WO2016088094A1 - Process for the preparation of baricitinib and an intermediate thereof - Google Patents

Process for the preparation of baricitinib and an intermediate thereof Download PDF

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Publication number
WO2016088094A1
WO2016088094A1 PCT/IB2015/059364 IB2015059364W WO2016088094A1 WO 2016088094 A1 WO2016088094 A1 WO 2016088094A1 IB 2015059364 W IB2015059364 W IB 2015059364W WO 2016088094 A1 WO2016088094 A1 WO 2016088094A1
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formula
pyrrolo
pyrimidin
methyl
chloro
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Md Abul Kalam AZAD
Gyanendra Pandey
Kaptan Singh
Mohan Prasad
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Sun Pharmaceutical Industries Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members

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  • the present invention provides a process for the preparation of baricitinib and intermediate thereof.
  • a second aspect of the present invention provides a process for the preparation of baricitinib of Formula I,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention provides a process for the preparation of baricitinib and an intermediate thereof. The present invention provides a convenient, economical, and industrially advantageous two-step process for the preparation of [4-(IH-pyrazol-4-yl)-7Hpyrrolo[2,3-d] pyrimidin-7-yl]methyl pivalate of Formula (II). The process of the present invention involves the use of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate as a base for reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula (III) with chloromethyl pivalate of Formula (IV), and the use of an unprotected pyrazole borolane of Formula (VIII) for the conversion of (4-chloro-7H-pyrrolo[2,3-d] pynmidin-7- yl)methyl 2,2-dimethylpropanoate of Formula V into [4-(1 H-pyrazol-4-yl)-7Hpyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula (II). The process of the present invention provides [4-(1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula (I) in high yield.

Description

PROCESS FOR THE PREPARATION OF BARICITINIB AND AN
INTERMEDIATE THEREOF
Field of the Invention
The present invention provides a process for the preparation of baricitinib and intermediate thereof.
Background of the Invention
Baricitinib is a Janus kinase (JAK) inhibitor. It is chemically designated as { 1 (ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]azetidin-3- yl}acetonitrile, having the structure as depicted in Formula I.
Figure imgf000002_0001
Formula I
U.S. Patent No. 8,158,616 discloses processes for the preparation of baricitinib of Formula I and [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II.
Figure imgf000002_0002
Formula II U.S. Patent No. 8, 158,616 involves a three-step process for the preparation of [4- (lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II as depicted in Scheme 1 below:
Scheme 1
Figure imgf000003_0001
Formula V
Figure imgf000003_0002
Formula VI
Figure imgf000003_0003
Formula II Formula VII
The process disclosed in U.S. Patent No. 8, 158,616 involves the use of sodium hydride as a base for reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV, and the use of a protected pyrazole borolane derivative of Formula VI for the conversion of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)methyl 2,2-dimethylpropanoate of Formula V into [4-(lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II. The use of sodium hydride is not suitable on an industrial scale due to its inflammable and hazardous nature. The use of a protected pyrazole borolane derivative of Formula VI increases the cost of the manufacturing process, as an additional deprotection step is required for obtaining [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl]methyl pivalate of Formula II.
Thus, there exists a need for the development of an economical and industrially advantageous process for the preparation of [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate of Formula II that avoids the use of sodium hydride and involves a lesser number of steps.
Summary of the Invention
The present invention provides a convenient, economical, and industrially advantageous two-step process for the preparation of [4-(lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II. The process of the present invention involves the use of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate as a base for reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV, and the use of an unprotected pyrazole borolane of Formula VIII for the conversion of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)methyl 2,2-dimethylpropanoate of Formula V into [4-(lH-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II. The process of the present invention provides [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II in high yield.
A first aspect of the present invention provides a process for the preparation of [4- (lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II,
Figure imgf000004_0001
Formula II comprising the steps of:
i) reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III
Figure imgf000005_0001
Formula III
with chloromethyl pivalate of Formula IV
Figure imgf000005_0002
Formula IV
in the presence of an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate as a base to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)methyl 2,2-dimethylpropanoate of Formula V; and
Figure imgf000005_0003
ii) reacting the (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2 dioxaborolan-2-yl)-lH-pyrazole of Formula VIII
Figure imgf000005_0004
Formula VIII to obtain the [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II.
A second aspect of the present invention provides a process for the preparation of baricitinib of Formula I,
Figure imgf000006_0001
Formula I
comprising the steps of:
i) reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III
Figure imgf000006_0002
Formula III
with chloromethyl pivalate of Formula IV
Figure imgf000006_0003
Formula IV
in the presence of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate base to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate of Formula V;
Figure imgf000007_0001
Formula V
ii) reacting the (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole of Formula VIII
Figure imgf000007_0002
Formula VIII
to obtain [4-( lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II; and
Figure imgf000007_0003
Formula II
iii) reacting the [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II with [l-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile of Formula IX
Figure imgf000008_0001
Formula IX
to obtain baricitinib of Formula I.
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 number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to a temperature in the range of about 20°C to about 35°C.
The reaction of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV is carried out in the presence of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate as a base. Examples of alkali and alkaline earth metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide. Examples of alkali and alkaline earth metal carbonates include sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. In an embodiment of the present invention, the reaction of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV is carried out in the presence of potassium carbonate.
The reaction of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV is carried out at ambient temperature in the presence of a solvent. Examples of solvents include hydrocarbons, ethers, chlorinated
hydrocarbons, ketones, amides, sulphoxides, water, and mixtures thereof. Examples of hydrocarbons include benzene, toluene, and xylene. Examples of ethers include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane. Examples of chlorinated hydrocarbons include dichloromethane and chloroform. Examples of ketones include acetone, dimethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone. Examples of amides include N,N-dimethylformamide and N,N- dimethylacetamide. Examples of sulphoxides include dimethyl sulphoxide and diethyl sulphoxide. In an embodiment of the present invention, the solvent used is N,N- dimethylformamide .
The reaction of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV is carried out in about 4 hours to about 24 hours. In an embodiment of the present invention, the reaction is carried out in about 14 hours to about 18 hours.
The reaction of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole of Formula VIII is carried out in the presence of a base in a solvent. The base may be selected from the group consisting of inorganic and organic bases. Examples of inorganic bases include alkali and alkaline earth metal hydroxides, carbonates, and bicarbonates. Examples of alkali and alkaline earth metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide. Examples of alkali and alkaline earth metal carbonates include sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of organic bases include N,N-diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4-dimethylaminopyridine, 1 ,4- diazabicyclo[2.2.2]octane, and l,8-diazabicyclo[5.4.0]undec-7-ene. In an embodiment of the present invention, potassium carbonate is used as the base. Examples of solvents include hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, water, and mixtures thereof. Examples of hydrocarbons include benzene, toluene, and xylene. Examples of ethers include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane. Examples of chlorinated hydrocarbons include dichloromethane and chloroform. Examples of ketones include acetone, dimethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone. Examples of amides include N,N- dimethylformamide and N,N-dimethylacetamide. Examples of sulphoxides include dimethyl sulphoxide and diethyl sulphoxide. In an embodiment of the present invention, the reaction of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole of Formula VIII is carried out in the presence of water and 1,4-dioxane.
The reaction of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole of Formula VIII is initiated by adding a palladium catalyst. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium(0) and tetrakis(tri(o- tolyl)phosphine)palladium(O). In an embodiment of the present invention, the catalyst used is tetrakis(triphenylphosphine)palladium(0).
The reaction of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole of Formula VIII is carried out at ambient temperature to the reflux temperature of the solvent. In an embodiment of the present invention, the reaction is carried out at a temperature of about 65°C to about 90°C.
The reaction of (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole of Formula VIII is carried out in about 4 hours to about 24 hours. In an embodiment of the present invention, the reaction is carried out in about 14 hours to about 18 hours.
The isolation of [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V is carried out by concentration, precipitation, cooling, filtration, centrifugation, or a combination thereof, followed by drying. Drying is carried out under reduced pressure at a temperature of about 35°C to about 60°C for about 5 hours to about 24 hours.
The reaction of [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II with 2-(l-ethylsufonyl)azetidin-3-ylidene)acetonitrile of Formula IX to obtain baricitinib of Formula I may be carried out by the process disclosed in U.S. Patent No. 8, 158,616, which is incorporated herein by reference.
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 examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1 : Preparation of (4-chloro-7H-pyrrolor2.3-dlpyrimidin-7-yl)methyl 2.2- dimethylpropanoate (Formula V)
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (25 g; Formula III), potassium carbonate (27 g), and chloromethyl pivalate (27 g; Formula IV) were added to a reaction vessel containing N,N-dimethylformamide (100 mL) at ambient temperature. The reaction mixture was stirred for 14 hours. The progress of the reaction was monitored by thin layer chromatography. Water (250 mL) was added to the reaction mixture, and then the mixture was stirred for 2 hours. The reaction mixture was filtered, then washed with water (50 mL), and then dried under reduced pressure at 40°C to 45°C for 12 hours to obtain (4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate.
Yield: 98.85%
Example 2: Preparation of r4-(lH-pyrazol-4-yl)-7H-pyrrolor2.3-dlpyrimidin-7-yllmethyl pivalate (Formula II)
(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate (10 g; Formula V), water (50 mL), and potassium carbonate (15.5 g) were added into a reaction vessel at ambient temperature. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (8.7 g; Formula VIII), 1,4-dioxane (100 mL), and
tetrakis(triphenylphosphine)palladium(0) (0.08 g) were added to the reaction mixture. The reaction mixture was heated to a temperature of 80°C to 85°C, and then stirred at the same temperature for 14 hours. The progress of the reaction was monitored by thin layer chromatography. On completion, ethyl acetate (100 mL) was added to the reaction mixture. The contents were stirred for 1 hour, then filtered through a Hyflo®, and then washed with ethyl acetate (40 mL). The organic layer was separated, and then concentrated under reduced pressure to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate.
Yield: 82.27%

Claims

We claim:
1. A process for the preparation of [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl]methyl pivalate of Formula II,
Figure imgf000012_0001
Formula II
comprising the steps of:
i) reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III
Figure imgf000012_0002
Formula III
with chloromethyl pivalate of Formula IV
Figure imgf000012_0003
Formula IV
in the presence of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate base to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate of Formula V; and
Figure imgf000013_0001
Formula V
ii) reacting the (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-pyrazole of Formula VIII
Figure imgf000013_0002
Formula VIII
to obtain the [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II.
A process for the preparation of baricitinib of Formula I,
Figure imgf000013_0003
Formula I
comprising the steps of:
i) reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula III
Figure imgf000014_0001
Formula III
with chloromethyl pivalate of Formula IV
Figure imgf000014_0002
Formula IV
in the presence of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate base to obtain (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate of Formula V;
Figure imgf000014_0003
Formula V
reacting the (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2- dimethylpropanoate of Formula V with 4-(4,4,5,5-tetramethyl-l,3,
2- dioxaborolan-2-yl)- lH-pyrazole of Formula VIII
Figure imgf000014_0004
Formula VIII to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II; and
H
Figure imgf000015_0001
Formula II
iii) reacting the [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula II with [l-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile of Formula IX
Figure imgf000015_0002
Formula IX
to obtain baricitinib of Formula I.
3. The process according to claim 1 or 2, wherein the alkali or alkaline earth metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide.
4. The process according to claim 1 or 2, wherein the alkali or alkaline earth metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate.
5. The process according to claim 1 or 2, wherein the alkali metal bicarbonate is selected from sodium bicarbonate and potassium bicarbonate. The process according to claim 1 or 2, wherein the reaction of 4-chloro-7H- pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV is carried out at ambient temperature.
The process according to claim 1 or 2, wherein the reaction of 4-chloro-7H- pyrrolo[2,3-d]pyrimidine of Formula III with chloromethyl pivalate of Formula IV is carried out in the presence of a solvent selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, water, and mixtures thereof.
The process according to claim 1 or 2, wherein the reaction of (4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate of Formula V with 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole of Formula VIII is carried out in the presence of an organic or inorganic base.
The process according to claim 7, wherein the solvent is selected from the group consisting of hydrocarbons, ethers, chlorinated hydrocarbons, ketones, amides, sulphoxides, water, and mixtures thereof.
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