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【结 构 式】

【分子编号】22758

【品名】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

【CA登记号】

【 分 子 式 】C51H85NO13Si

【 分 子 量 】948.32034

【元素组成】C 64.59% H 9.03% N 1.48% O 21.93% Si 2.96%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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).

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

该中间体在本合成路线中的序号:(VII)

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.

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

该中间体在本合成路线中的序号:(VII)

Protection of ascomycin (I) by means of tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of 2,6-lutidine provided the 14,4''-disilylated derivative (II). Selective removal of the 4''-silyl group of (II) with para-toluenesulfonic acid in MeOH-CH2Cl2 yielded the 14-protected compound (III). This was converted to allyl ether (V) upon treatment with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid. Dihydroxylation of the allyl double bond of (V) with OsO4 and N-methylmorpholine-N-oxide, followed by oxidative cleavage of the resulting diol (VI) with sodium metaperiodate furnished aldehyde (VII).

1 Sinclair, P.J.; Goulet, J.; Wong, F.; Goulet, M.; Parsons, W.H.; Wyvratt, Matthew, J.; O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity. US 5349061 .
2 Sinclair, P.J.; Organ, H.M.; Wong, F.; Goulet, M.; Parsons, W.H.; Wyvratt, Matthew, J.; O-Aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity. US 5565560 .
3 Wong, F.; Holmes, M.A.; Armstrong, H.M.; et al.; Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity. Bioorg Med Chem Lett 1999, 9, 14, 2089-94.
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) 33687 (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4

该中间体在本合成路线中的序号:(VII)

Addition of 2-naphthylmagnesium bromide (VIII) produced the corresponding carbinol as a diastereomeric mixture, from which the required isomer (IX) was isolated by preparative TLC. Finally, the silyl protecting group was cleaved by treatment with HF in pyridine.

1 Sinclair, P.J.; Organ, H.M.; Wong, F.; Goulet, M.; Parsons, W.H.; Wyvratt, Matthew, J.; O-Aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity. US 5565560 .
2 Sinclair, P.J.; Goulet, J.; Wong, F.; Goulet, M.; Parsons, W.H.; Wyvratt, Matthew, J.; O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity. US 5349061 .
3 Wong, F.; Holmes, M.A.; Armstrong, H.M.; et al.; Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity. Bioorg Med Chem Lett 1999, 9, 14, 2089-94.
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) 33688 bromo(2-naphthyl)magnesium C10H7BrMg 详情 详情
(IX) 33689 (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-[[(2S)-2-hydroxy-2-(2-naphthyl)ethyl]oxy]-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 C61H93NO13Si 详情 详情
Extended Information