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【结 构 式】 
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【药物名称】 【化学名称】4-[2-(2-Cyclopentylethyl)-5-oxazolyl]-N-[4-[2-[2(R)-hydroxy-2-(3-pyridinyl)ethylamino]ethyl]phenyl]benzenesulfonamide 【CA登记号】173902-04-0, 173900-95-3 (undefined isomer) 【 分 子 式 】C31H36N4O4S 【 分 子 量 】560.72097 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, beta3-Adrenoceptor Agonists |
合成路线1
The chlorination of 2-acetylpyridine (I) with N-chlorosuccinimide in ethereal HCl gives 2-(chloroacetyl)pyridine (II), which is reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF yielding (R)-2-chloro-1-(2-pyridyl)ethanol (III). The epoxidation of (III) with K2CO3 in refluxing acetone affords the epoxide (IV), which is condensed with 4-(2-aminoethyl)aniline (V) in refluxing methanol providing (R)-2-[2-(4-aminophenyl)ethylamino]-1-(2-pyridyl)ethanol (VI). The selective protection of the secondary amino group of (VI) with tert-butoxycarbonyl anhydride in THF gives the carbamate (VII) (1), which is condensed with 4-[2-(2-cyclopentylethyl)oxazol-5-yl]phenylsulfonyl chloride (VIII) in pyridine yielding the sulfonamide (IX). Finally, this compound is deprotected with trifluoroacetic acid.
| 【1】 Ok, H.O.; Candelore, M.R.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 114. |
| 【2】 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 . |
| 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) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (II) | 26549 | 2-chloro-1-(3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (III) | 26550 | (1R)-2-chloro-1-(3-pyridinyl)-1-ethanol | C7H8ClNO | 详情 | 详情 | |
| (IV) | 26551 | 3-[(2R)oxiranyl]pyridine | C7H7NO | 详情 | 详情 | |
| (V) | 26552 | (1R)-2-[(4-aminophenethyl)amino]-1-(3-pyridinyl)-1-ethanol | C15H19N3O | 详情 | 详情 | |
| (VI) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (VII) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 | |
| (VIII) | 26719 | tert-butyl 4-[([4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C36H44N4O6S | 详情 | 详情 |
合成路线2
The intermediate sulfonyl chloride (VIII) has been obtained as follows: The reaction of phenacyl bromide (X) with sodium azide in hot DMF gives the azide (XI), which is condensed with 3-cyclopentylpropionyl chloride (XII) by means of LDA yielding the enol ester (XIII). The cyclization of (XIII) by means of triethyl phosphite in refluxing hexane affords 2-(2-cyclopentylethyl)-5-phenyloxazole (XIV), which is finally sulfonated with chlorosulfonic acid to afford the target sulfonyl chloride (VIII).
| 【1】 Ok, H.O.; Candelore, M.R.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 114. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 | |
| (X) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (XI) | 26720 | 2-azido-1-phenyl-1-ethanone | C8H7N3O | 详情 | 详情 | |
| (XII) | 26721 | 3-cyclopentylpropanoyl chloride | 104-97-2 | C8H13ClO | 详情 | 详情 |
| (XIII) | 26722 | (Z)-2-azido-1-phenylethenyl 3-cyclopentylpropanoate | C16H19N3O2 | 详情 | 详情 | |
| (XIV) | 26723 | 2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole | C16H19NO | 详情 | 详情 |
合成路线3
The cyclization of phenacyl bromide (I) with acetamide (II) by heating at 130 C gives 2-methyl-5-phenyloxazole (III), which is brominated with NBS in CCl4 to yield the dibromo derivative (IV). The condensation of (IV) with cyclopentylmethylmagnesium bromide (V) by means of Li2CuCl4 affords 4-bromo-2-(2-cyclopentylethyl)-5-phenyloxazole (VI), which is debrominated by hydrogenation with H2 over Pd(OH)2 in methanol, providing 2-(2-cyclopentylethyl)-5-phenyloxazole (VII). The sulfonation of the phenyl ring of (VII) with chlorosulfonic acid gives the sulfonyl chloride (VIII), which is condensed with the aniline derivative (IX) by means of pyridine in dichloromethane to yield the sulfonamide (X). Finally, elimination of the Boc protecting group of (X) by means of HCl in methanol affords the target compound.
| 【1】 Candelore, M.R.; Ok, H.O.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3-adrenergic receptor agonist. Bioorg Med Chem Lett 2000, 10, 14, 1531. |
| 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) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (II) | 50352 | Acetamide; Acetic acid amide; Ethanamide | 60-35-5 | C2H5NO | 详情 | 详情 |
| (III) | 50348 | 2-methyl-5-phenyl-1,3-oxazole | C10H9NO | 详情 | 详情 | |
| (IV) | 50349 | 4-bromo-2-(bromomethyl)-5-phenyl-1,3-oxazole | C10H7Br2NO | 详情 | 详情 | |
| (V) | 50350 | bromo(cyclopentylmethyl)magnesium | C6H11BrMg | 详情 | 详情 | |
| (VI) | 50351 | 4-bromo-2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole | C16H18BrNO | 详情 | 详情 | |
| (VII) | 26723 | 2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole | C16H19NO | 详情 | 详情 | |
| (VIII) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 | |
| (IX) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (X) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 |