Tofacitinib

Tofacitinib Basic information
Product Name:Tofacitinib
Synonyms:3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;CP 690550;3-Piperidinamine, 1-(cyanoacetyl)-4-methyl-N-methyl-N-1H-pyrrolo(2,3-D)pyrimidin-4-yl-, (3R,4R)-;CP-690550(Tasocitinib,CP690550);CP 690550(Tasocitinib);Tasocitinib;3-((3R,4R)-4-Methyl-3-(Me...;Tasocitinib (CP 690550)
CAS:477600-75-2
MF:C16H20N6O
MW:312.38
EINECS:689-145-4
Product Categories:Inhibitors;Inhibitor;API;477600-75-2
Mol File:477600-75-2.mol
Tofacitinib Structure
Tofacitinib Chemical Properties
density 1.3
storage temp. -20°C
solubility Soluble in DMSO (up to 100 mg/ml) or in Ethanol (up to 100 mg/ml).
form Pale powder.
pka6.04±0.60(Predicted)
color Off-white
Stability:Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
CAS DataBase Reference477600-75-2
Safety Information
HS Code 29335990
Hazardous Substances Data477600-75-2(Hazardous Substances Data)
MSDS Information
Tofacitinib Usage And Synthesis
DescriptionIn November 2012, the US FDA approved tofacitinib (also referred to as CP-690550) for the treatment of adult patients with moderate to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. Tofacitinib is the first small molecule kinase inhibitor approved for the treatment of RA. Tofacitinib is an inhibitor of the four subtypes of Janus kinase (JAK): JAK1, JAK2, JAK3, and Tyk2. The JAKs are intracellular, nonreceptor tyrosine kinases that play important roles in the signal transduction pathway of many cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) and are involved in the propagation of inflammation in RA. Tofacitinib acts by inhibiting the phosphorylation and activation of signal transducers and activators of transcription (STATs), thereby suppressing the production of inflammatory mediators in joint tissue. At the enzyme level, tofacitinib inhibits JAKs 1, 2, 3, and Tyk2 with IC50s of 3.2, 4.1, 1.6, and 34 nM, respectively. At the cellular level, tofacitinib inhibits the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50s of 406, 56, and 1377 nM, respectively.
Chemical PropertiesLight Pink to Pale Orange Solid
OriginatorPfizer (United States)
UsesCP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis
DefinitionChEBI: A pyrrolopyrimidine that is pyrrolo[2,3-d]pyrimidine substituted at position 4 by an N-methyl,N-(1-cyanoacetyl-4-methylpiperidin-3-yl)amino moiety. Used as its citrate salt to treat moderately to severely ctive rheumatoid arthritis.
IndicationsThe JAK family includes four isoforms, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). Ruxolitinib (Jakafi(R), Incyte Corp.) was the first approved JAK inhibitor, which inhibits both JAK1 and JAK2, used for the treatment of different types of myelofibrosis. Tofacitinib (Xeljanz(R), Pfizer) was approved by FDA as a JAK3-selective inhibitor for the treatment of rheumatoid arthritis and is one of the only two FDA-approved kinase inhibitors for non-oncological indications.
Brand nameXeljanz
SynthesisCommercially available aminopyridine 171 was reacted with dimethyl dicarbonate in the presence of potassium t-butoxide to give the methyl carbamate 172 in 87% yield. Hydrogenation of this carbamate 172 in the presence of 20 wt% of 5% Rh/C (JM type C101023-5) in acetic acid followed by reductive amination with benzaldehyde and sodium triacetoxy borohydride furnished the cis-benzyl protected piperidine 173 in 73% yield. Reduction of the methyl carbamate within 173 with lithium aluminum hydride (LAH) in THF gave the corresponding methyl amino piperidine which was isolated as the dihydrochloride salt 174 in 87% yield. Enantiomeric resolution of the methyl amino piperidine was achieved by freebasing the di-hydrochloride salt 174 with sodium hydroxide and then conversion to the di-toluol-L-tartaric acid salt followed by crystallization to give 175 in 42% yield and 98.6% ee. The enantioenriched tartrate salt 175 was then directly reacted with dichloride 176 (obtained from reaction of commercial 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (178) with phosphorous oxychloride) in the presence of potassium carbonate in water to give the coupled product 177 in essentially quantitative yield. Hydrogenation of intermediate 177 with DeGussa?ˉs catalyst triggered concomitant debenzylation and chloride removal, and this was followed by installation of the cyanoacetate group and subsequent treatment with citric acid to provide tofacitinib citrate (XXVII) in 90% yield.

Synthesis_477600-75-2

References1) Jiang et al. (2008), Examining the chirality, confirmation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitril (CP-690,550); J. Mol. Chem., 51 8012 2) Cutolo and Meroni (2013), Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis; J. Inflamm. Res., 6 129 3) Martina et al. (2016), Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro; Transplant. Proc., 48 3046 4) Moisan et al. (2015), White-to-brown metabolic conversion of human adipocytes by JAK inhibition; Nat. Cell Biol., 17 57 5) Dowty et al. (2014), Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis; J. Pharmacol. Exp. Ther., 348 165
Tofacitinib Preparation Products And Raw materials
PLX4032 (1-Benzyl-4-Methyl-1,2,5,6-tetrahydropyridin-3-yl)carbaMic acid Methyl ester Lenvatinib Ibrutinib Sunitinib Malate Dacomitinib (PF299804) N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Trametinib Pictilisib Palbociclib Cabozantinib N-((3R,4R)-1-benzyl-4-Methylpiperidin-3-yl)-2-chloro-N-Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-aMine Axitinib N-((3R,4R)-1-benzyl-4-Methylpiperidin-3-yl)-N-Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-aMine Tofacitinib citrate Nilotinib hydrochloride anhydrous Tofacitinib DEAZAPURINE

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