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【结 构 式】 
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【药物名称】SUN-C5174 【化学名称】5-[3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl]-8(S)-hydroxy-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one 【CA登记号】191592-36-6, 191592-35-5 ((S)-isomer), 191592-09-3 (undefined isomer) 【 分 子 式 】C22H29FN4O2 【 分 子 量 】400.50043 |
【开发单位】Daiichi Suntory Pharma (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Treatment of Peripheral Obstructive Vascular Disease, 5-HT2 Antagonists |
合成路线1
The condensation of 1-methylpyrole-3-carboxylic acid (I) with beta-alanine benzyl ester (II) by means of diethyl phosphorocyanidate (PCA) in DMF gives the corresponding amide (III), which is debenzylated with H2 over Pd/C in THF yielding the substituted beta-alanine (IV). The cyclization of (IV) by means of polyphosphoric acid (PPA) at 100 C affords the pyrroloazepine (V), which is alkylated with 1-bromo-3-chloropropane (VI) and potassium tert-butoxide in THF giving the 3-chloropropyl derivative (VII). The condensation of (VII) with 1-(4-fluorophenyl)piperazine (VIII) by means of K2CO3 and NaI in refluxing acetonitrile yields the expected addition product (IX), which is selectively reduced at the 8-position with NaBH4 in ethanol affording the 8-hydroxy derivative (X) as a racemic mixture. Finally, this compound is submitted to optical resolution by chiral chromatography providing the target chiral compound.
| 【1】 Shibata, M.; Ogata, A.; Hayashi, Y.; Kamei, T.; Mizuno, A.; Shimamoto, T.; Takiguchi, C.; Inomata, N.; Nakanishi, K.; Oka, N.; Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds. Chem Pharm Bull 2000, 48, 5, 623. |
| 【2】 Mizuno, A.; Shibata, M.; Iwamori, T.; Shimamoto, T.; Nakanishi, K.; Inomata, N. (Suntory Ltd.); Pyrroloazepine derivs.. EP 0807632; US 5962448; WO 9720845 . |
| 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) | 30193 | 1-methyl-1H-pyrrole-3-carboxylic acid | C6H7NO2 | 详情 | 详情 | |
| (II) | 30194 | benzyl 3-aminopropanoate | 27019-47-2 | C10H13NO2 | 详情 | 详情 |
| (III) | 30195 | benzyl 3-[[(1-methyl-1H-pyrrol-3-yl)carbonyl]amino]propanoate | C16H18N2O3 | 详情 | 详情 | |
| (IV) | 30196 | N-[(1-methyl-1H-pyrrol-3-yl)carbonyl]-beta-alanine | C9H12N2O3 | 详情 | 详情 | |
| (V) | 30197 | 1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione | C9H10N2O2 | 详情 | 详情 | |
| (VI) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (VII) | 30198 | 5-(3-chloropropyl)-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione | C12H15ClN2O2 | 详情 | 详情 | |
| (VIII) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |
| (IX) | 30199 | 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione | C22H27FN4O2 | 详情 | 详情 | |
| (X) | 30200 | 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-8-hydroxy-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one | C22H29FN4O2 | 详情 | 详情 |
合成路线2
The condensation of 1-methylpyrrole-3-carboxylic acid (I) with 3-(3-chloropropylamino)propionic acid ethyl ester (II) by means of WSC and TEA gives the corresponding amide (III), which is hydrolyzed with NaOH to yield the amino acid (IV). The cyclization of (IV) by means of Ms-OH and P2O5 affords the pyrroloazepinedione (V), which is condensed with 1-(4-fluorophenyl)piperazine (VI) by means of K2CO3 or NaHCO3 and NaI to provide the adduct (VII). Finally, this compound is regioselectively monoreduced with NaBH4 to give the racemic alcohol (VIII), which is submitted to optical resolution by crystallization of its L-(+)-tartrate salt to afford the target (S)-enantiomer.
| 【1】 Shibata, M.; Ogata, A.; Hayashi, Y.; Kamei, T.; Mizuno, A.; Shimamoto, T.; Takiguchi, C.; Inomata, N.; Nakanishi, K.; Oka, N.; Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds. Chem Pharm Bull 2000, 48, 5, 623. |
| 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) | 30193 | 1-methyl-1H-pyrrole-3-carboxylic acid | C6H7NO2 | 详情 | 详情 | |
| (II) | 50957 | ethyl 3-[(3-chloropropyl)amino]propanoate | C8H16ClNO2 | 详情 | 详情 | |
| (III) | 50958 | ethyl 3-[(3-chloropropyl)[(1-methyl-1H-pyrrol-3-yl)carbonyl]amino]propanoate | C14H21ClN2O3 | 详情 | 详情 | |
| (IV) | 50959 | N-(3-chloropropyl)-N-[(1-methyl-1H-pyrrol-3-yl)carbonyl]-beta-alanine | C12H17ClN2O3 | 详情 | 详情 | |
| (V) | 30198 | 5-(3-chloropropyl)-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione | C12H15ClN2O2 | 详情 | 详情 | |
| (VI) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |
| (VII) | 30199 | 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione | C22H27FN4O2 | 详情 | 详情 | |
| (VIII) | 30200 | 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-8-hydroxy-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one | C22H29FN4O2 | 详情 | 详情 |