WO2020183295A1 - Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof - Google Patents

Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2020183295A1
WO2020183295A1 PCT/IB2020/051837 IB2020051837W WO2020183295A1 WO 2020183295 A1 WO2020183295 A1 WO 2020183295A1 IB 2020051837 W IB2020051837 W IB 2020051837W WO 2020183295 A1 WO2020183295 A1 WO 2020183295A1
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formula
tofacitinib
compound
process according
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Inventor
Rama Shankar
Pareshkumar Keshavlal Patel
Dhavalkumar Bharatbhai VASHI
Ranjitkumar Ravatbhai PADA
Ganesh Bhanudas DHEPE
Viralkumar Arvindbhai DOSHI
Jaydip Ghanshyambhai RAJPARA
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Intas Pharmaceuticals Ltd
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Intas Pharmaceuticals Ltd
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Priority to EP20771100.3A priority Critical patent/EP3938370A4/en
Priority to US17/435,605 priority patent/US12269830B2/en
Priority to CA3132109A priority patent/CA3132109A1/en
Publication of WO2020183295A1 publication Critical patent/WO2020183295A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof.
  • Tofacitinib is inhibitor of the enzyme Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), it interferes with the JAK-STAT signaling pathway. Tofacitinib is chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin- 4-ylamino- -oxo-1- piperidinepropanenitrile, 2-hydroxy-1,2,3- propanetricarboxylate (1:1). Its empirical formula i C 16 H 20 N 6 O.C 6 H 8 O 7 . US Patent No.
  • WO2014/195978 A2 discloses use of acetic acid in debenzylation step of process for preparation of tofacitinib and pharmaceutically acceptable salt thereof.
  • the main object of present invention is to provide an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof.
  • process comprises debenzylation of intermediate of formula (III) in presence of metal catalyst and pivalic acid.
  • Another object of the present invention is to provide an improved process for preparation of tofacitinib citrate having dihydro impurity less than 0.2%.
  • Yet another object of the present invention is to provide process for preparation of tofacitinib citrate using substantially pure intermediate of formula (II).
  • the present invention provides an improved process for preparation of tofacitinib (I) or its pharmaceutically acceptable salt
  • the present invention provides an improved process for preparation of tofacitinib or its salt
  • Yet another aspect of present invention is to provide a process for preparation of substantially pure tofacitinib citrate which comprises:
  • Yet another aspect of the present invention is to provide a process for preparation of substantially pure tofacitinib citrate having dihydro impurity (A) less than 0.2%, preferably less than 0.05%.
  • the main embodiment of present invention provides a process for preparation of tofacitinib citrate
  • intermediate of formula (VI) can be prepared by reacting compound of formula (VII) with compound of formula (VIII) as represented in stage I of above mentioned scheme. Which is further reacted with compound of formula (V) to obtain compound of formula (IV).
  • Compound of formula (IV) is hydrolyzed using alkali and water to obtain compound of formula (III), which is debenzylated by metal catalysts in presence of pivalic acid to obtain compound of formula (II).
  • the metal catalyst can be selected from any suitable catalyst like palladium, platinum ruthenium or like.
  • debenzylation is carried out in presence of palladium catalyst.
  • the process for preparation of intermediate of formula (II) wherein, said process is carried out in presence of pivalic acid is carried out in presence of suitable solvent such as aromatic hydrocarbon, alkanols or water.
  • suitable solvent such as aromatic hydrocarbon, alkanols or water.
  • the reaction is carried out in presence of isopropanol, toluene, n-butanol, ethanol, water or mixture thereof.
  • the intermediate of formula (VI) obtained from stage I can be further converted to intermediate of formula (III) by any process known in the art.
  • the intermediate of formula (III) can be subjected to debenzylation in presence pivalic acid metal catalyst such as palladium.
  • the reaction can be carried out in presence of any suitable solvent such as n-butanol, water.
  • the intermediate of formula (II) obtained after debenzylation is converted to tofacitinib citrate.
  • the crude tofacitinib citrate can be isolated from the reaction mixture by filtration and recrystallized to obtain substantially pure tofacitinib citrate.
  • N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 7gm was added to aqueous solution of Sodium hydroxide (39.16gm). Reaction mixture was heated to 95-100°C and stirred. After completion of reaction, reaction mixture was cooled to 25-30°C and filtered.
  • Tofacitinib crude thus obtained (lOgm) was dissolved in water (300ml) at 80-90°C. Charcoal (0.5gm) was added to the reaction mixture and stirred for 30min. Charcoal was filtered and washed with hot water. Filtrate thus obtained was cooled to room temperature for 5-6 hr. and filtered. Solid thus obtained was washed with acetone and dried to obtain substantially pure tofacitinib citrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof. (I)

Description

PROCESS FOR PREPARATION OF TOFACITINIB AND
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
RELATED APPLICATION
This application is related to Indian Provisional Application No. IN 201921009802 filed on 13th March, 2020 and is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
The following discussion of prior art is intended to present the invention in appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however reference to any prior-art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
“Tofacitinib” is inhibitor of the enzyme Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), it interferes with the JAK-STAT signaling pathway. Tofacitinib is chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin- 4-ylamino- -oxo-1- piperidinepropanenitrile, 2-hydroxy-1,2,3- propanetricarboxylate (1:1). Its empirical formula i C16H20N6O.C6H8O7. US Patent No. RE41783, US7265221 and US7301023 discloses (3R,4R)-4- methyl-3-(methyl-7H-pyrrolo [2,3 -d]pyrimidin-4-ylamino)- -oxo-1- piperidinepropanenitrile and process for its preparation. The W02007/012953 A2 discloses process for preparation of tofacitinib wherein chiral purity of intermediate is very poor (84% cis isomer, having 68% ee), and also the process is silent about the chirality of the final tofacitinib citrate produced by this intermediate.
WO2014/195978 A2 discloses use of acetic acid in debenzylation step of process for preparation of tofacitinib and pharmaceutically acceptable salt thereof.
Org. Process Res. Dev. 2014, 18 (12), pp 1714-1720 discloses process for preparation of tofacitinib.
In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of tofacitinib and pharmaceutically acceptable salt thereof.
OBJECTS OF THE INVENTION
The main object of present invention is to provide an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof.
Figure imgf000003_0001
wherein, process comprises debenzylation of intermediate of formula (III) in presence of metal catalyst and pivalic acid.
Figure imgf000004_0001
Another object of the present invention is to provide an improved process for preparation of tofacitinib citrate having dihydro impurity less than 0.2%.
Yet another object of the present invention is to provide process for preparation of tofacitinib citrate using substantially pure intermediate of formula (II).
SUMMARY OF THE INVENTION
In one aspect the present invention provides an improved process for preparation of tofacitinib (I) or its pharmaceutically acceptable salt
Figure imgf000004_0002
comprising, debenzylation of N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine intermediate of formula (III) in presence of metal catalyst and pivalic acid.
Figure imgf000004_0003
converting the resultant intermediate of formula (II) to tofacitinib citrate. In another aspect the present invention provides an improved process for preparation of tofacitinib or its salt;
Figure imgf000005_0001
comprising, debenzylation of N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine intermediate of formula (III) in presence of palladium catalyst and pivalic acid.
Figure imgf000005_0002
converting the resultant intermediate of formula (II) to tofacitinib citrate.
Yet another aspect of present invention is to provide a process for preparation of substantially pure tofacitinib citrate which comprises:
a) reacting compound of formula (VIII) with compound of formula (VII) to obtain compound of formula (VI);
Figure imgf000005_0003
b) reacting intermediate of formula (VI) and formula (V) in presence of water and alkali to obtain compound of formula (IV)
Figure imgf000006_0001
c) converting compound of formula (IV) to compound of formula (III)
Figure imgf000006_0002
d) debenzylating compound of formula (III) in presence of pivalic acid and palladium catalyst to obtain compound of formula (II); and
Figure imgf000006_0003
e) converting resultant compound of formula (II) to tofacitinib citrate f) optionally purifying to obtain substantially pure tofacitinib citrate.
Yet another aspect of the present invention is to provide a process for preparation of substantially pure tofacitinib citrate having dihydro impurity (A) less than 0.2%, preferably less than 0.05%.
Figure imgf000007_0001
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of present invention provides a process for preparation of tofacitinib citrate;
Figure imgf000007_0002
accordingly, the complete process of present invention can be represented by following scheme.
Figure imgf000008_0001
For the purpose of present invention intermediate of formula (VI) can be prepared by reacting compound of formula (VII) with compound of formula (VIII) as represented in stage I of above mentioned scheme. Which is further reacted with compound of formula (V) to obtain compound of formula (IV).
Compound of formula (IV) is hydrolyzed using alkali and water to obtain compound of formula (III), which is debenzylated by metal catalysts in presence of pivalic acid to obtain compound of formula (II). Wherein the metal catalyst can be selected from any suitable catalyst like palladium, platinum ruthenium or like. Preferably debenzylation is carried out in presence of palladium catalyst.
In an embodiment the process for preparation of intermediate of formula (II) wherein, said process is carried out in presence of pivalic acid. The process for preparation of compound of formula (II) can be carried out in presence of suitable solvent such as aromatic hydrocarbon, alkanols or water. Suitably the reaction is carried out in presence of isopropanol, toluene, n-butanol, ethanol, water or mixture thereof.
The intermediate of formula (VI) obtained from stage I can be further converted to intermediate of formula (III) by any process known in the art. For the purpose of present invention the intermediate of formula (III) can be subjected to debenzylation in presence pivalic acid metal catalyst such as palladium. The reaction can be carried out in presence of any suitable solvent such as n-butanol, water. The intermediate of formula (II) obtained after debenzylation is converted to tofacitinib citrate. The crude tofacitinib citrate can be isolated from the reaction mixture by filtration and recrystallized to obtain substantially pure tofacitinib citrate.
Table 1: Summary of Debenzylation process of Tofacitinib
Figure imgf000010_0001
Figure imgf000011_0001
EXAMPLES
Example 1: 4-chloro-7-tosyl-7H pyrrolo[2,3-d]pyrimidine (VI)
In a three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, 4-methylbenzenesulfonyl chloride (86.9gm) in acetone (300ml) was added to the reaction mixture of 4-chloro-7H pyrrolo[2,3-d ] pyrimidine (50gm), sodium hydroxide (19.6gm) and purified water (400ml). The resultant reaction mixture was stirred for completion of reaction and filtered. Resulting wet-cake was washed and dried at 40-50°C under vacuum to obtained 4-chloro-7-tosyl-7H pyrrolo[2,3-d]pyrimidine (VI). Example 2: N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-tosyl-7H- pyrrolo [2,3-d] pyrimidin-4-amine (IV)
In a three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, 4-chloro-7-tosyl-7H pyrrolo[2,3-d]pyrimidine (60gm) was added to the mixture of potassium carbonate (140gm) in purified water (780ml) and Bis-(3R,4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine di-p-toluoyl- L-tartarate. The reaction mixture thus obtained was heated up to 90-100°C. After completion of the reaction, reaction mixture was cooled, filtered and washed with purified water. Wet-cake thus obtained was purified with methanol (390ml) and dried under vacuum to obtain N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N- methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
Example 3: N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H- pyrrolo [2,3-d] pyrimidin-4-amine (III)
In a three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (7gm) was added to aqueous solution of Sodium hydroxide (39.16gm). Reaction mixture was heated to 95-100°C and stirred. After completion of reaction, reaction mixture was cooled to 25-30°C and filtered. Resulting wet-cake was washed with water and dried under vacuum to obtain N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine.
Example 4: N-methyl-N-((3R,4R)-4-ethylpiperidin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine (II)
In a three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H- pyrrolo [2,3-d] pyrimidin-4-amine (lOgm) and catalytic amount of pivalic acid was added to purified water (50ml), to the reaction mixture 10% Pd/C was added. The resulting reaction mixture was treated with hydrogen. After completion of reaction catalyst was filtered and washed with water. Filtrate thus obtained was basified with aqueous sodium hydroxide and product was extracted with n- butanol to obtain N-methyl-N-((3R,4R)-4-ethylpiperidin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine.
Example 5: Tofacitinib citrate (crude)
In a three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, N-methyl-N-((3R,4R)-4-ethylpiperidin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine (9.5gm) was added to n-butanol (45ml). To the resulting solution ethyl cyanoacetate (13gm) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6gm) were added and maintained at 40-50°C. After completion of reaction aqueous citric acid solution was added and stirred. Solid thus obtained was cooled and washed with n-butanol then dried to obtain tofacitinib citrate.
Example 6: Tofacitinib citrate (purification)
In a three neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, Tofacitinib crude thus obtained (lOgm) was dissolved in water (300ml) at 80-90°C. Charcoal (0.5gm) was added to the reaction mixture and stirred for 30min. Charcoal was filtered and washed with hot water. Filtrate thus obtained was cooled to room temperature for 5-6 hr. and filtered. Solid thus obtained was washed with acetone and dried to obtain substantially pure tofacitinib citrate.

Claims

We Claim:
1. A process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof
5
Figure imgf000014_0001
comprising:
a) debenzylation of N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)- N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine intermediate of formula (III) in presence of metal catalyst and pivalic acid to obtain intermediate of formula (II); and
Figure imgf000014_0002
b) converting the compound of formula (II) to tofacitinib or its salt.
2. The process according to claim 1, wherein metal catalyst is selected from a group comprising palladium, platinum, ruthenium.
3. The process according to claim 1, comprising
a) debenzylating compound of formula (III) in presence of pivalic acid and metal catalyst to obtain a compound of formula (II); and
Figure imgf000015_0001
b) converting compound of formula (II) to tofacitinib having impurity of formula (A) less than 0.2%.
5
Figure imgf000015_0002
4. The process according to claim 3 wherein the tofacitinib is having impurity of formula (A) less than 0.05%.
5. The process according to claim 1, comprising:
a) debenzylating compound of formula (III) in presence of pivalic acid and metal catalyst to obtain a compound of formula (II)
Figure imgf000015_0003
b) converting compound of formula (II) to tofacitinib having less than 0.2% of impurity of formula (A); and
c) reacting tofacitinib with citric acid to obtain citrate salt of tofacitinib.
6. The process according to claim 1, comprising;
a) debenzylating compound of formula (III) in presence of metal catalyst and pivalic acid to obtain compound of formula (II); and
b) reacting compound of formula (II) with Ethyl cyanoacetate and citric acid to obtain tofacitinib citrate having impurity of formula (A) less than 0.2%.
7. The process according to claim 1, wherein the debenzylation is carried out in the presence of solvent selected from aromatic hydrocarbons, alkanols, water and mixture thereof.
8. The process according to claim 7, wherein the solvent is selected from toluene, xylene, isopropanol, n-butanol, methanol, ethanol and water or mixture thereof.
9. The process according to claim 1, wherein tofacitinib or pharmaceutically acceptable salt thereof is having dihydro impurity of formula (A) less than 0.2%, more preferably less than 0.05%.
10. A tofacitinib or its pharmaceutically acceptable salt (I) having dihydro impurity (A) less than 0.2%
Figure imgf000016_0001
wherein the process comprises;
a) debenzylating compound of formula (III) in presence of pivalic acid and palladium catalyst to obtain a compound of formula (II)
Figure imgf000017_0001
b) converting compound of formula (II) to tofacitinib having less than 0.2% of impurity of formula (A); and
c) reacting tofacitinib with citric acid to obtain citrate salt of tofacitinib.
PCT/IB2020/051837 2019-03-13 2020-03-04 Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof Ceased WO2020183295A1 (en)

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EP20771100.3A EP3938370A4 (en) 2019-03-13 2020-03-04 Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof
US17/435,605 US12269830B2 (en) 2019-03-13 2020-03-04 Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof
CA3132109A CA3132109A1 (en) 2019-03-13 2020-03-04 Process for preparation of tofacitinib and pharmaceutically acceptable salt thereof

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IN201921009802 2019-03-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115236261A (en) * 2022-05-10 2022-10-25 汉瑞药业(荆门)有限公司 HPLC-UV detection method for purity of tofacitinib intermediate
US20220402924A1 (en) * 2019-10-31 2022-12-22 Aarti Industries Limited Process for the preparation of tofacitinib and intermediates thereof

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WO2007012953A2 (en) 2005-07-29 2007-02-01 Pfizer Products Inc. Pyrrolo[2,3-d]pyrimidine derivatives; their intermediates and synthesis
US7265221B2 (en) 1999-12-10 2007-09-04 Pfizer, Inc. Pyrrolo[2,3-d]pyrimidine compounds
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
WO2014102826A1 (en) 2012-12-28 2014-07-03 Glenmark Pharmaceuticals Limited; The present invention relates to process for the preparation of tofacitinib and intermediates thereof.
WO2014195978A2 (en) 2013-06-05 2014-12-11 Msn Laboratories Limited PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
WO2018172821A1 (en) 2017-03-23 2018-09-27 Phalanx Labs Private Limited Novel tofacitinib addition salts and process for the preparation thereof

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US7265221B2 (en) 1999-12-10 2007-09-04 Pfizer, Inc. Pyrrolo[2,3-d]pyrimidine compounds
USRE41783E1 (en) 1999-12-10 2010-09-28 Pfizer Inc. Pyrrolo[2,3-D]pyrimidine compounds
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
WO2007012953A2 (en) 2005-07-29 2007-02-01 Pfizer Products Inc. Pyrrolo[2,3-d]pyrimidine derivatives; their intermediates and synthesis
WO2014102826A1 (en) 2012-12-28 2014-07-03 Glenmark Pharmaceuticals Limited; The present invention relates to process for the preparation of tofacitinib and intermediates thereof.
US9670160B2 (en) * 2012-12-28 2017-06-06 Glenmark Pharmaceuticals Limited Process for the preparation of tofacitinib and intermediates thereof
WO2014195978A2 (en) 2013-06-05 2014-12-11 Msn Laboratories Limited PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
WO2018172821A1 (en) 2017-03-23 2018-09-27 Phalanx Labs Private Limited Novel tofacitinib addition salts and process for the preparation thereof

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See also references of EP3938370A4

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220402924A1 (en) * 2019-10-31 2022-12-22 Aarti Industries Limited Process for the preparation of tofacitinib and intermediates thereof
CN115236261A (en) * 2022-05-10 2022-10-25 汉瑞药业(荆门)有限公司 HPLC-UV detection method for purity of tofacitinib intermediate
CN115236261B (en) * 2022-05-10 2024-04-19 武汉海特生物创新医药研究有限公司 HPLC-UV detection method for tofacitinib intermediate purity

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