DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

INTRODUCTION
Aspects of the present application relate to process and polymorphic forms of tofacitinib citrate, which are useful in making pharmaceutically acceptable dosage forms.
BACKGROUND OF THE INVENTION
Tofacitinib citrate, chemically named as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile,2-hydroxy-1,2,3-propane tricarboxylate (1:1), having a molecular formula of C16H20N6O•C6H8O7 and the following chemical structure:

It is marketed in the US as XELJANZ for oral administration as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) white round, immediate-release film-coated tablet for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
Tofacitinib is an inhibitor of protein kinases, such as the enzyme Janus Kinase 3 ("JAK3"). It has also been investigated as an immunosuppressive agent for the therapy of several conditions such as organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications, where immunosuppression would be desirable (see WO 03/048126). Tofacitinib, as well as certain pharmaceutically acceptable salts thereof, is described in WO 01/042246 and WO 02/096909. WO 03/048162 describes crystalline and amorphous forms of the mono-citrate salt of Tofacitinib. WO 2012/135338 and WO 2013/090490 describe processes for preparing certain other Tofacitinib salts.
The occurrence of different polymorphs is possible for some compounds. A single compound may give rise to a variety of solid forms having distinct physical properties. This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Because polymorphic forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all polymorphic forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances.
The existence and possible number of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug can exhibit very different solubility and dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic forms of tofacitinib mono citrate.
SUMMARY OF THE INVENTION
In first embodiment, the present application provides processes for the preparation of crystalline tofacitinib citrate, comprising:
a) Providing a solution of tofacitinib citrate in a solvent or mixture of solvents; and
b) Isolating crystalline tofacitinb citrate.
In second embodiment, the present application provides process for the preparation of a compound of formula (VII) or salt thereof;

which comprises:
(a) Converting a compound of formula (VI) to a compound of formula (VII) or salt thereof.

wherein ‘P’ is a nitrogen protecting group.
In third embodiment, the present application provides process for the preparation of a compound of formula (I) or salt thereof;

which comprises:
a) converting a compound of formula (II)

to a compound of formula (III) or salt thereof.

wherein ‘P’ is a Nitrogen protecting group
b) converting a compound of formula (III) or salt thereof to a compound of formula (IV)

c) converting a compound of formula (IV) to a compound of formula (V) or salt thereof

d) converting a compound of formula of (V) or salt thereof to a compound of formula (VI)

e) converting a compound of formula of (VI) or salt thereof to a compound of formula (VII) or salt thereof

f) converting a compound of formula of (VII) or salt thereof to a compound of formula (VIII) or salt thereof

g) reacting a compound of formula (VIII) or salt thereof, with a compound of formula (IX) to give compound of formula (X)

Formula (IX)

Formula (X)
h) converting the compound of formula (X) to a compound of formula (XI)

i) converting the compound of formula (XI) to a compound of formula (XII)

j) converting the compound of formula (XII) to a compound of formula (XIII)

k) converting the compound of formula (XIII) to a compound of formula (I)

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts a PXRD pattern of crystalline tofacitinib citrate, obtained by the procedure of Example 1-23.
DETAILED DESCRIPTION
In one embodiment, the present application provides processes for the preparation of crystalline tofacitinib citrate, comprising:
a) Providing a solution of tofacitinib citrate in a solvent or mixture of solvents; and
b) Isolating crystalline tofacitinb citrate.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing tofacitinib citrate that is obtained in the course of its synthesis; or
ii) dissolving tofacitinib citrate in a solvent or mixture of solvents.
Any physical form of tofacitinib citrate may be utilized for providing the solution of tofacitinib citrate in step a).
In embodiments, tofacitinib citrate obtained in the course of its synthesis can be dissolved in any suitable solvent such as methanol, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane; water; or any mixtures of one or more of these solvents.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 150°C, less than about 130°C, less than about 100°C, less than about 70°C, less than about 40°C, less than about 20°C, less than about 0°C, or any other suitable temperatures, as long as a clear solution of tofacitinib citrate is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step b) involves isolating crystalline tofacitinib citrate from the solution obtained in step a). Isolation of crystalline tofacitinib citrate in step b) may involve methods including cooling, crash cooling , concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, evaporation, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which tofacitinib citrate is less soluble or poorly soluble. An anti-solvent has no adverse effect on the quality of tofacitinib citrate and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as hexanes, heptane, cyclohexane, or methylcyclohexane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate; Ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile or propionitrile; aromatic hydrocarbons such as toluene, xylene; or any mixtures thereof.
Suitable temperatures for isolation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperatures.
The isolated crystalline tofacitinib citrate may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the tofacitinib citrate is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
Crystalline tofacitinib citrate together with one or more pharmaceutically acceptable excipients of the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In second embodiment, the present application provides process for the preparation of a compound of formula (VII) or salt thereof;

which comprises:
(a) converting a compound of formula (VI) to a compound of formula (VII) or salt thereof.

wherein ‘P’ is a nitrogen protecting group.
The protecting group that may be used include but are not limited to carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3, 4-dimethoxybenzyl, p-methoxyphenyl, tosyl or the likes thereof.
Step (a) of the second embodiment may be affected in the presence of suitable reducing agent. Suitable reducing reagent that may be used includes but not limited to alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium Trialkoxy borohydrides, lithium trialkoxyaluminium hydrides, sodium triacetoxy borohydride, borane/diborane, borane-THF, borane-DMS etc or the like; sodium dithionite in alkaline medium; any combination thereof; or any other suitable reducing agent known in the art.
Step (a) may be affected in the presence of methylamine. The methylamine that may be used include but not limited to methylamine in methanol, ethanol, THF, water or the likes thereof. The concentration of methylamine in the solution may vary from about 0.1 M to 10 M.
Step (a) may be affected in presence of catalyst which include but not limited to trichlorotriazine, BF3:OEt2, Titanium chloride, titanium isopropoxide or any other suitable reagent known in the art.
Step (a) may be affected in presence of suitable solvent. Suitable solvents that may be used include, but are not limited to: water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.
Suitable temperatures for the reaction of step (a) of the first embodiment, step (a) of the tenth embodiment and step (a) of the eighteenth embodiment may be less than about 150 0C, less than about 100 0C, less than about 80 0C, less than about 60 0C, less than about 40 0C, less than about 30 0C, less than about 20 0C, less than about 10 0C, less than about 0 0C, less than about -10 0C, less than about -20 0C, less than about -30 0C, less than about -40 0C or any other suitable temperatures.
Step (a) of the first embodiment may be optionally carried out in an inert atmosphere such as nitrogen or argon.
The reaction mixture obtained in step (a) of the first embodiment may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.
The product of step (a) of the first embodiment may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
Isolation of compound may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
Suitable solvents that may be used for isolation of compound include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; and any mixtures thereof.
The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 150 0C, less than about 120 0C, less than about 100 0C, less than about 80 0C, less than about 60 0C, less than about 40 0C or any other suitable temperatures as long as the compound is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 hour to about 24 hours, or longer.
Optionally the product in step (a) of the first embodiment may be further used with or without isolation.
In third embodiment, the present application provides process for the preparation of a compound of formula (I) or salt thereof;

which comprises:
a) converting a compound of formula (II)

to a compound of formula (III) or salt thereof.

wherein ‘P’ is a Nitrogen protecting group
b) converting a compound of formula (III) or salt thereof to a compound of formula (IV)

c) converting a compound of formula (IV) to a compound of formula (V) or salt thereof

d) converting a compound of formula of (V) or salt thereof to a compound of formula (VI)

e) converting a compound of formula of (VI) or salt thereof to a compound of formula (VII) or salt thereof

f) converting a compound of formula of (VII) or salt thereof to a compound of formula (VIII) or salt thereof

g) reacting a compound of formula (VIII) or salt thereof, with a compound of formula (IX) to give compound of formula (X)

Formula (IX)

Formula (X)
h) converting the compound of formula (X) to a compound of formula (XI)

i) converting the compound of formula (XI) to a compound of formula (XII)

j) converting the compound of formula (XII) to a compound of formula (XIII)

k) converting the compound of formula (XIII) to a compound of formula (I)

The protecting groups that may be used include but are not limited to carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3, 4-dimethoxybenzyl, p-methoxyphenyl, tosyl or the likes thereof.
Suitable reducing reagent that may be used includes but not limited to alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; sodium dithionite in alkaline medium; any combination thereof; or any other suitable reducing agent known in the art.
Suitable lewis acids that may be used include but not limited to boron containing reagents, aluminium containing reagent such as BF3: TBME (t-butyl methyl ether); BF3:OEt2; BF3: O(CH2CH2CH2CH3)2; BF3:THF; and the like; alkyl aluminum halides, dialkyl aluminum halides, trialkyl aluminum, and aluminum halides (e.g., AlCl3 and AlBr3); trichlorotriazine, transition metal ions or any other suitable reagent known in the art.
Suitable bases that may be used include, but not limited to organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, diazabicycloundecene, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, or the like; inorganic bases, such as for example, alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; lithium bis(trimethylsilyl)amide alkali metal hydroxides, such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; and ion exchange resins including resins bound to ions, such as for example, sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium ions, or the like; or any other suitable bases.
Step (a) may be affected in presence of suitable solvent. Suitable solvents that may be used include, but are not limited to: water, alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. The term “anti-solvent” refers to a liquid that, when combined with a solution of tofacitinib citrate, reduces solubility of the tofacitinib citrate in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as aging, seeding, cooling, scratching and/or concentrating. Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp. Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic or alicyclic hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8aliphatic hydrocarbons, ligroin, petroleum ethers, or mixtures thereof.
“Aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of an aromatic hydrocarbon solvent include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10aromatic hydrocarbons, or mixtures thereof.
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include but are not limited to diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example 1: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (27 ml) and methanol (43 ml) were charged into round bottom flask at 28 0C. The contents were stirred and heated to 65 0C. The stirring was maintained for 20 minutes at 65 0C. The solution was filtered for particle free solution. The filterate was cooled to 28 0C and concentrated under reduced pressure at 70 0C. The concentrated material was cooled to 0 0C and filtered. The filtered material was dried under reduced pressure at 50 0C for 2 hours to obtain the desired polymorph.
Example 2: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (35 ml) and ethanol (35 ml) were charged into round bottom flask at 28 0C. The contents were stirred and heated to 70 0C. The stirring was maintained for 20 minutes at 70 0C. The solution was filtered for particle free solution. The filterate was cooled to 28 0C and concentrated under reduced pressure at 70 0C. The concentrated material was cooled to 0 0C and filtered. The filtered material was dried under reduced pressure at 50 0C for 2 hours to obtain the desired polymorph.
Example 3: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (28.1 ml) and acetone (40.6 ml) were charged into round bottom flask at 28 0C. The contents were stirred and heated to 60 0C. The stirring was maintained for 20 minutes at 60 0C. The solution was filtered for particle free solution. The filterate was cooled to 28 0C and concentrated under reduced pressure at 60 0C. The concentrated material was cooled to 0 0C and filtered. The filtered material was dried under reduced pressure at 50 0C for 2 hours to obtain the desired polymorph.
Example 4: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (35 ml) and acetonitrile (35 ml) were charged into round bottom flask at 28 0C. The contents were stirred and heated to 70 0C. The stirring was maintained for 20 minutes at 70 0C. The solution was filtered for particle free solution. The filterate was cooled to 28 0C and concentrated under reduced pressure at 70 0C. The concentrated material was cooled to 0 0C and filtered. The filtered material was dried under reduced pressure at 50 0C for 2 hours to obtain the desired polymorph.
Example 5: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (9 ml) and methanol (13 ml) were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 6: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (15 ml) and ethanol (15 ml) were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 7: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (9 ml) and acetone (13 ml) were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 8: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (10 ml) and acetonitrile (10 ml) were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 9: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (30 ml) were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 10: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and methanol (30 ml) were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 11: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (17ml) - 1, 4-dioxane (3 ml) mixture were charged into round bottom flask at 28 0C. The contents were stirred for 18 hours at 28 0C. The contents were filtered and dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 12: Preparation of crystalline tofacitinib citrate
Methyl tert-butyl ether (100 ml) was added to RBF at 28 0C. Tofacitinib citrate (500 mg) dissolved in water (50 ml) was added to MTBE under stirring and maintained for 4 hours. The contents were subjected to fast evaporation under reduced pressure to obtain the desired polymorph.
Example 13: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (50 mL) were charged into a round bottom flask. The contents were stirred and heated to 80 0C for 45 minutes. The contents were filtered for particle free solution and cooled to 28 0C. Acetonitrile (100 mL) was added and contents were cooled to 0 0C. The contents were concentrated under reduced pressure at 80 0C. The contents were cooled to 0 0C and filtered. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired material.
Example 14: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (50 mL) were charged into a round bottom flask. The contents were stirred and heated to 80 0C for 45 minutes. The contents were filtered for particle free solution and cooled to 28 0C. 1-butanol (100 mL) was added and contents were cooled to 0 0C. The contents were concentrated under reduced pressure at 70 0C. The contents were cooled to 0 0C and filtered. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired material.
Example 15: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (35 mL) and Methyl isobutyl ketone (65 mL) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 80 0C for 20 minutes. The contents were filtered for particle free solution. The solution was distilled under reduced pressure at 80 0C. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 16: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (35 mL) and isopropyl alcohol (65 mL) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 80 0C for 20 minutes. The contents were filtered for particle free solution. The solution was distilled under reduced pressure at 80 0C. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 17: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (100 mL) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 80 0C for 20 minutes. The contents were filtered for particle free solution. The solution was distilled under reduced pressure at 80 0C. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 18: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (50 mL) and 2-butanone (50 ml) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 80 0C for 20 minutes. The solution was distilled under reduced pressure at 80 0C and the material was chased with n-heptane. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 19: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg), water (50 mL) and 2-butanol (50 ml) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 80 0C for 20 minutes. The solution was distilled under reduced pressure at 80 0C and the material was chased with n-heptane. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 20: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (50 mL) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 70 0C for 35 minutes. The contents were filtered for particle free solution. The solution was added to round bottom flask containing isopropyl alcohol (100 mL) at 28 0C. The contents were stirred for 48 hours at 28 0C and then distilled under reduced pressure at 70 0C. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 21: Preparation of crystalline tofacitinib citrate
Tofacitinib citrate (500 mg) and water (50 mL) were charged into the round bottom flask at 28 0C. The contents were stirred and heated to 70 0C for 35 minutes. The contents were filtered for particle free solution. The solution was added to round bottom flask containing 2-butanone (100 mL) at 28 0C. The contents were stirred for 48 hours at 28 0C and filtered. The material was dried under reduced pressure at 50 0C for 4 hours to obtain the desired polymorph.
Example 22: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile,2-hydroxy-1,2,3-propane tricarboxylate
(i) 1-benzyl-4-methylpyridinium chloride
4-methylpyridine (500g) and acetone (2.0 litres) were charged into a round bottom flask and heated to 55-60 0C. Benzyl chloride (1545 ml) dissolved in acetone (500 mL) was added to the above mixture at 55-60 0C and the contents were maintained for 16 hours. The reaction mass was cooled to 5-10 0C and stirred for 1 hour. The reaction mass was filtered and washed with acetone (500 mL). The material was dried under reduced pressure at 50 0C to afford the title compound. Yield: 1.125 Kg
(ii) 1-benzyl-4-methyl-1, 2, 3, 6-tetrahydropyridine
1-benzyl-4-methylpyridinium chloride (1.125 Kg) and methanol (3.075 litres) were taken into a round bottom flask under inert atmosphere at 25-30 0C. The contents were cooled to 0-5 0C and sodium borohydride (0.241 kg) was added over a period of 3-4 hours. The temperature of the reaction mass was raised to 25-30 0C and stirred at 25-30 0C for 16 hours. The reaction mass was cooled to 0-5 0C and quenched with water (1.125 litre). The reaction mass temperature was raised to 25-30 0C and stirred for 30 minutes. The reaction mass was filtered over celite bed and washed with dichlormethane (2.25 litre). The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (1.125 litres x 2). The organic layers were combined and washed with water (1.125 litres) and brine solution (1.125 litres). The organic layer was dried over anhydrous sodium sulphate and distilled under reduced pressure at 45 0C to afford the title compound. Yield: 890 g
(iii) 1-benzyl-4-methylpiperidin-3-ol 4-methylbenzenesulfonate
1-benzyl-4-methyl-1, 2, 3, 6-tetrahydropyridine (890 g), tetrahydrofuran (4.45 litres) and sodium borohydride (270 g) were taken into a round bottom flask under inert atmosphere at 25-30 0C. The contents were cooled to 0-5 0C and BF3. Etherate (47-49 %, 1720 mL) was added slowly over a period of 1 hour. The temperature of the reaction mass was raised to 25-30 0C and the reaction was maintained for 2 hours. The reaction mass was cooled to 0-5 0C and quenched with ice cold water. 2N NaOH solution (1184 ml) was added and stirred for 30 minutes. 30 % H2O2 solution (1184 ml) was added to the reaction mass at 35-40 0C and stirred for 2 hours at 25-30 0C. The reaction mass was cooled to 10-15 0C and 5N HCl solution (1335 mL) was added. 6N NaOH solution (2.94 litres) was added and the temperature of the reaction was raised to 25-30 0C. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane (1335 ml x 2). The organic layers were combined and washed with brine solution (890 ml). The organic layer was dried over anhydrous sodium sulphate and distilled under reduced pressure at 45 0C. The distilled mass was dissolved in acetone (890 ml) and methyl tert-butyl ether (2.67 litres) and the contents were heated to 55- 60 0C. Para toluene sulfonic acid (994 g) was dissolved in acetone (1335 ml) and added to the above reaction mass. The contents were stirred for 30 minutes at 55 0C and at 5-10 0C for 1 hour. The reaction mass was filtered and washed with acetone (2.22 litres) and methyl tert-butyl ether (890 ml). The filtered material was dried under reduced pressure for 4-6 hours to afford the title compound. Yield: 1.6 kg
(iv) 1-benzyl-4-methylpiperidin-3-one
1-benzyl-4-methylpiperidin-3-ol 4-methylbenzenesulfonate (1000 g), dichloromethane (5.0 litres) and 2N NaOH solution (2.5 litres) were charged into a round bottom flask at 25-30 0C. The contents were stirred for 15 minutes and organic and aqueous layers were seperated. The organic layer was washed with brine solution (2.5 litres) and dried over anhydrous sodium sulphate. The solution was concentrated under reduced pressure at 25-30 0C to obtain the concentrated mass. In a sepereate round bottom flask dichloromethane (5.0 litres) and oxalyl chloride (380 ml) were charged and cooled to -75 0C to -78 0C. To this was added a mixture of dichloromethane (2.5 litres) and dimethylsulphoxide (467 ml) over a period of 1.5 to 2 hours. The reaction contents were stirred for 30 minutes at -75 0C to -78 0C. The concentrated mass obtained above was dissolved in dichloromethane (2.5 litres) and was added to the above reaction contents over a period of 1.5 to 2 hours at -75 0C to -78 0C. The reaction mass was maintained for 30 minutes at -75 0C to -78 0C. Triethyl amine (1830 ml) was added to the reaction mass over a period of 2 hours. The reaction mass was maintained for 16 hours at 25-30 0C. The reaction mass was quenched with ice cold water (5.0 litres) and stirred for 30 minutes at 25-30 0C. The aqueous and organic layers were separated. The organic layer was washed with ice cold water (3x 5.0 litres) followed by brine solution (2.5 litres). The organic layer was dried over anhydrous sodium sulphate and distilled under reduced pressure at 40-45 0C to afford the title compound. Yield: 550 g
(v) 1-benzyl-N,4-dimethylpiperidin-3-amine hydrochloride
1-benzyl-4-methylpiperidin-3-one (550 g) and methanol (2.75 lit) were charged into a reactor at 25-30 0C under inert atmosphere. The contents were cooled to 0-5 0C and methyl amine in THF (2M, 5.0 Litre) was charged to the above contents at 3 0C. Cyanuric chloride (24.8 g) was added to the above reaction mass at 2 0C and the reaction contents were stirred for 16 hours at 25-30 0C. The reaction mass was cooled to 0-5 0C and sodium borohydride (102 g) was added to the reaction mass over a period of 30 minutes at 3 0C. The reaction mass tempereature was raised to 25-30 0C and stirred for 1 hour. The reaction mass was cooled to 5-10 0C and quenched with ice cold water (5.0 lit). The reaction mass was concentrated under reduced pressure at 45-50 0C. The compound was extracted with DCM (2 x 2.5 litres) and the combined layers were washed with brine solution (2.5 litres). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 45 0C. The concentrated mass was diluted in ethanol (500 mL) and HCl gas was passed for 24 hours. The obtained reaction mass was diluted with methyl tert-butyl ether (2.5 litres) and stirred for 2 hours. The reaction mass was filtered and washed with methyl tert-butyl ether (2.5 litres). The filtered mass was dried under reduced pressure at 25-30 0C for 24 hours to obtain the title product.
Yield: 310 g
(vi) (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine-(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate
1-benzyl-N,4-dimethylpiperidin-3-amine hydrochloride (225 g) and dichloromethane (2.17 litre) were charged into a round bottom flask at 25-30 0C. 2N NaOH solution (1.7 litres) was added to the above flask and stirred for 30 minutes at 25-30 0C. The aqueous and organic layers were seperated and organic layer was washed with brine solution (930 ml). The organic layer was dried over anhydrous sodium sulphate solution and distilled under reduced pressure at 40-45 0C to obtain the concentrated mass. The concentrated mass, methanol (562 ml) and water (562 ml) were charged into a round bottom flask at 25-30 0C. Di-Para-Toluoyl-L-TartaricAcid (239 g) was charged and the reaction contents were heated to 70-80 0C. The reaction was maintained for 1 hour at 70-80 0C. The reaction mass was gradually cooled to 25-30 0C over a period of 2 hours. The reaction mass was cooled to 5-10 0C and maintained for 12-14 hours. The temperature of the reaction mass was raised to 25-30 0C and was filtered and washed with mixture containing containing methanol and water (790 ml, 1:1). The filtered material was dride under reduced pressure at 25-30 0C for 6-8 hours to obtain the desired material. Yield: 195 g
(vii) 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 g), acetone (5.0 litres) and para toluenesulfonyl chloride (682 g) were charged into a round bottom flask at 25-30 0C. The contents were cooled to 0-5 0C. 2M sodium hydroxide solution (1950 ml) was added to the reaction mass at 0-5 0C. The reaction mass maintained for 6 hours at 25-30 0C. The reaction mass was filtered and washed with acetone and water mixture (1000 ml, 1:1). The filtered material was dried under reduced pressure for 6-8 hours at 25-30 0C to afford the title compound. Yield: 910 g
(viii) N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine-(2R,3R)-2,3-bis((4-methylbenzoyl)oxy) succinate (190 g) and water (570 ml) were charged into a round bottom flask at 25-30 0C. 4-chloro-7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (121 g) and potassium carbonate (162.6 g) were added to the above contents and heated to 100-105 0C. The reaction mass was maintained for 16 hours at 100-105 0C. the reaction mass was cooled to 25-30 0C over a period of 2 hours and the reaction mass was filtered and washed with water (570 ml). The filtered material was washed with methyl tert-butyl ether (380 ml). The wet material was dried under reduced pressure at 25-30 0C for 5-6 hours to afford the title compound. Yield: 153 g.
(ix) N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 g) and 50 % aqueous sodium hydroxide solution (3.75 litre) were charged into a round bottom flask at 25-30 0C and heated to 100-110 0C. The reaction contents were stirred for 16 hours at 100-110 0C. The reaction mass was cooled to 25-30 0C, water (3.0 litre) was charged and stirred for 1 hour at 25-30 0C. The reaction mass was filtered and washed with water (750 ml). The filtered material was dried under reduced pressure at 25-30 0C for 6-8 hours to afford the title compound. Yield: 85 g
(x) N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 g), methanol (800 ml), 2N aqueous HCl soution (160 ml) and 20% palladium hydroxide solution were charged into parr hydrogenation flask at 25-30 0C under inert atmosphere. The reaction mass was degassed under inert atmosphere by applying hydrogen pressure. The parr hydrogenation flask was filled with hydrogen pressure (50 PSI) and the reaction mass was maintained for 16 hours at 50 PSI hydrogen pressure by shaking. The reaction mass was filtered through celite bed and was washed with methanol (400 ml). The filterate was concentrated under reduced pressure at 50 0C. The aqueous layer pH was adjusted to 8-9 by adding 1N aqueous sodium hydroxide solution (264 ml). The aqueous layer was extracted twice with dichloromethane (800 ml, 400 ml). The organic layers were combined and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at 40-45 0C to afford the title compound. Yield: 50 g
(xi) 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 g), 1-butanol (150 ml), diazabicycloundecene (21.7 ml) and ethylcyanoacetate (44 ml) into a round bottom flask at 25-30 0C under inert atmosphere. The reaction contents were heated to 40-45 0C and maintained for 17 hours. The reaction mass was concentratred under reduced pressure at 50 0C. The concentrated mass was diluted with ethyl acetate (600 ml) and pH was adjusted to 1-2 by adding 1N aqueous HCl solution (1.25 litres). The contents were stirred for 30 minutes and aqueous and organic layers were seperated. The aqueous layer was washed with ethyl acetate (2x450 ml) and aqueous and organic layers were seperated. The pH of the aqueous layer was adjusted to 8-9 with solid sodium bicarbonate (225 g) and the aqueous layer was extracted with dichloromethane (2x 625 ml). The combined organic layer was washed with brine solution (2x 625 ml) and dried over anhydrous sodium sulphate. The organic layer was distilled under reduced pressure at 40-45 0C to afford the tiltle compound.
Yield: 58 g
(xii) 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile 2-hydroxypropane-1,2,3-tricarboxylate
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (95 g) and ethanol (380 ml) were charged into a round bottom flask at 25-30 0C under inert atmosphere. In a separate flask 50% Citric acid solution was prepared by adding Citric acid mohydrate (64 g) and water (128 ml). The prepared 50% Citric acid solution was added to the above flask at 25-30 0C over a period of 10-15 minutes. The reaction mass was stirred for 1 hour and filtered. The filtered material was washed with ethanol (190 ml) and dried under reduced pressure at 25-30 0C for 6-8 hours to afford the titled material. Yield: 132 g
Example 23: Preparation of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile 2-hydroxypropane-1,2,3-tricarboxylate
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (18 g) and ethanol (72 ml) were charged into a round bottom flask at 25-30 0C. 50% aqueous Citric acid solution (14.5 g) was added to the above flask at 25-30 0C over a period of 10-15 minutes. The reaction mass was stirred for 1 hour at 25-30 0C and concentrated under reduced pressure at 45-50 0C. The reaction mass was filtered was washed with ethanol (18 ml) and dried under reduced pressure at 25-30 0C for 4-6 hours to afford the titled material.
Yield: 24.5 g ,CLAIMS:WE CLAIM:

1. A process for the preparation of a compound of formula (VII) or salt thereof;

Formula (VII)
comprising reacting a compound of formula (VI) or salt thereof;

Formula (VI)
wherein P is a nitrogen protecting group;
with methyl amine in the presence of reducing reagent and catalyst.
2. The process of claim 1, wherein the nitrogen protecting group is selected from benzyl (Bn), benzoyl, acetyl, tosyl, carboxybenzyl (Cbz), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl, carbamate, p-methoxybenzyl, 3, 4-dimethoxybenzyl and p-methoxyphenyl.
3. The process of claim 1, wherein the reducing agent is selected from lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE), diisobutyl aluminium hydride, sodium Trialkoxy borohydrides, lithium trialkoxyaluminium hydrides, sodium triacetoxy borohydride, borane/diborane, borane-THF and borane-DMS.
4. The process of claim 1, wherein the catalyst is selected from trichlorotriazine (TCT), BF3:OEt2, Titanium chloride and titanium isopropoxide.
5. The process of claim 4, wherein the catalyst is trichlorotriazine (TCT).
6. A process for the preparation of 1-benzyl-N,4-dimethylpiperidin-3-amine comprising reacting 1-benzyl-4-methylpiperidin-3-one with methyl amine in the presence of sodium borohydride and trichlorotriazine (TCT).
7. The process of claim 6, further comprising additional conversion of 1-benzyl-N,4-dimethylpiperidin-3-amine to Tofacitinib or salt thereof.
8. A process for the preparation of crystalline Tofacitinib citrate comprising:
a) preparing a solution of Tofacitinib citrate in a solvent or mixture of solvents; wherein the solvent is selected from water, methanol, ethanol, 2-butanol, acetone, 1,4 dioxane and methyl isobutyl ketone (MIBK) or mixtures thereof; and
b) isolating the crystalline tofacitinb citrate.
9. A process for the preparation of crystalline Tofacitinib citrate comprising:
a) preparing a solution of Tofacitinib citrate in a solvent or mixture of solvents; wherein the solvent is selected from water, methanol, ethanol, 2-butanol, acetone, 1,4 dioxane and methyl isobutyl ketone (MIBK) or mixtures thereof;
b) adding anti solvent to the solution obtained in step a)
wherein the anti-solvent is selected from methyl tert-butyl ether (MTBE), acetonitrile, 1-butanol, isopropanol and 2-butanone or mixture thereof; and
c) isolating the crystalline tofacitinb citrate.
10. A process for the preparation of Tofacitinib or salt thereof comprising:
a) reacting a compound of formula (VI) or salt thereof;

Formula (VI)
with methyl amine in the presence of in the presence of sodium borohydride and trichlorotriazine (TCT) to produce compound of formula (VII) or salt thereof;.

Formula (VII)
b) converting a compound of formula of (VII) or salt thereof to a compound of formula (VIII) or salt thereof;

Formula (VIII)
c) reacting a compound of formula (VIII) or salt thereof with a compound of formula (IX)

Formula (IX)
to produce compound of formula (X);

Formula (X)
d) converting the compound of formula (X) to a compound of formula (XI);

Formula (XI)
e) converting the compound of formula (XI) to a compound of formula (XII);

Formula (XII)
f) converting the compound of formula (XII) to a compound of formula (XIII); and

Formula (XIII)
g) optionally converting the compound of formula (XIII) to its pharmaceutically acceptable thereof.
wherein P is a Nitrogen protecting group.