|
【结 构 式】 
|
【分子编号】15234 【品名】2-Naphthalenethiol; 2-Naphthylhydrosulfide 【CA登记号】91-60-1 |
【 分 子 式 】C10H8S 【 分 子 量 】160.23952 【元素组成】C 74.96% H 5.03% S 20.01% |
合成路线1
该中间体在本合成路线中的序号：(III)AY-31,637 may be synthesized by either of two routes: 1) Dilithiation of 2,4-thiazolidinedione (I) with two equivalents of n-butyllithium, followed by sulfonylation with 2-naphthylsulfonyl chloride (VI). 2) Coupling of 2-mercaptonaphthalene (III) and 5-bromo-2,4-thiazolidinedione (II) by the addition of two equivalents of lithium diisopropylamide gives 5-(2-naphthylthio)-2,4-thiazolidinedione (IV). Oxidation of this compound with excess hydrogen peroxide in acetic acid at 60 C gives the corresponding sulfone, AY-31,637.
| 【1】 Zask, A.; Jirkovsky, I. (American Home Products Corp.); 5-[(1- and 2-Naphthalenyl)sulfonyl]-2,4-thiazolidinediones and derivs. Thereof. US 4997948 . |
| 【2】 McCaleb, M.L.; Jirkovsky, I.; Zask, A.; Nowicki, J.W.; Synthesis and antihyperglycemic activity of 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones. J Med Chem 1990, 33, 5, 1418-23. |
| 【3】 Zask, A.; McCaleb, M.L.; AY-31,637. Drugs Fut 1991, 16, 6, 505. |
| 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) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (II) | 13875 | 5-Bromo-1,3-thiazolidine-2,4-dione | C3H2BrNO2S | 详情 | 详情 | |
| (III) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
| (IV) | 13876 | 5-(2-Naphthylsulfanyl)-1,3-thiazolidine-2,4-dione | C13H9NO2S2 | 详情 | 详情 | |
| (V) | 13877 | 3,5-Dilithiothiazolidine-2,4-dione | C3HLi2NO2S | 详情 | 详情 | |
| (VI) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 2-naphthalenethiol (I) with 2-methyleneglutaronitrile (II) followed by treatment first with concentrated hydrochloric acid and then with p-toluenesulfonic acid in methanol gives racemic acid, which is resolved into optically pure (R)-4-methoxycarbonyl-2-(2-naphthylthiomethyl)butyric acid (IV) by use of (R)-(+)-alpha-methylbenzylamine (III). The treatment of compound (IV), first with thionyl chloride and then with N-(3-methoxypropyl)-N-pentylamine (V), affords (R)-methyl 4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylthio)pentanoate (VI). Oxidation of compound (VI) with m-chloroperbenzoic acid followed by treatment with 1N sodium hydroxide gives (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl) pentanoic acid (VII), which is finally converted into KSG-504 by treatment with L-arginine.
| 【1】 Kitazawa, M.; Akahane, M.; Yamazaki, Y.; Kobayashi, M.; KSG-504. Drugs Fut 1995, 20, 5, 472. |
| 【2】 Kitazawa, M.; Akahane, M.; Nakano, Y.; Tsubaki, A.; Sato, K.; Ban, M.; Kobayashi, M. (Kissei Pharmaceutical Co., Ltd.); Napthylsulfonylalkanoic acid cpds. EP 0433064; JP 1991193756; JP 1991197453; JP 1992210956; US 5177069 . |
| 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) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
| (II) | 63962 | 2-methylenepentanedinitrile | C6H6N2 | 详情 | 详情 | |
| (III) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IV) | 15235 | (2R)-5-methoxy-2-[(2-naphthylsulfanyl)methyl]-5-oxopentanoic acid | C17H18O4S | 详情 | 详情 | |
| (V) | 12130 | N-(3-Methoxypropyl)-N-pentylamine; N-(3-Methoxypropyl)-1-pentanamine | C9H21NO | 详情 | 详情 | |
| (VI) | 15236 | methyl (4R)-5-[(3-methoxypropyl)(pentyl)amino]-4-[(2-naphthylsulfanyl)methyl]-5-oxopentanoate | C26H37NO4S | 详情 | 详情 | |
| (VII) | 15237 | (4R)-5-[(3-methoxypropyl)(pentyl)amino]-4-[(2-naphthylsulfonyl)methyl]-5-oxopentanoic acid | C25H35NO6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)2-Naphtalenethiol (I) was treated with ethyl 4-bromobutyrate (II) and NaH to give thioether (III). Alkylation of (III) with isobutyl iodide (IV) in the presence of LDA afforded racemic (V), which was then hydrolyzed to the acid (VI) on treatment with litium hydroxide. Coupling of racemic acid (VI) with (S)-leucinol (VII) yielded a mixture of diastereomeric amides, which were separated by column chromatography. Diastereoisomer (VIII) was oxidized with m-chloroperbenzoic acid to give sulfone (IX), and was further oxidized with DMSO and sulfur trioxide-pyridine complex to produce the target aldehyde.
| 【1】 Chatterjee, S.; et al.; Nonpeptidic inhibitors of recombinant human calpain; I. Bioorg Med Chem Lett 1997, 7, 3, 287-290. |
| 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) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 18167 | ethyl 4-(2-naphthylsulfanyl)butanoate | C16H18O2S | 详情 | 详情 | |
| (IV) | 18168 | 1-iodo-2-methylpropane | 513-38-2 | C4H9I | 详情 | 详情 |
| (V) | 18169 | ethyl 4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanoate | C20H26O2S | 详情 | 详情 | |
| (VI) | 18170 | 4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanoic acid | C18H22O2S | 详情 | 详情 | |
| (VII) | 18171 | L-(+)-leucinol; (S)-2-amino-4-methyl-1-pentanol; (2S)-2-amino-4-methyl-1-pentanol | 7533-40-6 | C6H15NO | 详情 | 详情 |
| (VIII) | 18172 | (2R)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanamide | C24H35NO2S | 详情 | 详情 | |
| (IX) | 18173 | (2R)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-methyl-2-[2-(2-naphthylsulfonyl)ethyl]pentanamide | C24H35NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)2,6-Diamino-4-hydroxypyrimidine (I) was cyclized with 1,3-dichloroacetone (II) in DMF at room temperature, and the resulting unstable furopyrimidine (III) was rapidly purified by a short column of silica gel and stored at -20 C. Then, the nucleophilic displacement reaction of chloride (III) with 2-naphthalenethiol (IV) in the presence of potassium carbonate in DMSO yielded the desired thioether.
| 【1】 Gangjee, A.; et al.; Selective Pneumocystis carinii dihydrofolate reductase inhibitors: Design, synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2, 3-d]pyrimidines. J Med Chem 1998, 41, 8, 1263. |
| 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) | 14811 | 2,4-Diamino-6-hydroxypyrimidine; 2,6-diamino-4-pyrimidinol | 56-06-4 | C4H6N4O | 详情 | 详情 |
| (II) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (III) | 18884 | 5-(chloromethyl)furo[2,3-d]pyrimidine-2,4-diamine; 2-amino-5-(chloromethyl)furo[2,3-d]pyrimidin-4-ylamine | C7H7ClN4O | 详情 | 详情 | |
| (IV) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The title compound was prepared starting from the phosphinic dipeptide (I). Deprotection of the tert-butyl ester of (I) under acidic conditions afforded the carboxylic acid (II). This was then coupled with tryptophan amide (III) using EDC and HOBt to produce (IV). Finally, conjugate addition of 2-naphthalenethiol (V) to (IV) in the presence of NaOEt furnished the target thioether.
| 【1】 Matziari, M.; Georgiadis, D.; Dive, V.; Yiotakis, A.; Convenient synthesis and diversification of dehydroalaninyl phosphinic peptide analogues. Org Lett 2001, 3, 5, 659. |
| 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) | 48204 | (1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl[2-(tert-butoxycarbonyl)-2-propenyl]phosphinic acid | C24H30NO6P | 详情 | 详情 | |
| (II) | 48205 | 2-[[((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)(hydroxy)phosphoryl]methyl]acrylic acid | C20H22NO6P | 详情 | 详情 | |
| (III) | 48206 | (2S)-2-amino-3-(1H-indol-3-yl)propanamide | C11H13N3O | 详情 | 详情 | |
| (IV) | 48207 | 2-([[(1S)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethyl]amino]carbonyl)-2-propenyl((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)phosphinic acid | C31H33N4O6P | 详情 | 详情 | |
| (V) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |