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【结 构 式】 
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【药物名称】Xyz-033mp 【化学名称】3(S)-[5-Benzyl-3-[2-methyl-1(S)-(1-naphthylcarboxamido)propyl]-4,5-dihydroisoxazol-5-ylcarboxamido]-5-(2,6-dichlorobenzoyloxy)-4-oxopentanoic acid 【CA登记号】331778-84-8 【 分 子 式 】C38H35Cl2N3O8 【 分 子 量 】732.62395 |
【开发单位】LG Chem (Originator) 【药理作用】GASTROINTESTINAL DRUGS, Hepatoprotectants, Liver and Biliary Tract Disorders, Treatment of, Apoptosis Inhibitors, Caspase Inhibitors |
合成路线1
Swern oxidation of N-Boc-S-valinol (I) provided aldehyde (II). After conversion of (II) to the corresponding oxime (III) upon treatment with hydroxylamine, chlorination with N-chlorosuccinimide gave the hydroximinoyl chloride (IV). Reaction of ethyl 2-(bromomethyl)acrylate (V) with phenyllithium (VI) in the presence of CuCN produced ethyl 2-benzylacrylate (VII). The dipolar cycloaddition of the nitrile oxide generated from (IV) to acrylate (VII) furnished the isoxazoline (VIII) as a diastereomeric mixture. The N-Boc protecting group of (VIII) was then cleaved with trifluoroacetic acid to give amine (IX), which was coupled with 2-naphthoic acid (X), yielding amide (XI). The carboxylic acid (XII), resulting from the basic hydrolysis of ethyl ester (XI), was then coupled with the glutamate ester (XIII) to give (XIV).
| 【1】 Chung, H.-H.; Park, M.-J.; Min, C.-H.; Kang, C.-Y.; Park, T.-K.; Chang, H.-K.; Lee, T.-H.; Moon, K.-Y.; Kim, E.E.-K.; Oh, Y.-L.; Kim, Y.-M. (LG Chem Ltd.); Caspase inhibitor. WO 0121599; WO 0121600 . |
| 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) | 48024 | tert-butyl (1S)-1-(hydroxymethyl)-2-methylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (II) | 47805 | tert-butyl (1S)-1-formyl-2-methylpropylcarbamate | C10H19NO3 | 详情 | 详情 | |
| (III) | 48025 | tert-butyl (1S)-1-[(hydroxyimino)methyl]-2-methylpropylcarbamate | C10H20N2O3 | 详情 | 详情 | |
| (IV) | 48026 | tert-butyl (1S)-1-[chloro(hydroxyimino)methyl]-2-methylpropylcarbamate | C10H19ClN2O3 | 详情 | 详情 | |
| (V) | 11328 | ethyl 2-(bromomethyl)acrylate | 17435-72-2 | C6H9BrO2 | 详情 | 详情 |
| (VI) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (VII) | 48027 | ethyl 2-benzylacrylate | C12H14O2 | 详情 | 详情 | |
| (VIII) | 48028 | ethyl 5-benzyl-3-[(1S)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-4,5-dihydro-5-isoxazolecarboxylate | C22H32N2O5 | 详情 | 详情 | |
| (IX) | 48029 | ethyl 3-[(1S)-1-amino-2-methylpropyl]-5-benzyl-4,5-dihydro-5-isoxazolecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (X) | 10106 | 1-Naphthoic acid | 86-55-5 | C11H8O2 | 详情 | 详情 |
| (XI) | 48030 | ethyl 5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolecarboxylate | C28H30N2O4 | 详情 | 详情 | |
| (XII) | 48031 | 5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolecarboxylic acid | C26H26N2O4 | 详情 | 详情 | |
| (XIII) | 48032 | 4-(tert-butyl) 1-methyl (2S)-2-aminobutanedioate | C9H17NO4 | 详情 | 详情 | |
| (XIV) | 48033 | 4-(tert-butyl) 1-methyl (2S)-2-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]butanedioate | C35H41N3O7 | 详情 | 详情 |
合成路线2
The methyl ester group of (XIV) was then hydrolyzed with NaOH, and the resulting carboxylic acid (XV) was activated as the mixed anhydride (XVI) with isobutyl chloroformate. Addition of diazomethane to anhydride (XVI) followed by treatment of the intermediate diazo ketone with HBr gave the bromo ketone (XVII). The bromide group of (XVII) was then displaced with 2,6-dichlorobenzoic acid (XVIII) to produce the dichlorobenzoate ester (XIX). The tert-butyl ester group of (XIX) was finally cleaved by treatment with trifluoroacetic acid.
| 【1】 Chung, H.-H.; Park, M.-J.; Min, C.-H.; Kang, C.-Y.; Park, T.-K.; Chang, H.-K.; Lee, T.-H.; Moon, K.-Y.; Kim, E.E.-K.; Oh, Y.-L.; Kim, Y.-M. (LG Chem Ltd.); Caspase inhibitor. WO 0121599; WO 0121600 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 48033 | 4-(tert-butyl) 1-methyl (2S)-2-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]butanedioate | C35H41N3O7 | 详情 | 详情 | |
| (XV) | 48034 | (2S)-2-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]-4-(tert-butoxy)-4-oxobutyric acid | C34H39N3O7 | 详情 | 详情 | |
| (XVI) | 48035 | C39H47N3O9 | 详情 | 详情 | ||
| (XVII) | 48036 | tert-butyl (3S)-3-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]-5-bromo-4-oxopentanoate | C35H40BrN3O6 | 详情 | 详情 | |
| (XVIII) | 41964 | 2,6-dichlorobenzoic acid | 50-30-6 | C7H4Cl2O2 | 详情 | 详情 |
| (XIX) | 48037 | (3S)-3-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]-5-(tert-butoxy)-2,5-dioxopentyl 2,6-dichlorobenzoate | C42H43Cl2N3O8 | 详情 | 详情 |