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【结 构 式】

【药物名称】CGP-75176

【化学名称】N-(Methoxycarbonyl)-L-tert-leucine N2-[2(S)-hydroxy-3(S)-[N-(methoxycarbonyl)-L-tert-leucylamino]-4-phenylbutyl]-N2-[4-(2-methyl-5-tetrazolyl)benzyl]hydrazide

【CA登记号】198904-13-1

【 分 子 式 】C35H51N9O7

【 分 子 量 】709.85282

【开发单位】Novartis (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1合成路线2合成路线3

合成路线1

Cycloaddition of sodium azide to 4-formylbenzonitrile (I) yielded tetrazole (II), which was protected with 2-phenylpropene (III) in the presence of methanesulfonic acid to give (IV). Subsequent condensation of (IV) with tert-butyl carbazate afforded hydrazone (V), which was further reduced to the benzylhydrazine (VI) employing NaBH3CN and p-toluenesulfonic acid. Opening of the trifluoroacetyl-protected epoxide (VII) with hydrazine (VI) gave hydrazinoalcohol (VIII). After hydrolysis of the trifluoroacetamide group of (VIII) with K2CO3, the resulting amine (IX) was coupled with N-methoxycarbonyl-L-tert-leucine (X) by means of EDC and HOBt to provide amide (XI).

参考文献 中间体
【1】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 .
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) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(II) 28449 4-(2H-1,2,3,4-tetraazol-5-yl)benzaldehyde 74815-22-8 C8H6N4O 详情 详情
(III) 28450 1-isopropenylbenzene 98-83-9 C9H10 详情 详情
(IV) 28451 4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzaldehyde C17H16N4O 详情 详情
(V) 28452 tert-butyl 2-((Z)-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]phenyl]methylidene)-1-hydrazinecarboxylate C22H26N6O2 详情 详情
(VI) 28453 tert-butyl 2-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate C22H28N6O2 详情 详情
(VII) 28454 2,2,2-trifluoro-N-[(1S)-1-[(2R)oxiranyl]-2-phenylethyl]acetamide C12H12F3NO2 详情 详情
(VIII) 28455 tert-butyl 2-[(2S,3S)-2-hydroxy-4-phenyl-3-[(2,2,2-trifluoroacetyl)amino]butyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate C34H40F3N7O4 详情 详情
(IX) 28456 tert-butyl 2-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate C32H41N7O3 详情 详情
(X) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
(XI) 28457 tert-butyl (5S,6S,9S)-6-benzyl-9-(tert-butyl)-5-hydroxy-3-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-8,11-dioxo-12-oxa-2,3,7,10-tetraazatridecan-1-oate C40H54N8O6 详情 详情

合成路线2

Deprotection of the Boc group of XI) by treatment with HCl furnished hydrazine (XII), which was coupled with N-methoxycarbonyl-L-tert-leucine (X) to afford bisamide (XIII). The alpha,alpha-dimethyl benzyl protecting group of (XIII) was then removed with 80% H2SO4, and the deprotected tetrazole (XIV) was finally alkylated with CH3I to provide the title compound.

参考文献 中间体
【1】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
(XI) 28457 tert-butyl (5S,6S,9S)-6-benzyl-9-(tert-butyl)-5-hydroxy-3-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-8,11-dioxo-12-oxa-2,3,7,10-tetraazatridecan-1-oate C40H54N8O6 详情 详情
(XII) 28458 methyl (1S)-1-([[(1S,2S)-1-benzyl-2-hydroxy-3-(1-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]hydrazino)propyl]amino]carbonyl)-2,2-dimethylpropylcarbamate C35H46N8O4 详情 详情
(XIII) 28459 methyl (1S,4S,5S,10S)-4-benzyl-1,10-di(tert-butyl)-5-hydroxy-7-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-2,9,12-trioxo-13-oxa-3,7,8,11-tetraazatetradec-1-ylcarbamate C43H59N9O7 详情 详情
(XIV) 28460 methyl (1S,4S,5S,10S)-4-benzyl-1,10-di(tert-butyl)-5-hydroxy-2,9,12-trioxo-7-[4-(2H-1,2,3,4-tetraazol-5-yl)benzyl]-13-oxa-3,7,8,11-tetraazatetradec-1-ylcarbamate C34H49N9O7 详情 详情

合成路线3

In a variation of this procedure, aryl tetrazole (II) was alkylated with ICH3 to provide methyltetrazole (XV). Condensation of (XV) with tert-butyl carbazate afforded hydrazone (XVI), which was reduced to the benzylhydrazine (XVII) by means of NaBH3CN and p-toluenesulfonic acid. Opening of the Boc-protected epoxide (XVIII) with hydrazine (XVII) gave hydrazinoalcohol (XIX). Acid deprotection of both Boc groups of (XIX) furnished diamino compound (XX), which was finally coupled with N-methoxycarbonyl-L-tert-leucine (X) by means of TPTU.

参考文献 中间体
【1】 New aza-dipeptide analogues as potent and orally a. J Med Chem 1998, 41, 18, 3387.
【2】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 28449 4-(2H-1,2,3,4-tetraazol-5-yl)benzaldehyde 74815-22-8 C8H6N4O 详情 详情
(X) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
(XV) 28461 4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzaldehyde C9H8N4O 详情 详情
(XVI) 28462 tert-butyl 2-[(Z)-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)phenyl]methylidene]-1-hydrazinecarboxylate C14H18N6O2 详情 详情
(XVII) 28463 tert-butyl 2-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzyl]-1-hydrazinecarboxylate C14H20N6O2 详情 详情
(XVIII) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(XIX) 28464 tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzyl]-1-hydrazinecarboxylate C29H41N7O5 详情 详情
(XX) 28465 (2S,3S)-3-amino-1-[1-[4-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)benzyl]hydrazino]-4-phenyl-2-butanol C19H25N7O 详情 详情
Extended Information