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【结 构 式】 
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【分子编号】47802 【品名】Trimethylacetic acid methyl ester; 2,2-Dimethylpropionic acid methyl ester; Methyl Trimethylacetate; pivalic acid methyl ester; methyl pivalate 【CA登记号】598-98-1 |
【 分 子 式 】C6H12O2 【 分 子 量 】116.16008 【元素组成】C 62.04% H 10.41% O 27.55% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II), which is cyclized with methyl or ethyl orthoformate and Ts-OH, yielding the 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V), which is treated with HCl in dioxane to provide the amino alcohol (VI). The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC, HOBT and NMM in DMF gives the corresponding amide (VIII), which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX). Finally, this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.
| 【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. |
| 【3】 Spruce, L.W.; Gyorkos, A. (Cortech, Inc.); Serine protease inhibitors. JP 2001192398; JP 2001507679; WO 9824806 . |
| 【2】 Ohmoto, K.; Matsuoka, S.; Sekioka, T.; Imanishi, H.; Hirota, Y.; Kawabata, K.; Nakai, H.; Yamamoto, T.; Horiuchi, T.; Odagaki, Y.; Toda, M.; Design and synthesis of new orally active nonpeptide inhibitors of human neutrophil elastase. J Med Chem 2000, 43, 26, 4927. |
| 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) | 47805 | tert-butyl (1S)-1-formyl-2-methylpropylcarbamate | C10H19NO3 | 详情 | 详情 | |
| (V) | 47806 | tert-butyl (1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate | C16H29N3O4 | 详情 | 详情 | |
| (VI) | 47807 | (2S)-2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanol | C11H21N3O2 | 详情 | 详情 | |
| (VII) | 47808 | 2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid | C20H17N3O5 | 详情 | 详情 | |
| (VIII) | 47809 | benzyl 1-[2-([(1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropyl]amino)-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate | C31H36N6O6 | 详情 | 详情 | |
| (IX) | 47810 | benzyl 1-[2-[((1S)-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 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |