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【结 构 式】 
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【分子编号】20208 【品名】diethyl 2-benzylmalonate 【CA登记号】607-81-8 |
【 分 子 式 】C14H18O4 【 分 子 量 】250.29452 【元素组成】C 67.18% H 7.25% O 25.57% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.
| 【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 . |
| 【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (VI) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 49460 | Dimethyl benzylidenemalonate | C12H12O4 | 详情 | 详情 | |
| (IX) | 49461 | dimethyl 2-benzylmalonate | C12H14O4 | 详情 | 详情 | |
| (X) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XII) | 37482 | diethyl 2-benzylidenemalonate | 5292-53-5 | C14H16O4 | 详情 | 详情 |
| (XIII) | 20208 | diethyl 2-benzylmalonate | 607-81-8 | C14H18O4 | 详情 | 详情 |
| (XIV) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XV) | 55230 | 3-(acetylsulfanyl)-2-benzylpropanoic acid | C12H14O3S | 详情 | 详情 | |
| (XVI) | 55228 | N-p-Tosylglycine benzyl ester | C16H17NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |