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【结 构 式】 
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【分子编号】17634 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine 【CA登记号】2488-15-5 |
【 分 子 式 】C10H19NO4S 【 分 子 量 】249.3312 【元素组成】C 48.17% H 7.68% N 5.62% O 25.67% S 12.86% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 4-aminobenzamide (I) with N-(tert-butoxycarbonyl)-L-methionine (II) by means of 2-chloro-1-methylpyridinium iodide (CMPI) and N-methylmorpholine (NMM) in DMF gives the corresponding methioninamide (III), which is cyclized by means of trimethylsulfonium iodide and K2CO3 in hot DMSO yielding the pyrrolidinone (IV). The dehydration of (IV) with trifluoroacetic anhydride in THF affords the corresponding nitrile (V), which is deprotected with dry HCl in ethyl acetate giving the amine (VI). The condensation of (VI) with beta-alanine ethyl ester (VII) and carbonyl diimidazole (CDI) in pyridine yields the substituted urea (VIII), which is treated with hydroxylamine hydrochloride and triethylamine in ethyl acetate to afford the N-hydroxybenzamidine (IX). Finally, this compound is hydrogenated with H2 over Pd/C in acetic acid.
| 【1】 Castañer, J.; Merlos, M.; Leeson, P.A.; Orbofiban Acetate. Drugs Fut 1998, 23, 11, 1190-1198. |
| 【2】 Abood, N.A.; Flynn, D.L.; Laneman, S.A.; Nosal, R.; Schretzman, L.A. (Pharmacia Corp.); Process for the preparation of amidino phenyl pyrrolidine betal-alanine urea analogs. US 5484946 . |
| 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) | 16778 | 4-aminobenzamide; p-aminobenzamide | 2835-68-9 | C7H8N2O | 详情 | 详情 |
| (II) | 17634 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine | 2488-15-5 | C10H19NO4S | 详情 | 详情 |
| (III) | 17635 | tert-butyl (1S)-1-[[4-(aminocarbonyl)anilino]carbonyl]-3-(methylsulfanyl)propylcarbamate | C17H25N3O4S | 详情 | 详情 | |
| (IV) | 17636 | tert-butyl (3S)-1-[4-(aminocarbonyl)phenyl]-2-oxopyrrolidinylcarbamate | C16H21N3O4 | 详情 | 详情 | |
| (V) | 17637 | tert-butyl (3S)-1-(4-cyanophenyl)-2-oxopyrrolidinylcarbamate | C16H19N3O3 | 详情 | 详情 | |
| (VI) | 17638 | 4-[(3S)-3-amino-2-oxopyrrolidinyl]benzonitrile | C11H11N3O | 详情 | 详情 | |
| (VII) | 17639 | beta-Alanine, ethyl ester; ethyl 3-aminopropanoate | 924-73-2 | C5H11NO2 | 详情 | 详情 |
| (VIII) | 17640 | ethyl 3-[([[(3S)-1-(4-cyanophenyl)-2-oxopyrrolidinyl]amino]carbonyl)amino]propanoate | C17H20N4O4 | 详情 | 详情 | |
| (IX) | 17641 | ethyl 3-([[((3S)-1-[4-[amino(hydroxyimino)methyl]phenyl]-2-oxopyrrolidinyl)amino]carbonyl]amino)propanoate | C17H23N5O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)N-(tert-Butoxycarbonyl)-L-methionine (I) was converted to mixed anhydride (III) upon treatment with isobutyl chloroformate (II). Subsequent condensation of (III) with hydroxylamine gave hydroxamic acid (IV). Finally, the Boc group was cleared with trifluoroacetic acid in anisole to furnish the target methionine hydroxamate).
| 【1】 Lee, J.; Kang, M.K.; Chun, M.W.; Jo, Y.J.; Kwak, J.H.; Kim, S.; Methionine analogues as inhibitors of methionyl-tRNA synthetase. Bioorg Med Chem Lett 1998, 8, 24, 3511. |
| 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) | 17634 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine | 2488-15-5 | C10H19NO4S | 详情 | 详情 |
| (II) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (III) | 20090 | N-(Tert-butoxycarbonyl)-L-methionine isobutoxycarbonyl anhydride | C15H27NO6S | 详情 | 详情 | |
| (IV) | 20091 | tert-butyl (1S)-1-[(hydroxyamino)carbonyl]-3-(methylsulfanyl)propylcarbamate | C10H20N2O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Coupling of N-Boc-L-methionine (VIII) with 3-chlorobenzylamine (IX) using PyBOP provided amide (X). Methylation of the sulfide group of (X) with iodomethane gave rise to the sulfonium salt (XI), which was further cyclized to pyrrolidinone (XII) by treatment with lithium bis(trimethylsilyl)amide in cold THF. Acid deprotection of the Boc group of (XII) furnished amine (XIII). This was finally subjected to reductive alkylation with aldehyde (VII) in the presence of sodium cyanoborohydride to provide the corresponding (imidazolylmethyl)amine.
| 【1】 Bell, I.M.; et al.; Design and biological activity of (S)-4-(5-{[1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency. J Med Chem 2001, 44, 18, 2933. |
| 【2】 Beshore, D.C.; Bell, I.M.; Gallicchio, S.N.; Sisko, J.T.; Zartman, C.B.; Lumma, W.C. Jr. (Merck & Co., Inc.); Inhibitors of prenyl-protein transferase. WO 0117992 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (VIII) | 34459 | (3-chlorophenyl)methanamine; 3-chlorobenzylamine | 4152-90-3 | C7H8ClN | 详情 | 详情 |
| (IX) | 17634 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine | 2488-15-5 | C10H19NO4S | 详情 | 详情 |
| (X) | 49995 | tert-butyl (1S)-1-[[(3-chlorobenzyl)amino]carbonyl]-3-(methylsulfanyl)propylcarbamate | C17H25ClN2O3S | 详情 | 详情 | |
| (XI) | 49996 | [(3S)-3-[(tert-butoxycarbonyl)amino]-4-[(3-chlorobenzyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide | C18H28ClIN2O3S | 详情 | 详情 | |
| (XII) | 49997 | tert-butyl (3S)-1-(3-chlorobenzyl)-2-oxopyrrolidinylcarbamate | C16H21ClN2O3 | 详情 | 详情 | |
| (XIII) | 49998 | (3S)-3-amino-1-(3-chlorobenzyl)-2-pyrrolidinone | C11H13ClN2O | 详情 | 详情 |