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【结 构 式】 
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【药物名称】OM-99-1 【化学名称】L-Valyl-L-asparaginyl-L-leucyl-psi[(S)-CH(OH)CH2]-L-alanyl-L-alanyl-L-glutamyl-L-phenylalanine 【CA登记号】271601-63-9 【 分 子 式 】C36H57N7O11 【 分 子 量 】763.89599 |
【开发单位】University of Illinois (Originator), University of Oklahoma Health Sci. Cent. (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, beta-Secretase (BACE) Inhibitors |
合成路线1
Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |
合成路线2
Preparation of the title compound was carried out by solid-phase peptide synthesis, starting from Wang resin bounded to N-Fmoc-phenylalanine (XII). Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII), which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt). Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV). Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI), intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII), (XVIII) and (XX), respectively. (Scheme 28685901b).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 | |
| (XII) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (XIII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XIV) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (XV) | 40634 | (2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid | C18H26N2O5 | 详情 | 详情 | |
| (XVI) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (XVII) | 40635 | (2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid | C21H31N3O6 | 详情 | 详情 | |
| (XVIII) | 40636 | (5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid | C37H64N4O8Si | 详情 | 详情 | |
| (XIX) | 40637 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid | C38H32N2O5 | 详情 | 详情 | |
| (XX) | 40638 | (5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid | C60H84N6O10Si | 详情 | 详情 |
合成路线3
Coupling-deprotection cycle with N-Fmoc-valine (XXI) furnished the peptide resin (XXII). Finally, removal of the side-chain protecting groups and cleavage from the resin by means of 95% trifluoroacetic acid yielded the title compound (Scheme 28685901c).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 40638 | (5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid | C60H84N6O10Si | 详情 | 详情 | |
| (XXI) | 19932 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid | C20H21NO4 | 详情 | 详情 | |
| (XXII) | 40639 | (2S,5S,8S,11R,13S,14S,17S,20S)-20-amino-2-benzyl-5-[3-(tert-butoxy)-3-oxopropyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-14-isobutyl-8,11,21-trimethyl-4,7,10,16,19-pentaoxo-17-[2-oxo-2-(tritylamino)ethyl]-3,6,9,15,18-pentaazadocosan-1-oic acid | C65H93N7O11Si | 详情 | 详情 |