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477600-75-2

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  • High Quality 99% 477600-75-2 3-((3R,4R)-4-Methyl-3-(Methyl(7H-pyrrolo[2,3-d]pyriMidin-4-yl)aMino)piperidin-1-yl)-3-oxopropanenitrile Manufacturer

    Cas No: 477600-75-2

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477600-75-2 Usage

Description

In 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 Properties

Light Pink to Pale Orange Solid

Uses

CP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis

Definition

ChEBI: 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.

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.

Brand name

Xeljanz

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

477600-75-2SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 19, 2017

Revision Date: Aug 19, 2017

1.Identification

1.1 GHS Product identifier

Product name tofacitinib

1.2 Other means of identification

Product number -
Other names Tofacitinib

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

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