(2S,3S)-2-phenyl-3-piperidinol -Drug Synthesis Database

【结构式】

【分子编号】64498

【品名】(2S,3S)-2-phenyl-3-piperidinol

【CA登记号】

【分子式】C₁₁H₁₅NO

【分子量】177.24624

【元素组成】C 74.54% H 8.53% N 7.9% O 9.03%

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：(XII)

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

合成路线2

该中间体在本合成路线中的序号：(VIII)

The cyclization of benzaldehyde (I) with methyl 4-nitrobutyrate (II) and ammonium acetate in refluxing acetic acid gives 5-nitro-6-phenylpiperidone (III), which is treated with ozone and t-BuOK in dichloromethane/methanol to yield 2-phenylpiperidine-3,6-dione (IV). The reduction of (IV) by means of LiAlH4 in THF affords 2-phenylpiperidin-3-ol (V) as a mixture of cis- and trans-isomers. The reaction of (V) with TsOH, followed by crystallization in methanol/ethyl acetate provides the corresponding tosylate (VI) as the (rac)(cis)-isomer. The neutralization of the tosylate (VI) with Na2CO3 in ethyl acetate/water gives 2-phenylpiperidin-3-ol (VII) as a racemic cis mixture, which is submitted to optical resolution with (+)-dibenzoyltartaric acid to yield (+)(cis)-(VIII). The reaction of (VIII) with Boc2O affords the N-protected compound (IX), which is alkylated with 3,5-bis(trifluoromethyl)benzyl bromide (X) and NaH to provide the benzyl ether (XI). Finally, this compound is N-deprotected by means of TFA to obtain the target piperidine.

参考文献中间体

合成目标

【1】 Baker, R.; Harrison, T.; Swain, C.J.; Williams, B.J. (Merck Sharp & Dohme Ltd.); Azacyclic cpds., processes for their preparation and pharmaceutical compsns. containing them. EP 0528495; EP 0600952; JP 1994510034; WO 9304040 .

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)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(II)	64492	methyl 4-nitrobutanoate		C₅H₉NO₄	详情	详情
(III)	64493	5-nitro-6-phenyl-2-piperidinone		C₁₁H₁₂N₂O₃	详情	详情
(IV)	64494	6-phenyl-2,5-piperidinedione		C₁₁H₁₁NO₂	详情	详情
(V)	64495	(cis),(trans)2-phenyl-3-piperidinol		C₁₁H₁₅NO	详情	详情
(VI)	64496	(rac)(cis)3-hydroxy-2-phenylpiperidinium 4-methylbenzenesulfonate		C₁₈H₂₃NO₄S	详情	详情
(VII)	64497	(rac)(cis)[(2S,3S)-2-phenyl-3-piperidinol]		C₁₁H₁₅NO	详情	详情
(VIII)	64498	(2S,3S)-2-phenyl-3-piperidinol		C₁₁H₁₅NO	详情	详情
(IX)	64499	tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(X)	27677	1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene	32247-96-4	C₉H₅BrF₆	详情	详情
(XI)	64500	tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate		C₂₅H₂₇F₆NO₃	详情	详情

Extended Information