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【结 构 式】

【分子编号】47804

【品名】2-(tert-butyl)-1,3,4-oxadiazole

【CA登记号】

【 分 子 式 】C6H10N2O

【 分 子 量 】126.15828

【元素组成】C 57.12% H 7.99% N 22.21% O 12.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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:(III)

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
Extended Information