allyl 2,2,2-trichloroethanimidoate -Drug Synthesis Database

【结构式】

【分子编号】22755

【品名】allyl 2,2,2-trichloroethanimidoate

【CA登记号】51479-73-3

【分子式】C₅H₆Cl₃NO

【分子量】202.46688

【元素组成】C 29.66% H 2.99% Cl 52.53% N 6.92% O 7.9%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XIX)

The carbinol intermediate (XV) has also been obtained as follows: Alkylation of 4-(tert-butyldiphenylsilyloxy)-3(S)-hydroxybutyric acid methyl ester (XVIII) with allyl trichloroacetylimidate (XIX) and trifluoromethanesulfonic acid gives the allyl ether (XX), which is reduced with DIBAL in toluene to afford the alcohol (XXI). Ozonolysis of (XXI) with O3 in methanol provides the hydroxyaldehyde (XXII), which is reduced with NaBH4 in methanol, giving diol (XXIII). Reaction of (XXIII) with MsCl and TEA in ether yields the dimesylate (XXIV), which is treated with NaI in hot acetone to provide the diiodide (XXV). Cyclization of (XXV) with 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XI) by means of Cs2CO3 in DMF gives the hexacyclic compound (XXVI), which is demethylated as before by reaction with KOH in refluxing ethanol to the hexacyclic furan derivative (XXVII) and then treated with HMDS in hot methanol to give the demethylated pyrrole derivative (XXVIII). Finally, this compound is desilylated with HCl to the carbinol (XV).

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026.
【2】 Jirousek, M.R.; Gillig, J.R.; Gonzalez, C.M.; et al.; (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and related analogues: Isozyme selective inhibitors of protein kinase Cbeta. J Med Chem 1996, 39, 14, 2664.
【3】 Heath, W.F. Jr.; Jirousek, M.R.; McDonald, J.H. III; Rito, C.J. (Eli Lilly and Company); Protein kinase C inhibitors. CA 2137203; EP 0657458; JP 1995238044; US 5624949 .

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)	41012	3,4-di(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione	113963-68-1	C₂₁H₁₅N₃O₂	详情	详情
(XV)	41013	(18S)-18-(hydroxymethyl)-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione		C₂₆H₂₃N₃O₄	详情	详情
(XVIII)	41019	methyl (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxybutanoate		C₂₁H₂₈O₄Si	详情	详情
(XIX)	22755	allyl 2,2,2-trichloroethanimidoate	51479-73-3	C₅H₆Cl₃NO	详情	详情
(XX)	41020	methyl (3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]butanoate		C₂₄H₃₂O₄Si	详情	详情
(XXI)	41021	(3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-1-butanol		C₂₃H₃₂O₃Si	详情	详情
(XXII)	41022	2-[[(1S)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-hydroxypropyl]oxy]acetaldehyde		C₂₂H₃₀O₄Si	详情	详情
(XXIII)	41023	(3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-(2-hydroxyethoxy)-1-butanol		C₂₂H₃₂O₄Si	详情	详情
(XXIV)	41024	(3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-[2-[(methylsulfonyl)oxy]ethoxy]butyl methanesulfonate		C₂₄H₃₆O₈S₂Si	详情	详情
(XXV)	41025	tert-butyl(diphenyl)silyl (2S)-4-iodo-2-(2-iodoethoxy)butyl ether; tert-butyl[[(2S)-4-iodo-2-(2-iodoethoxy)butyl]oxy]diphenylsilane		C₂₂H₃₀I₂O₂Si	详情	详情
(XXVI)	41026	(18S)-18-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-methyl-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione		C₄₃H₄₃N₃O₄Si	详情	详情
(XXVII)	41027	(18S)-18-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4,17-dioxa-14,21-diazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione		C₄₂H₄₀N₂O₅Si	详情	详情
(XXVIII)	41028	(18S)-18-([[tert-butyl(diphenyl)silyl]oxy]methyl)-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione		C₄₂H₄₁N₃O₄Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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3

该中间体在本合成路线中的序号：(IV)

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).

参考文献中间体

合成目标

【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

Extended Information