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【结 构 式】 
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【分子编号】47823 【品名】2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone 【CA登记号】 |
【 分 子 式 】C11H19N3O2 【 分 子 量 】225.29088 【元素组成】C 58.64% H 8.5% N 18.65% O 14.2% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of intermediate acetic acid (IV) with 2-tert-butyl-5-(DL-valyl)-1,3,4-oxadiazole (XIII) by means of methyl chloroformate and NMM gives the corresponding amide (XIV), which is finally reduced with H2 over Pd/C in MeOH.
| 【1】 Yamamoto, T.; Okuma, M.; Ohmoto, K.; et al.; Development of orally active nonpeptidic inhibitors of human neutrophil elastase. J Med Chem 2001, 44, 8, 1268. |
| 【2】 Okada, T.; Hachiya, K.; Motoi, T.; Kojima, T.; Hashimoto, S. (Ono Pharmaceutical Co., Ltd.); Pyrimidine derivs., process for preparing the derivs. and drugs containing the same as the active ingredient. WO 0123361 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47814 | 2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid | C12H9N3O5 | 详情 | 详情 | |
| (XIII) | 47823 | 2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone | C11H19N3O2 | 详情 | 详情 | |
| (XIV) | 47824 | N-(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)-2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetamide | C23H26N6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The intermediate oxadiazole (VIII) has been obtained as follows: The reaction of methyl pivalate (I) with refluxing hydrazine hydrate gives the corresponding hydrazide (II), which is cyclized with methyl orthoformate catalyzed by Ts-OH to yield 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N2-(tert-butoxycarbonyl)-N1-methoxy-N1-methyl-DL-valinamide (VI) by means of LDA in THF affords the acylated oxadiazole (VII), which is finally deprotected with HCl in ethyl acetate to provide the target intermediate (VIII).
| 【1】 Kojima, T.; Hachiya, K.; Ohmoto, K. (Ono Pharmaceutical Co., Ltd.); 1,3,4-Oxadiazole derivs. and process for producing the same. EP 1162199; WO 0055145 . |
| 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) | 47802 | Trimethylacetic acid methyl ester; 2,2-Dimethylpropionic acid methyl ester; Methyl Trimethylacetate; pivalic acid methyl ester; methyl pivalate | 598-98-1 | C6H12O2 | 详情 | 详情 |
| (II) | 47803 | Pivalic acid hydrazide; 2,2-dimethylpropanohydrazide | C5H12N2O | 详情 | 详情 | |
| (III) | 47804 | 2-(tert-butyl)-1,3,4-oxadiazole | C6H10N2O | 详情 | 详情 | |
| (IV) | 51959 | N-(tert-butoxycarbonyl)valine | C10H19NO4 | 详情 | 详情 | |
| (V) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (VI) | 51958 | tert-butyl 1-[[methoxy(methyl)amino]carbonyl]-2-methylpropylcarbamate | C12H24N2O4 | 详情 | 详情 | |
| (VII) | 51957 | tert-butyl 1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropylcarbamate | C16H27N3O4 | 详情 | 详情 | |
| (VIII) | 47823 | 2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone | C11H19N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The reaction of 3-(2,2-dimethoxyethyl)-2-phenyl-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid (IX) with isobutyl chloroformate and hydroxylamine gives the corresponding hydroxamic acid (X), which is acylated with Ac2O in pyridine to yield the acetoxy compound (XI). The degradation of (XI) by reaction with DBU in refluxing THF affords the amine (XII), which is protected with benzyl chloroformate (XIII) and NaHCO3, providing the carbamate (XIV). The hydrolysis of the dimethylacetal group of (XIV) with HCl in hot acetic acid gives the acetaldehyde derivative (XV), which is oxidized with NaClO2 in tert-butanol/water yielding the corresponding acetic acid derivative (XVI). The condensation of (XVI) with the intermediate amine (VIII) by means of ethyl chloroformate and NMM in THF affords the amide (XVII), which is hydrogenolyzed with H2 over Pd/C in order to eliminate its carbamate protecting group and provide the target racemic 285811.
| 【1】 Kojima, T.; Hachiya, K.; Ohmoto, K. (Ono Pharmaceutical Co., Ltd.); 1,3,4-Oxadiazole derivs. and process for producing the same. EP 1162199; WO 0055145 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 47823 | 2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone | C11H19N3O2 | 详情 | 详情 | |
| (IX) | 51960 | 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxylic acid | C15H16N2O5 | 详情 | 详情 | |
| (X) | 51961 | 1-(2,2-dimethoxyethyl)-N-hydroxy-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxamide | C15H17N3O5 | 详情 | 详情 | |
| (XI) | 51962 | 5-[[(acetoxy)amino]carbonyl]-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone | C17H19N3O6 | 详情 | 详情 | |
| (XII) | 51963 | 5-amino-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone | C14H17N3O3 | 详情 | 详情 | |
| (XIII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XIV) | 51964 | benzyl 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate | C22H23N3O5 | 详情 | 详情 | |
| (XV) | 51965 | benzyl 6-oxo-1-(2-oxoethyl)-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate | C20H17N3O4 | 详情 | 详情 | |
| (XVI) | 47808 | 2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid | C20H17N3O5 | 详情 | 详情 | |
| (XVII) | 51966 | benzyl 1-[2-[(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate | C31H34N6O6 | 详情 | 详情 |