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【结 构 式】 
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【分子编号】32894 【品名】(3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C18H20N2O5S2 【 分 子 量 】408.49928 【元素组成】C 52.92% H 4.93% N 6.86% O 19.58% S 15.7% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The silylation of D-penicillamine (I) with dimethylhexylsilyl chloride (Dmhs-Cl) and DBU gives the ester (XI), which is cyclized with 1,2-dichloroethane and DBU in DMF, yielding 2,2-dimethylthiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XII). The sulfonation of (XII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XIII), which is desilylated in refluxing methanol to give the free acid (XIV) Finally, this compound is treated with oxalyl chloride and hydroxylamine in dichloromethane.
| 【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150. |
| 【2】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 . |
| 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) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (VI) | 32887 | 4-(4-pyridinyloxy)benzenesulfonyl chloride | C11H8ClNO3S | 详情 | 详情 | |
| (XI) | 32891 | dimethyl(1,1,2-trimethylpropyl)silyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate | C13H29NO2SSi | 详情 | 详情 | |
| (XII) | 32892 | dimethyl(1,1,2-trimethylpropyl)silyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate | C15H31NO2SSi | 详情 | 详情 | |
| (XIII) | 32893 | dimethyl(1,1,2-trimethylpropyl)silyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate | C26H38N2O5S2Si | 详情 | 详情 | |
| (XIV) | 32894 | (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylic acid | C18H20N2O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The cyclization of D-penicillamine (I) with 1,2-dichloroethane by means of DBU and TMS-Cl in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid (XV), which is treated with isobutylene (XVI) and sulfuric acid in dioxane to yield the corresponding tert-butyl ester (XVII). The sulfonation of (XVII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid tert-butyl ester (XVIII), which is finally treated with HCl in refluxing dioxane to give the previously reported free acid intermediate (XIV). The cyclization of D-penicillamine methyl ester (XIX) with 1,2-dibromoethane by means of DBU in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid methyl ester (XX), which is sulfonated with the sulfonyl chloride (VI) as before, affording 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid methyl ester (XXI). Finally, this compound is hydrolyzed with refluxing aqueous HCl to yield the previously reported intermediate (XIV).
| 【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150. |
| 【2】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 . |
| 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) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (VI) | 32887 | 4-(4-pyridinyloxy)benzenesulfonyl chloride | C11H8ClNO3S | 详情 | 详情 | |
| (XIV) | 32894 | (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylic acid | C18H20N2O5S2 | 详情 | 详情 | |
| (XV) | 32895 | (3S)-2,2-dimethyl-3-thiomorpholinecarboxylic acid | C7H13NO2S | 详情 | 详情 | |
| (XVI) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (XVII) | 32896 | tert-butyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate | C11H21NO2S | 详情 | 详情 | |
| (XVIII) | 32897 | tert-butyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate | C22H28N2O5S2 | 详情 | 详情 | |
| (XIX) | 32898 | methyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate; methyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate | C6H13NO2S | 详情 | 详情 | |
| (XX) | 32899 | methyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate | C8H15NO2S | 详情 | 详情 | |
| (XXI) | 32900 | methyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate | C19H22N2O5S2 | 详情 | 详情 |