Pimecrolimus, ASM-998, ASM-981, SDZ-ASM-981, Elidel, -Drug Synthesis Database

【结构式】

【药物名称】Pimecrolimus, ASM-998, ASM-981, SDZ-ASM-981, Elidel

【化学名称】[1R,9S,12S(1'R,3'R,4'S),13R,14S,17R,21S,23S,24R,25S,27R]-12-[2-(4-Chloro-3-methoxycyclohexyl)-1(E)-methylvinyl]-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(E)-ene-2,3,10,16-tetraone
　　　　　　[3S(1'R,3'R,4'S),4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS]-3-[2-(4-Chloro-3-methoxycyclohexyl)-1(E)-methylvinyl]-15,19-epoxy-8-ethyl-15,19-dihydroxy-14,16-dimethoxy-4,10,12,18-tetramethyl-1,4,5,6,7,8,11,12,13,14,15,16,17,18,19,20,21,23,24,25,26,26a-docosahydro-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21-tetraone

【CA登记号】137071-32-0

【分子式】C₄₃H₆₈ClNO₁₁

【分子量】810.47451

【开发单位】Novartis (Originator)

【药理作用】Asthma Therapy, Atopic Dermatitis, Agents for, Dermatologic Drugs, OCULAR MEDICATIONS, Ophthalmic Drugs, RESPIRATORY DRUGS, Cytokine Production Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

参考文献中间体

【1】 Gyollai V, Szabo C 2006. Methods for preparing pimecmlimus. W0 2006060614

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

合成路线2

参考文献中间体

【1】 Grassberger M, Horvath A. 2006. Process for the preparation of heteroatoms-containing tricyclic ascomycin analogs. W0 2006040111

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

合成路线3

参考文献中间体

【1】 Bulusu MARC, Waldstatten P．Schuk G．et al. 2004. Novel analoges of ascomycin with modification in the amino acid unit through photochemistry: the synthesis of 5,6-dehydroascomycin, SDZ ASQ 871. Tetrahedron Lett, 45: 2523～2526

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

合成路线4

The silylation of the known compound FK-520 by means of tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the disilylated compound (II), which is selectively monodesilylated by means of 40% HF in acetonitrile for 2 h at 0 C yielding the monosilylated compound (III). The chlorination of (III) by means of triphenylphosphine in refluxing CCl4 gives the chloro derivative (IV), which is finally desilylated with 40% HF in acetonitrile at room temperature.

参考文献中间体

【1】 Graul, A.; Castaner, J.; SDZ-ASM-981. Drugs Fut 1998, 23, 5, 508.
【2】 Baumann, K.; Emmer, G. (Novartis AG; Novartis Deutschland GmbH); Heteroatoms-containing tricyclic cpds. AU 9165843; EP 0427680; JP 1991223291; US 5352671; US 5912238 .
【3】 Okuhara, M.; Tanaka, H.; Goto, T.; Kino, T.; Hatanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Tricyclo cpds., a process for their production and pharmaceutical compsn. containing the same. AU 8550596; EP 0184162; JP 1991072483; JP 1991072484; JP 1995224066; JP 1999012281; JP 1999343294; US 4894366; US 4929611; US 4956352; US 5110811; US 5254562; US 5266692; US 5565559 .

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)	14952	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4R)-3,4-dimethoxycyclohexyl]-1-methylethenyl]-17-ethyl-1-hydroxy-14,23,25-trimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone	C₄₅H₇₃NO₁₂	详情	详情
(III)	14953	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1-hydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-14,23,25-trimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone	C₄₄H₇₁NO₁₂	详情	详情
(IV)	14954	(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylethenyl]-17-ethyl-1-hydroxy-14,23,25-trimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone	C₄₄H₇₀ClNO₁₁	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)