-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-Ethyl-1,14-dihydroxy-23,25-dimethoxy-12-[2-[4(R)-[2(S)-hydroxy-2-(2-naphthyl)ethoxy]-3(R)-methoxycyclohex-1(R)-yl]-1(E)-methylvinyl]-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone

【CA登记号】160583-67-5 (non-specified steroch.)

【分子式】C₅₅H₇₉NO₁₃

【分子量】962.24178

【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1

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

【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2

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.

参考文献中间体

【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	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

合成路线3

The condensation of the 32-OH of ascomycin (I) with the diazoketone (II) by means of a Rh catalyst gives the addition product (III), which is silylated at the 24-OH with TES-Cl yielding the silyl ether (IV). The reduction of the new carbonyl group of (IV) with the chiral reducing agent (S)-OAB/BH3 and TEA affords the silylated target compound (V), which is finally treated with HCl to eliminate the TES- group.

参考文献中间体

【1】 Nelson, T.D.; et al.; Rhodium-carbenoid-mediated intermolecular O-H insertion reactions: A dramatic additive effect. Application in the synthesis of an ascomycin derivative. Tetrahedron Lett 2000, 41, 12, 1877.

中间体序号	中间体编号	品名	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)	38024	2-diazo-1-(2-naphthyl)-1-ethanone	C₁₂H₈N₂O	详情	详情
(III)	38025		C₅₅H₇₇NO₁₃	详情	详情
(IV)	38026		C₆₁H₉₁NO₁₃Si	详情	详情
(V)	38027		C₆₁H₉₃NO₁₃Si	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)