tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】62266

【品名】tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate

【CA登记号】

【分子式】C₁₆H₂₁NO₃

【分子量】275.34768

【元素组成】C 69.79% H 7.69% N 5.09% O 17.43%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIX)

). The hydroxylation of the double bond of (XIV) by means of (Sia)2BH and H2O2 affords the pentanol (XV), which is treated with MsCl and TEA to provide the mesylate (XVI). The cyclization of (XVI) by means of t-BuOK in THF gives the piperidine (XVII), which is desilylated by means of TBAF to yield the piperidinol (XVIII). The oxidation of (XVIII) by means of DMP affords the piperidinone (XIX), which is treated with O-methylhydroxylamine and pyridine to provide the O-methyloxime (XX). The reduction of (XX) with BH3/THF gives the cis-disubstituted piperidine (XXI), which is submitted to a reductocondensation with 2-methoxybenzaldehyde (XXII) by means of NaBH3CN in methanol to yield the secondary amine (XXIII). Finally, the carbamate group of (XXIII) is cleaved by means of HCl in methanol to provide the target piperidine derivative

参考文献中间体

合成目标

【1】 Yamazaki, N.; et al.; Enantioselective synthesis of NK-1 receptor antagonists (+)-CP-99,994 and (+)-CP-122,721. Tetrahedron Lett 2002, 43, 44, 7979.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	62261	tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-4-pentenylcarbamate		C₂₂H₃₇NO₃Si	详情	详情
(XV)	62262	tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-1-phenylpentylcarbamate		C₂₂H₃₉NO₄Si	详情	详情
(XVI)	62263	(5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-phenylpentyl methanesulfonate		C₂₃H₄₁NO₆SSi	详情	详情
(XVII)	62264	tert-butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-phenyl-1-piperidinecarboxylate		C₂₂H₃₇NO₃Si	详情	详情
(XVIII)	62265	tert-butyl (2S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(XIX)	62266	tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₁NO₃	详情	详情
(XX)	62267	tert-butyl (2S)-3-(methoxyimino)-2-phenyl-1-piperidinecarboxylate		C₁₇H₂₄N₂O₃	详情	详情
(XXI)	31756	tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₄N₂O₂	详情	详情
(XXII)	12568	2-Methoxybenzaldehyde; o-Methoxybenzaldehyde	135-02-4	C₈H₈O₂	详情	详情
(XXIII)	31757	tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate		C₂₄H₃₂N₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

The cyclization of (S)-glutamic acid (I) by means of H2SO4 and NaNO2 gives the gamma lactone (II), which is treated with hot SOCl2 to yield the corresponding acyl chloride (III). The reaction of (III) with 4-methoxybenzylamine (IV) affords the expected amide (V), which is submitted to rearrangement in the presence of t-BuOK in THF to provide piperidinedione (VI). The reaction of (VI) with Tbdps-Cl and imidazole gives the silyl ether (VII), which is reduced with NaBH4 in methanol to yield a mixture of regioisomers (VIII). The phenyl migration in (VIII) was easily promoted by reaction with BF3/Et2O through the nonisolated intermediate cis-(IX) to yield (X). The reduction of (X) by means of LiAlH4 in THF affords the N-protected hydroxypiperidine (XI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol to provide the free hydroxypiperidine (XII). The reprotection of (XII) with Boc2O gives the carbamate-protected piperidine (XIII), which is oxidized by means of DMSO, (COCl)2 and DIEA in dichloromethane to yield piperidone (XIV). The reaction of (XIV) with NH2OH and K2CO3 affords the corresponding oxime (XV), which is treated with Ac2O in THF to provide the O-acetyloxime (XVI). The reduction of (XVI) with BH3/Me2S in hot THF gives the expected amine (XVII), which is condensed with 2-methoxybenzaldehyde (XVIII) in THF to yield the imine (XIX). The reduction of (XIX) with NaBH4 in methanol affords the protected benzylamine (XX), which is finally deprotected by means of HCl in methanol to provide CP-99,994.

参考文献中间体

合成目标

【1】 Wei, B.-G.; Huang, P.-Q.; Liu, L.-X.; Ruan, Y.-P.; Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon. Org Lett 2003, 5, 11, 1927.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
cis-(IX)	64777	(5S,6S)-5-{[tert-butyl(fluoro)phenylsilyl]oxy}-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone		C₂₉H₃₄FNO₃Si	详情	详情
(I)	12005	L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid	56-86-0	C₅H₉NO₄	详情	详情
(II)	12006	(R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid	53558-93-3	C₅H₆O₄	详情	详情
(III)	64772	(2S)-5-oxotetrahydro-2-furancarbonyl chloride		C₅H₅ClO₃	详情	详情
(IV)	15098	4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine	2393-23-9	C₈H₁₁NO	详情	详情
(V)	64773	(2S)-N-(4-methoxybenzyl)-5-oxotetrahydro-2-furancarboxamide		C₁₃H₁₅NO₄	详情	详情
(VI)	64774	(3S)-3-hydroxy-1-(4-methoxybenzyl)-2,6-piperidinedione		C₁₃H₁₅NO₄	详情	详情
(VII)	64775	(3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-(4-methoxybenzyl)-2,6-piperidinedione		C₂₉H₃₃NO₄Si	详情	详情
(VIII)	64776	(5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-hydroxy-1-(4-methoxybenzyl)-2-piperidinone		C₂₉H₃₅NO₄Si	详情	详情
(X)	64778	(5S,6S)-5-hydroxy-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone		C₁₉H₂₁NO₃	详情	详情
(XI)	64779	(2S,3S)-1-(4-methoxybenzyl)-2-phenyl-3-piperidinol		C₁₉H₂₃NO₂	详情	详情
(XII)	64498	(2S,3S)-2-phenyl-3-piperidinol		C₁₁H₁₅NO	详情	详情
(XIII)	64499	tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(XIV)	62266	tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₁NO₃	详情	详情
(XV)	64780	tert-butyl (2S)-3-(hydroxyimino)-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₂N₂O₃	详情	详情
(XVI)	64781	tert-butyl (2S)-3-[(acetyloxy)imino]-2-phenyl-1-piperidinecarboxylate		C₁₈H₂₄N₂O₄	详情	详情
(XVII)	31756	tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₄N₂O₂	详情	详情
(XVIII)	12568	2-Methoxybenzaldehyde; o-Methoxybenzaldehyde	135-02-4	C₈H₈O₂	详情	详情
(XIX)	64782	tert-butyl (2S,3S)-3-{[(E)-(2-methoxyphenyl)methylidene]amino}-2-phenyl-1-piperidinecarboxylate		C₂₄H₃₀N₂O₃	详情	详情
(XX)	31757	tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate		C₂₄H₃₂N₂O₃	详情	详情

Extended Information