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【结 构 式】 
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【药物名称】 【化学名称】4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-[4-[2-[N-[2-[N-[3-(dimethylamino)propyl]-N-methylamino]ethyl]carbamoyl]-1H-pyrrol-1-ylsulfonyl]-2-nitrophenyl]semicarbazide 【CA登记号】 【 分 子 式 】C35H42N8O6S 【 分 子 量 】702.83899 |
【开发单位】Novartis (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiarthritic Drugs, Non-Opioid Analgesics, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Bradykinin B2 Antagonists |
合成路线1
The precursor triamine (VI) is prepared as follows. Ethanolamine (I) is protected as the N-Cbz derivative (II) upon treatment with N-(benzyloxycarbonyloxy)succinimide. Subsequent tosylation of (II) to yield (III), followed by displacement of the tosylate of (III) with trimethyl propanediamine (IV) furnishes the protected triamine (V). Then, Cbz group hydrogenolysis in (V) in the presence of Pd/C gives rise to triamine (VI).
| 【1】 Dziadulewicz, E.K.; et al.; Nonpeptide bradykinin B2 receptor antagonists: Conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists. J Med Chem 2002, 45, 11, 2160. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 30663 | N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione | 13139-17-8 | C12H11NO5 | 详情 | 详情 |
| (I) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (II) | 32497 | benzyl 2-hydroxyethylcarbamate | 77987-49-6 | C10H13NO3 | 详情 | 详情 |
| (III) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (IV) | 28165 | N-[3-(dimethylamino)propyl]-N-methylamine | 4543-96-8 | C6H16N2 | 详情 | 详情 |
| (V) | 61665 | benzyl 2-[[3-(dimethylamino)propyl](methyl)amino]ethylcarbamate | C16H27N3O2 | 详情 | 详情 | |
| (VI) | 61664 | N~1~-(2-aminoethyl)-N~1~,N~3~,N~3~-trimethyl-1,3-propanediamine | C8H21N3 | 详情 | 详情 |
合成路线2
Sulfonylation of pyrrole-2-carboxylic acid (VII) with 4-chloro-3-nitrobenzenesulfonyl chloride (VIII) in the presence of butyllithium leads to sulfonamide (IX). Chloride displacement in (IX) with hydrazine hydrate in refluxing THF affords the phenylhydrazine derivative (X). This is further coupled with isocyanate (XI) to produce the semicarbazide (XII). Finally, condensation of carboxylic acid (XII) with amine (VI), via activation as the mixed anhydride with isopropyl chloroformate, yields the title pyrrolecarboxamide.
| 【1】 Dziadulewicz, E.K.; et al.; Nonpeptide bradykinin B2 receptor antagonists: Conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists. J Med Chem 2002, 45, 11, 2160. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 61664 | N~1~-(2-aminoethyl)-N~1~,N~3~,N~3~-trimethyl-1,3-propanediamine | C8H21N3 | 详情 | 详情 | |
| (VII) | 31796 | Pyrrole-2-carboxylic acid; 1H-pyrrole-2-carboxylic acid | 634-97-9 | C5H5NO2 | 详情 | 详情 |
| (VIII) | 42318 | 4-chloro-3-nitrobenzenesulfonyl chloride | 97-08-5 | C6H3Cl2NO4S | 详情 | 详情 |
| (IX) | 61660 | 1-[(4-chloro-3-nitrophenyl)sulfonyl]-1H-pyrrole-2-carboxylic acid | C11H7ClN2O6S | 详情 | 详情 | |
| (X) | 61661 | 1-[(4-hydrazino-3-nitrophenyl)sulfonyl]-1H-pyrrole-2-carboxylic acid | C11H10N4O6S | 详情 | 详情 | |
| (XI) | 61662 | 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl isocyanate; 5-isocyanato-10,11-dihydro-5H-dibenzo[a,d]cycloheptene | C16H13NO | 详情 | 详情 | |
| (XII) | 61663 | 1-[(4-{2-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylamino)carbonyl]hydrazino}-3-nitrophenyl)sulfonyl]-1H-pyrrole-2-carboxylic acid | C27H23N5O7S | 详情 | 详情 |