CP-690550, -Drug Synthesis Database

【结构式】

【药物名称】CP-690550

【化学名称】(3R,4R)-3-[4-Methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile

【CA登记号】477600-75-2

【分子式】C₁₆H₂₀N₆O

【分子量】312.3698

【开发单位】Pfizer, Inc. (US).

【药理作用】JAK3 inhibitor, Immunosuppressant, Treatment of rheumatoid arthritis, Treatment of transplant rejection

合成路线1 合成路线2

合成路线1

Racemic CP-690550 can be obtained by the following method. Reductive amination of 1-benzyl-4-methylpiperidin-3-one (I) with methylamine and sodium triacetoxyborohydride in THF gives N-methyl-1-benzyl-4-methylpiperidin-3-amine (II), which is condensed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (III) by means of triethylamine in a sealed tube at 100 °C to yield the tertiary amine (IV). After deprotection of (IV) by catalytic hydrogenolysis over Pd(OH)2/C, the debenzylated piperidine (V) is acylated with cyanoacetyl chloride (VI) and pyridine in CH2Cl2 to provide the target compound (1). Scheme 1.

参考文献中间体

【1】 Blumenkopf, T.A., Flanagan, M.E., Munchhof, M.J. (Pfizer Products Inc.). Pyrrolo[2,3-d]pyrimidine cpds. EP 1235830, JP 2003516405, US 2001053782, US 6627754, WO 0142246.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	65390	1-benzyl-4-methylpiperidin-3-one		C₁₂H₁₇NO	详情	详情
(II)	65391	1-Benzyl-N,4-dimethylpiperidin-3-amine; (1-Benzyl-4-methylpiperidin-3-yl)methylamine	384338-23-2	C₁₄H₂₂N₂	详情	详情
(III)	60046	4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine	3680-69-1	C₆H₄ClN₃	详情	详情
(IV)	65392	N-Methyl-N-[(3RS,4RS)-4-methyl-1-(phenylmethyl)-3-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine		C₂₀H₂₅N₅	详情	详情
(V)	65393	N-Methyl-N-[(3RS,4RS)-4-methyl-3-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine		C₁₃H₁₉N₅	详情	详情
(VI)	65394	cyanoacetyl chloride		C₃H₂ClNO	详情	详情

合成路线2

An enantioselective synthesis of the (3R,4R)-isomer has also been reported. Quaternization of 3-(methoxycarbonylamino)-4-methylpyridine (VII) with benzyl chloride in toluene at 80 °C, followed by reduction of the resulting pyridinium salt (VIII) with NaBH4 in ethanol, yields the tetrahydropyridine (IX). Enantioselective hydrogenation of (IX) in the presence of chiral rhodium catalyst in ethanol, and subsequent purification of the obtained piperidine by crystallization as the corresponding di-p-toluoyltartrate salt, provides the pure (3R,4R)-enantiomer (X). This is then condensed with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (XI) by means of K2CO3 in boiling water to give the tertiary amine (XII), which is subjected to simultaneous debenzylation and dechlorination by means of H2 and Pd(OH)2/C to yield the deprotected piperidine (XIII) (2). This compound is finally condensed with cyanoacetyl chloride (VI) (prepared from cyanoacetic acid [XIV] and oxalyl chloride) by means of triethylamine in dichloromethane to obtain the chiral CP-690550 (2, 3). Scheme 2.

参考文献中间体

【2】 Hawkins, J.M., Makowski, T.M., Ruggeri, S.G., Rutherford, J.L., Urban, F.J. (Pfizer Products Inc.). Pyrrolo[2,3-d]pyrimidine derivatives; their intermediates and synthesis. JP 2007039455, WO 2007012953.
【3】 Flanagan, M.E., Li, Z.J. (Pfizer, Inc.). Novel crystalline cpd. JP 2005511696, US 2003130292, WO 03048162.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	65394	cyanoacetyl chloride		C₃H₂ClNO	详情	详情
(VII)	65395	3-(methoxycarbonylamino)-4-methylpyridine		C₈H₁₀N₂O₂	详情	详情
(VIII)	65396	1-benzyl-3-(methoxycarbonylamino)-4-methylpyridinium chloride		C₁₅H₁₇ClN₂O₂	详情	详情
(IX)	65397			C₁₅H₂₀N₂O₂	详情	详情
(X)	65398	(3R,4R)-1-Benzyl-N,4-dimethylpiperidin-3-amine	477600-70-7	C₁₄H₂₂N₂	详情	详情
(XI)	65399	2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine; 2,4-Dichloro-1H-pyrrolo[2,3-d]pyrimidine	90213-66-4	C₆H₃Cl₂N₃	详情	详情
(XII)	65400			C₂₀H₂₄ClN₅	详情	详情
(XIII)	65401	N-Methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	477600-74-1	C₁₃H₁₉N₅	详情	详情
(XIV)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)