aspect of the present invention is to provide a novel process for the preparation of sorafenib tosylate form III from sorafenib base through sorafenib tosylate methanol solvate.
  • One aspect of the present invention is to provide a process for the preparation of Sorafenib tosylate form III, comprising the steps of:
  • step (b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and
  • step (c) drying the solid of step (c) to obtain sorafenib tosylate form III.
  • Another aspect of the present invention is to provide a process for the preparation of sorafenib tosylate form III, comprising the steps of:
  • step (b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,
  • the present invention is related to a process for the preparation of Sorafenib tosylate form III, wherein suspending sorafenib base in methanol, adding methanolic solution of para toluene sulfonic acid to this solution, isolating sorafenib tosylate methanol solvate and drying sorafenib tosylate methanol solvate to obtain sorafenib tosylate form III.
  • One embodiment of the present invention is to provide a process for the preparation of Sorafenib tosylate form III, comprising the steps of:
  • step (b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and
  • step (c) drying the solid of step (c) to obtain sorafenib tosylate form III.
  • Another embodiment of the present invention is to provide a process for the preparation of sorafenib tosylate form III, comprising the steps of:
  • step (b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,
  • Sorafenib base and methanol is charged into a four necked round bottom flask.
  • the reaction mass is heated to 55-60°C.
  • Solution of p- toluene sulfonic acid in Methanol [p- toluene sulfonic acid in of cold methanol ( ⁇ 0-5°C)] is added to the above solution at 55-60°C in 15-20 minutes.
  • the reaction mass is heated to 60- 65°C and maintained for 2h.
  • the reaction mass is cooled to 40-45°C and maintained for 45- 60 minutes.
  • the solid is filtered and washed with methanol.
  • Solid (methanol solvate) is dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for 12h to get sorafenib tosylate form III.
  • methyl p-toulene sulfonate is a potentially genotoxic impurity. This impurity limitation is achieved through drying sorafenib tosylate methanol solvate in fluid bed drier.
  • Fig-1 Powder X-ray diffractogram of sorafenib tosylate form III.
  • Sorafenib base 125 g, 0.269 mole
  • methanol 1875 ml
  • the reaction mass was heated to 55-60°C.
  • Solution of p- toluene sulfonic acid in methanol [56.2g p-toluene sulfonic acid (0.296 mole) in 90 ml of cold methanol ( ⁇ 0-5°C)] was added to the above solution at 55-60°C in 15-20 minutes.
  • the reaction mass was heated to 60-65°C and maintained for 2h.
  • the reaction mass was cooled to 40-45°C and maintained for 45-60 minutes.
  • the solid was filtered and washed with methanol.
  • Methyl-p-toluene sulfonate Below detection limit.
  • Sorafenib base 50 g, 0.108 mole
  • methanol 625 ml
  • the reaction mass was heated to 55-60°C.
  • Solution of p- toluene sulfonic acid in methanol [21.5 g p-toluene sulfonic acid (0.113 mole) in 35 ml of cold methanol ( ⁇ 0-5°C)] was added to the above solution at 55-60°C in 15-20 minutes.
  • the reaction mass was heated to 60-65°C and maintained for 2h.
  • the reaction mass was cooled to 40-45°C and maintained for 45-60 minutes.
  • the solid was filtered and washed with methanol.
  • Methyl-p-toluene sulfonate Below detection limit.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a process for the preparation of sorafenib tosylate form III from sorafenib base through sorafenib tosylate methanol solvate. The present invention relates to an improved process for the preparation of Sorafenib tosylate form III with high purity and high yield. The present process controls the genotoxic impurities content in final API.

Description

PROCESS FOR THE PREPARATION OF SORAFENIB TOSYLATE
POLYMORPH III
Field of the Invention:
The present invention relates to an improved process for the preparation of Sorafenib tosylate form III with high purity and high yield. The present process controls the genotoxic impurities content in final API.
Background of the Invention:
Sorafenib tosylate is chemically known as 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido }phenoxy)N2methylpyridine-2-carboxamide 4-methylbenzenesulfonate and structurally represented as below.
Figure imgf000003_0001
Sorafenib tosylate is marketed as Nexavar® by Bayer for treatment of advanced renal cell carcinoma (primary kidney cancer).
Sorafenib and its salts, such as the tosylate salt and a process for preparation thereof are disclosed in US7351834.
US8877933 described Polymorph I, Polymorph II, Polymorph III, methanol solvate and ethanol solvate of sorafenib tosylate. According to this patent, sorafenib tosylate polymorph III can be prepared by suspending sorafenib tosylate form II in methanol at room temperature, maintained for one week and then filtered to obtain a residual solid. The residual solid was heat-treated at 150° C, for 30 minutes to obtain sorafenib tosylate polymorph III.
As per US8217061 patent, sorafenib tosylate polymorph III can be prepared by providing a suspension comprising sorafenib tosylate and a solvent selected from methanol, a mixture of methanol and N-methyl-2-pyrrolidone, a mixture of methanol and dimethyl sulfoxide to obtain sorafenib tosylate methanol solvate and then drying the sorafenib tosylate methanol solvate at 80 to 90° C. WO2014118807A1 describes sorafenib tosylate form III preparation from sorafenib tosylate ethanol solvate.
The present inventors have found a novel process for the preparation of Sorafenib tosylate form III with high purity. The present process is cost effective and feasible in large scale production also. The present process controls the genotoxic impurities content in final API.
Summary of the Invention:
The main aspect of the present invention is to provide a novel process for the preparation of sorafenib tosylate form III from sorafenib base through sorafenib tosylate methanol solvate.
One aspect of the present invention is to provide a process for the preparation of Sorafenib tosylate form III, comprising the steps of:
a) adding sorafenib base in methanol,
b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and
d) drying the solid of step (c) to obtain sorafenib tosylate form III.
Another aspect of the present invention is to provide a process for the preparation of sorafenib tosylate form III, comprising the steps of:
a) adding sorafenib base in methanol,
b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,
d) optionally washing the methanol solvate with methanol,
e) drying sorafenib tosylate methanol solvate in fluid bed drier at 80-95°C to obtain sorafenib tosylate form III.
Detailed description of the Invention:
The present invention is related to a process for the preparation of Sorafenib tosylate form III, wherein suspending sorafenib base in methanol, adding methanolic solution of para toluene sulfonic acid to this solution, isolating sorafenib tosylate methanol solvate and drying sorafenib tosylate methanol solvate to obtain sorafenib tosylate form III. One embodiment of the present invention is to provide a process for the preparation of Sorafenib tosylate form III, comprising the steps of:
a) adding sorafenib base in methanol,
b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and
d) drying the solid of step (c) to obtain sorafenib tosylate form III.
Another embodiment of the present invention is to provide a process for the preparation of sorafenib tosylate form III, comprising the steps of:
a) adding sorafenib base in methanol,
b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,
d) optionally washing the methanol solvate with methanol,
e) drying sorafenib tosylate methanol solvate in fluid bed drier at 80-95°C to obtain sorafenib tosylate form III.
According to the present invention, Sorafenib base and methanol is charged into a four necked round bottom flask. The reaction mass is heated to 55-60°C. Solution of p- toluene sulfonic acid in Methanol [p- toluene sulfonic acid in of cold methanol (~0-5°C)] is added to the above solution at 55-60°C in 15-20 minutes. The reaction mass is heated to 60- 65°C and maintained for 2h. The reaction mass is cooled to 40-45°C and maintained for 45- 60 minutes. The solid is filtered and washed with methanol. Solid (methanol solvate) is dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for 12h to get sorafenib tosylate form III.
According to the present invention, methyl p-toulene sulfonate is a potentially genotoxic impurity. This impurity limitation is achieved through drying sorafenib tosylate methanol solvate in fluid bed drier.
Advantages of the present Invention:
• The genotoxic impurity is very well controlled in final API.
• The present process is cost effective and feasible in large scale production also. Brief description of drawings:
Fig-1 : Powder X-ray diffractogram of sorafenib tosylate form III.
The below examples are provided for illustrative purpose only and are not intended to limit the scope of invention.
Experimental section:
Example-1: Preparation of Sorafenib tosylate form III
Sorafenib base (125 g, 0.269 mole) and methanol (1875 ml) were charged into a 3.0L four necked round bottom flask. The reaction mass was heated to 55-60°C. Solution of p- toluene sulfonic acid in methanol [56.2g p-toluene sulfonic acid (0.296 mole) in 90 ml of cold methanol (~0-5°C)] was added to the above solution at 55-60°C in 15-20 minutes. The reaction mass was heated to 60-65°C and maintained for 2h. The reaction mass was cooled to 40-45°C and maintained for 45-60 minutes. The solid was filtered and washed with methanol. Solid (methanol solvate) was dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for l2h to get Sorafenib tosylate form III. (Yield: 144.7g, theoretical 84.5%)
Methyl-p-toluene sulfonate: Below detection limit.
HPLC purity: 99.98%
Example-2: Preparation of Sorafenib tosylate form III
Sorafenib base (50 g, 0.108 mole) and methanol (625 ml) were charged into a 2.0L four necked round bottom flask. The reaction mass was heated to 55-60°C. Solution of p- toluene sulfonic acid in methanol [21.5 g p-toluene sulfonic acid (0.113 mole) in 35 ml of cold methanol (~0-5°C)] was added to the above solution at 55-60°C in 15-20 minutes. The reaction mass was heated to 60-65°C and maintained for 2h. The reaction mass was cooled to 40-45°C and maintained for 45-60 minutes. The solid was filtered and washed with methanol. Solid (methanol solvate) was dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for 12h to get Sorafenib tosylate form -III. (Yield is 54.18 g, Theoretical 79.1%)
Methyl-p-toluene sulfonate: Below detection limit.
HPLC purity: 99.97%

Claims

Claims:
1. A process for the preparation of Sorafenib tosylate form III, comprising the steps of:
a) adding sorafenib base in methanol,
b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and
d) drying the solid of step (c) to obtain sorafenib tosylate form III.
2. The process according to claim 1, wherein drying is carried out in fluid bed drier at 80-95°C.
3. A process for the preparation of sorafenib tosylate form III, comprising the steps of: a) adding sorafenib base in methanol,
b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,
d) optionally washing the methanol solvate with methanol,
e) drying sorafenib tosylate methanol solvate in fluid bed drier at 80-95°C to obtain sorafenib tosylate form III.
4. The process according to claim 3, the obtained sorafenib tosylate form III is dried preferably at 85-90°C.
5. The process according to claim 3, the obtained sorafenib tosylate form III is having HPLC purity greater than 99%.
6. A process for the preparation of sorafenib tosylate form III by drying sorafenib tosylate methanol solvate in fluid bed drier at 85-90°C.
PCT/IN2019/050084 2018-02-06 2019-02-05 Process for the preparation of sorafenib tosylate polymorph iii WO2019155486A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2231612A1 (en) * 2008-01-17 2010-09-29 Sicor, Inc. Polymorph form iii of sorafenib tosylate, sorafenib tosylate methanol solvate and sorafenib tosylate ethanol solvate, and processes for preparation thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2231612A1 (en) * 2008-01-17 2010-09-29 Sicor, Inc. Polymorph form iii of sorafenib tosylate, sorafenib tosylate methanol solvate and sorafenib tosylate ethanol solvate, and processes for preparation thereof

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