Crizotinib;PF-02341066;PF-2341066, -Drug Synthesis Database

【结构式】

【药物名称】Crizotinib;PF-02341066;PF-2341066

【化学名称】3-[1(R)-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]pyridin-2-amine

【CA登记号】877399-52-5；877399-53-6 (monoacetate)

【分子式】C₂₁H₂₂Cl₂FN₅O

【分子量】450.337

【开发单位】National Cancer Institute (US); Pfizer, Inc. (US)

【药理作用】ALK/Met inhibitor；Oncolytic

合成路线1 合成路线2

合成路线1

Reaction of 5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine (I) with Boc2O by means of DMAP in DMF gives the protected aniline (II), which is condensed with bis(pinacolato)-diboron (III) by means of a Pd catalyst and KOAc in DMSO to yield the N-protected boronic ester (IV). Deprotection of the amino group of compound (IV) by means of HCl in dioxane/dichloromethane affords the boronic ester (V), which is condensed with 1-(1-Boc-piperidin-4-yl)-4-bromo-1H-pyrazole (VI) by means of PdCl2(PPh3)2 and Na2CO3 in hot DME/water to provide the adduct (VII). Finally, this compound is N-deprotected by means of HCl in dioxane/dichloromethane, as before .

参考文献中间体

【1】 Cui, J.J., Funk, L.A., Jia, L. et al. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors. EP 1786785, JP 2008510790, US 2006046991, WO 2006021884.
【2】 Cui, J.J., Funk, L.A., Jia, L. et al. (Pfizer, Inc.). Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors. EP 1784396, JP 2008510788, WO 2006021881.

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)	68698	5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine;(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine		C₁₃H₁₀BrCl₂FN₂O	详情	详情
(II)	68697			C₂₃H₂₆BrCl₂FN₂O₅	详情	详情
(III)	53342	4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester	73183-34-3	C₁₂H₂₄B₂O₄	详情	详情
(IV)	68696			C₂₉H₃₈BCl₂FN₂O₇	详情	详情
(V)	68695	(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine		C₁₉H₂₂BCl₂FN₂O₃	详情	详情
(VI)	68694	1-(1-Boc-piperidin-4-yl)-4-bromo-1H-pyrazole;4-(4-Bromopyrazol-1-yl)piperidine-1-carboxylicacid tert-butyl ester	877399-50-3	C₁₃H₂₀BrN₃O₂	详情	详情
(VII)	68693	(R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate		C₂₆H₃₀Cl₂FN₅O₃	详情	详情

合成路线2

Mitsunobu coupling between 1(S)-(2,6-dichloro-3-fluorophenyl) ethanol (VIII) and 3-hydroxy-2-nitropyridine (IX) in the presence of DIAD and PPh3 affords ether (X), which by subsequent nitro group reduction using iron and HCl in EtOH yields the aminopyridine (XI). Bromination of compound (XI) by treatment with N-bromosuccinimide provides the bromopyridine (I), which is then submitted to palladium-catalyzed coupling with the pyrazolyl boronate (XII) to give adduct (VII). Finally, the N-Boc protecting group is removed by treatment with HCl .

参考文献中间体

【1】 Tran-Dube, M., Shen, H., Yamazaki, S. et al. Lead optimization of 2-amino-3-benzyloxy-5-pyrazol-4-yl-pyridine for the discovery of clinical candidate PF-2341066 as potent and highly selective c-Met inhibitor. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 105.

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)	68698	5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine;(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine		C₁₃H₁₀BrCl₂FN₂O	详情	详情
(VII)	68693	(R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate		C₂₆H₃₀Cl₂FN₅O₃	详情	详情
(VIII)	68699	1(S)-(2,6-dichloro-3-fluorophenyl)ethanol;(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol	877397-65-4	C₈H₇Cl₂FO	详情	详情
(IX)	26207	2-nitro-3-pyridinol	15128-82-2	C₅H₄N₂O₃	详情	详情
(X)	68700	(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine		C₁₃H₉Cl₂FN₂O₃	详情	详情
(XI)	68701	(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine		C₁₃H₁₁Cl₂FN₂O	详情	详情
(XII)	68702	tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate		C₁₉H₃₂BN₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)