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【结 构 式】 
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【药物名称】Osemozotan hydrochloride, MCI-242, MKC-242 【化学名称】2(S)-[3-(1,3-Benzodioxol-5-yloxy)propylaminomethyl]-1,4-benzodioxane hydrochloride 【CA登记号】137275-80-0, 137275-81-1 (free base), 137331-63-6 (racemate), 137275-87-7 (R-isomer) 【 分 子 式 】C19H22ClNO5 【 分 子 量 】379.84389 |
【开发单位】Mitsubishi Pharma (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Receptor Agonists |
合成路线1
Condensation of 2(R)-(tosyloxymethyl)-1,4-benzodioxane (I) with 5-(3-aminopropoxy)-1,3-benzodioxole (II) by means of triethylamine in refluxing acetonitrile, followed by salification with HCl in ethyl acetate/isopropanol. (1,2)
| 【1】 Tracy, M.; Castaner, J.; Prous, J.; MKC-242. Drugs Fut 1997, 22, 3, 225. |
| 【2】 Iwata, H.; Baba, A.; Matsuda, T.; Egawa, M.; Tobe, A.; Saito, K. (Mitsubishi Chemical Corp.); Optically active alkylene-dioxybenzene derivs. and their use in therapy. EP 0446921; JP 1991264528; US 5168099; US 5234948 . |
| 【3】 Iwata, H.; Bab, A.; Matsuda T.; Egawa, M.; Tobe, A.; Saito, K. (Institut Pasteur); Alkylenedioxybenzene derivs. and anxiolytic agent containing them. EP 0139555; ES 8608046; JP 1985155195; US 4686281 . |
合成路线2
A new synthesis of MKC-242 has been described: The tosylation of 2,2-dimethyl-1,3-dioxolane-4(R)-methanol (I) with tosyl chloride in pyridine gives the expected tosylate (II), which is condensed with pyrocatechol monobenzyl ether (III) by means of NaH in N-methylpyrrolidone (NMP) yielding 4(S)-(2-benzyloxyphenoxymethyl)-2,2-dimethyl-1,3-dioxolane (IV). The hydrolysis of the dioxolane ring with hot acetic acid affords the diol (V), which is tosylated with tosyl chloride, triethylamine and dimethylaminopyridine (DMAP) in dichloromethane to give the ditosylate (VI). The debenzylation of (VI) with H2 over Pd/C in methanol/ethyl acetate yields the phenol (VII), which is cyclized by means of K2CO3 in NMP affording 2(R)-(tosyloxymethyl)-1,4-benzodioxane (VIII). Finally, this compound is condensed with 3-(1,3-benzodioxol-5-yloxy)propylamine (IX) by means of ethyl diisopropylamine in NMP. The amine (IX) used as second starting compound has been obtained as follows: The condensation of N-(3-bromopropyl)phthalimide (X) with 5-hydroxy-1,3-benzodioxole (XI) by means of NaH in hot NMP gives N-[3-(1,3-benzodioxol-5-yloxy)propyl]phthalimide (XII), which is then treated with hydrazine in refluxing methanol to obtain amine (IX).
| 【1】 Sugano, M.; Saito, K.; Yamabe, H.; Chaki, H.; Abe, M.; Tabata, R.; Synthesis and 5-HT1A affinity of an optically active benzodioxane derivative MKC-242; a novel anxiolytic and antidepressant agent. 214th ACS Natl Meet (Sept. 7-11, Las Vegas) 1997, Abst MEDI 019. |
| 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) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (II) | 15208 | (S)-(+)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluenesulfonate; [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23735-43-5 | C13H18O5S | 详情 | 详情 |
| (III) | 15209 | Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol | 6272-38-4 | C13H12O2 | 详情 | 详情 |
| (IV) | 15210 | benzyl 2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]phenyl ether; (4R)-4-[[2-(benzyloxy)phenoxy]methyl]-2,2-dimethyl-1,3-dioxolane | C19H22O4 | 详情 | 详情 | |
| (V) | 15211 | (2S)-3-[2-(benzyloxy)phenoxy]-1,2-propanediol | C16H18O4 | 详情 | 详情 | |
| (VI) | 15212 | (1S)-2-[2-(benzyloxy)phenoxy]-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C30H30O6S | 详情 | 详情 | |
| (VII) | 15213 | (1S)-2-(2-hydroxyphenoxy)-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C23H24O6S | 详情 | 详情 | |
| (VIII) | 15214 | (2S)-2-[(4-methylphenoxy)methyl]-2,3-dihydro-1,4-benzodioxine; (2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylphenyl ether | C16H16O3 | 详情 | 详情 | |
| (IX) | 15206 | 3-(1,3-benzodioxol-5-yloxy)-1-propanamine; 3-(1,3-benzodioxol-5-yloxy)propylamine | C10H13NO3 | 详情 | 详情 | |
| (X) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (XI) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XII) | 15218 | 2-[3-(1,3-benzodioxol-5-yloxy)propyl]-1H-isoindole-1,3(2H)-dione | C18H15NO5 | 详情 | 详情 |