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【结 构 式】 
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【分子编号】15719 【品名】4-methoxybenzenesulfonyl chloride 【CA登记号】98-68-0 |
【 分 子 式 】C7H7ClO3S 【 分 子 量 】206.64948 【元素组成】C 40.69% H 3.41% Cl 17.16% O 23.23% S 15.52% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 4-aminophenol (I) with 2-chloro-3-nitropyridine (II) in DMF at 100 C gives 4-(3-nitropyridin-2-ylamino)phenol (III), which is reduced with H2 over Pd/C in THF-methanol to afford 4-(3-aminopyridin-2-ylamino)phenol (IV). Finally, this compound is condensed with 4-methoxybenzenesulfonylchloride (V) by means of pyridine in THF.
| 【1】 Yoshino, H.; Ueda, N.; Sugumi, H.; Niijima, J.; Kotake, Y.; Okada, T.; Koyanagi, N.; Watanabe, T.; Asada, M.; Yoshimatsu, K.; Iijima, A.; Nagasu, T.; Tsukahara, K.; Kitoh, K. (Eisai Co., Ltd.); Sulfonamide derivs. EP 0472053; JP 1993039256; US 5250549; US 5292758; US 5332751; US 5434172 . |
| 【2】 Niijima, J.; Yoshino, H.; Ueda, N.; et al.; Novel sulfonamides as potential, systemically active antitumor agents. J Med Chem 1992, 35, 13, 2496-7. |
| 【3】 Hoshi, A.; Castaner, J.; E-7010. Drugs Fut 1993, 18, 11, 995. |
| 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) | 15715 | 4-Aminophenol | 123-30-8 | C6H7NO | 详情 | 详情 |
| (II) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (III) | 15717 | 4-[(3-nitro-2-pyridinyl)amino]phenol | C11H9N3O3 | 详情 | 详情 | |
| (IV) | 15718 | 4-[(3-amino-2-pyridinyl)amino]phenol | C11H11N3O | 详情 | 详情 | |
| (V) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Wittig reaction between 2-nitrobenzyltriphenylphosphonium bromide (I) and pyridine-4-carboxaldehyde (II) provided the olefin adduct (IIIa-b) as a mixture of geometric isomers. After, nitro group reduction employing SnCl2, the desired E-isomer (VII), was isolated from the reaction mixture by fractional crystallization. In an alternative approach to intermediate (VII), condensation between 2-nitrobenzaldehyde (IV) and 4-picoline (V) in refluxing acetic anhydride furnished the E-olefin (VI), which was subsequently reduced with SnCl2 to the desired aniline (VII). Acylation of amine (VII) with 4-methoxybenzenesulfonyl chloride (VIII) in pyridine gave sulfonamide (IX). Subsequent oxidation of the pyridine ring to the corresponding N-oxide (X) was accomplished by treatment with peracetic acid at 70 C. The sulfonamide N was finally acetylated in boiling acetic anhydride.
| 【1】 Matsuura, A.; Matsuda, M. (Nippon Shinyaku Co., Ltd.); Aminostilbazole derivs. and medicine. EP 0754682; WO 9527699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 58544 | 9-amino-3-ethyl-3,7-dihydro-6H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-one | C10H10N6O | 详情 | 详情 | |
| (IIIb),(VI) | 58555 | 4-[(E)-2-(2-nitrophenyl)ethenyl]pyridine | C13H10N2O2 | 详情 | 详情 | |
| (I) | 58553 | (2-nitrobenzyl)(triphenyl)phosphonium bromide | C25H21BrNO2P | 详情 | 详情 | |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (IV) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 58556 | 2-[(E)-2-(4-pyridinyl)ethenyl]aniline; 2-[(E)-2-(4-pyridinyl)ethenyl]phenylamine | C13H12N2 | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 58557 | 4-methoxy-N-{2-[(E)-2-(4-pyridinyl)ethenyl]phenyl}benzenesulfonamide | C20H18N2O3S | 详情 | 详情 | |
| (X) | 58558 | 4-[(E)-2-(2-{[(4-methoxyphenyl)sulfonyl]amino}phenyl)ethenyl]-1-pyridiniumolate | C20H18N2O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of D-isoleucine (I) with 4-methoxy-benzenesulfonyl chloride (II) in the presence of Et3N afforded sulfonyl derivative (III), which was subsequently converted to tert-butyl ester (V) upon treatment with dimethylformamide di-tert-butyl acetal (IV). Alkylation of (V) with benzyl bromide and K2CO3 in DMF provided the N-benzyl compound (VI). Then, the tert-butyl ester of (VI) was deprotected with HCl in CH2Cl2, and the resulting carboxylic acid (VII) was condensed with O-tert-butyl hydroxylamine using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to give the tert-butyl hydroxamate (VIII). The target hydroxamic acid was then obtained by deprotection of (VIII) with HCl in dichloroethane containing one equivalent of EtOH.
| 【1】 MacPherson, L.J.; et al.; Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 1997, 40, 16, 2525. |
| 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) | 21073 | (2R,3S)-2-amino-3-methylpentanoic acid | C6H13NO2 | 详情 | 详情 | |
| (II) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (III) | 21075 | (2R,3S)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoic acid | C13H19NO5S | 详情 | 详情 | |
| (IV) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
| (V) | 21077 | tert-butyl (2R,3S)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoate | C17H27NO5S | 详情 | 详情 | |
| (VI) | 21078 | tert-butyl (2R,3S)-2-[benzyl[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoate | C24H33NO5S | 详情 | 详情 | |
| (VII) | 21079 | (2R,3S)-2-[benzyl[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoic acid | C20H25NO5S | 详情 | 详情 | |
| (VIII) | 21080 | (2R,3S)-2-[benzyl[(4-methoxyphenyl)sulfonyl]amino]-N-(tert-butoxy)-3-methylpentanamide | C24H34N2O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of D-valine (I) with 4-methoxybenzenesulfonyl chloride (II) in the presence of Et3N afforded sulfonyl derivative (III), which was subsequently converted to tert-butyl ester (V) upon treatment with dimethylformamide di-tert-butyl acetal (IV). Alkylation of (V) with 2-picolyl chloride-HCl (VI) and K2CO3 in DMF provided the N-(2-picolyl) compound (VII). Then, the tert-butyl ester of (VII) was deprotected with HCl in CH2Cl2, and the resulting carboxylic acid (VIII) was condensed with O-tert-butyl hydroxylamine using N-(3-dimethylaminopropyl)-N'-ethylcarbo-diimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to give the tert-butyl hydroxamate (IX). The target hydroxamic acid was then obtained by deprotection of (IX) with HCl in dichloroethane containing one equivalent of EtOH.
| 【1】 MacPherson, L.J.; et al.; Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 1997, 40, 16, 2525. |
| 【2】 MacPherson, L.J.; Parker, D.T.; Jeng, A.Y. (Novartis Corp.); Arylsulfonamido-substd. hydroxamic acids. US 5506242; US 5552419 . |
| 【3】 MacPherson, L.J.; Parker, D.T. (Novartis Corp.); Arylsulfonamido-substd. hydroxamic acids. US 5646167 . |
| 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) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (II) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (III) | 21058 | (2R)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbutyric acid | C12H17NO5S | 详情 | 详情 | |
| (IV) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
| (V) | 21060 | tert-butyl (2R)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbutanoate | C16H25NO5S | 详情 | 详情 | |
| (VI) | 21061 | 2-(chloromethyl)pyridine hydrochloride | 6959-47-3 | C6H7Cl2N | 详情 | 详情 |
| (VII) | 21062 | tert-butyl (2R)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutanoate | C22H30N2O5S | 详情 | 详情 | |
| (VIII) | 21063 | (2R)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutyric acid hydrochloride | C18H23ClN2O5S | 详情 | 详情 | |
| (IX) | 21064 | (2R)-N-(tert-butoxy)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutanamide | C22H31N3O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The selective protection of piperazine-2-carboxylic acid (I) with tert-butoxycarbonyl anhydride gives the carbamate (II), which is sulfonated with 4-methoxybenzenesulfonyl chloride (II) and triethylamine yielding the sulfonamide (IV). The esterification and simultaneous deprotection of (IV) with SOCl2 and methanol affords the methyl ester (V), which is treated with benzyl chloroformate (VI) and triethylamine to afford the benzyloxycarbonyl derivative (VII). Finally, this compound is treated with KOH and hydroxylamine in methanol to provide the target hydroxamic acid.
| 【1】 Pikul, S.; Natchus, M.G.; Cheng, M.; et al.; Design and synthesis of piperazine-based MMP inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 044. |
| 【2】 De, B.; Natchus, M.G.; Pikul, S.; Almstead, N.G.; Matthews, R.S.; Taiwo, Y.O.; Cheng, M. (The Procter & Gamble Co.); 1,4-Heterocyclic metalloprotease inhibitors. EP 0923563; EP 0925287; WO 9808825; WO 9808827 . |
| 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) | 25933 | 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
| (II) | 25934 | 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | C10H18N2O4 | 详情 | 详情 | |
| (III) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IV) | 25935 | 4-(tert-butoxycarbonyl)-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylic acid | C17H24N2O7S | 详情 | 详情 | |
| (V) | 25936 | methyl 1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 25938 | 1-benzyl 3-methyl 4-[(4-methoxyphenyl)sulfonyl]-1,3-piperazinedicarboxylate | C21H24N2O7S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The selective protection of piperazine-2-carboxylic acid (I) with tert-butoxycarbonyl anhydride gives the carbamate (II), which is sulfonated with 4-methoxybenzenesulfonyl chloride (II) and triethylamine yielding the sulfonamide (IV). The esterification and simultaneous deprotection of (IV) with SOCl2 and methanol affords the methyl ester (V), which is treated with phosgene and N-benzyl-N-methylamine (VI) to afford the cyclic urea derivative (VII). Finally, this compound is treated with KOH and hydroxylamine in methanol to provide the target hydroxamic acid.
| 【1】 De, B.; Natchus, M.G.; Pikul, S.; Almstead, N.G.; Matthews, R.S.; Taiwo, Y.O.; Cheng, M. (The Procter & Gamble Co.); 1,4-Heterocyclic metalloprotease inhibitors. EP 0923563; EP 0925287; WO 9808825; WO 9808827 . |
| 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) | 25933 | 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
| (II) | 25934 | 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | C10H18N2O4 | 详情 | 详情 | |
| (III) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IV) | 25935 | 4-(tert-butoxycarbonyl)-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylic acid | C17H24N2O7S | 详情 | 详情 | |
| (V) | 25936 | methyl 1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VI) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (VII) | 25937 | methyl 4-[[benzyl(methyl)amino]carbonyl]-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C22H27N3O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)The Grignard reaction of vinyloxirane (I) with phenylmagnesium bromide and CuCN in THF gives 4-phenyl-2-buten-1-ol (II), which is submitted to a Sharpless epoxidation with t-BuOOH and Ti(Oi-Pr)4 in dichloromethane in the presence of (-)-diethyl tartrate [(-)-DET] yielding the chiral epoxide (III). The reaction of (III) with Ti(Oi-Pr)2(N3)2 in refluxing benzene affords the 3(S)-azido-4-phenylbutane-1,2(S)-diol (IV), which is epoxidized with 2-acetoxy-2-methylpropionyl chloride (A) and NaOMe in THF to give the chiral azidoepoxide (V). The reaction of (V) with isobutylamine (VI) in hot isopropanol yields the secondary amine (VII), which is condensed with 4-methoxyphenylsulfonyl chloride (VIII) in pyridine affording the sulfonamide (IX). The reduction of the azido group of (IX) with H2 over Pd/C in methanol provides (X) with a primary amino group that is finally condensed with the succinimidinyl carbonate (XI) by means of triethylamine in acetonitrile.
| 【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687. |
| 【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 【3】 Ghosh, A.K.; et al.; Potent HIV protease inhibitors: The development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36, 16, 2300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 | |
| (A) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (I) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (II) | 32806 | (E)-4-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (III) | 32807 | [(2R,3S)-3-benzyloxiranyl]methanol | 116949-62-3 | C10H12O2 | 详情 | 详情 |
| (IV) | 14544 | (2S,3S)-3-azido-4-phenyl-1,2-butanediol | C10H13N3O2 | 详情 | 详情 | |
| (V) | 14547 | (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane | C10H11N3O | 详情 | 详情 | |
| (VI) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VII) | 32809 | (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol | C14H22N4O | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 32810 | N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide | C21H28N4O4S | 详情 | 详情 | |
| (X) | 32811 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide | C21H30N2O4S | 详情 | 详情 | |
| (XI) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Sulfonylation of methyl 3-methylanthranilate (I) with 4-methoxybenzenesulfonyl chloride (II) provided the sulfonamide (III). This was then N-alkylated with 3-picolyl chloride hydrochloride (IV) in the presence of K2CO3 to afford (V). Ester (V) hydrolysis with LiOH or NaOH provided carboxylic acid (VI), which was further activated as the corresponding acid chloride (VII) using oxalyl chloride in the presence of DMF. Coupling of acid chloride (VII) with hydroxylamine hydrochloride furnished the target hydroxamic acid, which was finally treated with HCl to produce the title hydrochloride salt.
| 【1】 Levin, J.I.; DiJoseph, J.F.; Du, M.T.; et al.; The discovery of anthranilic acid-based MMP inhibitors. Part 1. SAR of the 3-position. Bioorg Med Chem Lett 2001, 11, 2, 235. |
| 【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) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (III) | 48425 | methyl 2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbenzoate | C16H17NO5S | 详情 | 详情 | |
| (IV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (V) | 48426 | methyl 2-[[(4-methoxyphenyl)sulfonyl](3-pyridinylmethyl)amino]-3-methylbenzoate | C22H22N2O5S | 详情 | 详情 | |
| (VI) | 48427 | 2-[[(4-methoxyphenyl)sulfonyl](3-pyridinylmethyl)amino]-3-methylbenzoic acid | C21H20N2O5S | 详情 | 详情 | |
| (VII) | 48428 | 2-[[(4-methoxyphenyl)sulfonyl](3-pyridinylmethyl)amino]-3-methylbenzoyl chloride | C21H19ClN2O4S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Nitration of 3-benzoylpyridine (I) with KNO3 in sulfuric acid yielded the meta-nitrobenzoyl derivative (II). Wadsworth-Emmons reaction of ketone (II) with triethyl phosphonoacetate produced the unsaturated ester (IIIa-b) as a mixture of geometric isomers. Nitro group reduction in (IIIa-b) employing Fe and HCl gave aniline (IVa-b), which was condensed with 4-methoxybenzenesulfonyl chloride (V) to afford sulfonamide (VIa-b). After conversion of the pyridine ring of (VIa-b) to the corresponding N-oxide (VIIa-b) with m-chloroperbenzoic acid, the sulfonamide N atom of (VIIa-b) was alkylated with isopropyl iodide and K2CO3 to produce (VIIIa-b). Reduction of the N-oxide of (VIIIa-b) by means of Fe and HOAc, followed by basic hydrolysis of the ethyl ester, furnished acid (IXa-b). This was then coupled with O-t-butyldimethylsilyl hydroxylamine to provide, after separation of the Z/E isomeric mixture, the desired hydroxamic acid.
| 【1】 Hirata, T.; et al.; Discovery of potent, highly selective, and orally active propenohydroxamate TNF-alpha converting enzyme (TACE) inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 262. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 51303 | ethyl (E)-3-(3-nitrophenyl)-3-(3-pyridinyl)-2-propenoate | C16H14N2O4 | 详情 | 详情 | |
| (IIIb) | 51304 | ethyl (Z)-3-(3-nitrophenyl)-3-(3-pyridinyl)-2-propenoate | C16H14N2O4 | 详情 | 详情 | |
| (IVa) | 51305 | ethyl (E)-3-(3-aminophenyl)-3-(3-pyridinyl)-2-propenoate | C16H16N2O2 | 详情 | 详情 | |
| (IVb) | 51306 | ethyl (Z)-3-(3-aminophenyl)-3-(3-pyridinyl)-2-propenoate | C16H16N2O2 | 详情 | 详情 | |
| (VIa) | 51307 | ethyl (E)-3-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoate | C23H22N2O5S | 详情 | 详情 | |
| (VIb) | 51308 | ethyl (Z)-3-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoate | C23H22N2O5S | 详情 | 详情 | |
| (VIIa) | 51309 | 3-[(E)-3-ethoxy-1-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate | C23H22N2O6S | 详情 | 详情 | |
| (VIIb) | 51310 | 3-[(Z)-3-ethoxy-1-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate | C23H22N2O6S | 详情 | 详情 | |
| (VIIIa) | 51311 | 3-[(Z)-3-ethoxy-1-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate | C26H28N2O6S | 详情 | 详情 | |
| (VIIIb) | 51312 | 3-[(E)-3-ethoxy-1-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate | C26H28N2O6S | 详情 | 详情 | |
| (IXa) | 51313 | (E)-3-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoic acid | C24H24N2O5S | 详情 | 详情 | |
| (IXb) | 51314 | (Z)-3-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoic acid | C24H24N2O5S | 详情 | 详情 | |
| (I) | 27766 | phenyl(3-pyridinyl)methanone | 5424-19-1 | C12H9NO | 详情 | 详情 |
| (II) | 51302 | (3-nitrophenyl)(3-pyridinyl)methanone | C12H8N2O3 | 详情 | 详情 | |
| (V) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |