L-732531, -Drug Synthesis Database

【结构式】

【药物名称】L-732531

【化学名称】[1R,9S,12S(1'R,3'R,4'R),13R,14S,17R,21S,23S,24R,25S,27R]-17-Ethyl-1,14-dihydroxy-12-[2-[4-[1-(2-hydroxyethyl)-1H-indol-5-yloxy]-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18(E)-ene-2,3,10,16-tetraone

【CA登记号】148365-48-4

【分子式】C₅₃H₇₈N₂O₁₃

【分子量】951.21821

【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1

Protection of 2-bromoethanol (I) upon treatment with 2-methoxypropene (II) gave a mixture of ketals (III) and (IV). This mixture was used for N-alkylation of 5-bromoindole (V) in the presence of KOH to afford, after ketal hydrolysis, 1-(2-hydroxyethyl)-5-bromoindole (VI) (1). Alternatively, compound (VI) was obtained by alkylation of 5-bromoindole (V) with ethylene oxide (VII) in the presence of NaOH in DMSO (2). The hydroxyl group of (VI) was then protected as the silyl ether (VII) by treatment with tert-butyldimethylsilyl chloride. Subsequent lithium-halogen exchange in (VIII) with tert-butyllithium, followed by reaction with bismuth trichloride provided the triindolyl bismuthane (IX) (1, 2). This was oxidized with either benzoyl peroxide (1) or peracetic acid (2) to produce the corresponding di(acyloxy) pentavalent bismuthanes (X).

参考文献中间体

【1】 Brands, K.M.J.; et al.; Mild aryl ether formation in the semisynthesis of the novel macrolide immunosuppressant L-732,531. J Org Chem 1998, 63, 19, 6721.
【2】 Sinclair, P.J.; Goulet, M.; Wong, F.; Parsons, W.H.; Goulet, J.; Wyvratt, M.J. (Merck & Co., Inc.); O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroaryl macrolides. EP 0532088; JP 1994116274; US 5252732; WO 9305058 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Xa)	26858	2-[5-(bis(acetoxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether		C₅₂H₇₈BiN₃O₇Si₃	详情	详情
(Xb)	26859	2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether		C₆₂H₈₂BiN₃O₇Si₃	详情	详情
(I)	10059	Ethylene bromohydrin; 2-Bromo-1-ethanol	540-51-2	C₂H₅BrO	详情	详情
(II)	17354	isopropenyl methyl ether; 2-methoxy-1-propene	116-11-0	C₄H₈O	详情	详情
(III)	26853	2-(2-bromoethoxy)-2-methoxypropane		C₆H₁₃BrO₂	详情	详情
(IV)	26854	1-(2-bromoethoxy)-1-methylethyl 2-bromoethyl ether		C₇H₁₄Br₂O₂	详情	详情
(V)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(VI)	26855	2-(5-bromo-1H-indol-1-yl)-1-ethanol		C₁₀H₁₀BrNO	详情	详情
(VII)	10393	Oxirane; Ethylene oxide	75-21-8	C₂H₄O	详情	详情
(VIII)	26856	2-(5-bromo-1H-indol-1-yl)ethyl tert-butyl(dimethyl)silyl ether		C₁₆H₂₄BrNOSi	详情	详情
(IX)	26857	2-(5-[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]bismuthino]-1H-indol-1-yl)ethyl tert-butyl(dimethyl)silyl ether		C₄₈H₇₂BiN₃O₃Si₃	详情	详情

合成路线2

Arylation of ascomycin (XI) with the pentavalent bismuthanes (X) under catalysis of cupric acetate produced a mixture of the required indolyl ether (XII) and minor amounts of bis(indolyl) ether (XIII). Finally, after desilylation of (XII) and (XIII) by acid treatment in MeOH, the title monoindolyl ether was isolated by column chromatography.

参考文献中间体

【1】 Brands, K.M.J.; et al.; Mild aryl ether formation in the semisynthesis of the novel macrolide immunosuppressant L-732,531. J Org Chem 1998, 63, 19, 6721.
【2】 Sinclair, P.J.; Goulet, M.; Wong, F.; Parsons, W.H.; Goulet, J.; Wyvratt, M.J. (Merck & Co., Inc.); O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroaryl macrolides. EP 0532088; JP 1994116274; US 5252732; WO 9305058 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Xa)	26858	2-[5-(bis(acetoxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether		C₅₂H₇₈BiN₃O₇Si₃	详情	详情
(Xb)	26859	2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether		C₆₂H₈₂BiN₃O₇Si₃	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)	26860	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-((1R,3R,4R)-4-[[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1,14-dihydroxy-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		C₅₉H₉₂N₂O₁₃Si	详情	详情
(XIII)	26861	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-14-[[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]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		C₇₅H₁₁₅N₃O₁₄Si₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)