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【结 构 式】 
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【分子编号】18171 【品名】L-(+)-leucinol; (S)-2-amino-4-methyl-1-pentanol; (2S)-2-amino-4-methyl-1-pentanol 【CA登记号】7533-40-6 |
【 分 子 式 】C6H15NO 【 分 子 量 】117.19124 【元素组成】C 61.49% H 12.9% N 11.95% O 13.65% |
合成路线1
该中间体在本合成路线中的序号：(VII)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2
该中间体在本合成路线中的序号：(VI)The condensation of L-valine (I) with 4-fluorobenzenesulfonyl chloride (II) by means of NaOH in THF/water gives N-(4-fluorobenzenesulfonyl)-L-valine (III), which is esterified with N-hydroxysuccinimide (IV) by means of EDC in dichloromethane to yield the activated ester (V). The condensation of (V) with L-leucinol (VI) by means of TEA in dichloromethane affords the N-(4-fluorobenzenesulfonyl)-L-valyl-L-leucinol (VII), which is finally oxidized with the SO3/Pyridine complex in DMSO/dichloromethane to provide the target leucinal derivative.
| 【1】 Fukiage, C.; et al.; SJA6017, a newly synthesized peptide aldehyde inhibitor of calpain: amelioration of cataract in cultured rat lenses. Biochim Biophys Acta 1997, 1361, 3, 304. |
| 【2】 Fukiage, C.; Azuma, M.; Inoue, J.; Nakamura, M.; Yoshida, Y. (Senju Pharmaceuticals Co., Ltd.); Angiogenesis inhibitor. EP 0771565; EP 0927716; EP 0928786; JP 1998147564; JP 1998147566; JP 2001233847; US 6057290; US 6214800 . |
| 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) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (II) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |
| (III) | 57911 | (2S)-2-{[(4-fluorophenyl)sulfonyl]amino}-3-methylbutanoic acid | C11H14FNO4S | 详情 | 详情 | |
| (IV) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (V) | 57912 | N-((1S)-1-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-2-methylpropyl)-4-fluorobenzenesulfonamide | C15H17FN2O6S | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 57913 | (2S)-2-{[(4-fluorophenyl)sulfonyl]amino}-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-3-methylbutanamide | C17H27FN2O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Synthesis of the second synthon: L-Leucinol (V) was converted into the protected derivative (VI) by treatment with tert-butoxycarbonyl anhydride in methylene chloride. Oxidation of compound (VI) with NaOCl and TEMPO in the presence of sodium bromide yielded the aldehyde (VII). This aldehyde (VII), when treated with sodium bisulfite overnight at -5 to 0 C, produced the sodium bisulfite salt derivative (VIII), which was treated with KCN to obtain the nitrile derivative (IX). This nitrile derivative (IX) was heated under reflux with concentrated HCl, and after several crystallizations, afforded the desired amino acid (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid (X). Amino acid (X) was dissolved in a mixture of water/dioxane and then treated with tert-butoxycarbonyl anhydride in the presence of TEA to yield the Boc derivative (XI), which was converted into the mixture of methyl esters (XII) in a conventional manner. Compound (XII) was heated with 2,4-dimethoxybenzaldehyde dimethyl acetal in THF in the presence of pyridinium p-toluensulfonate as catalyst to obtain the acetal (XIII). When hydrolyzed with potassium carbonate in aqueous methanol, acetal (XIII) yielded (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyloxazolidine-5-carboxylic acid (XIV).
| 【1】 Laccabue, D.; Pratesi, G.; BAY 59-8862. Drugs Fut 2001, 26, 6, 533. |
| 【2】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 47545 | 1-(dimethoxymethyl)-2,4-dimethoxybenzene; 2-(dimethoxymethyl)-5-methoxyphenyl methyl ether | C11H16O4 | 详情 | 详情 | ||
| (V) | 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 |
| (VI) | 47540 | BOC-Leucinol; tert-butyl (1S)-1-(hydroxymethyl)-3-methylbutylcarbamate | 82010-31-9 | C11H23NO3 | 详情 | 详情 |
| (VII) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (VIII) | 47541 | sodium (2S)-2-[(tert-butoxycarbonyl)amino]-4-methyl-1-sulfo-1-pentanolate | C11H22NNaO6S | 详情 | 详情 | |
| (IX) | 47542 | tert-butyl (1S)-1-[cyano(hydroxy)methyl]-3-methylbutylcarbamate | C12H22N2O3 | 详情 | 详情 | |
| (X) | 47543 | (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid | C7H15NO3 | 详情 | 详情 | |
| (XI) | 47547 | (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid | C12H23NO5 | 详情 | 详情 | |
| (XII) | 47544 | methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoate | C13H25NO5 | 详情 | 详情 | |
| (XIII) | 47546 | 3-(tert-butyl) 5-methyl (4S,5R)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-3,5-dicarboxylate | C22H33NO7 | 详情 | 详情 | |
| (XIV) | 47538 | (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-5-carboxylic acid | C21H31NO7 | 详情 | 详情 |