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【结 构 式】 
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【药物名称】 【化学名称】N-[2-(2-Benzoxazolyl)tetrahydrofuran-2-ylcarbonyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine 【CA登记号】 【 分 子 式 】C29H28N2O7 【 分 子 量 】516.55571 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Antiarthritic Drugs, Asthma Therapy, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Integrin alpha4beta1 (VLA-4) Antagonists |
合成路线1
N-Boc-L-tyrosine tert-butyl ester (I) was converted to the aryl triflate (II) by means of trifluoromethanesulfonic anhydride and pyridine. Palladium-catalyzed coupling of triflate (II) with 2,6-dimethoxyphenylboronic acid (III) furnished the biphenyl compound (IV). The N-Boc protecting group of (IV) was then selectively removed by treatment with sulfuric acid in tert-butyl acetate, yielding amino ester (V).
| 【1】 Yang, G.X.; Hagmann, W.K.; Doherty, G.; Chang, L.L.; Delaszlo, S.E. (Merck & Co., Inc.); Heterocycle amides as cell adhesion inhibitors. WO 0112183 . |
| 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) | 52092 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | C18H27NO5 | 详情 | 详情 | |
| (II) | 52093 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate | C19H26F3NO7S | 详情 | 详情 | |
| (III) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (IV) | 52094 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C26H35NO6 | 详情 | 详情 | |
| (V) | 52095 | tert-butyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C21H27NO4 | 详情 | 详情 |
合成路线2
Coupling of 2-tetrahydrofuroic acid (VI) with ortho-aminophenol (VII) by means of PyBOP gave the corresponding ortho-hydroxyanilide (VIII), which was cyclized to the benzoxazole (IX) in the presence of DEAD and triphenylphosphine. The lithium derivative of (IX) was acylated with methyl chloroformate to produce the carboxylate ester (X). Acid (XI), generated by basic hydrolysis of ester (X), was then coupled with amino ester (V) to afford amide (XII). The tert-butyl ester group of (XII) was finally cleaved to the title carboxylic acid by treatment with trifluoroacetic acid.
| 【1】 Yang, G.X.; Hagmann, W.K.; Doherty, G.; Chang, L.L.; Delaszlo, S.E. (Merck & Co., Inc.); Heterocycle amides as cell adhesion inhibitors. WO 0112183 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 52095 | tert-butyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C21H27NO4 | 详情 | 详情 | |
| (VI) | 52096 | Tetrahydrofuran-2-carboxylic Acid; 2-Tetrahydrofuroic acid | 16874-33-2 | C5H8O3 | 详情 | 详情 |
| (VII) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (VIII) | 52097 | N-(2-hydroxyphenyl)tetrahydro-2-furancarboxamide | C11H13NO3 | 详情 | 详情 | |
| (IX) | 52098 | 2-tetrahydro-2-furanyl-1,3-benzoxazole | C11H11NO2 | 详情 | 详情 | |
| (X) | 52099 | methyl 2-(1,3-benzoxazol-2-yl)tetrahydro-2-furancarboxylate | C13H13NO4 | 详情 | 详情 | |
| (XI) | 52100 | 2-(1,3-benzoxazol-2-yl)tetrahydro-2-furancarboxylic acid | C12H11NO4 | 详情 | 详情 | |
| (XII) | 52101 | tert-butyl (2S)-2-([[2-(1,3-benzoxazol-2-yl)tetrahydro-2-furanyl]carbonyl]amino)-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C33H36N2O7 | 详情 | 详情 |