cas 540737-29-9, Tofacitinib citrate | Articles data

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Preparation method of tofacitinib citrate
The invention discloses a preparation method of tofacitinib citrate. The method comprises the following steps: by taking 7-tert-butyloxycarbonyl-4-amino-7H-pyrrolo[2, 3-D]pyrimidine and 1-benzyl-4-methyl-piperidine-3-ketone as initial raw materials, carrying out condensation under a weak acidic condition, then carrying out N methylation, selective reduction, debenzylation and Boc removal, and carrying out ester exchange and citric acid salification at a high temperature to obtain the tofacitinib citrate. The method has the advantages of mild reaction conditions, simple post-treatment mode, reduction of the generation amount of hazardous wastes, environmental protection, cost saving, and facilitation of industrial production.
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(2021/04/21)

Synthesis method of tofacitinib citrate
The invention discloses a tofacitinib citrate synthesis method, belongs to the technical field of tofacitinib citrate preparation, and can effectively inhibit activity of Janus and JAK1 JAK3, block signal transduction of various inflammatory cytokines, and has an expensive catalyst application in the existing synthesis step. The method uses 1 - benzyl -4 - methyl -3 - (methylamino) piperidine hydrochloride as a raw material to prepare the tofacitinib citrate as a raw material, and then the citric acid tofacitinib citrate is obtained through twice refining 4 -7 - and the - 7H - yield and 2 the 3 - D purity of the tofacitinib citrate are improved.
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Paragraph 0019; 0032-0033; 0037-0039; 0043-0045; 0049; ...

(2021/12/07)

Process for the preparation of tofacitinib and intermediates thereof
Provided is a process for the preparation of high purity tofacitinib, which reduces formation of N-methyl impurity. The invention also provides novel intermediates used in the process to prepare tofacitinib. There is provided an improved process for the preparation of tofacitinib (I), comprising the steps of: adding cyanoacetic acid in molar equivalent 0.2-1.2 to compound of formula (II-S), followed by addition of carbodiimide coupling agent of formula (III), optionally reacting tofacitinib base with citric acid.
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(2021/05/07)

Preparation method of tofacitinib citrate
The invention relates to the field of medicine synthesis, and particularly discloses a preparation method of tofacitinib citrate. The preparation method comprises the following steps: S1, dissolving acompound SM1, a compound SM2 and an alkaline reagent in a solvent A, and performing a reaction to obtain a first compound; S2, taking and mixing a catalyst, a solvent B and the first compound, introducing hydrogen, and carrying out a catalytic hydrogenation reaction to obtain a second compound; S3, taking and mixing active anhydride, a solvent C and the second compound, and carrying out an acylation reaction to obtain a third compound, wherein R in the active anhydride comprises an alkyl group or an aryl group; and S4, taking and mixing citric acid, a solvent D and the third compound, and carrying out a salt-forming reaction to obtain a compound T that is the tofacitinib citrate. The preparation method has the advantages of easily available initial raw materials, no use of complex or toxic compounds, short synthesis process route, simple and convenient reaction operation of each step, high total yield and high productivity, and is suitable for large-scale industrial production.
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Page/Page column 8-14

(2020/02/14)

Preparation methods of tofacitinib citrate intermediate and tofacitinib citrate
The invention discloses preparation methods of a tofacitinib citrate intermediate and tofacitinib citrate. The preparation method of the tofacitinib citrate intermediate comprises: preparing N-(1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidine-3-yl)acetamide by using 3-amino-4-methyl-pyridine, acetyl chloride, benzyl chloride and sodium borohydride as raw materials; preparing 1-benzyl-N,4-dimethylpiperidine-3-amine by using the N-(1-benzyl-4-methyl-1,2,5,6-tetrahydropiperidine-3-yl)acetamide, hydrochloric acid, methylamine and sodium borohydride as raw materials; and carrying out resolution and dissociation on the 1-benzyl-N,4-dimethylpiperidine-3-amine, and carrying out salt forming with hydrochloric acid to obtain the product. The invention provides the new tofacitinib citrate intermediatepreparation method, wherein the use amount of the catalytic hydrogenation catalyst is reduced in the preparation process of tofacitinib citrate so as to reduce the cost, and the generation of N-alkylated impurities can be well controlled by adopting the isopropanol/water mixed solvent.
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Paragraph 0090-0093

(2020/01/25)

PROCESS FOR PREPARATION OF TOFACITINIB AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
The present invention relates to an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof. (I)
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(2020/09/27)

Tofacitinib citrate intermediate as well as preparation method and application thereof
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tofacitinib citrate intermediate as well as a preparation method and an application thereof. Whereinthe tofacitinib citrate intermediate is N-methyl-N-((3R, 4R)-4-methylpiperidine-3-yl)-7H-pyrrolo [2, 3-D] pyrimidine-4-amine dihydrochloride monohydrate. The preparation method comprises the followingsteps: adding N-methyl-N-((3R, 4R)-1-benzyl-4-methylpiperidine-3-yl)-N-methyl-7H-pyrrolo [2, 3-d] pyrimidine-4-amine into water and an organic solvent, then adding hydrochloric acid and palladium hydroxide carbon, introducing hydrogen to react, and filtering out the palladium hydroxide carbon; cooling to room temperature, dropwise adding an organic solvent, crystallizing, carrying out suction filtration, and drying to obtain the tofacitinib citrate intermediate. The method greatly improves the utilization rate of raw materials, reduces the production cost, and improves the product quality.
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Paragraph 0046; 0050-0052; 0055; 0056; 0057; 0060; 0061

(2020/12/10)

Synthesis method of tofacitinib citrate
The invention relates to the technical field of medicinal chemistry, and discloses a synthesis method of tofacitinib citrate. The method comprises 1) preparing 2,4-dihydroxy pyrrolopyrimidine: adding4-aminouracil and anhydrous sodium acetate into water (in a molar ratio of (1: 3)-(1: 5)), heating to 60-80 DEG C, slowly adding a 2-chloroacetaldehyde aqueous solution having a concentration of 40%,stirring to react for 4-6 hours, cooling to room temperature, filtering, washing a solid with water, and drying under reduced pressure to obtain 2,4-dihydroxy pyrrolopyrimidine. According to the synthesis method of tofacitinib citrate, through two times of impurity removal, the purity of the produced tofacitinib citrate finished product is higher, subsequent purification is not needed, the synthesis time is short, the process is simple, the method is suitable for factory production, the production time of the tofacitinib citrate finished product can be saved, the production efficiency of the tofacitinib citrate finished product is improved, and the tofacitinib citrate is more convenient to use.
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(2020/08/29)

Method for preparingtofacitinib citrate
The invention provides a method for preparing tofacitinib citrate. The method for preparing tofacitinib citratecomprises the following steps that1, N-methyl-N-((3R,4R)-4-methylpiperidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and ethyl cyanoacetate are added into methyl alcohol for condensation reaction to prepare and obtain 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;and 2,3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileis added to a mixed solvent and subjected to 80+/-5 DEG reflux, additionally, citric acid is dissolved in the mixed solvent and then added slowly to a reflux system forsalt forming reaction, cooling, filtration, washing, and drying to obtain 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile citrate. According to the method for preparing tofacitinib citrate, operation isconvenient, time consumption isless, the yield rate is high, product impurity is low,and purity is good.
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Page/Page column 5-10

(2019/10/29)

A Novel Tofacitinib Salt, Preparation Methods thereof and Pharmaceutical Compositions Comprising thereof
The present invention relates to tofacitinib camphorsulfonate monohydrate, a manufacturing method thereof, and a pharmaceutical composition comprising the same. Since tofacitinib camphorsulfonate monohydrate according to the present invention has an excellent effect equal to or more than all of them in terms of acceleration, stability according to severe storage conditions, photostability, thermal stability, pH stability, solubility, and the like as compared with tofacitinib citrate, the pharmaceutical composition of the present invention can be usefully used for preventing or treating diseases selected from a group consisting of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.COPYRIGHT KIPO 2019
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Paragraph 0097-0101

(2019/11/14)

Preparation method for tofacitinib citrate
The invention relates to the field of medicinal chemistry, and provides a preparation method for tofacitinib. ((3R,4R)-1-benzyl-4-methyl-piperidine-3-radical)-methyl-(7H-pyrrolo [2, 3-D] pyrimidine-4-radical)-amine is taken as a starting material, after the hydrogenation debenzylation reaction and amidation, tofacitinib is prepared, and after the tofacitinib and citric acid are salified, the tofacitinib citrate is obtained. According to the developed technology, the product quality is quite high, the purity is 99.9% or above, the content of any individual impurity is less than 0.1%, and the quality standard of tofacitinib citrate medicine as a registered active pharmaceutical ingredient is met. The hydrogenation reaction utilizes an aqueous hydrochloric acid solution as a solvent, and thehydrogenation reaction is quite safe, green and environmentally friendly.
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Paragraph 0045; 0048-0049

(2019/06/07)

Tofacitinib citrate crystal form compound as well as preparation method and application thereof
The invention discloses a tofacitinib citrate crystal form compound as well as a preparation method and application thereof. An X-ray powder diffraction pattern shows that the crystal form has characteristic diffraction peaks at the places where the 2[theta] degree values are as follows: 5.9 degrees, 9.0 degrees, 11.2 degrees, 11.7 degrees, 13.8 degrees, 14.1 degrees, 14.9 degrees, 15.3 degrees, 16.2 degrees, 16.4 degrees, 17.5 degrees, 17.6 degrees, 18.8 degrees, 18.9 degrees, 20.4 degrees, 20.7 degrees, 21.3 degrees, 21.6 degrees, 22.1 degrees, 22.2 degrees, 22.4 degrees, 23.2 degrees, 25.2degrees, 25.6 degrees, 26.3 degrees, 27.1 degrees, 27.3 degrees, 27.7 degrees, 28.2 degrees, 28.8 degrees, 29.4 degrees, 30.2 degrees, 30.3 degrees, 31.3 degrees, 33.0 degrees, 33.7 degrees, 34.6 degrees, 35.4 degrees, 36.1 degrees, 36.7 degrees, 37.9 degrees, 38.6 degrees, 39.2 degrees, 41.2 degrees, 41.6 degrees and 45.2 degrees +/-0.2 degrees, the characteristic diffraction peaks are differentfrom main peaks and peak intensity in the prior art, and the DSC conversion temperature is 213 +/-2 DEG C. The tofacitinib citrate crystal form compound provided by the invention has better water solubility and higher stability, the preparation method is simple and easy to operate, and the medication safety is greatly improved after the tofacitinib citrate crystal form compound is used to preparea pharmaceutical composition.
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Paragraph 0063-0091

(2019/11/20)

Preparation method of tofacitinib citrate
The invention discloses a preparation method of tofacitinib citrate. The method comprises the following steps: 1) performing a desalting reaction on a compound represented by a formula II shown in thedescription under basic conditions to obtain an intermediate represented by a formula III shown in the description; 2) in the presence of a basic ionic liquid, performing a reaction on the intermediate represented by the formula III, ethyl cyanoacetate and a base in an inert atmosphere to obtain a reaction liquid containing a tofacitinib base; and 3) adding citric acid monohydrate into the reaction liquid containing the tofacitinib base, and performing a salt formation reaction to obtain the tofacitinib citrate. According to the method provided by the invention, in the preparation process, anappropriate amount of the [Bmim]Im is added, a combination with a specific ratio of triethylamine to pyridine is selected as the base, and the ionic liquid is used as a solvent for the reaction and used as a catalyst to promote rapid progress of the reaction, and improves the yield and purity of the product.
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Paragraph 0042; 0046-0051; 0090-0097

(2019/07/29)

Preparation method of tofacitinib citrate
The invention relates to a preparation method of tofacitinib citrate, in particular to high-yield synthesis of tofacitinib citrate. The tofacitinib citrate is synthesized from raw materials including4-chloro-7-pyrrolo[2,3-d]pyrimidine, (BOC)2O, (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyl tartrate, Pd/C, cyanoacetic acid and citric acid through six steps including an aminoprotection reaction, an amination reaction, a debenzylation reaction, a condensation reaction, a deprotection reaction and a salt forming reaction. The synthesis route provides the preparation methodof tofacitinib citrate, and the preparation method is high in yield, low in cost, easy to operate and suitable for industrialization.
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(2018/09/08)

Refining method for tolfirinib citrate compound
The invention provides a refining method for a tofartinib citrate compound. The method comprises the following steps: preparing a tofartinib citrate crude product by a tofartinib crude product and citric acid monohydrate; adding a prepared mixed solvent, heating and stirring the mixture to be completely dissolved to obtain a clear solution, adding activated carbon, performing keeping warm and stirring, performing filtering, cooling a filtrate and performing recrystallization, performing filtering, washing a filter cake, and performing vacuum drying to obtain a tofatinib citrate refined product. The refining method has simple operation and high yield, the purity of tofartinib citrate reaches 99.93% or more, the maximum single impurity content is controlled to be 0.06% or less, and the totalimpurity content is controlled to be within 0.08%.
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Paragraph 0020; 0021; 0022; 0025; 0028

(2019/01/08)

Industrial production method of citric acid tofacitinib
The invention discloses an industrial production method of citric acid tofacitinib. The method comprises the following steps: (1) adding a compound SMA and a compound SMB to a mixed solvent 1 which comprises DMSO and purified water, and catalyzing through
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Paragraph 0083; 0084; 0085; 0086; 0089

(2018/03/25)

A tofacitinib citrate purification method
The invention belongs to the field of medicine synthesis and provides a tofacitinib citrate purification method which can effectively remove an impurity G. The method includes adding a tofacitinib citrate crude product to be purified into a mixed solvent, stirring and heating the mixture until the crude product is fully dissolved, cooling the mixture for crystallization, and performing filtrationand vacuum drying to obtain a purified tofacitinib citrate product. The method is simple to operate and suitable for industrial scale-up production, and has obvious impurity removing effects and a high yield.
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Paragraph 0025; 0030; 0031

(2019/01/08)

Preparation method of tofacitinib citrate
The invention discloses a preparation method of tofacitinib citrate. The preparation method comprises the following steps: stirring an organic solvent, a compound 3, 5 percent wet palladium on carbonand acetic acid until a mixture is suspended; conveying the mixture into a micro-reactor from a channel A; meanwhile, conveying alkylsilane into the micro-reactor from a channel B; controlling the temperature of the micro-reactor to 20 to 30 DEG C and carrying out reaction; carrying out post-treatment to obtain a compound 2; after uniformly mixing an alcohol type solvent, the compound 2, ethyl cyanoacetate and DBU (1,8-Diazabicyclo [5,4,0]undec-7-ene), conveying a mixture into the micro-reactor from the channel A; dissolving citric acid into a mixed solution of water and the alcohol type solvent, conveying a mixture into the micro-reactor from the channel B; controlling the temperature in the micro-reactor to 70 to 80 DEG C and carrying out reaction; cooling and crystallizing to obtain thetofacitinib citrate. The method provided by the invention has the advantages of controllable reaction condition and simplicity in operation; dangers caused by the fact that flammable and explosive gas is used are avoided and the safety is higher; reaction can be finished instantly and the reaction time is greatly shortened; debenzylation reaction and acylation reaction are complete and post-treatment is simple; the preparation method is suitable for industrial large-scale production. A formula is shown in the description.
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Paragraph 0042; 0043

(2018/07/30)

Preparation method of tofacitinib citrate compound
The invention discloses a preparation method of a tofacitinib citrate compound. According to the preparation method, 3-bromo-4-piperidone (II) and methyl magnesium bromide are subjected to Grignard reaction and dehydration reaction to obtain a compound III; the compound III is subjected to asymmetric hydrogenation to obtain a compound IV; the compound IV is subjected to substitution and acylationreaction to obtain a compound VI; the compound VI is subjected to deprotection and salt formation to prepare tofacitinib citrate (I). The preparation method has the advantages of simple technologicalroute, easiness for operation and high total yield and purity and is suitable for industrial production.
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(2019/01/11)

Method for preparing Tofacitinib citrate
The invention provides a method for preparing Tofacitinib citrate. The method comprises the steps of hydrochloric acid removal, amidation reaction, salt forming and the like. According to the method,the cost is low, the operation is simple and convenient, and the obtained product is high in purity, so that the method is applicable to industrial large-scale production.
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(2018/11/22)

EFFICIENT METHOD FOR THE PREPARATION OF TOFACITINIB CITRATE
Disclosed is a novel process for the synthesis of tofacitinib citrate on an industrial scale with high yields and purity starting with cis-(1-benzyl-4-methyl-piperidin-3-yl)methylamine bis-hydrochloride racemate (intermediate VIII), which comprises: 1. Condensation between intermediates VII and VIII to give intermediate VI 2. Hydrogenation of intermediate VI to give intermediate V 3. Resolution of intermediate V to give intermediate IV with enantiomeric purity >99% 4. Release of intermediate IV in a basic medium to give intermediate III 5. N-acylation reaction of intermediate III to give II (tofacitinib) 6. Salification of intermediate II to give tofacitinib monocitrate (I)
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(2016/10/31)

PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-?-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
The present invention relates to an improved 7H-pyrrolo[2,3-d]pyrimidin-4-yl-amino)-β-oxo-1-piperidine propanenitrile compound of formula-1 and its pharmaceutically acceptable salts.
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(2016/07/20)

Synthesis method for tofacitinib
The invention relates to a synthesis method for tofacitinib serving as a JAK inhibitor. According to the method, the tofacitinib is prepared by taking (4-picoline-3-yl)methyl carbamate as a raw material, and performing catalytic hydrogenation, benzyl protection, reduction, salification, separation, deprotection and amidation salification. The method specifically comprises the following steps: (1) performing catalytic hydrogenation and reduction on (4-picoline-3-yl)methyl carbamate in sulfuric acid and Pd/C; (2) reacting cis-(4-picoline-3-yl)methyl carbamate and benzyl chloride to obtain cis-(1-benzyl-4-methylpiperidine-3-yl)methyl carbamate; (3) performing HOBT catalytic condensation on N-[(3R,4R)-4-methylpiperidine-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine and cyanoacetic acid to obtain tofacitinib free alkali. The preparation method provided by the invention has easily obtained raw materials, mild reaction conditions, easiness and convenience in operation and high yield, and is suitable for industrial production.
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Paragraph 0031; 0032; 0033; 0034

(2017/07/19)

Preparation method of tofacitinib citrate
The invention belongs to the field of medicine and chemical engineering and particularly relates to a preparation method of tofacitinib citrate. The method comprises steps as follows: 1-benzyl-4-methyl-2,6-dihydro-3-piperidone taken as a starting material is subjected to an asymmetric reduction reaction, 1-benzyl-4-methyl-3-piperidone is obtained, and (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride is produced under the action of a chiral catalyst; (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochlorid and a paratoluensulfonyl chloride protection product 4-chloro-7-(methyl-4-benzenesulfonyl) pyrrolo[2,3-d]pyrimidine of 4-chloropyrrolo[2,3-d]pyrimidine are subjected to a condensation reaction, [(3R,4R)]-1-benzyl-4-methyl-piperidine-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine is obtained through deprotection, and tofacitinib citrate is obtained through debenzylation protection, an acylation reaction and citric acid salifying. The process route is short, the process cycle is short, chiral synthesis is performed by means of a catalyst, the product purity is improved, the cost is reduced, the yield is high, and the operation is simple and convenient.
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Paragraph 0063

(2016/10/17)

Method for synthesizing citric acid tofacitinib
The invention discloses an efficient and safe method for synthesizing citric acid tofacitinib. N-[(3R,4R)-1-benzyl-4-methylpiperidine-3-base]-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine is used as the raw material, Pd/C and HCOOH reduction debenzylation is conducted, condensation is conducted under the catalysis of an EDCI or EDCI, HOBT and triethylamine compound system with cyanoacetic acid, and salifying is conducted with citric acid in acetone to obtain citric acid tofacitinib. By the adoption of the synthesis method, potential safety hazards caused by hydrogen and ammonium formate are avoided, debenzylation reaction and amidation are thorough, no side reaction is caused basically, reaction time is shortened greatly, yield is high, aftertreatment is easy, and citric acid tofacitinib can be prepared efficiently and safely.
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Paragraph 0045; 0051; 0052; 0065; 0066-0070

(2016/12/26)

Preparation method of JAKs inhibitor drug tofacitinib
The invention discloses a preparation method of JAKs inhibitor drug tofacitinib. The preparation method is characterized by comprising the following steps: (1) taking 2, 4-dichloro-7Hpyrolle[2,3-D]pyrimidine as a raw material to react with halogenated benzyl to prepare a compound II in the existence of alkali; (2) allowing (3R, 4R)-N,4-dimethyl-1-(phenyl-methyl)-3-piperidylamine hydrochloride to react with 7-benzyl-2,4-dichloro-7Hpyrolle[2, 3-D]pyrimidine in the existence of alkali to prepare a compound IV; (3) catalyzing the compound IV obtained in the step (2) to have hydrogenation reaction in the existence of a metal catalyst to obtain a compound V; (4) coupling and joining the compound V obtained in the step (3) with cyanoacetic acid in the existence of a condensation agent to obtain a compound VI; and (5) salifying the compound VI obtained in the step (4) and citric acid to obtain tofacitinib. The method is simple and short in synthetic route, simple in the operation of various reaction processes, capable of recycling the solvents, little in pollution, and suitable for industrialized mass production.
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Paragraph 0020

(2016/10/10)

A PROCESS FOR THE PREPARATION OF TOFACITINIB CITRATE
The present invention provides a process for the preparation of tofacitinib citrate of Formula I. Specifically, the present invention provides an enzymatic route for the preparation of tofacitinib of Formula II, which is converted to tofacitinib citrate of Formula I.
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Page/Page column 6; 7

(2016/09/15)

SOLID FORMS OF TOFACITINIB SALTS
Solid and crystalline forms of tofacitinib hydrochloride and tofacitinib hydrobromide, processes for the preparation thereof and processes for the use thereof in preparing tofacitinib citrate are provided.
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Paragraph 0214

(2015/09/22)

TOFACITINIB CITRATE
Crystalline particle of tofacitinib citrate, process for the preparation of a crystalline particle of tofacitinib citrate, pharmaceutical composition, substantially pure amorphous form of tofacitinib citrate, process for preparing the substantially pure amorphous form of tofacitinib citrate, and use of the crystalline particle of tofacitinib citrate, and the pharmaceutical composition are provided.
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Page/Page column 12

(2015/04/28)

THE PRESENT INVENTION RELATES TO PROCESS FOR THE PREPARATION OF TOFACITINIB AND INTERMEDIATES THEREOF.
The present invention relates to process for the preparation of tofacitinib and intermediates thereof.
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Paragraph 0297

(2014/07/21)

PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATING DRY EYE DISORDERS
Ophthalmic compositions comprising Inhibitors of Janus kinase-3 (“Jak3”) are useful for treating dry eye disorders and other disorders requiring the wetting of the eye.
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(2013/11/19)

PROCESSES FOR PREPARING TOFACITINIB SALTS
The present invention is directed to Tofacitinib acid addition salts and solid state forms thereof, particularl amorphons tofacitinib acetate, y as well as pharmaceutical compositions comprising one or more of them. The present invention further provides a process for producing Tofacitinib acid addition salt, in particular, Tofacitinib mono citrate salt.
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Page/Page column 31

(2012/10/18)

Discovery of CP-690,550: A potent and selective janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection
There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
Flanagan, Mark E.,Blumenkopf, Todd A.,Brissette, William H.,Brown, Matthew F.,Casavant, Jeffrey M.,Shang-Poa, Chang,Doty, Jonathan L.,Elliott, Eileen A.,Fisher, Michael B.,Hines, Michael,Kent, Craig,Kudlacz, Elizabeth M.,Lillie, Brett M.,Magnuson, Kelly S.,McCurdy, Sandra P.,Munchhof, Michael J.,Perry, Bret D.,Sawyer, Perry S.,Strelevitz, Timothy J.,Subramanyam, Chakrapani,Sun, Jianmin,Whipple, David A.,Changelian, Paul S.
experimental part
p. 8468 - 8484
(2011/02/26)

PIPERIDINE INHIBITORS OF JANUS KINASE 3
The present invention relates to a new piperidine inhibitors of Janus Kinase 3 activity, pharmaceutical compositions thereof, and methods of use there-of.
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Page/Page column 54-55

(2010/11/05)

Mild and efficient DBU-catalyzed amidation of cyanoacetates
A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.
Price, Kristin E.,Larrivee-Aboussafy, Claude,Lillie, Brett M.,McLaughlin, Robert W.,Mustakis, Jason,Hettenbach, Kevin W.,Hawkins, Joel M.,Vaidyanathan, Rajappa
supporting information; experimental part
p. 2003 - 2006
(2009/09/30)

PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES; THEIR INTERMEDIATES AND SYNTHESIS
This invention relates to methods and intermediates useful for the synthesis of pyrrolo [2,3-d] pyrimidine compounds. Specifically novel synthetic methods and intermediates for the synthesis of 3- {(3R, 4R)-4-methyl-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-amino}-piperidin-1-yl)-3-oxo-propionitrile and its corresponding citrate salt are disclosed.
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Page/Page column 23-24

(2010/11/25)

Novel crystalline compound
This invention relates to novel amorphous and crystallline forms of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt, useful as inhibitors of protein kinases, and to their methods of preparation.
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(2008/06/13)