(1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】59613

【品名】(1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid

【CA登记号】

【分子式】C₂₇H₄₀O₈

【分子量】492.6098

【元素组成】C 65.83% H 8.18% O 25.98%

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：(I)

Sordarin (I) was isolated from culture broths of Sordaria araneosa. Protection of the carboxyl group of (I) as the benzhydryl ester (II) was effected by treatment with diphenyl diazomethane. The 2'-hydroxyl group of (II) was subsequently blocked as the carbonate ester (III) by selective acylation with benzyl chloroformate in the presence of DMAP. Subsequent esterification of the 3'-hydroxyl of (III) with octanoyl chloride (IV) furnished the octanoate ester (V). The benzhydryl ester and benzyl carbonate protecting groups of (V) were finally removed by catalytic hydrogenation over Pd/C.

参考文献中间体

合成目标

【1】 Fraile, M.T.; Ruiz, J.R.; Gómez de las Heras, F.; García-Ochoa, S.; Arribas, E.M.; Castro, J.; Clemens, I.R.; Cuevas, J.C.; Chicharro, J.; Antifungal sordarins. Synthesis and structure-activity relationships of 3'-O-substituted derivatives. Bioorg Med Chem Lett 2002, 12, 2, 117.
【2】 Hayes, M.; Wildman, H.; Dawson, M.; Chalk, P.; Hall, R.; Ruiz Gomez, J.R. (GlaxoSmithKline plc); Antifungal sordarin derivs.. EP 0711783; EP 0791007; JP 1999502188; US 6054478; WO 9614327 .

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)	59613	(1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid		C₂₇H₄₀O₈	详情	详情
(II)	59614	benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₄₀H₅₀O₈	详情	详情
(III)	59615	benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-{[((2R,3S,4R,5S,6R)-3-{[(benzyloxy)carbonyl]oxy}-4-hydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]methyl}-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₄₈H₅₆O₁₀	详情	详情
(IV)	11123	Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride	111-64-8	C₈H₁₅ClO	详情	详情
(V)	59616	benzhydryl (1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4R,5R,6R)-3-{[(benzyloxy)carbonyl]oxy}-5-methoxy-6-methyl-4-(octanoyloxy)tetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₅₆H₇₀O₁₁	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The hydrolysis of Zofimarin (I) with NaOMe in methanol gives the sodium salt of the deacylated compound (II), which is treated with Pmb-Cl in DMF to yield the p-methoxybenzyl ester (III). The protection of the formyl group of (III) by means of ethyleneglycol, trimethyl orthoformate and TsOH affords the ethylene ketal (IV), which is oxidized at the vicinal diol group by means of NaIO4 in methanol/water to provide the dialdehyde (V). The reductocyclization of (V) with allylamine (VI) by means of NaBH3CN and AcOH in acetonitrile leads to the perhydro oxazepine derivative (VII), which is deallylated by means of Rh(PPh3)3Cl in aqueous ethanol to give compound (VIII). The alkylation of (VIII) with 2-methylallyl bromide (IX) by means of NaHCO3 and NaI in ethanol yields the protected precursor (X), which is finally treated with TFA in dichloromethane to provide the target zofimarin derivative.

参考文献中间体

合成目标

【1】 Fukuoka, T.; Kamai, Y.; Kakuta, M.; Kaneko, S.; Arai, M.; Uchida, T.; Konosu, T.; Kuwahara, S.; Design, synthesis, and in vitro activity of RS-135853, a novel zofimarin-related antifungal agent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-824.
【2】 Kaneko, S.; Uchida, T.; Arai, M.; Kounosu, T. (Sankyo Co., Ltd.); Zofimarin derivs. having an oxazepan ring. JP 2002161086; WO 0223541 .

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)	60326	(1R,2S,4R,5R,8R,9S)-9-formyl-2-[({(2R,3S,4S,5R,6R)-4-[(2Z,4E)-2,4-hexadienoyloxy]-3-hydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl}oxy)methyl]-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid		C₃₃H₄₆O₉	详情	详情
(II)	59613	(1R,2S,4R,5R,8R,9S,11R)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid		C₂₇H₄₀O₈	详情	详情
(III)	60327	4-methoxybenzyl (1R,2S,4R,5R,8R,9S)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₃₅H₄₈O₉	详情	详情
(IV)	60328	4-methoxybenzyl (1R,2S,4R,5R,8R,9S)-2-({[(2R,3S,4S,5S,6R)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}methyl)-9-(1,3-dioxolan-2-yl)-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₃₇H₅₂O₁₀	详情	详情
(V)	60329	4-methoxybenzyl (1R,2S,4R,5R,8R,9S)-9-(1,3-dioxolan-2-yl)-13-isopropyl-2-{[((1R)-1-{[(1R,2R)-2-methoxy-1-methyl-3-oxopropyl]oxy}-2-oxoethyl)oxy]methyl}-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₃₇H₅₀O₁₀	详情	详情
(VI)	13672	Allylamine; 2-Propen-1-amine	107-11-9	C₃H₇N	详情	详情
(VII)	60330	4-methoxybenzyl (1R,2S,4R,5R,8R,9S)-2-({[(2R,6S,7R)-4-allyl-6-methoxy-7-methyl-1,4-oxazepan-2-yl]oxy}methyl)-9-(1,3-dioxolan-2-yl)-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₄₀H₅₇NO₈	详情	详情
(VIII)	60331	4-methoxybenzyl (1R,2S,4R,5R,8R,9S)-9-(1,3-dioxolan-2-yl)-13-isopropyl-2-({[(2R,6S,7R)-6-methoxy-7-methyl-1,4-oxazepan-2-yl]oxy}methyl)-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₃₇H₅₃NO₈	详情	详情
(IX)	40015	3-bromo-2-methyl-1-propene	1458-98-6	C₄H₇Br	详情	详情
(X)	60332	4-methoxybenzyl (1R,2S,4R,5R,8R,9S)-9-(1,3-dioxolan-2-yl)-13-isopropyl-2-({[(2R,6S,7R)-6-methoxy-7-methyl-4-(2-methyl-2-propenyl)-1,4-oxazepan-2-yl]oxy}methyl)-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate		C₄₁H₅₉NO₈	详情	详情

Extended Information