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【结 构 式】 
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【药物名称】 【化学名称】N-[1-Amidino-2-hydroxypiperidin-3(R)-yl]-3(S)-(benzylsulfonamido)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide trifluoroacetate 【CA登记号】 【 分 子 式 】C28H35F3N6O8S 【 分 子 量 】672.68575 |
【开发单位】Corvas (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
6-Methoxy-alpha-tetralone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine in the presence of sodium acetate. Subsequent Beckmann rearrangement of (II) employing polyphosphoric acid produced a mixture of two regioisomeric lactams from which the required 1-benzazepine (III) was isolated by flash chromatography. Iodination of (III) to give (IV) was carried out following a previously described metodolgy. Displacement of the iodolactam (IV) with ammonia in aqueous ethanol furnished the racemic primary amine, which was resolved by means of L-pyroglutamic acid. The desired (S)-amine (V) was protected as the benzyl carbamate (VII) by treatment with N-(benzyloxycarbonyloxy)succinimide (VI). Then, selective alkylation of the lactam ring nitrogen of (VII) with tert-butyl bromoacetate in the presence of lithium hexamethyldisilazide provided ester (VIII). After hydrogenolysis of the carbobenzoy moiety of (VIII), the resulting amino lactam (IX) was condensed with benzylsulfonyl chloride (X) to give sulfonamide (XI). Deprotection of the tert-butyl ester of (XI) with trifluoroacetic acid afforded carboxylic acid (XII), which was coupled with nitroargininal ethyl aminal (XIII), yielding amide (XIV).
| 【1】 Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 17594 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone | 1078-19-9 | C11H12O2 | 详情 | 详情 |
| (II) | 38125 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone oxime | C11H13NO2 | 详情 | 详情 | |
| (III) | 38126 | 7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H13NO2 | 详情 | 详情 | |
| (IV) | 38127 | 3-iodo-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H12INO2 | 详情 | 详情 | |
| (V) | 38128 | (3S)-3-amino-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H14N2O2 | 详情 | 详情 | |
| (VI) | 30663 | N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione | 13139-17-8 | C12H11NO5 | 详情 | 详情 |
| (VII) | 38129 | benzyl (3S)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate | C19H20N2O4 | 详情 | 详情 | |
| (VIII) | 38130 | tert-butyl 2-((3S)-3-[[(benzyloxy)carbonyl]amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C25H30N2O6 | 详情 | 详情 | |
| (IX) | 38131 | tert-butyl 2-[(3S)-3-amino-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C17H24N2O4 | 详情 | 详情 | |
| (X) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (XI) | 38132 | tert-butyl 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C24H30N2O6S | 详情 | 详情 | |
| (XII) | 38133 | 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C20H22N2O6S | 详情 | 详情 | |
| (XIII) | 38136 | C8H17N5O3 | 详情 | 详情 | ||
| (XIV) | 38134 | C28H37N7O8S | 详情 | 详情 |
合成路线2
Hydrogenolysis of the nitro group from the guanidine (XIV) provided (XV). Then, mild acid hydrolysis of the ethyl acetal of (XV) furnished the title compound, which was finally isolated as the corresponding trifluoroacetate salt.
| 【1】 Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573. |