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【结 构 式】

【药物名称】OM-99-2

【化学名称】L-Glutamyl-L-valyl-L-asparaginyl-L-leucyl-psi[(S)-CH(OH)CH2]-L-alanyl-L-alanyl-L-glutamyl-L-phenylalanine
　　　　　　L-Glutamyl-L-valyl-L-asparaginyl-(2R,4S,5S)-5-amino-4-hydroxy-2,7-dimethyloctanoyl-L-alanyl-L-glutamyl-L-phenylalanine

【CA登记号】

【 分 子 式 】C41H64N8O14

【 分 子 量 】893.01243

【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合成路线2合成路线3

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).

参考文献 中间体
【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), (XX), (XXII) and (XXIII), respectively. (Scheme 28686001b).

参考文献 中间体
【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

Sequential coupling-deprotection cycles with N- N-Fmoc-valine (XXI), and N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) furnished the peptide resins (XXII) and (XXIII), respectively. Finally, removal of the side-chain protecting groups and cleavage from the resin by means of 95% trifluoroacetic acid yielded the title compound.) (Scheme 28686001c)

参考文献 中间体
【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
(XIV) 22258 (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid 104091-08-9 C24H27NO6 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
(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
(XXIII) 40640 　 C74H108N8O14Si 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)