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【结 构 式】

【药物名称】L-733725

【化学名称】[3S-[3*R[E(1S*,3S*4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-3-[2-[4-[4-(3,5-Dimethoxyphenyl)-1H-imidazol-2-ylmethoxy]-3-methoxycyclohexyl]-1-methylethenyl]-8-ethyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetraone

【CA登记号】150250-95-6

【 分 子 式 】C55H81N3O14

【 分 子 量 】1008.27052

【开发单位】Merck & Co. (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6

合成路线1

Ascomycin (I) was protected as the C24,C32-bis(tert-butyldimethyl- silyl)ether (II), and then was selectively desilylated at the C32 position with p-toluenesulfonic acid in MeOH-CH2Cl2. The resulting monosilylated compound (III) was treated with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid to provide the C32 allyl ether (V). Subsequent dihydroxylation of the allyl group of (V) using N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 afforded glycol (VI), and further oxidative cleavage of (VI) with sodium metaperiodate produced aldehyde (VII).

参考文献 中间体
【1】 Goulet, M.; Wyvratt, M.J.; Sinclair, P.J.; Wong, F. (Merck & Co., Inc.); Imidazolidyl macrolides having immunosuppressive activity. EP 0536896; JP 1994510303; US 5247076; WO 9305059 .
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) 14951 (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron C43H69NO12 详情 详情
(II) 22753 (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone C55H97NO12Si2 详情 详情
(III) 22754 (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone C49H83NO12Si 详情 详情
(IV) 22755 allyl 2,2,2-trichloroethanimidoate 51479-73-3 C5H6Cl3NO 详情 详情
(V) 22756 (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4R)-4-(allyloxy)-3-methoxycyclohexyl]-1-methylethenyl]-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone C52H87NO12Si 详情 详情
(VI) 22757 (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-[(1R,3R,4R)-4-(2,3-dihydroxypropoxy)-3-methoxycyclohexyl]-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone C52H89NO14Si 详情 详情
(VII) 22758 2-([(1R,2R,4R)-4-[(E)-2-((1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-en-12-yl)-1-propenyl]-2-methoxycyclohexyl]oxy)acetaldehyde C51H85NO13Si 详情 详情

合成路线2

The aryl imidazole (IX) was then constructed by cyclization of (VII) with 3,5-dimethoxyphenylglyoxal (VIII) and ammonia in MeOH yielding (IX). Finally, the title compound was obtained by desilylation of (IX) with HF in pyridine-THF.

参考文献 中间体
【1】 Goulet, M.T.; McAlpine, S.R.; Staruch, M.J.; Koprak, S.; Dumont, F.J.; Cryan, J.G.; Wiederrecht, G.J.; Rosa, R.; Wilusz, M.B.; Peterson, L.B.; Wyvratt, M.J.; Parsons, W.H..; C32-O-imidazol-2-yl-methyl ether derivatives of the immunosuppressant ascomycin with improved therapeutic potential. Bioorg Med Chem Lett 1998, 8, 16, 2253.
【2】 Goulet, M.; Wyvratt, M.J.; Sinclair, P.J.; Wong, F. (Merck & Co., Inc.); Imidazolidyl macrolides having immunosuppressive activity. EP 0536896; JP 1994510303; US 5247076; WO 9305059 .
【3】 Sinclair, P.J.; Wong, F.; Wyvratt, M.J.; Goulet, M. (Merck & Co., Inc.); Imidazolidyl macrolides having immunosuppressive activity. US 5344925 .
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) 22758 2-([(1R,2R,4R)-4-[(E)-2-((1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-en-12-yl)-1-propenyl]-2-methoxycyclohexyl]oxy)acetaldehyde C51H85NO13Si 详情 详情
(VIII) 22759 1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone C10H12O5 详情 详情
(IX) 22760 (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[5-(3,5-dimethoxyphenyl)-1H-imidazol-2-yl]methoxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone C61H95N3O14Si 详情 详情

合成路线3

In a further procedure, 3,5-dimethoxybenzoic acid (X) was converted to the acetophenone (XI) using methyllithium. Treatment of (XI) with phenyltrimethylammonium tribromide provided the dibromoacetophenone (XII) which, upon reaction with morpholine at 55 C, followed by hydrolysis with aqueous HCl, gave the phenylglyoxal (VIII). Alternatively, (VIII) was prepared directly by treating acetophenone (XI) with DMSO and HBr or by oxidation with SeO2. Condensation of the phenylglyoxal (VIII) with methyl glyoxylate hemiacetal (XIII) and ammonium acetate produced the phenylimidazole (XIV), which was protected as the tetrahydrofuranyl derivative (XVI) with dihydrofuran and catalytic p-TsOH. Reduction of the protected imidazole ester (XVI) with LiBH4 provided alcohol (XVII), and then reaction of (XVII) with trichloroacetonitrile in the presence of DBU furnished the acetimidate (XVIII). Finally, the target compound was obtained by reaction of ascomycin (I) with trichloroacetimidate (XVIII) in the presence of fluoboric acid etherate, followed by hydrolytic deprotection.

参考文献 中间体
【1】 Mathre, D.J.; Sohar, P.; Shuman, R.F.; Song, Z. (Merck & Co., Inc.); Process for the preparation of imidazolyl macrolide immunosuppressants. JP 1999512096; US 5777105; WO 9708182 .
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) 14951 (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron C43H69NO12 详情 详情
(VIII) 22759 1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone C10H12O5 详情 详情
(X) 22761 3,5-dimethoxybenzoic acid 1132-21-4 C9H10O4 详情 详情
(XI) 22762 1-(3,5-dimethoxyphenyl)-1-ethanone 39151-19-4 C10H12O3 详情 详情
(XII) 22763 2,2-dibromo-1-(3,5-dimethoxyphenyl)-1-ethanone C10H10Br2O3 详情 详情
(XIII) 22764 methyl 2-hydroxy-2-methoxyacetate 19757-97-2 C4H8O4 详情 详情
(XIV) 22765 methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate C13H14N2O4 详情 详情
(XV) 22766 2,3-dihydrofuran 1191-99-7 C4H6O 详情 详情
(XVI) 22767 methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate C17H20N2O5 详情 详情
(XVI) 22768 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol C16H20N2O4 详情 详情
(XVIII) 22769 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate C18H20Cl3N3O4 详情 详情

合成路线4

The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylate hemiacetal (II) and ammonium acetate in acetonitrile gives the imidazole derivative (III), which is protected with dihydrofuran (IV) and TsOH, yielding compound (V). The reduction of the ester group of (V) with LiBH4 affords the carbinol (VI), which is esterified with trichloroacetonitrile (VII) to provide the trichloroacetimidate (VIII). The condensation of (VIII) with ascomycin (IX) by means of CF3SO3H in N,N-dimethylpivalamide gives the adduct (X), which is finally deprotected with hot aqueous CF3SO3H.

参考文献 中间体
【1】 Song, Z.; et al.; Highly chemoselective trichloroacetimidate-mediated alkylation of ascomycin: A convergent, practical synthesis of the immunosuppressant L-733,725. J Org Chem 1999, 64, 6, 1859.
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) 22759 1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone C10H12O5 详情 详情
(II) 22764 methyl 2-hydroxy-2-methoxyacetate 19757-97-2 C4H8O4 详情 详情
(III) 22765 methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate C13H14N2O4 详情 详情
(IV) 22766 2,3-dihydrofuran 1191-99-7 C4H6O 详情 详情
(V) 22767 methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate C17H20N2O5 详情 详情
(VI) 22768 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol C16H20N2O4 详情 详情
(VII) 42279 2,2,2-trichloroacetonitrile; Trichloromethylcyanide 545-06-2 C2Cl3N 详情 详情
(VIII) 22769 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate C18H20Cl3N3O4 详情 详情
(IX) 14951 (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron C43H69NO12 详情 详情
(X) 42280 (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-((1R,3R,4R)-4-[[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methoxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,2 C59H87N3O15 详情 详情

合成路线5

The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylic acid (II) and ammonium acetate in acetonitrile gives the aryl imidazole (III), which is protected with dihydrofuran (IV) and Ts-OH, yielding compound (V). The regioselective lithiation of (V) with n-BuLi, followed by reaction with labeled 14CO2 provides the carboxylic acid (VI), which is esterified with MeI and CaO in DMSO to furnish the methyl ester (VII). The reduction of the ester group of (VII) with LiBH4 affords the carbinol (VIII), which is esterified with trichloroacetonitrile (IX) to provide the trichloroacetimidate (X).

参考文献 中间体
【1】 Egan, M.A.M.; et al.; Carbon-14 labeling of a potential new immunoregulant agent. J Label Compd Radiopharm 2000, 43, 11, 1095.
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) 22759 1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone C10H12O5 详情 详情
(II) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(III) 42281 4-(3,5-dimethoxyphenyl)-1H-imidazole; 3-(1H-imidazol-4-yl)-5-methoxyphenyl methyl ether C11H12N2O2 详情 详情
(IV) 22766 2,3-dihydrofuran 1191-99-7 C4H6O 详情 详情
(V) 42282 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole; 3-methoxy-5-(1-tetrahydro-2-furanyl-1H-imidazol-4-yl)phenyl methyl ether C15H18N2O3 详情 详情
(VI) 42283 lithium 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate C16H17LiN2O5 详情 详情
(VI) 45345 lithium 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate C16H17LiN2O5 详情 详情
(VII) 22767 methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate C17H20N2O5 详情 详情
(VII) 45346 methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate C17H20N2O5 详情 详情
(VIII) 22768 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol C16H20N2O4 详情 详情
(VIII) 45347 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol C16H20N2O4 详情 详情
(IX) 42279 2,2,2-trichloroacetonitrile; Trichloromethylcyanide 545-06-2 C2Cl3N 详情 详情
(X) 22769 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate C18H20Cl3N3O4 详情 详情

合成路线6

The condensation of (X) with ascomycin (XI) by means of CF3SO3H in N,N-dimethylpivalamide gives the adduct (X), which is finally deprotected with hot aqueous CF3SO3H.

参考文献 中间体
【1】 Egan, M.A.M.; et al.; Carbon-14 labeling of a potential new immunoregulant agent. J Label Compd Radiopharm 2000, 43, 11, 1095.
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) 22769 [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate C18H20Cl3N3O4 详情 详情
(XI) 14591 2-Amino-1,3,4-thiadiazole; 1,3,4-Thiadiazol-2-amine; 1,3,4-Thiadiazol-2-ylamine 4005-51-0 C2H3N3S 详情 详情
(XII) 42280 (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-((1R,3R,4R)-4-[[4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methoxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,2 C59H87N3O15 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)