477600-75-2 Usage
Description
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile, also known as tofacitinib (CP-690550), is a pyrrolo[2,3-d]pyrimidine derivative that serves as a Janus kinase (JAK) inhibitor. It is characterized by its light pink to pale orange solid appearance and is used in the treatment of rheumatoid arthritis. Tofacitinib is the first small molecule kinase inhibitor approved for RA treatment, targeting the JAK1, JAK2, JAK3, and Tyk2 subtypes, which play a crucial role in the signal transduction pathway of various cytokines and inflammation propagation in RA.
Uses
Used in Pharmaceutical Industry:
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile is used as a Janus kinase inhibitor for the treatment of moderately to severely active rheumatoid arthritis. It works by inhibiting the phosphorylation and activation of signal transducers and activators of transcription (STATs), thereby suppressing the production of inflammatory mediators in joint tissue.
Brand Name:
The brand name for 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile is Xeljanz, which is approved by the US FDA for the treatment of adult patients with moderate to severe rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
Indications
The 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.
Synthesis
Commercially 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’s 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.
References
1) 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
Check Digit Verification of cas no
The CAS Registry Mumber 477600-75-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,7,7,6,0 and 0 respectively; the second part has 2 digits, 7 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 477600-75:
(8*4)+(7*7)+(6*7)+(5*6)+(4*0)+(3*0)+(2*7)+(1*5)=172
172 % 10 = 2
So 477600-75-2 is a valid CAS Registry Number.
InChI:InChI=1/C16H20N6O/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/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13-/m1/s1