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【结 构 式】 
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【分子编号】67858 【品名】(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid 【CA登记号】 |
【 分 子 式 】C13H7F6N3O2 【 分 子 量 】351.208 【元素组成】C 44.46% H 2.01% F 32.46% N 11.96% O 9.11% |
合成路线1
该中间体在本合成路线中的序号：(IX)Reaction of 3,4-bis(trifluoromethyl)benzonitrile (I) with NaSH by means of MgCl2 in DMF gives 3,5-bis(trifluoromethyl)benzothioamide (II), which by cyclization with hydrazine hydrate (III) and HCOOH in DMF provides 3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazole (IV). Esterification of propiolic acid (V) with i-PrOH in the presence of BF3·Et2O at 90 °C affords isopropyl propiolate (VI), which is iodinated with NaI in AcOH at 110 °C to obtain isopropyl (Z)-3-iodoacrylate (VII). Condensation of triazole derivative (IV) with isopropyl (Z)-3-iodoacrylate (VII) in the presence of DABCO in DMF yields intermediate (VIII), which is subjected to ester hydrolysis with LiOH in H2O/THF to provide the corresponding carboxylic acid (IX). Finally, acid (IX) is coupled with 2-hydrazinopyrazine (X) in the presence of T3P and DIEA in CH2Cl2/EtOAc .
| 【1】 McCauley, D., Shacham, S., Sandanayaka, V.P., Shechter, S. (Karyopharma Therapeutics, Inc.). Hydrazide containing nuclear transporter modulators and uses thereof. EP 2736887, JP 2014521652, KR 2014066179, US 2014235653, WO 2013019548. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 66713 | 2-Hydrazinopyrazine | 54608-52-5 | C4H6N4 | 详情 | 详情 |
| (I) | 67851 | 3,5-bis(trifluoromethyl)benzonitrile | 27126-93-8 | C9H3F6N | 详情 | 详情 |
| (II) | 67852 | 3,5-bis(trifluoromethyl)benzothioamide | 317319-15-6 | C9H5F6NS | 详情 | 详情 |
| (III) | 67853 | hydrazine hydrate | 7803-57-8 | H4N2.H2O | 详情 | 详情 |
| (IV) | 67854 | 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole | C10H5F6N3 | 详情 | 详情 | |
| (V) | 41770 | propiolic acid | 471-25-0 | C3H2O2 | 详情 | 详情 |
| (VI) | 67855 | isopropyl propiolate | C6H8O2 | 详情 | 详情 | |
| (VII) | 67857 | isopropyl (Z)-3-iodoacrylate | C6H9IO2 | 详情 | 详情 | |
| (VIII) | 67856 | (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate | C16H13F6N3O2 | 详情 | 详情 | |
| (IX) | 67858 | (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid | C13H7F6N3O2 | 详情 | 详情 |