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【结 构 式】 
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【分子编号】48629 【品名】benzyl 1-benzyl-2-oxoethylcarbamate; N-(benzyloxycarbonyl)-L-phenylalaninal 【CA登记号】59830-60-3 |
【 分 子 式 】C17H17NO3 【 分 子 量 】283.32692 【元素组成】C 72.07% H 6.05% N 4.94% O 16.94% |
合成路线1
该中间体在本合成路线中的序号：(XI)Protection of phenylalaninol (X) as the corresponding benzyl carbamate, followed by Swern oxidation of the alcohol function, furnished N-(benzyloxycarbonyl)phenylalaninal (XI). Aldehyde (XI) was then converted to cyanohydrin (XII) upon treatment with acetone cyanohydrin and Et3N. Reaction of (XII) with an in situ-generated ethanolic solution of HCl gave imidate (XIII). Methyl 4-hydroxy-3-aminobenzoate (XV) was prepared by esterification of 4-hydroxy-3-nitrobenzoic acid (XIV) followed by catalytic hydrogenation of the nitro group. Condensation of imidate (XIII) with the aminophenol (XV) in refluxing EtOH gave rise to the benzoxazole derivative (XVI). After hydrogenolytic cleavage of the carbobenzoxy group of (XVI), the resulting amine (XVII) was coupled with the intermediate pyrimidineacetic acid (IX) in the presence of EDC and HOBt, yielding amide (XVIII). The secondary alcohol of (XVIII) was then oxidized to the corresponding ketone (XIX) using a modified Pfitzner-Moffatt reaction. The carbobenzoxy protecting group of (XIX) was finally removed by treatment with trifluoromethanesulfonic acid in the presence of anisole.
| 【1】 Ashimori, A.; Akahoshi, F.; Sakashita, H.; et al.; Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic alpha-keto heterocycles as novel inhibitors of human chymase. J Med Chem 2001, 44, 8, 1286. |
| 【2】 Akahoshi, F.; Ashimori, A.; Yoshimura, T.; Eda, M.; Sakashita, H.; Nakajima, M.; Imada, T. (Welfide Corporation); Novel heterocyclic amide cpds. and medicinal uses thereof. EP 0940400; US 6080738; WO 9818794 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 48627 | 2-[5-[[(benzyloxy)carbonyl]amino]-2-(3-methoxyphenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid | C21H19N3O6 | 详情 | 详情 | |
| (X) | 48628 | 2-amino-3-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (XI) | 48629 | benzyl 1-benzyl-2-oxoethylcarbamate; N-(benzyloxycarbonyl)-L-phenylalaninal | 59830-60-3 | C17H17NO3 | 详情 | 详情 |
| (XII) | 48630 | benzyl 1-benzyl-2-cyano-2-hydroxyethylcarbamate | C18H18N2O3 | 详情 | 详情 | |
| (XIII) | 48631 | ethyl 3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutanimidoate | C20H24N2O4 | 详情 | 详情 | |
| (XIV) | 48632 | 3-Nitro-4-hydrobenzoic acid; 3-Nitro-4-hydroxybenzoic acid; 4-Hydroxy-3-nitrobenzoic acid | 616-82-0 | C7H5NO5 | 详情 | 详情 |
| (XV) | 19366 | methyl 3-amino-4-hydroxybenzoate | 536-25-4 | C8H9NO3 | 详情 | 详情 |
| (XVI) | 48633 | methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1-hydroxy-3-phenylpropyl)-1,3-benzoxazole-5-carboxylate | C26H24N2O6 | 详情 | 详情 | |
| (XVII) | 48634 | methyl 2-(2-amino-1-hydroxy-3-phenylpropyl)-1,3-benzoxazole-5-carboxylate | C18H18N2O4 | 详情 | 详情 | |
| (XVIII) | 48635 | methyl 2-[2-([2-[5-[[(benzyloxy)carbonyl]amino]-2-(3-methoxyphenyl)-6-oxo-1(6H)-pyrimidinyl]acetyl]amino)-1-hydroxy-3-phenylpropyl]-1,3-benzoxazole-5-carboxylate | C39H35N5O9 | 详情 | 详情 | |
| (XIX) | 48636 | methyl 2-[2-([2-[5-[[(benzyloxy)carbonyl]amino]-2-(3-methoxyphenyl)-6-oxo-1(6H)-pyrimidinyl]acetyl]amino)-3-phenylpropanoyl]-1,3-benzoxazole-5-carboxylate | C39H33N5O9 | 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 intermediate 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) has been obtained as follows. The esterification of N-(benzyloxycarbonyl)-DL-phenylalanine (I) with methyl iodide and KHCO3 in DMF gives the corresponding methyl ester (II), which is reduced with LiCl and NaBH4 in THF to yield protected DL-phenylalaninol (III). The oxidation of (III) by means of 2,2,6,6-tetramethylpiperdine-1-oxyl free radical (TEMPO), NaBr and NaClO in ethyl acetate/toluene affords protected DL-phenylalaninal (IV), which is condensed with ethyl 2-bromo-2,2-difluoroacetate (V) by means of Zn in THF to provide the 2,2-difluoropentanoic ester (VI). The reaction of ester (VI) with benzylamine (VII) in THF gives the corresponding amide (VIII), which is finally deprotected by means of H2 over Pd/C in methanol/dioxane to yield the target 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) intermediate.
| 【1】 Kobayashi, F.; Naito, K.; Yoshikawa, T.; Kuwahara, S.; Imada, T.; Komorita, N. (Mitsubishi Pharma Corp.); IgE antibody production inhibitors and autoimmune diseases inhibitors. EP 1062949; US 6528514; WO 9945928 . |
| 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) | 58077 | N-[(benzyloxy)carbonyl]phenylalanine | C17H17NO4 | 详情 | 详情 | |
| (II) | 57836 | methyl 2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanoate | C18H19NO4 | 详情 | 详情 | |
| (III) | 58078 | benzyl 1-benzyl-2-hydroxyethylcarbamate | C17H19NO3 | 详情 | 详情 | |
| (IV) | 48629 | benzyl 1-benzyl-2-oxoethylcarbamate; N-(benzyloxycarbonyl)-L-phenylalaninal | 59830-60-3 | C17H17NO3 | 详情 | 详情 |
| (V) | 40673 | ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester | 667-27-6 | C4H5BrF2O2 | 详情 | 详情 |
| (VI) | 57837 | ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-difluoro-5-phenylpentanoate | C21H23F2NO4 | 详情 | 详情 | |
| (VII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VIII) | 57838 | benzyl 1-benzyl-4-(benzylamino)-3,3-difluoro-4-oxobutylcarbamate | C26H26F2N2O3 | 详情 | 详情 | |
| (IX) | 57839 | 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide | C18H20F2N2O | 详情 | 详情 |