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【结 构 式】 
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【药物名称】Irbesartan, BMS-186295, SR-47436, Avapro, Karvea, Aprovel 【化学名称】2-Butyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]spiro[2-imidazoline-4,1'-cyclopentane]-5-one 【CA登记号】138402-11-6 【 分 子 式 】C25H28N6O 【 分 子 量 】428.54151 |
【开发单位】Sanofi-synthélabo (Originator), Bristol-Myers Squibb (Licensee), Shionogi (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Diabetic Nephropathy, Agents for, ENDOCRINE DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Diabetic Complications, Angiotensin AT1 Antagonists |
合成路线1
The reaction of cyclopentanone (I) with sodium cyanide, NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II), which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III). The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V), which, without isolation, is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI). This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene. The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X). Cyclization of (X) with tributyltin azide in refluxing xylene, followed by reaction with trityl chloride in DMF, affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI). Finally, this compound is hydrolyzed to irbesartan with HCl in methanol/THF. The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
| 【1】 Casas, A.; Merlos, M.; Castaner, J.; Irbesartan. Drugs Fut 1997, 22, 5, 481. |
| 【2】 Bernhart, C.; Breliere, J.-C.; Clement, J.; Nisato, D.; Perreaut, P. (Sanofi-Synthélabo ); Heterocyclic N-substd. derivs., their preparation and the pharmaceutical compsns. containing them. EP 0454511; FR 2659967; FR 2665702; JP 1992506222; JP 1998279566; US 5270317; WO 9114679 . |
| 【3】 Caron, A.; Chantreux, D.; Bouloumie, C. (Sanofi-Synthelabo ); Method for the preparation of a tetrazole deriv. under two crystalline forms and novel crystalline form of this deriv. EP 0708103 . |
| 【4】 Bernhart, C.A.; Perreaut, P.M.; Ferrari, B.P.; et al.; A new series of imidazolones: Highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem 1993, 36, 22, 3371-80. |
| 【5】 Bernhart, C.; Clement, J.; Ferrari, B.; et al.; Spiro-dihydro-imidazolones, a new class of non-peptide angiotensin II receptor antagonists. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-084.A.. |
| 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) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (II) | 15114 | 1-aminocyclopentanecarbonitrile | C6H10N2 | 详情 | 详情 | |
| (III) | 15115 | 1-Amino-1-cyclopentane carboxamide; 1-Aminocyclopentanecarboxamide | 17193-28-1 | C6H12N2O | 详情 | 详情 |
| (IV) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (V) | 15117 | N-[1-(aminocarbonyl)cyclopentyl]pentanamide; 1-(pentanoylamino)cyclopentanecarboxamide | C11H20N2O2 | 详情 | 详情 | |
| (VI) | 15118 | 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 1,3-Diazaspirol[4,4]non-1-en-4-one,2-butyl | 151257-01-1 | C11H18N2O | 详情 | 详情 |
| (VII) | 15119 | ethyl 1-aminocyclopentanecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (VIII) | 15120 | ethyl pentanimidoate | C7H15NO | 详情 | 详情 | |
| (IX) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (X) | 15122 | 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl][1,1'-biphenyl]-2-carbonitrile | C25H27N3O | 详情 | 详情 | |
| (XI) | 15121 | 2-butyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one | C44H42N6O | 详情 | 详情 |