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【结 构 式】 
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【药物名称】SUN-N8075 【化学名称】1-(4-Amino-2,3,5-trimethylphenoxy)-3-[4-[4-(4-fluorobenzyl)phenyl]piperazin-1-yl]propan-2(S)-ol dimethanesulfonate 【CA登记号】224450-56-0, 224450-44-6 (free base) 【 分 子 式 】C31H44FN3O8S2 【 分 子 量 】669.83803 |
【开发单位】Daiichi Suntory Pharma (Originator), Taisho (Licensee) 【药理作用】Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Lipid Peroxidation Inhibitors, Sodium Channel Blockers, T-Type Calcium Channel Blockers |
合成路线1
Chemoselective protection of the amino group of 2,3,5-trimethyl-4-aminophenol (I) with di-tert-butyl dicarbonate (Boc)2O in THF gives compound (II), which is then treated with NaH and (S)-glycidyl 3-nitrobenzenesulfonate (III) to yield epoxypropane (IV). On the other hand, treatment of 4,4'-difluorobenzophenone (V) with piperazine (VI) in acetonitrile in the presence of Et3N gives derivative (VII), which is reduced with Et3siH in the presence of H2SO4 and TFA to afford piperazine (VIII). Condensation of epoxypropane (IV) with piperazine (VIII) in refluxing 2-propanol furnishes compound (IX), which is finally converted into the desired product by first removal of the Boc group by exposure to TFA in CH2Cl2, followed by treatment with methanesulfonic acid (MeSO3H).
| 【2】 Nakanishi, K.; Annoura, H.; Tamura, S. (Suntory Ltd.); Arylpiperidinopropanol and arylpiperazinopropanol derivs. and pharmaceuticals containing the same. CA 2276373; EP 0958280; WO 9923072 . |
| 【1】 Tamura-Horikawa, Y.; Miyajima, A.; Tamura, S.; Annoura, H.; Imajo, S.; Toba, T.; Takemoto, N.; Nakanishi, K.; Discovery of (2S)-1-(4-amino-2,3,5-trimethylphenoxy)-3-(4-[4-(4-fluorobenzyl)phenyl)-1-piperazinyl)-2-propanol dimethanesulfonate (SUN N8075): A dual Na+ and Ca2+ channel blocker with antioxidant activity. J Med Chem 2000, 43, 18, 3372. |
| 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) | 45629 | 4-amino-2,3,5-trimethylphenol | C9H13NO | 详情 | 详情 | |
| (II) | 45630 | tert-butyl 4-hydroxy-2,3,6-trimethylphenylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (III) | 45631 | (2S)oxiranylmethyl 4-nitrobenzenesulfonate | C9H9NO6S | 详情 | 详情 | |
| (IV) | 45632 | tert-butyl 2,3,6-trimethyl-4-[(2S)oxiranylmethoxy]phenylcarbamate | C17H25NO4 | 详情 | 详情 | |
| (V) | 45633 | bis(4-fluorophenyl)methanone; 4,4'-Difluorobenzophenone | 345-92-6 | C13H8F2O | 详情 | 详情 |
| (VI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VII) | 45634 | (4-fluorophenyl)[4-(1-piperazinyl)phenyl]methanone | C17H17FN2O | 详情 | 详情 | |
| (VIII) | 45635 | 1-[4-(4-fluorobenzyl)phenyl]piperazine | C17H19FN2 | 详情 | 详情 | |
| (IX) | 45636 | tert-butyl 4-[((2S)-3-[4-[4-(4-fluorobenzyl)phenyl]-1-piperazinyl]-2-hydroxypropyl)oxy]-2,3,6-trimethylphenylcarbamate | C34H44FN3O4 | 详情 | 详情 |