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【结 构 式】 
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【分子编号】68457 【品名】2-isobutyramidothiazole-4-carboxylic acid 【CA登记号】 |
【 分 子 式 】C8H10N2O3S 【 分 子 量 】214.24508 【元素组成】C 44.85% H 4.7% N 13.08% O 22.4% S 14.97% |
合成路线1
该中间体在本合成路线中的序号：(XXXVIII)ortho-Metalation of N-Boc-m-anisidine (XXXII) with BuLi in cold THF, followed by bromination with perfluorooctyl bromide, gives N-Boc-2-bromo-3-methoxyaniline (XXXIII), which by Boc group cleavage with HCl in diglyme at 100 °C provides 2-bromo-3-methoxyaniline hydrochloride (XXXIV). Friedel–Crafts acylation of bromoanisidine (XXXIV) with acetonitrile (XXXV) in the presence of BCl3 and AlCl3 in chlorobenzene at 100 °C affords 2’-amino-3’-bromo-4’-methoxyacetophenone (XXXVI) , which is then coupled with the acid chloride (XXXVII) [prepared by chlorination of 2-isobutyrylaminothiazole-4-carboxylic acid (XXXVIII) with either (COCl)2 in DMF/THF or SOCl2 in NMP by means of Et3N and DMAP in THF to provide the corresponding carboxamide (XXXIX) . Intramolecular cyclocondensation of the ketoamide (XXXIX) in the presence of either t-BuOK in DME at 80-85 °C or KOH in t-BuOH yields the quinolinol (XL), which is then chlorinated with POCl3 in dioxane at 75 °C to obtain the 4-chloroquinoline derivative (VII) .
| 【1】 Berkenbusch, T., Busacca, C.A., Jaeger, B., Varsolona, R.J. (Boehringer Ingelheim Pharma GmbH & Co. KG). Crystalline forms of a 2-thiazolyl-4-quinolinyl-oxy derivative, a potent HCV inhibitor. CN 102159571, EP 2331538, JP 2012502910, KR 2011059841, US 2010093792, WO 2010033444. |
| 【2】 Bhardwaj, P., Forgione, P., Goudreau, N. et al. (Boehringer Ingelheim International GmbH). Hepatitis C inhibitor compounds. EP 1654261, JP 2006528937, JP 2010043129, US 2005020503, US 2011177030, US 8067438, WO 2004103996. |
| 【3】 Patel, N., Senanayake, C.H., Wei, X., Yee, N.K. (Boehringer Ingelheim Pharma GmbH & Co. KG). Process for preparing sulfonyl quinolines. EP 2408768, WO 2010107965. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 68430 | N-(4-(8-bromo-4-chloro-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide | C17H15BrClN3O2S | 详情 | 详情 | |
| (XXXII) | 68452 | tert-butyl (3-methoxyphenyl)carbamate | C12H17NO3 | 详情 | 详情 | |
| (XXXIII) | 68453 | tert-butyl (2-bromo-3-methoxyphenyl)carbamate | C12H16BrNO3 | 详情 | 详情 | |
| (XXXIV) | 68454 | 2-bromo-3-methoxyaniline hydrochloride | C7H8BrNO.HCl | 详情 | 详情 | |
| (XXXV) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (XXXVI) | 68455 | 1-(2-amino-3-bromo-4-methoxyphenyl)ethanone;2’-amino-3’-bromo-4’-methoxyacetophenone | 923289-30-9 | C9H10BrNO2 | 详情 | 详情 |
| (XXXVII) | 68456 | 2-isobutyramidothiazole-4-carbonyl chloride | C8H9ClN2O2S | 详情 | 详情 | |
| (XXXVIII) | 68457 | 2-isobutyramidothiazole-4-carboxylic acid | C8H10N2O3S | 详情 | 详情 | |
| (XXXIX) | 68458 | N-(6-acetyl-2-bromo-3-methoxyphenyl)-2-isobutyramidothiazole-4-carboxamide | C17H18BrN3O4S | 详情 | 详情 | |
| (XL) | 68459 | N-(4-(8-bromo-4-hydroxy-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide | C17H16BrN3O3S | 详情 | 详情 |