540737-29-9

Basic information

• Product Name: Tofacitinib citrate
• Synonyms: 1-PIPERIDINEPROPANENITRILE, 4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YLAMINO)-BETA-OXO-, (3R,4R)-, 2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE (1:1);1-Piperidinepropanenitrile, 4-Methyl-3-(Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMino)-β-oxo-, (3R,4R)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1);Tofacitinib citrate (CP-690550);Tofacitinib citrate;Tasocitinib citrate;Tasocitinib citric acid s...;Xeljanz;CP-690550 (Tofacitinib citrate)
• CAS NO: 540737-29-9
• Molecular Formula: C16H20N6O.C6H8O7
• Molecular Weight: 504.497
• EINECS: 1592732-453-0
• Product Categories: Inhibitor;Inhibitors;JAK;STAT;API
• Mol File: 540737-29-9.mol

Chemical Properties

• Melting Point: 201 °C (decomp)
• Boiling Point: 585.8 °C at 760 mmHg
• Flash Point: 308.1 °C
• Appearance: white to beige/
• Storage Temp.: room temp
• Solubility: DMSO: soluble5mg/mL (clear solution; warmed)
• CAS DataBase Reference: Tofacitinib citrate(CAS DataBase Reference)
• NIST Chemistry Reference: Tofacitinib citrate(540737-29-9)
• EPA Substance Registry System: Tofacitinib citrate(540737-29-9)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 540737-29-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Tofacitinib citrate is used as a Janus kinase inhibitor for the treatment of severe active rheumatoid arthritis (RA) in adult patients with a history of inadequate response or intolerance to methotrexate. It is administered twice daily, either as monotherapy or in combination with methotrexate or other non-biological disease-modifying antirheumatic drugs (DMARDs).
Used in Research and Development:
Tofacitinib citrate is used as a ligand for human serum albumin in various studies, including fluorescence quenching, dynamic light scattering (DLS) measurements, differential scanning calorimetry, and molecular docking studies.
Used in Cartilage Research:
Tofacitinib citrate is used as a medium supplement for full-depth articular cartilage (FDC) explants to monitor cytokine-induced proteoglycan loss, which is essential for understanding the effects of the drug on cartilage health.
Used in Cancer Research:
Tofacitinib citrate is used as a Janus kinase inhibitor in MCF7 breast cancer cells, potentially offering insights into its application in cancer treatment and its effects on cancer cell behavior.

In vitro

CP-690550 is a specific, orally inhibitor of JAK3, it is 20-to 100-fold less potent for JAK2 and JAK1 with IC50 of 20 nM and 112 nM, respectively. CP-690550 doesn't have potent activity against 30 other kinases (all median IC50 > 3000 nM). CP-690,550 inhibits IL-2–induced proliferation with 30-fold greater potency than its effects on GM-CSF–induced proliferation. CP-690550 effectively inhibits a murine mixed lymphocyte reaction (MLR) (IC50 = 91 nM).? CP-690550 potently inhibits IL-4 induced upregulation of CD23 (IC50=57 nM) and class II major histocompatibility complex (MHCII) expression (IC50=71 nM) on murine B cells. A recent research indicates low dose of CP-690550 accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation.

In vivo

In a murine model of heterotopic heart transplantation (DBA2 donor heart into C57/BL6 host), CP-690550 results in a dose-dependent increase in survival of transplanted hearts.The EC50 (drug concentration in blood at which 50% of mice will maintain their graft for >28 days) to be ～60 ng/mL.CP-690550 prevents rejection of allogeneic kidneys in nonhuman primate (NHPs, macaca fascicularis) (MST of 62 and 83 days for the 50 to 100 ng/ml groups and 200 to 400 ng/ml groups, respectively). Mice chronically dosed with CP-690550 (1.5-15 mg/kg/day) demonstrate dose and time-dependent alterations in lymphocyte subsets when examined by flow cytometry. The most dramatic change observed is a 96% reduction in splenic NK1.1+TCRb-cell numbers following 21 days of treatment. Delayed-type hypersensitivity (DTH) responses in sensitized mice are reduced in a dose-dependent manner following treatment with CP-690550 (1.87–30 mg/kg, s.c.).

References

http://www.medicinenet.com/tofacitinib_citrate_xeljanz/article.htm

Biological Activity

tofacitinib citrate, also known as cp-690550 citrate, is a potent inhibitor of janus kinase 3 (jak3), a hematopoetic cell-restricted tyrosine kinase involved in signal transduction regulating lymphocyte survival, proliferation, differentiation, and apoptosis. the inhibition is jak3 specific with a selectivity 1000-fold more than other non-jak family kinases. besides inhibiting jaks (ic50 = 1 nm), tofacitinib citrate also inhibits janus kinase 2 (jak2) and janus kinase 1 (jak1) with 20- and 100-fold less in potency respectively. however, in a recent study, the binding affinities (ki) of tofacitinib citrate towards jak1, jak2, and jak3 were reported to be 1.6 nm, 21.7 nm, and 6.5 nm respectively.lalitha vijayakrishnan, r. venkataramanan and palak gulati. treating inflammation with the janus kinase inhibitor cp-690,550. trends in pharmacological sciences 2011: 32 (1); 25-34

Biochem/physiol Actions

Tofacitinib is a potent inhibitor of Janus kinase 3 (JAK3) with some JAK-1 inhibitory activity as well. It blocks downstream STAT signaling resulting in potent inhibition of inflammatory cytokines with resultant immunosuppressive and anti-inflammatory activity. Tofacitinib is being investigated for for several autoimmune disorders including, rheumatoid arthritis, psoriasis and dry eye.

Clinical Use

Potent, selective inhibitor of the Janus kinase family: Treatment of moderate to severe active rheumatoid arthritis

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration of tofacitinib reduced by rifampicin - avoid. Antifungals: concentration of tofacitinib increased by fluconazole and ketoconazole - adjust tofacitinib dose. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid. Ciclosporin: concentration of tofacitinib reduced - avoid. Tacrolimus: concentration of tofacitinib reduced - avoid. Vaccines: risk of generalised infections with live vaccines - avoid.ccccccc

Metabolism

70% metabolised in the liver by CYP3A4 (major) and CYP2C19 (minor). The 8 metabolites produced are inactive.

InChI:InChI=1S/C16H20N6O.C6H8O7/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16;7-3(8)1-6(13,5(11)12)2-4(9)10/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t11-,13+;/m1./s1

Upstream product

• 477600-74-1 tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate 
• 105-56-6 ethyl 2-cyanoacetate 
• 77-92-9 citric acid 
• 1252883-90-1 N-((3S,4S)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d] pyrimidin-4-amine 
• 56657-76-2 succinimidyl cyanoacetate 
• 1616760-91-8 methyl-(1-trityl-4-methylpiperidin-3-yl)carbamate 
• 1616833-40-9 1-triryI-N,4-dimethylpiperidin-3-amine 
• 1616760-93-0 (3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine 
• 934524-10-4 2,4-dichloro-7-p-methylbenzenesulfonyl-7H-pyrrole[2,3-d]pyrimidin-4-amine 
• 90213-66-4 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 
• 1616760-94-1 C₃₉H₃₈ClN₅O₂S 
• 1616760-95-2 C₂₀H₂₄ClN₅O₂S 
• 1616760-96-3 C₃₂H₃₂ClN₅ 
• 1616760-97-4 N-((3R,4R)-4-methyl-piperidin-3-yl)-N-methyl-2-chloro-7H-pyrrolo[2,3-D]pyrimidine-4-amine 

Relevant articles and documents

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.

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.

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.

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)

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.

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.

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.

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.

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.

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.