DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of tofacitinib and its pharmaceutically acceptable salt thereof. In particular, the present invention relates to an improved process for the preparation of tofacitinib citrate.
BACKGROUD OF INVENTION:
Tofacitinib also known as 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)piperidin-1-yl)-3-oxopropanenitrile of Formula I, is shown as below,

Formula I
Tofacitinib citrate salt of Formula Ia, has been approved in US and other countries for the treatment of certain patients with moderately to severely active rheumatoid arthritis [RA].

Formula Ia
Tofacitinib and its pharmaceutically acceptable salts have been first time disclosed in the US patent RE41,783, US patent 7,265,221 and US patent 7,301,023. The said patent family generically discloses a synthetic process for the preparation of tofacitinib and compounds analogous to tofacitinib. The process involves N-acylation of the piperidine moiety with cyanoacetic acid or derivatives thereof in the presence of base such as pyridine and a suitable organic solvent to give tofacitinib.
US patent 6,965,027 provides a process for the preparation of tofacitinib which involves amidation of (3R,4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine with cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester in the presence of ethanol and triethylamine at ambient temperature followed by washing and drying to provide crude tofacitinib. The said patent further describes the crystalline form of tofacitinib mono citrate salt.
In above mentioned patents, the amidation reaction has been executed in two steps via the activation of the cyanoacetic acid with an activating agent followed by reaction with piperidine moiety in the presence of triethylamine and ethanol.
In another US patent 8,309,716, a method for the preparation of tofacitinib is disclosed wherein N-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine is directly converted into tofacitinib by direct treatment with ethyl cyanoacetate in the presence of toluene and triethylamine. The reaction is heated upto 100°C followed by washing with water to provide tofacitinib.
An article, namely, Organic Letters, 2009 discloses a process for the preparation of tofacitinib wherein N-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine is treated with an alkyl cyanoacetate in the presence of the base. The base used herein is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) along with the solvent 1-butanol.
In several Chinese patent publications CN108276414, CN102875555, CN109776547, CN114437073 and CN11437073, similar method of preparing tofacitinib citrate has been disclosed. In all said patent publications piperidine moiety is treated with ethyl cyanoacetate in the presence of a base and solvent. The base used herein is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Further, the inventors of present application have found that the reaction of piperidine moiety with ethyl cyanoacetate in the presence of either of DBU or triethylamine in a suitable solvent does not reach to its completion. A certain percentage of the starting material i.e., piperidine moiety was found to be unreacted during reaction monitoring. This unreacted material or by-product influences the purity and yield of the final product. Also, the experiments as disclosed within the above said patent/ patent applications are silent about the purity of the final product.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
Even though, in synthetic organic chemistry getting a single end product with 100% purity is seldom wherein there is always a chance of having by-products. Because by-products or impurities can be formed through variety of side reactions, such as incomplete reaction, over reaction, isomerization, dimerization, rearrangement or unwanted reactions between starting materials or intermediate with chemical reagents or catalysts. Such impurities that remain within the formulation or API even in the small amounts can influence quality, safety and efficacy (QSE) of the product, thereby causing serious health hazards. Therefore, the limits and threshold values of those impurities should comply with the limits set and specified by official bodies and legislation (Pharmacopoeias and International conference on Harmonization (ICH) guidelines).
In order to overcome the aforementioned drawbacks in the prior art processes mainly due to the incompletion of the reaction, there is a need in the art to provide an improved process for the preparation of tofacitinib and its pharmaceutically acceptable salt thereof, wherein the amidation reaction reach to its completion Since, this is the final step in the synthesis of an active pharmaceutical ingredient i.e., tofacitinib, so mild conditions need to be opted to minimize the formation of the by-products.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient and industrial advantageous process for the preparation of highly pure tofacitinib and its pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide an effective process for the preparation of tofacitinib and its pharmaceutically acceptable salt thereof wherein the formation of by-products is controlled as per ICH guidelines.
One another object of the present invention is to provide a process for the preparation of tofacitinib and its pharmaceutically acceptable salt thereof in good purity.
SUMMARY OF INVENTION:
Accordingly, the present invention provides a simple, improved and cost-effective process for the synthesis of tofacitinib of formula I and its pharmaceutically acceptable salt thereof.

Formula I
According to an embodiment, the present invention provides an efficient process for the preparation of tofacitinib of formula I and its pharmaceutically acceptable salt thereof,

Formula I
which comprises of:
reacting N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine of the formula II

Formula II
with 2-cyano acetic acid alkyl ester

wherein R1 is selected from C1-C6 alkyl group,
in the presence of at least two bases in an organic solvent to obtain tofacitinib.
According to an embodiment, the present invention provides an efficient process for the preparation of tofacitinib citrate of Formula Ia,

Formula Ia
which comprises of:
i) reacting N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine of the formula II

Formula II
with 2-cyano acetic acid alkyl ester

wherein R1 is selected from C1-C6 alkyl group,
in the presence of at least two bases in an organic solvent,
ii) converting the resulting tofacitinib obtained in step (i), into tofacitinib citrate.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides an efficient process for the preparation of tofacitinib and its pharmaceutically acceptable salt thereof, wherein the use of two bases or more during amidation reaction leads to the completion of reaction thereby minimizing the possibilities of by-products formation.
As used herein, the term “ambient temperature” represents a temperature 25?± 5?.
As used herein, the term “DI water” refers to deionized water, water that contains few or no anions and cations present in the solution.
As used herein, the term “pharmaceutically acceptable salt” refers to acid addition salt selected from the group which may include but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, gluconic acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
As used herein, the term “highly pure” represents a compound having purity greater than 99.0 w/w by HPLC, preferably greater than 99.2% w/w by HPLC, more preferably greater than 99.5% w/w by HPLC and any individual impurity [identified] present in an amount less than 0.15% w/w by HPLC, any unidentified impurity present in an amount of less than 0.10% w/w by HPLC and total impurities present in an amount less than 0.5% w/w by HPLC.
In one embodiment the present invention provides a process for the preparation of tofacitinib of formula (I) and its pharmaceutically acceptable salt thereof comprising of reacting N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine of the formula II with 2-cyano acetic acid alkyl ester in the presence of at least two bases in an organic solvent to obtain tofacitinib. The process further involves conversion of tofacitinib of formula I into tofacitinib citrate.
In the possession of present inventors, the above reaction is carried out in at least two bases. The inventors of present application have found that the amidation reaction of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine with 2-cyano acetic acid alkyl ester in the presence of mixture of bases reach to completion thereby minimizing the percentage of unreacted reactant as compared to the prior art processes performed in the single base only.
The bases used may include an organic base, inorganic base or mixture thereof. The mixture of bases used herein consist of either a mixture of organic bases or a mixture of an organic base with an inorganic base.
The organic bases include, but are not limited to, amines such as diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, dimethylaminopyridine 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, N,N-dimethyl aniline, N-methyl morpholine (NMM), N,N-dimethyl amino pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]octane (DABCO), tetramethylpiperidine, tetramethylguanidine, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.
Inorganic bases include, but are not limited to alkali or alkaline earth metal carbonate, bicarbonate, hydroxide or phosphate such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, hydride such as sodium hydride, lithium hydride or potassium hydride, alkoxide such as sodium or potassium methoxide or ethoxide, tertiary butoxide and the like or mixtures thereof.
The “organic solvent” used in above reaction can be selected from but are not limited to “alcohol solvents” such as methanol, ethanol, isopropanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, petroleum ether and the like; “halogenated solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and water.
In one embodiment, the present invention provides conversion of tofacitinib of formula I into highly pure tofacitinib citrate of formula Ia by a process comprising treatment of tofacitinib of formula I with citric acid in a suitable solvent. The suitable solvent may include an alcohol such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; a ketone such as acetone, propanone, methylisobutylketone and the like; a nitrile such as acetonitrile, propanenitrile and the like; an ester such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; a haloalkane such as dichloromethane, chloroform and the like; an ether such as dimethyl ether, isopropyl ether, methyl tert-butyl ether and the like; an aromatic hydrocarbon such as toluene and the like; a hydrocarbon such as n-hexane, n-heptane and the like; dimethyl formamide; dimethylsulfoxide; dimethyl acetamide; tetrahydrofuran; N-methylpyrrolidone; water; and mixtures thereof. Specifically, tofacitinib citrate of formula Ia can be prepared by treating tofacitinib of formula I with citric acid in a mixture of acetone and water followed by heating and stirring for completion of salt formation and then isolating tofacitinib citrate salt.
Tofacitinib citrate of formula Ia can be further purified using same solvent system as used for citrate salt formation. In particular, tofacitinib citrate can be purified using a mixture of acetone and water, if desired, to achieve the desired purity.
The process of the present invention provides highly pure tofacitinib citrate wherein the level of individual specified, and unspecified impurities is controlled at a level of equal to or less than 0.15% and 0.10% respectively and total impurities at a level of less than 0.5% as per regulatory guidelines.
The tofacitinib citrate obtained by the process of the present invention is highly pure, having good solubility and high stability, wherein content of residual solvents is within the prescribed limit of ICH guidelines.
In another embodiment of the present invention, the starting compound of formula II can be prepared by the methods reported in the literature or by the process as given in the present specification. Specifically compound of formula II can be prepared by coupling of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine with cis N-benzyl-3-amino piperidine or salt thereof in the presence of a base such as potassium or sodium carbonate in a polar solvent or mixture of polar solvent such as water or water and 1,4-dioxane or dimethylsulfoxide (DMSO) at an elevated temperature in the range of about 50°C and about 150 °C, preferably 100 °C to obtain the coupled compound N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7-(4-methyl benzene-1-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
The coupled compound is then subjected to deprotection conditions appropriate for the particular nitrogen protecting group and conditions to remove the tosyl activating group. When the protecting group is a group labile to hydrogenolysis hydrogenating conditions may be employed such as hydrogen pressurized to 10-100 psi , and a hydrogenation catalyst such as Pd(OH)2 in a polar solvent or mixture polar solvents optionally in the presence of an acid, to remove nitrogen protecting group followed by an alkali base, for example, such as aqueous sodium hydroxide to remove the activating group when the activating group is tosyl, to afford a compound of the Formula II.
When both the activating group and the protecting group are labile to hydrogenolysis both may be removed by hydrogenation conditions in a single reaction vessel. Alternatively, either the protecting group or activating group may be removed first using one set of conditions followed by removal of the remaining group under a second set of conditions.
In a further embodiment of the present invention, the purification of compound of formula II can be performed by any suitable purification technique such as slurring in a suitable solvent, crystallization or acid base treatment. In particular purification of compound of formula II can be accomplished using acid base treatment. The process comprises the reaction of compound of formula II with an acid to obtain corresponding pharmaceutically acceptable acid addition salts of formula II followed by hydrolysis to obtain pure compound of formula II.
The compound of formula II can be treated with an acid in the presence of organic solvent to obtain the pharmaceutically acceptable acid addition salt of compound of formula II which can be purified by one or more methods selected from isolation, slurrying in a suitable solvent, liquid-liquid extraction, chromatography and treating with adsorbents. Further, the acid addition salt of compound of formula II can be hydrolyzed by addition of a base in the presence of organic solvent to obtain the pure compound of formula II.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned compound of formula II of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, , tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The suitable base can be selected from an inorganic base or organic base. The inorganic base may be selected from alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, alkali metal alkoxide such as sodium methoxide, potassium methoxide, alkali metal or alkaline earth metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, and the like. Preferably, sodium hydroxide.
The organic base may be selected from the group consisting of organic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tri-n-butylamine, N-methylmorpholine and the like.
The organic solvent may include an alcohol such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; a ketone such as acetone, propanone, methylisobutylketone and the like; a nitrile such as acetonitrile, propanenitrile and the like; an ester such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; a haloalkane such as dichloromethane, chloroform and the like; an ether such as dimethyl ether, isopropyl ether, methyl tert-butyl ether and the like; an aromatic hydrocarbon such as toluene and the like; a hydrocarbon such as n-hexane, n-heptane and the like; dimethyl formamide; dimethylsulfoxide; dimethyl acetamide; tetrahydrofuran; N-methylpyrrolidone; water; and mixtures thereof.
It is advantageous to use purified compound of formula II to reduce the multifaction of impurities in the later stages. Major advantage realized in the present invention is the use of at least two bases to fasten the reaction completion during amidation reaction to achieve high efficiency. Further compound of formula II has also been purified by acid base treatment.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Preparation of tofacitinib citrate
N-Methyl-N-((3R,4R)-4-methyl piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50g) was taken in toluene (250ml) at an ambient temperature followed by addition of 2-cyano acetic acid ethyl ester (150g), triethylamine (38.5g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10g). The reaction mixture was heated at 100-110°C and stirred for 24 hours till completion of the reaction as monitored by HPLC (unreacted Formula II < 0.11%). After the reaction completion, toluene was distilled out under vacuum at a temperature of 70-80°C. The resulting residue was then dissolved in a mixture of DI water (250ml) and ethyl acetate (250ml) and pH was adjusted to 2-3 by addition of aqueous hydrochloric acid (25ml). The reaction mixture was stirred, and layers were separated. The aqueous layer was then washed with ethyl acetate and basified (pH 12-14) with aqueous potassium hydroxide solution (40g in 400ml DI water). Thereafter, the aqueous layer was washed twice with methylene dichloride (250ml, 50ml) followed by washing with brine solution. The organic layer was then distilled out at 40-45°C under vacuum. The resulting residue was then crystallized using acetone (250ml) at 0-10°C followed by filtration and drying at 50-60°C for 15-25 hours to obtain tofacitinib (42g). The dried material thus obtained was dissolved in acetone (217 ml) followed by addition of citric acid (26.1g) & DI water (130ml). The reaction mixture was then heated to 50-60°C and stirred for 4-8 hours for completion of salt formation and then cooled to 0-10°C and maintained the temperature for 1-2 hours. The resulting solid was filtered and washed with acetone (11 ml) and dried at 50-60°C for 15-25 hours to obtain 52.2g of tofacitinib citrate having HPLC purity [w/w] = 99.89%; single highest impurity= 0.05% at 1.44 RRT; other impurities= 0.02% & 0.03%.
Example 2: Preparation of tofacitinib citrate
N-Methyl-N-((3R,4R)-4-methyl piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50g) was taken in toluene (250ml) at an ambient temperature followed by the addition of 2-cyano acetic acid ethyl ester (150g), triethylamine (38.5g) and 1,5-diazabicyclo(4.3.0)non-5-ene (9g). The reaction mixture was then heated to 100-110°C and stirred for 24 hours till completion of the reaction as monitored by HPLC (unreacted Formula II < 0.08%). After the reaction completion, toluene was distilled out under vacuum at a temperature 70-80°C. The resulting residue was then dissolved in mixture of DI water (250ml) and ethyl acetate (250ml) and pH was adjusted to 2-3 by addition of aqueous hydrochloric acid) (25ml). The reaction mixture was stirred and layers were separated. The aqueous layer was then washed with ethyl acetate (50ml) and basified (pH 12-14) with aqueous potassium hydroxide solution (40g in 400ml DI water). Afterwards the aqueous layer was washed twice with methylene dichloride (250ml, 50ml) followed by washing with brine solution. The organic layer was then distilled out at 40-45°C under vacuum. The resulting residue was then crystallized using acetone (250ml) at 0-10°C followed by filtration and drying at 50-60°C for 15-25 hours to get tofacitinib. The resulting tofacitinib was then dissolved in acetone (213 ml) followed by addition of citric acid (25.5g) and DI water (127ml). The reaction mixture was then heated to 50-60°C for 4-8 hours and then cooled at 0-10°C and stirred for 1-2 hours. The resulting solid was filtered and washed with acetone (11 ml) and dried at 50-60°C for 15-25 hours to obtain 51.2g of tofacitinib citrate having HPLC purity [w/w] = 99.79%; single highest impurity= 0.06% at 1.44 RRT.
Example 3: Preparation of tofacitinib citrate
N-Methyl-N-((3R,4R)-4-methyl piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50g) was taken in toluene (250ml) at an ambient temperature followed by addition of 2-cyano acetic acid ethyl ester (150g), N,N-diisopropylethylamine (40g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10g). The reaction mixture was heated at 100-110°C for 24 hours till completion of the reaction as monitored by HPLC (Unreacted Formula II < 0.32%). After the reaction completion, toluene was distilled out under vacuum at a temperature 70-80°C. The resulting residue was then dissolved in a mixture of DI water (250ml) and ethyl acetate (250ml) and pH was adjusted to 2-3 by addition of aqueous hydrochloric acid (25ml). The reaction mixture was stirred and layers were separated. The aqueous layer was then washed with ethyl acetate (50ml) and basified (pH 12-14) with aqueous potassium hydroxide solution (40g in 400ml DI water). Thereafter the aqueous was washed twice with methylene dichloride (250ml, 50ml) followed by washing with brine solution. The organic layer was then distilled out at 40-45°C under vacuum. The resulting residue was then crystallized using acetone (250ml) at 0-10°C and dried at 50-60°C for 15-25 hours to get tofacitinib (43.5g). The dried material thus obtained was dissolved in acetone (218 ml) was added at ambient temperature followed by addition of citric acid (26.1 g) & DI water (130ml). The reaction mixture was then heated to 50-60°C and stirred further for 4-8 hours and then cooled to 0-10°C and maintained the same temperature for 1-2 hours. The resulting solid was filtered and washed with acetone (11 ml) and dried at 50-60°C for 15-25 hours to obtain 52.2g of tofacitinib citrate having HPLC purity[w/w] = 99.80%; single highest impurity= 0.10% at 1.44 RRT.
Example 4: Preparation of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine (Formula II)
Step-1: Preparation of hydrochloride salt
Aqueous hydrochloric acid (60ml) was added to a solution of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine (50g) having HPLC purity (w/w) 95.94%, unknown impurity at RRT=0.68% in methanol (500ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The reaction mass was then cooled at a temperature 0-10°C and stirred for 2-3 hours. After reaction completion, solvent was removed under vacuum. The resulting solid mass was then washed with methanol (25ml) and dried at a temperature 50-60°C for 10-15 hours to obtain 56g of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine hydrochloride having HPLC purity[w/w] = 99.56%; unknown impurity= 0.35% at 1.40 RRT.
Step-2: Purification of hydrochloride salt
N-Methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine hydrochloride (50g) was taken in methanol (500ml) at a temperature 50-60°C and the reaction mixture was stirred for 1-2 hours. Afterwards, the reaction mass was cooled at a temperature 20-30°C and stirred for 2-3 hours. The reaction was then cooled at a temperature 0-10°C and stirred for 2-3 hours. After reaction completion, the resulting mass was filtered and washed with methanol (25ml) followed by drying at a temperature 50-60°C for 10-15 hours to obtain 41g of pure title compound having HPLC purity [w/w] = 99.81%; unknown impurity= 0.09% at 1.38 RRT.
Step-3: Hydrolysis of hydrochloride salt
N-Methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (50g) was added to the mixture of methylene dichloride (500ml) and DI water (500ml) at ambient temperature, followed by pH adjustment to 12-14 by addition of 10% aqueous sodium hydroxide solution. The resulting mixture was then extracted twice with methylene dichloride (100ml) and washed with 10% aqueous sodium hydroxide solution (100ml). The solvents were recovered from the resulting mixture at a temperature 40-45°C to obtain 40g of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine having HPLC purity[w/w] = 99.94%; unknown impurity at RRT 1.38= not detected.
Comparative example 1: Preparation of tofacitinib citrate
2-Cyano acetic acid ethyl ester (150g) and triethylamine (116g) were added to a solution of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Formula II) (50g) in toluene (250ml) at ambient temperature. The reaction mass was heated to 100°C for 24 hours and reaction was monitored by HPLC (unreacted Formula II=31.47%). The solvent was removed at 60-70°C under vacuum to obtain tofacitinib. To the resulting tofacitinib, acetone (350 ml) was added followed by citric acid (43g) and DI water (11.5ml). The reaction mixture was heated 50-60°C for 4-8 hours and then cooled at 0-10°C for 1-2 hours. The resulting solid was filtered and washed with acetone (150ml) and dried at 50-60°C for 15-25 hours to obtain tofacitinib citrate (32 g) having HPLC purity[w/w] =72.60%; single
Comparative example 2: Preparation of tofacitinib citrate
2-Cyano acetic acid ethyl ester (150g) and DBU (15g) were added to a solution of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Formula II) (50g) in toluene (250ml) at ambient temperature.The reaction mass was heated to 100-110°C for 24 hours & reaction was monitored by HPLC (unreacted Formula II=13.74%). The solvent was removed at 60-70°C to obtain tofacitinib. To the resulting tofacitinib acetone (218ml) was added at ambient temperature followed by addition of citric acid (26.1g) and DI water (130ml). The reaction mixture was heated 50-60°C for 4-8 hours and then cooled at 0-10°C for 1-2 hours. The resulting solid was filtered and washed with acetone (11ml) and dried at 50-60°C for 15-25 hours to obtain tofacitinib citrate (38 g) having HPLC purity[w/w] =97.47%; single highest impurity= 0.90% at 0.64 RRT.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim
1. A process for the preparation of tofacitinib of formula I or its pharmaceutically acceptable salt thereof,

Formula I
which comprises of:
reacting N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine of the formula II

Formula II
with 2-cyano acetic acid alkyl ester

wherein R1 is selected from C1-C6 alkyl group,
in the presence of at least two bases in an organic solvent to obtain tofacitinib.

2. The process as claimed in claim 1, wherein the base is selected from an organic base, inorganic base or mixture thereof.

3. The process as claimed in claim 2, wherein organic base is selected from the group consisting of amines such as diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, dimethylaminopyridine 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, N,N-dimethyl aniline, N-methyl morpholine (NMM), N,N-dimethyl amino pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]octane (DABCO), tetramethylpiperidine, tetramethylguanidine, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.

4. The process as claimed in claim 2, wherein inorganic base is selected from the group consisting of alkali or alkaline earth metal carbonate, bicarbonate, hydroxide or phosphate such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, hydride such as sodium hydride, lithium hydride or potassium hydride, alkoxide such as sodium or potassium methoxide or ethoxide, tertiary butoxide and the like or mixtures thereof.

5. The process as claimed in claim 1, organic solvent is selected from the group consisting of “alcohol solvents” such as methanol, ethanol, isopropanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, petroleum ether and the like; “halogenated solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and water.

6. The process as claimed in claim 1, wherein process further comprises conversion of tofacitinib of formula I into tofacitinib citrate of formula Ia.

7. The process as claimed in claim 6, wherein a process comprising treatment of tofacitinib of formula I with citric acid in a suitable solvent.

8. The process as claimed in claim 7, wherein the solvent is selected from the group consisting of alcohol such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; a ketone such as acetone, propanone, methylisobutylketone and the like; a nitrile such as acetonitrile, propanenitrile and the like; an ester such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; a haloalkane such as dichloromethane, chloroform and the like; an ether such as dimethyl ether, isopropyl ether, methyl tert-butyl ether and the like; an aromatic hydrocarbon such as toluene and the like; a hydrocarbon such as n-hexane, n-heptane and the like; dimethyl formamide; dimethylsulfoxide; dimethyl acetamide; tetrahydrofuran; N-methylpyrrolidone; water; and mixtures thereof.

9. A process for the preparation of tofacitinib citrate of Formula Ia,

Formula Ia
which comprises of:
i) reacting N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine of the formula II

Formula II
with 2-cyano acetic acid alkyl ester

wherein R1 is selected from C1-C6 alkyl group,
in the presence of at least two bases in an organic solvent,
ii) converting the resulting tofacitinib obtained in step (i), into tofacitinib citrate.
10. Highly pure tofacitinib citrate prepared by the process of any of proceeding claims.