【结 构 式】 |
【分子编号】20217 【品名】ethyl (3S)-3-benzyl-3-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C15H21NO2 【 分 子 量 】247.33728 【元素组成】C 72.84% H 8.56% N 5.66% O 12.94% |
合成路线1
该中间体在本合成路线中的序号:(X)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:(X)The reaction of (X) with N-(tert-butoxycarbonyl)-D-tryptophan (XI) by means of DCC and HOBT in ethyl acetate affords the expected condensation product (XII), which is deprotected with HCl in hot ethanol giving compound (XIII) with its amino group free. The reaction of (XIII) with 2-(tert-butoxycarbonylamino)isobutyric acid (XIV) by means of DCC and HOBT as before yields the expected condensation product (XV), which is finally deprotected with HCl in methanol as before to give the target compound.
【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 |
---|---|---|---|---|---|---|
(X) | 20217 | ethyl (3S)-3-benzyl-3-piperidinecarboxylate | C15H21NO2 | 详情 | 详情 | |
(XI) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
(XII) | 20220 | ethyl (3S)-3-benzyl-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-piperidinecarboxylate | C31H39N3O5 | 详情 | 详情 | |
(XIII) | 20221 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-benzyl-3-piperidinecarboxylate | C26H31N3O3 | 详情 | 详情 | |
(XIV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
(XV) | 20223 | ethyl (3S)-3-benzyl-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-piperidinecarboxylate | C35H46N4O6 | 详情 | 详情 |