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
• Article Data: 37

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

Description

Tofacitinib citrate, developed by Pfizer under the trade name Xeljanz, is a Janus kinase inhibitor used for treating rheumatoid arthritis in adult patients with a history of inadequate response or intolerance to methotrexate. It is a synthetic molecule with a molecular weight of 312.4 Da and is permeable through transcellular diffusion. Tofacitinib citrate is a citrate salt obtained by combining equimolar amounts of tofacitinib and citric acid.

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

• 384336-73-6 (3R,4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 
• 56657-76-2 succinimidyl cyanoacetate 
• 77-92-9 citric acid 
• 477600-74-1 tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate 
• 372-09-8 cyanoacetic acid 
• 923036-30-0 N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-(7-p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 
• 1252883-90-1 N-((3S,4S)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d] pyrimidin-4-amine 
• 105-56-6 ethyl 2-cyanoacetate 
• 3680-69-1 4-chloro-1H-pyrrolo[2,3-d]pyrimidine 
• 479633-63-1 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine 
• 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 

Relevant articles and documents

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.

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.