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【结 构 式】 
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【分子编号】64500 【品名】tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C25H27F6NO3 【 分 子 量 】503.4847392 【元素组成】C 59.64% H 5.41% F 22.64% N 2.78% O 9.53% |
合成路线1
该中间体在本合成路线中的序号：(XI)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2
该中间体在本合成路线中的序号：(XV)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 |