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【结 构 式】 
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【分子编号】26970 【品名】tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C17H34NO7P 【 分 子 量 】395.433262 【元素组成】C 51.64% H 8.67% N 3.54% O 28.32% P 7.83% |
合成路线1
该中间体在本合成路线中的序号：(Vb)The protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is finally deprotected and hydrolyzed with 6M HCl.
| 【1】 Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (IIa) | 26964 | benzyl 3-hydroxy-1-piperidinecarboxylate | C13H17NO3 | 详情 | 详情 | |
| (IIb) | 26965 | tert-butyl 3-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (IIIa) | 26966 | benzyl 3-oxo-1-piperidinecarboxylate | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 26967 | 1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate | 98977-36-7 | C10H17NO3 | 详情 | 详情 |
| (Va) | 26969 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C20H32NO7P | 详情 | 详情 | |
| (Vb) | 26970 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C17H34NO7P | 详情 | 详情 | |
| (VIIa) | 26972 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C23H34NO10P | 详情 | 详情 | |
| (VIIb) | 26973 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C20H36NO10P | 详情 | 详情 | |
| (VIIIa) | 26974 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C20H32NO6P | 详情 | 详情 | |
| (VIIIb) | 26975 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C17H34NO6P | 详情 | 详情 | |
| (I) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (IV) | 26968 | ethyl diethoxymethylphosphinate | C7H17O4P | 详情 | 详情 | |
| (VI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(Vb)The protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is deprotected with trifluoroacetic acid affording (IX) with its free NH group. The alkylation of (IX) with 4,4-diphenyl-3-butenyl bromide (X) provides the alkylated piperidinephosphinate (XI), which is finally hydrolyzed with refluxing 6M HCl.
| 【1】 Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (IIa) | 26964 | benzyl 3-hydroxy-1-piperidinecarboxylate | C13H17NO3 | 详情 | 详情 | |
| (IIb) | 26965 | tert-butyl 3-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (IIIa) | 26966 | benzyl 3-oxo-1-piperidinecarboxylate | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 26967 | 1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate | 98977-36-7 | C10H17NO3 | 详情 | 详情 |
| (Va) | 26969 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C20H32NO7P | 详情 | 详情 | |
| (Vb) | 26970 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C17H34NO7P | 详情 | 详情 | |
| (VIIa) | 26972 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C23H34NO10P | 详情 | 详情 | |
| (VIIb) | 26973 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C20H36NO10P | 详情 | 详情 | |
| (VIIIa) | 26974 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C20H32NO6P | 详情 | 详情 | |
| (VIIIb) | 26975 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C17H34NO6P | 详情 | 详情 | |
| (I) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (IV) | 26968 | ethyl diethoxymethylphosphinate | C7H17O4P | 详情 | 详情 | |
| (VI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (IX) | 27066 | 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinic acid | C21H26NO2P | 详情 | 详情 | |
| (X) | 24116 | 1-(4-bromo-1-phenyl-1-butenyl)benzene | C16H15Br | 详情 | 详情 | |
| (XI) | 27067 | ethyl 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinate | C23H30NO2P | 详情 | 详情 |