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【结 构 式】 
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【药物名称】TA-993 【化学名称】(-)-(2R,3R)-3-Acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2-(4-methylphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one maleate 【CA登记号】150591-06-3 【 分 子 式 】C27H32N2O7S 【 分 子 量 】528.62929 |
【开发单位】Tanabe Seiyaku (Originator) 【药理作用】Antiplatelet Therapy, Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis |
合成路线1
The required 2-amino-5-methylthiophenol (III) was obtained by basic hydrolysis of the aminobenzothiazole (II), which was prepared from p-toluidine (I) and in situ generated thiocyanogen. Reaction of thiophenol (III) with the arylglycidic ester (IV) produced the racemic threo-amino ester (V). After basic hydrolysis of the ester group of (V), the resultant amino acid was resolved by means of D-(4-hydroxyphenyl)glycine methyl ester. The required amino acid enantiomer (VI) was then cyclized to lactam (VII) by heating in xylene with azeotropic removal of water. N-alkylation of benzothiazepinone (VII) with 2-(dimethylamino)ethyl chloride (VIII) provided (IX). The secondary alcohol of (IX) was esterified with acetic anhydride, and the resultant compound was finally isolated as the corresponding maleate salt.
| 【1】 Inoue, H.; Konda, M.; Hashiyama, T.; Otsuka, H.; Watanabe, A.; Gaino, M.; Takahashi, K.; Date, T.; Okamura, K.; Takeda, M.; Narita, H.; Murata, S.; Odawara, A.; Sasaki, H.; Nagao, T.; Synthesis and biological evaluation of alkyl, alkoxy, alkylthio, or amino-substituted 2,3-dihydro-1, 5-benzothiazepin-4(5H)-ones. Chem Pharm Bull 1997, 45, 6, 1008. |
| 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) | 31228 | p-toluidine; 4-methylphenylamine | 106-49-0 | C7H9N | 详情 | 详情 |
| (II) | 59776 | 6-methyl-1,3-benzothiazol-2-ylamine; 6-methyl-1,3-benzothiazol-2-amine | C8H8N2S | 详情 | 详情 | |
| (III) | 59777 | 2-amino-5-methylbenzenethiol; 2-amino-5-methylphenylhydrosulfide | C7H9NS | 详情 | 详情 | |
| (IV) | 59778 | methyl (2S,3S)-3-(4-methylphenyl)-2-oxiranecarboxylate | C11H12O3 | 详情 | 详情 | |
| (V) | 59779 | methyl (2R,3R)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-hydroxy-3-(4-methylphenyl)propanoate | C18H21NO3S | 详情 | 详情 | |
| (VI) | 59780 | (2R,3R)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-hydroxy-3-(4-methylphenyl)propanoic acid | C17H19NO3S | 详情 | 详情 | |
| (VII) | 59781 | (2R,3R)-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C17H17NO2S | 详情 | 详情 | |
| (VIII) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (IX) | 59782 | (2R,3R)-5-[2-(dimethylamino)ethyl]-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C21H26N2O2S | 详情 | 详情 |