Description:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of tofacitinib and an intermediate thereof. Particularly, the present invention relates to a process for the preparation of a salt of 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, and its use in the preparation of tofacitinib or a pharmaceutically acceptable salt thereof. The present invention also provides a process for the preparation of tofacitinib or a pharmaceutically acceptable salt thereof, which is substantially free of a dimer impurity and a trimer impurity.
BACKGROUND OF THE INVENTION
Tofacitinib, also known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d] pyrimidin-4-ylamino)-ß-oxo-1­piperidinepropanenitrile, is represented by the compound of formula II (the “compound II”). The citrate salt of tofacitinib is represented by the compound of formula I (the “compound I”).

I II
Tofacitinib is described in U.S. Pat. No. RE41783 as a racemic compound, and in U.S. Pat. No. 7,301,023 as a specific enantiomer. The citrate salt of tofacitinib is described in U.S. Pat. No. 6,965,027. Tofacitinib, a Janus kinase (JAK) inhibitor, is indicated for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Tofacitinib is marketed in the USA as XELJANZ® and XELJANZ XR®. XELJANZ® is marketed in tablet and solution dosage form, whereas XELJANZ XR® is marketed in extended release tablet dosage form, for oral administration. XELJANZ® contains tofacitinib citrate as the active pharmaceutical ingredient (API), which is equivalent to 5 mg and 10 mg tofacitinib base in tablet and equivalent to 1mg per ml tofacitinib base in solution respectively. XELJANZ XR® also contains tofacitinib citrate as the active pharmaceutical ingredient (API), which is equivalent to 11 mg and 22 mg tofacitinib base respectively.
Various processes for the preparation of tofacitinib (the compound II) and/or its citrate salt (the compound I) are reported in the art.
U.S. Pat. No 7,301,023 (the US’023 patent) discloses a process for the preparation of tofacitinib (the compound II), wherein racemic (1-benzyl-4-methylpiperidin-3-yl)-methylamine is resolved using di-p-toluoyl-L-tartrate to obtain (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine, the obtained product is condensed with 4-chloropyrrolo[2,3-d]pyrimidine to obtain (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine, which is then debenzylated and condensed with cyano acetic acid derivative namely cyanoacetic acid 2,5-dioxopyrrolidin-1-yl ester to obtain tofacitinib (the compound II).
U.S. Pat No. RE41783 discloses a process similar to that described in the US’023 patent, however, there is no disclosure regarding resolution of the racemic (1-benzyl-4-methylpiperidin-3-yl)-methylamine, and the stereochemistry of the product.
There are certain disadvantages associated with the processes for the preparation of tofacitinib or a pharmaceutically acceptable salt thereof reported in the art, for instance, the reported processes result in the formation of undesired by-products or impurities which affect the quality of the product.
It is a known fact that providing drug substances having high purity is considered a critical aspect in pharmaceutical industry, particularly for ensuring the safety, efficacy and consistency of the pharmaceutical composition containing the drug substance.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof, represented by the following formula IA (the “compound IA”);

IA
wherein, A is selected from the group consisting of citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate;
wherein the process comprises the steps of;
a) reacting 6-aminopyrimidine-2,4(1H,3H)-dione, a compound of formula III (the “compound III”) with chloroacetaldehyde, a compound of formula IV (the “compound IV”) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol, a compound of formula V (the “compound V”),

III IV V
wherein M is selected from Na or K;
b) treating the compound V obtained in the step a) with an acid to obtain 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol, a compound of formula VI (the “compound VI”);

VI
c) converting the compound VI obtained in the step b) to tofacitinib (the “compound II”); and
d) optionally, converting the tofacitinib (the “compound II”) obtained in the step c) to its pharmaceutically acceptable salt, the compound IA.
The present invention provides a process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof represented by the following formula IA (the “compound IA”);

IA
wherein, A is selected from the group consisting of citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate;
wherein the process comprises the steps of;
a-1) reacting 6-aminopyrimidine-2,4(1H,3H)-dione, the compound of formula III (the “compound III”) with chloroacetaldehyde, the compound of formula IV (the “compound IV”) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, the compound of formula V (the “compound V”),

III IV V
wherein M is selected from Na or K;
b-1) treating the compound V obtained in the step a-1) with an acid to obtain 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol, the compound of formula VI (the “compound VI”);

VI
c-1) treating the compound VI obtained in the step b-1) with a halogenating agent to obtain 2,4-dihalo-7H-pyrrolo[2,3-d] pyrimidine, the compound of formula VII (the “compound VII”),

VII
wherein X is a halogen selected from Cl, Br or I;
d-1) reacting the compound VII obtained in the step c-1) with a tosylating agent to obtain a compound of formula VIII (the “compound VIII”),

VIII
wherein “Ts” refers to tosyl;
e-1) reacting the compound VIII obtained in the step d-1) with (3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine, the compound of formula IX (the “compound IX”) to obtain a compound of formula X (the “compound X”);

IX X
wherein “Tr” refers to trityl; Ts refers to tosyl and X is as defined above;
f-1) reacting the compound X obtained in the step e-1) with a base followed by an acid to obtain a compound of formula XI (the “compound XI”),

XI
wherein X is as defined above;
g-1) converting the compound XI obtained in the step f-1) to tofacitinib (the “compound II”); and
h-1) optionally, converting the tofacitinib (the “compound II”) obtained in the step g-1) to its pharmaceutically acceptable salt, the compound of formula IA (the “compound IA”).
The present invention also provides a process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof (the “compound IA”), which is substantially free of a dimer impurity and a trimer impurity (as described herein).
The present invention also provides a compound of formula V, wherein M is Na, represented by the compound of formula VA (the “compound VA”), wherein the content of dimer impurity and trimer impurity ranges from about 0.01% to about 0.5% w/w, as measured by HPLC;

VA.
The present invention further provides the crystalline form of the compound VA characterised by X-ray powder diffraction (XRPD) pattern having peak reflections at 9.06, 13.98, 14.59, 16.88, and 18.23±0.2 degrees 2 theta.
The present invention further provides impurities of tofacitinib referred to as the compounds of formulae A and B (as described herein).
These and other aspects of the present invention will be apparent from the following description, and reference to the accompanying drawings.
BRIEF DESCRIPTION OF DRAWING
Figure 1: X-ray powder diffraction (XRPD) graph of crystalline form of compound VA.

DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof, represented by the following formula IA (the “compound IA”);

IA
wherein, A is selected from the group consisting of citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate;
wherein the process comprises the steps of;
a) reacting 6-aminopyrimidine-2,4(1H,3H)-dione, a compound of formula III (the “compound III”) with chloroacetaldehyde a compound of formula IV (the “compound IV”) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol, a compound of formula V (the “compound V”),

III IV V
wherein M is selected from Na or K;
b) treating the compound V obtained in the step a) with an acid to obtain 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, a compound of formula VI (the “compound VI”);

VI
c) converting the compound VI obtained in the step b) to tofacitinib (the “compound II”); and
d) optionally, converting the tofacitinib (the “compound II”) obtained in the step c) to its pharmaceutically acceptable salt, the compound IA.
The term “pharmaceutically acceptable salts” as used herein may be used interchangeably with the term “salts”, and includes, but not limited to salts selected from citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate salts of tofacitinib.
Tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof (the “compound IA”) obtained by the process of the present invention is substantially free of the impurities referred to as the dimer impurity, a compound of formula A (the “compound A”) and the trimer impurity, a compound of formula B (the “compound B”).

A B
The term “substantially free” as used herein, unless otherwise defined, refers to tofacitinib (the “compound II”), or a pharmaceutically acceptable salt (the “compound IA”) that contains the dimer impurity, the compound A and the trimer impurity, the compound B in a range from about 0.01 % to about 0.5 % w/w, as measured by HPLC (High-performance liquid chromatography).
As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
It is a known fact that it is not always straightforward to remove impurities formed in the process for the preparation of a drug substance. The present inventors have found a method for the removal of the dimer impurity, the compound A and the trimer impurity, the compound B, which is formed in the process for the preparation of tofacitinib or its pharmaceutically acceptable salts, and its removal was found to be difficult.
In another aspect, the present invention provides a process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof represented by the following formula IA (the “compound IA”);

IA
wherein, A is selected from the group consisting of citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate;
wherein the process comprises the steps of;
a-1) reacting 6-aminopyrimidine-2,4(1H,3H)-dione, the compound of formula III (the “compound III”) with chloroacetaldehyde, the compound of formula IV (the “compound IV”) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, the compound of formula V (the “compound V”),

III IV V
wherein M is selected from Na or K;
b-1) treating the compound V obtained in the step a-1) with an acid to obtain 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, the compound of formula VI (the “compound VI”);

VI
c-1) treating the compound VI obtained in the step b-1) with a halogenating agent to obtain 2,4-dihalo-7H-pyrrolo[2,3-d] pyrimidine, the compound of formula VII (the “compound VII”),

VII
wherein X is a halogen selected from Cl, Br or I;
d-1) reacting the compound VII obtained in the step c-1) with a tosylating agent to obtain a compound of formula VIII (the “compound VIII”),

VIII
wherein “Ts” refers to tosyl;
e-1) reacting the compound VIII obtained in the step d-1) with (3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine, the compound of formula IX (the “compound IX”) to obtain a compound of formula X (the “compound X”);

IX X
wherein “Tr” refers to trityl; Ts refers to tosyl and X is as defined above;
f-1) reacting the compound X obtained in the step e-1) with a base followed by an acid to obtain a compound of formula XI (the “compound XI”),

XI
wherein X is as defined above;
g-1) converting the compound XI obtained in the step f-1) to tofacitinib (the “compound II”); and
h-1) optionally, converting the tofacitinib (the “compound II”) obtained in the step g-1) to a pharmaceutically acceptable salt, the compound of formula IA (the “compound IA”).
In one embodiment, in the process of the present invention, the step a) or the step a-1) is carried out in the presence of a solvent selected from water, a hydrocarbon solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, and cyclohexane; a chlorinated solvent selected from the group consisting of dichloromethane, dichloroethane, and chloroform; a nitrile solvent selected from the group consisting of acetonitrile, propionitrile, and butyronitrile; an ester solvent selected from the group consisting of ethyl acetate, butyl acetate, isopropyl acetate, and isobutyl acetate; an ether selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; a ketone selected from the group consisting of acetone, cyclohexanone, methyl ethyl ketone, and isobutyl ketone; a polar aprotic solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, and dimethylsulfoxide; an alcohol selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and isobutyl alcohol; or a mixture of one or more solvents.
In another embodiment, in the process of the present invention, the step a) or the step a-1) is carried out in water.
In yet another embodiment, in the process of the present invention, the alkali metal salt of an organic acid used in the step a) or the step a-1) is selected from sodium acetate or potassium acetate.
In another embodiment, in the process of the present invention, the base used in the step a) or the step a-1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
In one embodiment, in the process of the present invention, the reaction in the step a) or the step a-1) is carried out at a temperature ranging from about 5°C to about 40°C.
The compound V obtained by the process of the present invention is isolated, and characterised.
In an aspect, the present invention provides a compound of formula V, wherein M is Na, represented by the compound of formula VA (the “compound VA”) wherein the content of each of the dimer impurity (the “compound A”) and the trimer impurity (the “compound B”) is in the range from about 0.01% to about 0.5% w/w, as measured by HPLC.

VA
In another embodiment, the present invention provides the compound VA, wherein the content of each of the dimer impurity (the “compound A”) and the trimer impurity (the “compound B”) is in the range from about 0.01% to about 0.2% w/w, as measured by HPLC.
In an aspect, the present invention provides a crystalline form of the compound VA characterised by X-ray powder diffraction (XRPD) pattern having peak reflections at 9.06, 13.98, 14.59, 16.88, and 18.23 ±0.2 degrees 2 theta.
In an embodiment, the present invention provides the crystalline form of the compound VA, wherein the content of each of the dimer impurity, the compound A and the trimer impurity, the compound B is in the range from about 0.01% to about 0.5% w/w, as measured by HPLC.
In a further embodiment, the present invention provides the crystalline form of the compound VA, wherein the content of each of the dimer impurity, the compound A and the trimer impurity, the compound B, is in the range from about 0.01% to about 0.2% w/w, as measured by HPLC.
In one embodiment, in the process of the present invention, in the step b) or the step b-1), the reaction is carried out in the presence of a solvent selected from water, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol; or a mixture thereof.
In one embodiment, in the process of the present invention, in the step b) or the step b-1), the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, acetic acid or trifluoroacetic acid.
In one embodiment, in the process of the present invention, in the step b) or the step b-1), the reaction is carried out at a temperature ranging from about 10°C to about 40°C.
In one embodiment, in the process of the present invention, in the step c-1), the reaction is carried out in the presence of a hydrocarbon solvent selected from toluene, xylene, benzene, chlorobenzene, cyclohexane, or a mixture thereof.
In one embodiment, in the process of the present invention, in the step c-1), the halogenating agent is selected from phosphorous oxychloride, thionyl chloride, phosphorous pentachloride or oxalyl chloride.
In one embodiment, in the process of the present invention, in the step c-1), the reaction is carried out in the presence of a base selected from the group consisting of methylamine, dimethylamine, dipropylamine, tripropylamine, tributylamine, N,N-dimethylcyclohexylamine trimethylamine, ethylamine, propylamine, butylamine, triethylamine, N,N-diisopropylethylamine, aniline, N,N-dimethyl aniline, N,N-diethyl aniline, N-methylpiperidine, N-methyl morpholine, pyridine and piperidine.
In one embodiment, in the process of the present invention, in the step c-1) the reaction is carried out at a temperature ranging from about 50°C to about 140°C.
In one embodiment, in the process of the present invention, in the step (d-1), the reaction is carried out in a solvent selected from ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
In one embodiment, in the process of the present invention, in the step (d-1), the reaction is carried out in the presence of a base selected from the hydroxides such as sodium hydroxide, potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate; or bicarbonates such as sodium bicarbonate, potassium bicarbonate.
In one embodiment, in the process of the present invention, in the step (d-1), the reaction is carried out at a temperature ranging from about 15°C to about 90?.
In an embodiment, in the process of the present invention, in the step (e-1), the reaction is carried out in presence of a solvent selected from ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
In one embodiment, in the process of the present invention, in the step (e-1), the reaction is carried out in the presence of a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
In one embodiment, in the process of the present invention, in the step (e-1), the reaction is carried out at a temperature ranging from about 15°C to about 90?.
In one embodiment, in the process of the present invention, in the step (f-1), the reaction is carried out in the presence of solvent selected from ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
In one embodiment, in the process of the present invention, in the step (f-1), the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
In one embodiment, in the process of the present invention, in the step (f-1), the acid is selected from acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, nitric acid, oxalic acid, malonic acid, succinic acid, phosphoric acid, maleic acid, fumaric acid, ethanedisulfonic acid, citric acid, oxalic acid, sulphuric acid, p-toluene sulphonic acid or methane sulfonic acid.
In one embodiment, in the process of the present invention, in the step (f-1), the reaction is carried out at a temperature ranging from about 15°C to about 90?.
In one embodiment, in the process of the present invention, the step (g-1) relating to conversion of the compound XI to tofacitinib (the compound II) involves subjecting the compound XI obtained in the step f) to dehalogenation by treating it with a catalyst, followed by treatment with methyl cyanoacetate in the presence of a base to obtain to tofacitinib (the “compound II”).
In an embodiment, in the process of the present invention, in the step (g-1), the compound XI (wherein X is Cl) is converted to tofacitinib (compound II) by subjecting it to dechlorination by treating it with a catalyst, followed by treatment with methyl cyanoacetate in the presence of a base.
In one embodiment, in the process of the present invention, in the step (g-1), the reaction is carried out in the presence of a solvent selected from water, alcohol such as methanol, ethanol, propanol, butanol and the like, ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
In one embodiment, in the process of the present invention, in the step (g-1), the catalyst used for dehalogenation of the compound XI is selected from bis[(2-diphenylphosphino)phenyl]ether, [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride, palladium on carbon (Pd/C), palladium acetate, palladium chloride, palladium hydroxide, tetrakis (triphenylphosphine)palladium(Pd(PPh3)4), tris(dibenzylideneacetone)-dipalladium [Pd2(dba)3], bis(dibenzylideneacetone)-palladium(0) (Pd(dba)2), bis(benzonitrile) dichloropalladium (II) ((C6H5CN)2PdCl2).
In one embodiment, in the process of the present invention, in the step (g-1), the base used in the reaction with methyl cyanoacetate is selected from methylamine, dimethylamine, trimethylamine, propylamine, dipropylamine, tripropylamine, butylamine, tributylamine, N,N-dimethylcyclohexylamine ethylamine, triethylamine, N,N-diisopropylethylamine, aniline, N,N-dimethyl aniline, N,N-diethyl aniline, N-methylpiperidine, N-methylmorpholine, pyridine, piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
In one embodiment, in the process of the present invention, in the step (g-1), tofacitinib, the compound II may be purified by one or more methods of purification known in the art such as charcoal treatment, acid-base purification, leaching, crystallization or combination thereof, wherein the solvent used in the purification step is selected from water, ethyl acetate, methylene chloride, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, isopropanol or a mixture thereof.
In one embodiment, in the process of the present invention, in the above step (h-1), the pharmaceutically acceptable salt of tofacitinib (the compound IA) is obtained by treating tofacitinib, the compound II with a suitable acid. The acid is used in the form of an aqueous solution or in the form of a solution in an organic solvent, wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol and butanol.
In one embodiment, in the process of the present invention, in the step (h-1) involving conversion of the tofacitinib, the compound II, to its pharmaceutically acceptable salt, the compound IA, is carried out in the presence of a solvent selected from water, alcohol such as methanol, ethanol, propanol, butanol and the like, ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone or a mixture thereof.
In one embodiment, in the process of the present invention, in the step (h-1), the acid used is citric acid to obtain the corresponding pharmaceutically acceptable salt, which is tofacitinib citrate, the compound I.
In one embodiment, in the process of the present invention, in the step (h-1), tofacitinib citrate, the compound I is purified by one or more purification methods known in the art, such as charcoal treatment, acid-base purification, leaching, crystallization or combination thereof, wherein the solvent used in the purification step is selected is selected from water, ethyl acetate, methylene chloride, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, isopropanol or mixtures thereof.
The compounds that are formed as impurities in the process of the preparation of tofacitinib, the compound II or a pharmaceutically acceptable salt thereof, the compound IA, are designated as the compound A and compound B respectively, which are structurally represented by the compounds of formulae A and B herein above.
In one embodiment, the present invention provides tofacitinib, the compound II, or the pharmaceutically acceptable salt thereof, the compound IA, having a chemical purity of at least 90% wherein the content of each of the compound A and the compound B is in the range from about 0.01% to about 0.5% w/w, as measured by HPLC.
In yet another embodiment, the present invention provides tofacitinib, the compound II or the pharmaceutically acceptable salt thereof, the compound IA, having a chemical purity of at least 99% wherein the content of each of the compound A and compound B is in the range from about 0.01% to about 0.5% w/w, as measured by HPLC.
In one embodiment, the present invention provides tofacitinib, the compound II or the pharmaceutically acceptable salt thereof, the compound IA, having a chemical purity of about 99.5% wherein the content of each of the compound of formula A and compound of formula B is in the range from about 0.01% to about 0.2 % w/w, as measured by HPLC.
In a preferred embodiment, the pharmaceutically acceptable salt of tofacitinib, the compound IA is the citrate salt, which is designated herein as the compound I.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.
Examples:
General Methods:
1. XRD method:
Incident Beam Optics:
PreFIX Module : Programmable Divergence Slit and Anti-scatter Slit
(Offset 0.00°)
Filter : Nickel
Soller Slit : Soller 0.02 rad
Mask : 10mm
Divergence Slit : PDS
Automatic, 10mm Irradiated length, Offset 0.00mm
Anti-scatter Slit : Slit Fixed 1/2°
Beam Knife : Beam Knife for MPD systems
Diffracted Beam Optics:
PreFIX Module : Pixcel (Offset 0.00°)
Soller Slit : Soller 0.02 rad
Anti-scatter Slit : Programmable Anti-scatter Slit
Automatic, 10mm Observed length, Offset 0.00mm
Detector : Pixcel Scanning Mode, Active length (2T) = 2.122°
Measurement Parameters:
Scan axis : Gonio
Scan mode : Continuous
Start angle (°) : 2.0
End angle (°) : 50.0
Step size (°) : 0.0131
Time per step (s) : 50

2. HPLC method:
High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:
Column: Zorbax XDB C18, 250 X 4.6 mm, 5µ
Column Temperature: 30°C
Mobile phase:
Mobile Phase A:
Buffer (100%)
Buffer: Sodium perchlorate monohydrate (1.4g), octane-1-sulfonic acid sodium salt (1.0g) in water (1000 ml.) Adjust pH 3.0 with perchloric acid.
Mobile Phase B:
Methanol (100%)
Time (min) % Mobile Phase A % Mobile Phase B
0.01 98 02
5.0 93 07
35 20 80
39 20 80
40 98 02
47 98 02

Diluent 1: Methanol: water (50:50, v/v)
Diluent 2: Dimethyl sulfoxide: Diluent 1 (10:90 v/v)
Flow Rate: 1.20 mL/Minute
Detection: UV 275 nm
Injection Volume: 15 µL

Example 1: 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol disodium salt (compound VA).
In a round bottom flask, 6-aminouracil (100 g), water (400 mL) and sodium acetate (129 g) were added to obtain a reaction mass. Chloroacetaldehyde (160.5g, ~55% in water) was slowly added to the reaction mass within a period of 5 to 6 hours, and the reaction mass was stirred for about 12 hours at a temperature in the range of 20? to 30?. After the completion of the reaction, the reaction mass was cooled to a temperature in the range of 10? to 15°C. The pH of the reaction mass was adjusted to 9.5-11 with 40% sodium hydroxide solution to obtain a clear solution. The reaction mass was stirred for a period of 10 minutes. The pH was adjusted to 12 to 14 with 40% sodium hydroxide solution to obtain a precipitate. The reaction mass was cooled to a temperature in the range of 5? to 10°C and stirred for a period of 60 minutes. The product was filtered, washed with chilled water, and dried under vacuum at a temperature in the range of 40? to 45°C to obtain the compound VA.
Yield: 107 gm.
Purity: 98.71% (as determined by HPLC).
Compound A (Dimer impurity): 0.03%, compound B (Trimer impurity): 0.05%.
NMR: 1H NMR (DMSO-d6, 400 MHz) d 11.38 (br, 1H), 6.53 (s, 1H), 6.18 (s, 1H),
XRD: XRPD peaks at 9.06, 13.98, 14.59, 16.88, 18.23 ±0.2 degrees 2 theta.

Example 2: 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (compound VI)
In a clean round bottom flask, 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol disodium salt (compound VA, 105g), water (1200 ml) were added, and stirred to obtain a clear solution. The pH of the solution was adjusted to 1-2 with concentrated HCl. The reaction mass with the precipitated solid was stirred for a period of 120 min at a temperature in the range of 20? to 30°C. The product was filterd, washed with water and dried in air tray drier (ATD) at a temperature in the range of 50? to 55°C to obtain the compound VI.
Yield: 75 gm.
Purity: 98.73% (as determined by HPLC).
Compound A (Dimer impurity): 0.02%, compound B (Trimer impurity): 0.07%.

Example 3 : 2,4-dichloro-7H-pyrrolo[2,3D]pyrimidine (compound VII, wherein X is Cl).
In round bottom flask, 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (compound VI as obtained in example 2, 100 gm), toluene (100 ml) and phosphorous oxychloride (304.40 gm) were added to obtain a reaction mass. The temperature of reaction mass was raised to a range of 70? to 80°C. N,N-diisopropylethyl amine (128.33 gm) was slowly added to the reaction mass at a temperature in the range of 70? to 80°C, and then the reaction mass was heated to a temperature in the range of 95? to 105°C. The reaction mass was stirred for a period of 20 hours at a temperature in the range of 95? to 105°C. After completion of the reaction, the reaction mass was cooled to a temperature in the range of 0? to 5°C. Water was added to the reaction mass and the reaction mass was stirred for a period of 2 hours at a temperature in the range of 10? to 30°C. The product was filtered and washed with water. In another round bottom flask, methanol (500 ml) and the above obtained product were added. The pH of the reaction mass was adjusted to 8-9 with aqueous ammonia solution. The reaction mass was stirred at a temperature in the range of 20? to 30°C for a period of 2 hours and then was further cooled to a temperature in the range of 0? to 5°C. The reaction mass was filtered and washed with methanol. The wet cake was dried at a temperature in the range of 45-50°C to obtain the compound VII.
Yield: 90 gm.
Purity: 99.91% (as determined by HPLC).
compound A (Dimer impurity): Not detected, compound B (Trimer impurity): 0.08%.

Example 4: Preparation of 2,4-dichloro-7-[(4-methylphenyl)sulphonyl]-7H-pyrrolo[2,3-d)pyrimidine (compound VIII):
In a round bottom flask, 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine (compound VII, 100 gm), acetone (1000 mL) and tosyl chloride (131.8 gm) were added at a temperature in the range of 20? to 30°C to obtain a reaction mass. To the reaction mass, sodium hydroxide solution (31.8g sodium hydroxide in 400ml water) was gradually added, and the reaction mass was stirred for 2 hrs at a temperature in the range of 20? to 30°C. After completion of the reaction, product was filtered and washed with mixture of acetone and water. The product was dried at a temperature in the range of 50? to 55°C.
Yield: 155gm
Purity: 98% (as determined by HPLC).

Example 5: Preparation of Preparation of 2-chloro-N-methyl-N-[(3R,4R)-4-methyl piperidine-3-yl]-7-pyrolo[2,3-d]pyrimidine-4-amine (compound XI):
In a round bottom flask, Dimethylformamide (700 ml), acetonitrile (300 ml), 2,4-dichloro-7-[(4-methylphenyl)sulphonyl]-7H-pyrrolo[2,3-d)pyrimidine (compound VIII, 100 gm), (3R,4R)-1-trityl-N, 4-dimethylpiperidine-3-amine (compound IX, 96.52 gm) and potassium carbonate (186.23 gm) were added. The reaction mass was heated to a temperature in the range of 65? to 70°C and was stirred for a period of 2 hours. After completion of the reaction, the reaction mass was cooled to a temperature in the range of 20? to 30°C. Water was added slowly to the reaction mass and the reaction mass was stirred for 4 hours at a temperature in the range of 20? to 30°C. The reaction mass was filterd and dried at a temperature in the range of 55? to 60°C to obtain a compound X (wherein X is Cl). In another round bottom flask, the product was added with acetone (1600 ml) and sodium hydroxide solution (32.39gm in 400ml water). The reaction mass was heated to a temperature in the range of 55? to 60°C. The reaction mass was stirred for a period of 2 hours at a temperature in the range of 55? to 60°C. The reaction mass was cooled to a temperature in the range of 20? to 30°C. Water (2750 ml) was added slowly to the reaction mass. The reaction mass was stirred for a period of 4 hours at a temperature in the range of 20? to 30°C. The product was filtered and washed with water. The wet product was dried in Air tray drier(ATD) at a temperature in the range of 55? to 60°C. In another round bottom flask, trifluroacetic acid (50 ml) and methylene chloride (300 ml ) were charged at a temperature in the range of 20? to 30°C and then cooled to a temperature in the range of 0? to 10°C. A solution of 2-chloro-N-Methyl-N-[(3R,4R)-1-trityl-4-methyl piperidine-3-yl]-7-pyrolo[2,3-d] pyrimidine-4-amine (100 gm) in methylene dichloride (600 ml) was slowly added to the reaction mass at a temperature in the range of 0? to 10°C. The reaction mass was stirred for a period of 1 to 2 hours at a temperature in the range of 0? to 10°C. After completion of the reaction, methylene chloride was distilled and degassed to obtain a residue. Water and ethyl acetate were added to the residue, the reaction mass was stirred and the layers were separated. The pH of the aqueous layer was adjusted to 9.0 with aqueous potassium carbonate solution. The reaction mass was stirred for a period of 4 to 5 hours. The product was filtered. The wet cake was added with ethyl acetate and was heated to a temperature in the range of 60? to 65°C, wherein it was stirred for a period of 2 hours. The reaction mass was cooled to a temperature in the range of 20? to 30°C. The product was filtered and washed with ethyl acetate. Wet product was dried at a temperature in the range of 50? to 55°C.
Yield: 121.4 gm
Purity: 99% (as determined by HPLC).
Example 6: Preparation of Tofacitinib (Compound II):
In round bottom flask, 2-chloro-N-Methyl-N-[(3R,4R)-4-methyl piperidine-3-yl]-7-pyrolo[2,3-d] pyrimidine-4-amine (compound XI) (100 gm) and water (2500 mL) were charged at a temperature in the range of 20? to 30°C to obtain a reaction mass. The reaction mass was heated to a temperature in the range of 50? to 60°C and was stirred for a period of 45 minutes. The reaction mass was filtered and washed with methanol at a temperature in the range of 50? to 60°C. The filtrate was cooled to a temperature in the range of 20? to 30°C and then was charged in an autoclave. The reaction mass was added with palladium on carbon (8 gm) and hydrogen pressure of 8 to 10 kg/cm2 was applied to the autoclave. The reaction mass was heated to a temperature in the range of 55? to 60°C and stirred for a period of 4 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to a temperature in the range of 20? to 30°C. The reaction mass was filtered and washed with methanol. The filtrate was distilled under vacuum at a temperature below 60°C to obtain the residue. The residue was added with acetonitrile (500 ml) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (163.24 gm) at a temperature in the range of 20? to 30°C. This was followed by addition of methyl cyano acetate (106.25 gm) under nitrogen. The reaction mass was stirred for a period of 6 to 7 hours at a temperature in the range of 20? to 30°C. After reaction was completed, the reaction mass was concentrated completely under vacuum below 30°C and was degassed for 2 hours to a temperature below 30°C to obtain the residue. The residue was added with water (700 ml) and ethyl acetate (500 ml). Aqueous Hydrochloric acid was added to adjust the pH below 2.0. The reaction mass was stirred and ethyl acetate layer was separated. The aqueous layer pH was adjusted to above 9.0 with aqueous potassium carbonate solution (190 g potassium carbonate in 380 ml water) and it was extracted with methylene dichloride (1500 ml). The reaction mass was distilled and degassed under vacuum below a temperature of 40°C to remove methylene chloride and to obtain tofacitinib.
Yield: 120 gm
Purity: 99.0% (as determined by HPLC).
Example 7: Preparation of Tofacitinib Citrate (Compound I):
The tofacitinib (100 gm) was added with acetone (700 ml) and was stirred for 15 minutes to obtain a clear solution. The reaction mass was added with citric acid aqueous solution (89.3 g in 300 ml water) and was heated to a temperature in the range of 50? to 55°C. The reaction mass was stirred for a period of 1 hour at a temperature in the range of 50? to 55°C. The reaction mass was cooled to a temperature in the range of 15? to 20°C and was stirred for a period of 6 hours. The product was filtered and was dried under vacuum at a temperature in the range of 55-60°C.
Yield: 88 gm
Purity: 99.9 % (as determined by HPLC).

Comparative Example Preparation of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (compound VI) [without isolating Compound VA, the disodium salt]:
In a round bottom flask, 6-aminouracil (100 gm), water (400 ml) and sodium acetate (129 gm) were added. Chloroacetaldehyde (160.5 gm, ~55% in water) was slowly added to the reaction mass within a period of 5 to 6 hours, and stirred the reaction mass for a period of 12 hours at a temperature in the range of 20? to 30°C. After the completion of the reaction, the reaction mass was cooled to a temperature in the range of 10? to 15°C. The reaction mixture was stirred for a period of 120 min at a temperature in the range of 10? to 15°C. The product was filtered and washed with water. The wet product was dried in air tray drier (ATD) at a temperature in the range of 50? to 55°C.
Yield: 105 gm.
Purity: 72.23% (as determined by HPLC).
compound A (Dimer impurity): 1.2%, compound B (Trimer impurity): 2.10%.
, Claims:We Claim:
1. A process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt thereof (the “compound IA”);

IA
wherein, A is selected from the group consisting of citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate;
wherein the process comprises the steps of;
a) reacting 6-aminopyrimidine-2,4(1H,3H)-dione, the compound of formula III (the “compound III”) with chloroacetaldehyde, the compound of formula IV (the “compound IV”) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol, the compound of formula V (the “compound V”),

III IV V
wherein M is selected from Na or K;
b) treating the compound V obtained in the step a) with an acid to obtain 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol, represented by the compound of formula VI (the “compound VI”);

VI
c) converting the compound VI obtained in the step b) to tofacitinib (the “compound II”); and
d) optionally, converting the tofacitinib (the “compound II”) obtained in the step c) to its pharmaceutically acceptable salt, the compound IA.
2. A process for the preparation of tofacitinib, the compound II, or a pharmaceutically acceptable salt, the compound IA, as claimed in claim 1, wherein the content of each of the compounds of formula A and the compound of formula B is in the range from about 0.01% to about 0.5% w/w as measured by HPLC.
3. A process as claimed in claim 1, wherein in the step (a) the solvent is selected from the group consisting of water, a hydrocarbon solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, and cyclohexane; a chlorinated solvent selected from the group consisting of dichloromethane, dichloroethane, and chloroform; a nitrile solvent selected from the group consisting of acetonitrile, propionitrile, and butyronitrile; an ester solvent selected from the group consisting of ethyl acetate, butyl acetate, isopropyl acetate, and isobutyl acetate; an ether selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; a ketone selected from the group consisting of acetone, cyclohexanone, methyl ethyl ketone, and isobutyl ketone; a polar aprotic solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, and dimethylsulfoxide; an alcohol selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and isobutyl alcohol; or a mixture thereof.
4. A process as claimed in claim 1, wherein in the step (a) an alkali metal salt of an organic acid selected from sodium acetate and potassium acetate, and the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
5. A process as claimed in claim 1, wherein in the step (a), the compound of formula V, wherein M is Na, represented by the compound of formula VA (the “compound VA”) has the content of each of the compound of formula A and the compound of formula B in the range from 0.01% to 0.5% w/w as measured by HPLC.

VA
6. A process as claimed in claim 1, wherein in the step (a), the compound of formula VA is in crystalline form and is characterized by X-ray powder diffraction (XRPD) having peak reflections at 9.06, 13.98, 14.59, 16.88, 18.23 ±0.2 degrees 2 theta.
7. A process as claimed in claim 1, wherein in the step (b), the solvent is selected from the group consisting of water, an alcohol selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and isobutyl alcohol; or a mixture thereof.
8. A process as claimed in claim 1, wherein in the step (b), the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid or trifluoroacetic acid.
9. A process for the preparation of tofacitinib (the “compound II”) or a pharmaceutically acceptable salt represented by the following formula IA (the “compound IA”) as claimed in claim 1;

IA
wherein, A is selected from the group consisting of citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate;
wherein the process comprises the steps of;
a-1) reacting 6-aminopyrimidine-2,4(1H,3H)-dione, the compound of formula III (the “compound III”) with chloroacetaldehyde, the compound of formula IV (the “compound IV”) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, the compound of formula V (the “compound V”),

III IV V
wherein M is selected from Na or K;
b-1) treating the compound V obtained in the above step a-1) with an acid to obtain 7H-pyrrolo[2,3-d] pyrimidine-2,4-diol, the compound of formula VI (the “compound VI”);

VI
c-1) treating the compound VI obtained in the above step b-1) with a halogenating agent to obtain 2,4- dihalo-7H-pyrrolo[2,3-d]pyrimidine, the compound of formula VII (the “compound VII”),

VII
wherein X is a halogen selected from Cl, Br or I;
d-1) reacting the compound VII obtained in the above step c-1) with a tosylating agent to obtain a compound of the formula VIII (the “compound VIII”),

VIII
wherein “Ts” refers to tosyl;
e-1) reacting the compound VIII obtained in the above step d-1) with (3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine, the compound of formula IX (the “compound IX”) to obtain a compound of the formula X (the “compound X”);

IX X
wherein “Tr” refers to trityl; Ts refers to tosyl and X is as defined above;
f-1) reacting the compound X obtained in the above step e-1) with a base followed by an acid to obtain a compound of the formula XI (the “compound XI”),

XI
wherein X is as defined above;
g-1) converting the compound XI obtained in the step f-1) to tofacitinib (the “compound II”); and
h-1) optionally, converting the tofacitinib (the “compound II”) obtained in the step g-1) to its pharmaceutically acceptable salt represented by the compound of formula IA (the “compound IA”).
10. Tofacitinib (the “compound II”) having the content of each of the compound of formula A and compound of formula B is in the range from about 0.01% to about 0.2 % w/w prepared by the process according to any one of the claims 1 and 9.