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【结 构 式】 
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【药物名称】 【化学名称】3endo-[1-(3,5-Dichlorophenylsulfonyl)pyrrolidin-2(S)-ylcarboxamido]bicyclo[2.2.1]heptane-2exo-carboxylic acid 【CA登记号】226066-12-2 (stereoisomer), 226066-14-4 (stereoisomer) 【 分 子 式 】C19H22Cl2N2O5S 【 分 子 量 】461.36759 |
【开发单位】Merck & Co. (Originator) 【药理作用】Asthma Therapy, RESPIRATORY DRUGS, Integrin alpha4beta1 (VLA-4) Antagonists |
合成路线1
Acylation of L-proline t-butyl ester (I) with 3,5-dichlorobenzenesulfonyl chloride (II) affords sulfonamide (III). The tert-butyl ester group of (III) is then cleaved by treatment with aqueous trifluoroacetic acid, yielding carboxylic acid (IV). Coupling of sulfonyl proline (IV) with the racemic 3-endo-amino-bicyclo[2.2.1]heptane-2-endo-carboxylate (V) leads to a mixture of four diastereoisomeric amides, resulting from carboxylate group epimerization. This mixture can be separated into two pairs of diastereoisomers (VI) and (VII) by flash chromatography. The desired diastereoisomeric mixture of esters (VII) is then hydrolyzed under alkaline conditions to furnish the title carboxylic acid along with its epimer (VIII).
| 【1】 Chang, L.L.; Truong, Q.; Doss, G.; et al.; Orally active, conformationally constrained small molecule VLA-4 antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 325. |
| 【2】 Hagmann, W.K.; MacCoss, M.; Chang, L. (Merck & Co., Inc.); Cyclic amino acid derivs. as cell adhesion inhibitors. JP 2001523711; US 6271252; WO 9926615 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(V) | 60436 | ethyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (I) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (II) | 59023 | 3,5-dichlorobenzenesulfonyl chloride | C6H3Cl3O2S | 详情 | 详情 | |
| (III) | 60434 | tert-butyl (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylate | C15H19Cl2NO4S | 详情 | 详情 | |
| (IV) | 60435 | (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | C11H11Cl2NO4S | 详情 | 详情 | |
| (VI) | 60437 | ethyl (1R,3S,4S)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate | C21H26Cl2N2O5S | 详情 | 详情 | |
| (VII) | 60438 | ethyl (1S,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate | C21H26Cl2N2O5S | 详情 | 详情 | |
| (VIII) | 60439 | (1S,2S,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylic acid | C19H22Cl2N2O5S | 详情 | 详情 |
合成路线2
In an alternative procedure, Diels-Alder condensation between methyl (E)-3-nitroacrylate (I) and cyclopentadiene (II) produces a mixture of bicyclic adducts (III) and (IV) in a 6:1 ratio. After chromatographic isolation of the major isomer (III), catalytic hydrogenation of its olefin double bond in the presence of PtO2 yields nitro ester (V). Subsequent nitro group reduction in (V) by transfer hydrogenation with ammonium formate and Pd/C produces the racemic amino ester (VI). Coupling of racemic (VI) with carboxylic acid (VII) leads to a mixture of diastereoisomeric amides (VIII) and (IX). Finally, after alkaline hydrolysis of its methyl ester function, the target carboxylic acid isomer is isolated by flash chromatography.
| 【1】 Chang, L.L.; Truong, Q.; Doss, G.; et al.; Orally active, conformationally constrained small molecule VLA-4 antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 325. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(V) | 60443 | methyl (1S,2R,3R,4R)-3-nitrobicyclo[2.2.1]heptane-2-carboxylate | C9H13NO4 | 详情 | 详情 | |
| rac-(VI) | 60444 | methyl (1S,2R,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate | C9H15NO2 | 详情 | 详情 | |
| (I) | 60440 | methyl (E)-3-nitro-2-propenoate | C4H5NO4 | 详情 | 详情 | |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 60441 | methyl (1R,2R,3R,4S)-3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate | C9H11NO4 | 详情 | 详情 | |
| (IV) | 60442 | methyl (1R,2S,3S,4S)-3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate | C9H11NO4 | 详情 | 详情 | |
| (VII) | 60435 | (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | C11H11Cl2NO4S | 详情 | 详情 | |
| (VIII) | 60445 | methyl (1S,2R,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate | C20H24Cl2N2O5S | 详情 | 详情 | |
| (IX) | 60446 | methyl (1R,2S,3S,4S)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate | C20H24Cl2N2O5S | 详情 | 详情 |