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【结 构 式】 
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【分子编号】64499 【品名】tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C16H23NO3 【 分 子 量 】277.36356 【元素组成】C 69.29% H 8.36% N 5.05% O 17.31% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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.
| 【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：(IX)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.
| 【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 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The esterification of L-phenylglycine (I) with AcCl and methanol gives the methyl ester (II), which is N-protected by means of Boc2O and TEA to yield the N-Boc derivative (III). The reduction of (III) with NaBH4 in ethanol/THF affords the alcohol (IV), which is oxidized by means of (COCl)2 and DMSO to provide the carbaldehyde (V). The reaction of (V) with vinylmagnesium bromide (VI) in THF gives the allyl alcohol (VII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (VIII). The alkylation of (VIII) with allyl bromide (IX) and NaH in DMF affords the N-allyl derivative (X), which is desilylated by means of TBAF and AcOH in THF to provide the allyl alcohol (XI). The ring closing metathesis reaction of (XI) with a Grubbs' catalyst in dichloromethane gives the tetrahydropyridine (XII), which is treated with H2 over Pd/C in ethanol to yield the chiral protected piperidine (XIII). The condensation of (XIII) with 3,5-bis(trifluoromethyl)benzyl bromide (XIV) by means of NaH in DMF affords the benzyl ether (XV), which is finally deprotected with TFA to provide the target piperidine.
| 【1】 Bhaskar, G.; Rao, B.V.; Stereoselective synthesis of L-733,060. Tetrahedron Lett 2003, 44, 5, 915. |
| 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) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 | |
| (III) | 12485 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 59225 | (R)-N-(tert-Butoxycarbonyl)-phenylglycinol; N-t-BOC-D-phenylglycinol | 102089-74-7 | C13H19NO3 | 详情 | 详情 |
| (V) | 45428 | tert-butyl (1S)-2-oxo-1-phenylethylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (VI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (VII) | 64501 | tert-butyl (1S,2S)-2-hydroxy-1-phenyl-3-butenylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (VIII) | 64502 | tert-butyl (1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenylcarbamate | C21H35NO3Si | 详情 | 详情 | |
| (IX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (X) | 64503 | tert-butyl allyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenyl)carbamate | C24H39NO3Si | 详情 | 详情 | |
| (XI) | 64504 | tert-butyl allyl[(1S,2S)-2-hydroxy-1-phenyl-3-butenyl]carbamate | C18H25NO3 | 详情 | 详情 | |
| (XII) | 64505 | tert-butyl (2S,3S)-3-hydroxy-2-phenyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (XIII) | 64499 | tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (XIV) | 27677 | 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene | 32247-96-4 | C9H5BrF6 | 详情 | 详情 |
| (XV) | 64500 | tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate | C25H27F6NO3 | 详情 | 详情 |