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【结 构 式】 
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【药物名称】 【化学名称】3(R)-[1-(3,5-Dichlorophenylsulfonyl)azetidin-2(S)-ylcarboxamido]-3-(4-methoxyphenyl)propionic acid 【CA登记号】309976-72-5 【 分 子 式 】C20H20Cl2N2O6S 【 分 子 量 】487.3622 |
【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
The Michael addition of the chiral amine (II) to methyl 4-(benzyloxy)cinnamate (I) in the presence of butyllithium produces diastereoselectively the amino ester (III) as the major isomer. After catalytic hydrogenolysis of the benzyl groups of (III), the resultant amino ester (IV) is converted to the N-Boc derivative (V) upon treatment with Boc2O. O-alkylation of phenol (V) with iodomethane in the presence of Cs2CO3 yields methyl ether (VI). The N-Boc group of (VI) is subsequently removed under acidic conditions to furnish (VII).
| 【1】 Kopka, I.E.; Mumford, R.A.; Lin, L.S.; et al.; The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 611. |
| 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) | 59017 | methyl (E)-3-[4-(benzyloxy)phenyl]-2-propenoate | C17H16O3 | 详情 | 详情 | |
| (II) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (III) | 59018 | methyl (3R)-3-[4-(benzyloxy)phenyl]-3-{benzyl[(1R)-1-phenylethyl]amino}propanoate | C32H33NO3 | 详情 | 详情 | |
| (IV) | 59019 | methyl (3R)-3-amino-3-(4-hydroxyphenyl)propanoate | C10H13NO3 | 详情 | 详情 | |
| (V) | 59020 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | C15H21NO5 | 详情 | 详情 | |
| (VI) | 59021 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C16H23NO5 | 详情 | 详情 | |
| (VII) | 59022 | methyl (3R)-3-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 |
合成路线2
Condensation of 3,5-dichlorobenzenesulfonyl chloride (VIII) with (S)-azetidine-2-carboxylic acid (IX) under Schotten-Baumann conditions gives sulfonamide (X). This is subsequently coupled with aminoester (VII) by means of PyBOP to afford amide (XI). The methyl ester group of (XI) is finally hydrolyzed to the target carboxylic acid employing LiOH.
| 【1】 Kopka, I.E.; Mumford, R.A.; Lin, L.S.; et al.; The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 611. |
| 【2】 Hagmann, W.K.; Durette, P.L.; Mumford, R.A.; Kopka, I.E.; Mills, S.G.; MacCoss, M.; Magriotis, P.A. (Merck & Co., Inc.); Substd. beta-alanine derivs. as cell adhesion inhibitors. WO 0071572 . |
| 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) | 59023 | 3,5-dichlorobenzenesulfonyl chloride | C6H3Cl3O2S | 详情 | 详情 | |
| (IX) | 26204 | (2S)-2-azetidinecarboxylic acid; (S)-(-)-Azetidine carboxylic acid | 2133-34-8 | C4H7NO2 | 详情 | 详情 |
| (X) | 59024 | (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-azetidinecarboxylic acid | C10H9Cl2NO4S | 详情 | 详情 | |
| (XI) | 59022 | methyl (3R)-3-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
| (XII) | 59025 | methyl (3R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]azetidinyl}carbonyl)amino]-3-(4-methoxyphenyl)propanoate | C21H22Cl2N2O6S | 详情 | 详情 |