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【结 构 式】 
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【药物名称】 【化学名称】N-(1,3-Benzodioxol-5-ylmethyl)-3-(3,5-difluorophenyl)-N-[3-(perhydroazepin-1-yl)propyl]isoxazol-5-amine 【CA登记号】359418-53-4, 359418-52-3 (hydrochloride), 359418-54-5 (trifluoroacetate) 【 分 子 式 】C26H29F2N3O3 【 分 子 量 】469.53613 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, PAR1 Antagonists |
合成路线1
The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III), which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V). Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine. The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX), which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X). Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate. Alternatively, the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)
| 【1】 Nantermet, P.G.; et al.; Discovery of a nonpeptide small molecule antagonist of the human platelet thrombin receptor (PAR-1). Bioorg Med Chem Lett 2002, 12, 3, 319. |
| 【2】 Freidinger, R.M.; Selnick, H.G.; Connolly, T.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Isoxazole thrombin receptor antagonists. GB 2356198 . |
| 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) | 33669 | 1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine | 2620-50-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (III) | 56910 | N-(1,3-benzodioxol-5-ylmethyl)acrylamide | C11H11NO3 | 详情 | 详情 | |
| (IV) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |
| (V) | 56911 | 3-(1-azepanyl)-N-(1,3-benzodioxol-5-ylmethyl)-1-propanamine; N-[3-(1-azepanyl)propyl]-N-(1,3-benzodioxol-5-ylmethyl)amine | C17H26N2O2 | 详情 | 详情 | |
| (VI) | 56912 | 5-chloro-3-(3,5-difluorophenyl)isoxazole | C9H4ClF2NO | 详情 | 详情 | |
| (VII) | 56913 | 3,5-Difluorobenzoyl chloride | 129714-97-2 | C7H3ClF2O | 详情 | 详情 |
| (VIII) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (IX) | 56914 | ethyl 3-(3,5-difluorophenyl)-3-oxopropanoate | C11H10F2O3 | 详情 | 详情 | |
| (X) | 56915 | 3-(3,5-difluorophenyl)-5-isoxazolol | C9H5F2NO2 | 详情 | 详情 | |
| (XI) | 56916 | 3,5-Difluoroacetophenone | 123577-99-1 | C8H6F2O | 详情 | 详情 |
| (XII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |