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【结 构 式】 
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【分子编号】32887 【品名】4-(4-pyridinyloxy)benzenesulfonyl chloride 【CA登记号】 |
【 分 子 式 】C11H8ClNO3S 【 分 子 量 】269.70816 【元素组成】C 48.99% H 2.99% Cl 13.14% N 5.19% O 17.8% S 11.89% |
合成路线1
该中间体在本合成路线中的序号：(VI)1) The esterification of D-penicillamine (I) with trimethylsilyl chloride and DBU in DMF gives the expected ester (II), which is cyclized with 1,2-dibromoethane by means of DBU and DIEA in DMF and protected at the amino group with Fmoc-Cl and NMM to afford 4-(9-fluorenylmethoxycarbonyl)-2,2-dimethylthiomorpholine-3(S)-carboxylic acid (III), which by treatment with O-[tert-butyl(diphenyl)silyl]hydroxylamine (TBDPSO-NH2) and EDC in dichloro-methane yields the silylated carbohydroxamic acid (IV). The removal of the Fmoc group of (IV) with diethylamine in THF affords (V), which is sulfonated with 4-(4-pyridyloxy)phenylsulfonyl chloride (VI) and NMM in dichloroethane to give the protected prinomastat (VII). Finally, this compound is desilylated with concentrated HCl in methanol. The intermediate (VI) is obtained by condensation of 4-chloropyridine (VIII) with phenol (IX) at 150 C to give 4-phenoxypyridine (X), which is then sulfonated with chlorosulfonic acid and treated with oxalyl chloride to afford the desired sulfonyl chloride (VI).
| 【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150. |
| 【2】 Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses. US 5753653 . |
| 【3】 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 |
| (II) | 32883 | trimethylsilyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate | C8H19NO2SSi | 详情 | 详情 | |
| (III) | 32884 | (3S)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2,2-dimethyl-3-thiomorpholinecarboxylic acid | C22H23NO4S | 详情 | 详情 | |
| (IV) | 32885 | 9H-fluoren-9-ylmethyl (3S)-3-[([[tert-butyl(diphenyl)silyl]oxy]amino)carbonyl]-2,2-dimethyl-4-thiomorpholinecarboxylate | C38H42N2O4SSi | 详情 | 详情 | |
| (V) | 32886 | (3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-3-thiomorpholinecarboxamide | C23H32N2O2SSi | 详情 | 详情 | |
| (VI) | 32887 | 4-(4-pyridinyloxy)benzenesulfonyl chloride | C11H8ClNO3S | 详情 | 详情 | |
| (VII) | 32888 | (3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxamide | C34H39N3O5S2Si | 详情 | 详情 | |
| (VIII) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (IX) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (X) | 32890 | 4-phenoxypyridine; phenyl 4-pyridinyl ether | 4783-86-2 | C11H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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3
该中间体在本合成路线中的序号：(VI)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 |
合成路线4
该中间体在本合成路线中的序号：(II)Acylation of methyl 3-methylanthranilate (I) with 4-(4-pyridyloxy)benzenesulfonyl chloride (II) gave sulfonamide (III). Subsequent N-alkylation of the sulfonamide function with iodomethane in the presence of NaH afforded the N-methyl sulfonamide (IV). Basic hydrolysis of the ester group of (IV) yielded carboxylic acid (V), which was further activated as the acid chloride (VI) upon treatment with oxalyl chloride. Finally, reaction of acid chloride (VI) with hydroxylamine yielded the corresponding hydroxamic acid.
| 【1】 Levin, J.I.; et al.; The discovery of anthranilic acid-based MMP inhibitors. Part 2: SAR of the 5-position P11 groups. Bioorg Med Chem Lett 2001, 11, 16, 2189. |
| 【2】 Gu, Y.; Nelson, F.C.; Zask, A.; Du, M.T.; Levin, J.I.; Venkatesan, M. (American Cyanamid Co.); Preparation and use of orthosulfonamido aryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors. US 5929097 . |
| 【3】 Nelson, F.C.; Venkatesan, A.M.; Levin, J.I.; Du, M.T.; Gu, Y.; Zask, A. (American Cyanamid Co.); The preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors. WO 9816503 . |
| 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) | 48424 | methyl 2-amino-3-methylbenzoate | C9H11NO2 | 详情 | 详情 | |
| (II) | 32887 | 4-(4-pyridinyloxy)benzenesulfonyl chloride | C11H8ClNO3S | 详情 | 详情 | |
| (III) | 51112 | methyl 3-methyl-2-([[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoate | C20H18N2O5S | 详情 | 详情 | |
| (IV) | 51113 | methyl 3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoate | C21H20N2O5S | 详情 | 详情 | |
| (V) | 51114 | 3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoic acid | C20H18N2O5S | 详情 | 详情 | |
| (VI) | 51115 | 3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoyl chloride | C20H17ClN2O4S | 详情 | 详情 |