Palbociclib, -Drug Synthesis Database

【结构式】

【药物名称】Palbociclib

【化学名称】6-Acetyl-8-cyclopentyl-5-methyl-2-[5-(1-piperazinyl)pyridin-2-ylamino]pyrido[2,3-d]pyrimidin-7(8H)-one

【CA登记号】571190-30-2;571189-11-2 (as hydrochloride)

【分子式】C₂₄H₂₉N₇O₂

【分子量】447.5328

【开发单位】Pfizer Inc. (US)

【药理作用】Cyclin CDK4/CDK6 Inhibitor;Oncolytic

合成路线1 合成路线2

合成路线1

Treatment of 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (I) with 2-benzenesulfonyl-3-phenyl-oxaziridine (II) in CH2Cl2 results in the corresponding sulfoxide (III) . Subsequent displacement of the methylsulfinyl group of compound (III) with 2-amino-5-(4-Boc-1-piperazinyl)pyridine (IV) in boiling toluene provides the diarylamine adduct (V), which is subjected to Stille coupling with (ethoxyvinyl)tributylstannane (VI) in the presence of Pd(PPh3)4 to give the ethoxyvinyl derivative (VII). Finally, compound (VII) is submitted to simultaneous enol ether hydrolysis and cleavage of the Boc-protecting group by means of HCl in CH2Cl2 .

参考文献中间体

【1】 Toogood, P.L., Harvey, P.J., Repine, J.T. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005, 48(7): 2388-406.
【2】 Barvian, M.R., Quin, J. III, Sheehan, D.J. et al. (Pfizer Inc.). 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 1470124, JP 2005519909, US 2003149001, US 6936612, WO 2003062236.

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)	68142	6-bromo-8-cyclopentyl-5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one		C₁₄H₁₆BrN₃OS	详情	详情
(II)	31834	3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine	63160-13-4	C₁₃H₁₁NO₃S	详情	详情
(III)	68143	6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one		C₁₄H₁₆BrN₃O₂S	详情	详情
(IV)	68144	tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate		C₁₄H₂₂N₄O₂	详情	详情
(V)	68145	tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate		C₂₇H₃₄BrN₇O₃	详情	详情
(VI)	19760	ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane	97674-02-7	C₁₆H₃₄OSn	详情	详情
(VII)	61701	tert-butyl 4-(6-((8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate		C₃₁H₄₁N₇O₄	详情	详情

合成路线2

Amination of 5-bromo-2,4-dichloropyrimidine (VIII) with cyclopentylamine (IX) in EtOH gives 5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine (X), which is then cyclized with crotonic acid (XI) by means of DIEA, TOTP, PdCl2(PhCN)2 in THF at 70 °C followed by treatment with Ac2O to yield the 8H-pyrido[2,3-d]pyrimidinone derivative (XII). Bromination of compound (XII) with Br2 in the presence of NaOAc in AcOH provides the 6-bromopyrido[2,3-d]pyrimidinone derivative (XIII), which is then coupled with the aminopyridine derivative (IV) in the presence of LiHMDS in toluene to afford intermediate (V). Condensation of the bromo derivative (V) with butylvinylether (XIV) in the presence of DIEA, PdCl2(dppf)2.CH2Cl2 complex in n-BuOH at 95 °C affords the 6-(1-butoxyvinyl)dihydropyrido[2,3-d]pyrimidine derivative (XV) . Finally, intermediate (XV) is treated with isethionic acid (XVI) —previously prepared by acidification of sodium isethionate (XVII) with HCl in i-PrOH in MeOH/H2O at 55 °C followed by TEA in MeOH .
The aminopyridine intermediate (IV) can be prepared by condensation of Boc-piperazine (XVIII) with 5-bromo-2-nitropyridine (XIX) in the presence of TEA in DMSO at 65-70 °C to give the nitropyridine derivative (XX), which is then reduced in the presence of H2 over Pd(OH)2/C in i-PrOH .
The key intermediate diarylamine adduct (V) can also be obtained directly by coupling aminopyridine derivative (IV) with the 2-methanesulfonylpyrido[2,3-d]pyrimidinone derivative (XXI) .

参考文献中间体

【1】 Toogood, P.L., Harvey, P.J., Repine, J.T. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005, 48(7): 2388-406.
【2】 Barvian, M.R., Quin, J. III, Sheehan, D.J. et al. (Pfizer Inc.). 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 1470124, JP 2005519909, US 2003149001, US 6936612, WO 2003062236.
【4】 Beylin, V.G., Blackburn, A.C., Erdman, D.T., Toogood, P.L. (Pfizer, Inc.).Isethionate salt of a selective CDK4 inhibitor. EP 1648889, JP 2007530425, US 2005059670, WO 2005005426.
【3】 Erdman, D.T., Flamme, C.M., Nelson, J.D. (Pfizer Products, Inc.). Synthesis of 2-(pyridine-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 2069344, JP 2008094834, US 2008125588, US 7781583, WO 2008032157.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	68144	tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate		C₁₄H₂₂N₄O₂	详情	详情
(V)	68145	tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate		C₂₇H₃₄BrN₇O₃	详情	详情
(VIII)	68146	5-bromo-2,4-dichloropyrimidine	36082-50-5	C₄HBrCl₂N₂	详情	详情
(IX)	28850	cyclopentanamine	1003-03-8	C₅H₁₁N	详情	详情
(X)	68147	5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine;5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine		C₉H₁₁BrClN₃	详情	详情
(XI)	20599	(E)-2-butenoic acid; crotonic acid	3724-65-0	C₄H₆O₂	详情	详情
(XII)	68148	2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₁₃H₁₄ClN₃O	详情	详情
(XIII)	68149	6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₁₃H₁₃BrClN₃O	详情	详情
(XIV)	59983	1-butoxyethylene; butyl vinyl ether	111-34-2	C₆H₁₂O	详情	详情
(XV)	68150	tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate		C₃₃H₄₅N₇O₄	详情	详情
(XVI)	13359	2-Hydroxy-1-ethanesulfonic acid	107-36-8	C₂H₆O₄S	详情	详情
(XVII)	68151	sodium isethionate；sodium 2-sulfoethanolate		C₂H₅NaO₄S	详情	详情
(XVIII)	13225	N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate	143238-38-4	C₉H₁₈N₂O₂	详情	详情
(XIX)	68152	5-bromo-2-nitropyridine；2-Nitro-5-bromopyridine;3-Bromo-6-nitropyridine	39856-50-3	C₅H₃BrN₂O₂	详情	详情
(XX)	68153	tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate		C₁₄H₂₀N₄O₄	详情	详情
(XXI)	68154	6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one		C₁₄H₁₆BrN₃O₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1) FDA Approved Drug Products(19)