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【结 构 式】 
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【分子编号】48627 【品名】2-[5-[[(benzyloxy)carbonyl]amino]-2-(3-methoxyphenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid 【CA登记号】 |
【 分 子 式 】C21H19N3O6 【 分 子 量 】409.39848 【元素组成】C 61.61% H 4.68% N 10.26% O 23.45% |
合成路线1
该中间体在本合成路线中的序号：(IX)3-Methoxybenzonitrile (I) was converted to the corresponding imidate (II) by treatment with ethanolic HCl. Condensation of (II) with aminoacetaldehyde diethyl acetal (III) gave amidine (IV), which was cyclized with diethyl ethoxymethylenemalonate (V) in refluxing ethanol to yield the pyrimidinone (VI). Hydrolysis of the ethyl ester function of (VI) by treatment with LiI in hot pyridine provided acid (VII). This was subjected to a Curtius rearrangement with diphenylphosphoryl azide, and the intermediate isocyanate was condensed with benzyl alcohol to produce the benzyl carbamate (VIII). Acid hydrolysis of the diethyl acetal group of (VIII), followed by oxidation of the resulting aldehyde with sodium chlorite, furnished the carboxylic acid (IX).
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 36250 | 3-methoxybenzonitrile | 1527-89-5 | C8H7NO | 详情 | 详情 |
| (II) | 34363 | ethyl 3-methoxybenzenecarboximidoate | C10H13NO2 | 详情 | 详情 | |
| (III) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (IV) | 48623 | N-(2,2-diethoxyethyl)-3-methoxybenzenecarboximidamide | C14H22N2O3 | 详情 | 详情 | |
| (V) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (VI) | 48624 | ethyl 1-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylate | C20H26N2O6 | 详情 | 详情 | |
| (VII) | 48625 | 1-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid | C18H22N2O6 | 详情 | 详情 | |
| (VIII) | 48626 | benzyl 1-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate | C25H29N3O6 | 详情 | 详情 | |
| (IX) | 48627 | 2-[5-[[(benzyloxy)carbonyl]amino]-2-(3-methoxyphenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid | C21H19N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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 |