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【结 构 式】 
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【分子编号】20214 【品名】ethyl (3S)-3-benzyl-2-oxo-3-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C15H19NO3 【 分 子 量 】261.3208 【元素组成】C 68.94% H 7.33% N 5.36% O 18.37% |
合成路线1
该中间体在本合成路线中的序号：(VII)1) The reaction of diethyl-2-benzylmalonate (I) with acrylonitrile (II) by means of sodium ethoxide in methyl-tert-butyl ether gives diethyl 2-benzyl-2-(2-cyanoethyl)malonate (III), which is reduced with H2 over Pd/C in ethanol/aq. HCl yielding diethyl 2-(3-aminopropyl-2-benzylmalonate (IV). The protection of (IV) with tert-butoxycarbonyl anhydride affords carbamate (V), which is regioselectively hydrolyzed with porcine liver estearase giving 2(S)-benzyl-5-(tert-butoxycarbonylamino)-2-(ethoxycarbonyl)pentanoic acid (VI). The deprotection of the amino group of (VI) with trifluoroacetic acid, followed by cyclization by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in methyl-tert-butyl ether gives piperidone (VII), which is protected with tert-butoxycarbonyl anhydride yielding 3(S)-benzyl-1-(tert-butoxycarbonyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (VIII). The reduction of (VIII) with lithium triethylborohydride gives the 2-hydroxy deerivative (IX), which is dehydroxylated with triethylsilane in dichloromethane and deprotected with boron trifluoride ethearate to yield 2(S)-benzylpiperidine-2-carboxylic acid ethyl ester (X). 2) The reduction of the piperidone (VII) to the piperidine (X) can also be performed by reaction of (VII) with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide] in refluxing toluene to give the corresponding piperidinethione (XIV), which is then desulfurized by means of Raney Nickel and NaBH4 in THF/water yielding the desired piperidine (X).
| 【1】 Maligres, P.E.; et al.; Preparation of (S)-3-carbethoxy-3-benzylpiperidine and the growth hormone secretagogue L-163,540. J Org Chem 1998, 63, 25, 9548. |
| 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) | 20208 | diethyl 2-benzylmalonate | 607-81-8 | C14H18O4 | 详情 | 详情 |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 20210 | diethyl 2-benzyl-2-(2-cyanoethyl)malonate | C17H21NO4 | 详情 | 详情 | |
| (IV) | 20211 | diethyl 2-(3-aminopropyl)-2-benzylmalonate | C17H25NO4 | 详情 | 详情 | |
| (V) | 20212 | diethyl 2-benzyl-2-[3-[(tert-butoxycarbonyl)amino]propyl]malonate | C22H33NO6 | 详情 | 详情 | |
| (VI) | 20213 | (2S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-2-(ethoxycarbonyl)pentanoic acid | C20H29NO6 | 详情 | 详情 | |
| (VII) | 20214 | ethyl (3S)-3-benzyl-2-oxo-3-piperidinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VIII) | 20215 | 1-(tert-butyl) 3-ethyl (3S)-3-benzyl-2-oxo-1,3-piperidinedicarboxylate | C20H27NO5 | 详情 | 详情 | |
| (IX) | 20216 | 1-(tert-butyl) 3-ethyl (3S)-3-benzyl-2-hydroxy-1,3-piperidinedicarboxylate | C20H29NO5 | 详情 | 详情 | |
| (X) | 20217 | ethyl (3S)-3-benzyl-3-piperidinecarboxylate | C15H21NO2 | 详情 | 详情 | |
| (XVI) | 20218 | ethyl (3R)-3-benzyl-2-thioxo-3-piperidinecarboxylate | C15H19NO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The condensation of BMS-207147 (I) with 3-(chloromethyl)benzoic acid chloromethyl ester (II) (obtained by esterification of 3-(chloromethyl)benzoyl chloride (III) with paraformaldehyde and ZnCl2) by means of KH in THF gives the adduct (IV), which is condensed with phosphoric acid di-tert-butyl ester (V) to yield the phosphate (V). Finally, this compound is hydrolyzed with TFA in dichloromethane and treated with NaHCO3 to provide the target sodium salt.
| 【1】 Hudyma, T.W.; Zheng, X.; Clark, J.; et al.; BMS-292655, a soluble prodrug of the clinically efficacious antifungal triazole, BMS-207147 (ravuconazole). 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-816. |
| 【2】 Hudyma, T.W.; Kim, O.K.; Zheng, X. (Bristol-Myers Squibb Co.); Water soluble prodrugs of azole cpds.. WO 0030655 . |
| 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) | 60212 | 4-{2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile | C22H17F2N5OS | 详情 | 详情 | |
| (II) | 60213 | chloromethyl 3-(chloromethyl)benzoate | C9H8Cl2O2 | 详情 | 详情 | |
| (III) | 25107 | 3-(chloromethyl)benzoyl chloride | 63024-77-1 | C8H6Cl2O | 详情 | 详情 |
| (IV) | 20214 | ethyl (3S)-3-benzyl-2-oxo-3-piperidinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (V) | 60215 | bis(1,1-dimethylethyl) hydrogen phosphate | C8H19O4P | 详情 | 详情 | |
| (VI) | 60216 | {[2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl]oxy}methyl 3-[({bis[(1,1-dimethylethyl)oxy]phosphoryl}oxy)methyl]benzoate | C39H42F2N5O7PS | 详情 | 详情 |