(3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-1-butanol -Drug Synthesis Database

【结构式】

【分子编号】41021

【品名】(3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-1-butanol

【CA登记号】

【分子式】C₂₃H₃₂O₃Si

【分子量】384.59078

【元素组成】C 71.83% H 8.39% O 12.48% Si 7.3%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIX)

Alternatively, compound (XV) can also be obtained as follows: Reduction of (S)-maleate (XVI) with BMS-NaBH4 in THF, followed by O-protection with TBDPS-Cl and imidazole, yields alcohol (XVII), which is first allylated with allyl trichloroacetimidate (XVIII) catalyzed by triflic acid in cyclohexanes and then reduced with DIBAL in THF to provide compound (XIX). Ozonolysis of (XIX) in MeOH, followed by reductive quench with NaBH4, gives diol (XX), which is then converted into bismesylate (XXI) by treatment with MsCl and Et3N in ether. Compound (XXI) is subjected to a double Finkelstein reaction with NaI in acetone in the presence of NaHCO3 to yield bisiodide (XXII) (1), which is then coupled with 3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) by means of Cs2CO3 in DMF to give intermediate (XV).

参考文献中间体

合成目标

【1】 Engel, G.L.; Farid, N.A.; Faul, M.M.; Jirousek, M.R.; Richardson, L.A.; Winneroski, L.L. Jr. (Eli Lilly and Company); Protein kinase C inhibitor. EP 0776895; JP 1999500149; US 5710145; WO 9718809 .

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)	41016	(18S)-4-methyl-18-[(trityloxy)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		C₄₆H₃₉N₃O₄	详情	详情
(XVI)	11806	dimethyl (2S)-2-hydroxybutanedioate	617-55-0	C₆H₁₀O₅	详情	详情
(XVII)	41019	methyl (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxybutanoate		C₂₁H₂₈O₄Si	详情	详情
(XVIII)	51944	N-(trichloromethyl)-3-butenamide		C₅H₆Cl₃NO	详情	详情
(XIX)	41021	(3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-1-butanol		C₂₃H₃₂O₃Si	详情	详情
(XX)	41023	(3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-(2-hydroxyethoxy)-1-butanol		C₂₂H₃₂O₄Si	详情	详情
(XXI)	51948	(7S)-2,11,11-trimethyl-7-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)-2-methylene-10,10-diphenyl-3,6,9-trioxa-2lambda(6)-thia-10-sila-1-dodecene; tert-butyl(diphenyl)silyl (2S)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethoxy)butyl ether		C₂₈H₄₄O₄S₂Si	详情	详情
(XXII)	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

合成路线2

该中间体在本合成路线中的序号：(XXI)

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

Extended Information