ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】29901

【品名】ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate

【CA登记号】

【分子式】C₁₅H₂₆O₇S

【分子量】350.43324

【元素组成】C 51.41% H 7.48% O 31.96% S 9.15%

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：(VIII)

1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III), which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV). The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V), which is dehydrated with SO2Cl2 in dichloromethane, giving the cyclohexenecarboxylate (VI). The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII), which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII). The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX), which is opened with sodium azide and ammonium chloride in ethanol/water, resulting in the the azido alcohol (X). The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI), which is opened by means of sodium azide in hot DMF to the azidoamine (XII). The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII), which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.

参考文献中间体

合成目标

【1】 Rohloff, J.C.; Kent, K.M.; Postich, M.J.; et al.; Practical total synthesis of the anti-influenza drug GS-4104. J Org Chem 1998, 63, 13, 4545.
【2】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189.
【3】 McGee, L.R.; Kent, K.M.; Portich, M.J.; Kim, C.U.; Williams, M.A.; Zhang, L.; Prisbe, E.J.; Rohloff, J.C.; Munger, J.D.; St. John, D.E. (Gilead Sciences Inc.); Preparation of cyclohexene carboxylate derivs.. WO 9807685 .
【4】 Postich, M.J.; Williams, M.A.; Rohloff, J.C.; Prisbe, E.J.; McGee, L.R.; Kent, K.M.; Munger, J.D.; Zhang, L.; Kim, C.U.; Kelly, D.E. (Gilead Sciences Inc.); Preparation of carbocyclic cpds.. US 5886213 .
【5】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Mills, R.G.; Hitchcock, M.J.M.; Dahl, T.C.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Cpds. containing six-membered rings, processes for their preparation, and their use as medicaments. EP 1015417; WO 9914185 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIII)	29906	ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate		C₁₆H₂₆N₄O₄	详情	详情
(I)	11524	D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid	77-95-2	C₇H₁₂O₆	详情	详情
(II)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(III)	29896	(1R,2R,6R,8S)-8-hydroxy-4,4-dimethyl-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one		C₁₀H₁₄O₅	详情	详情
(IV)	29897	ethyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate		C₁₂H₂₀O₆	详情	详情
(V)	29898	ethyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-5-carboxylate		C₁₃H₂₂O₈S	详情	详情
(VI)	29899	ethyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate		C₁₃H₂₀O₇S	详情	详情
(VII)	29900	ethyl (3aR,7R,7aR)-2,2-diethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate		C₁₅H₂₄O₇S	详情	详情
(VIII)	29901	ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate		C₁₅H₂₆O₇S	详情	详情
(IX)	29902	ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate		C₁₄H₂₂O₄	详情	详情
(X)	29903	ethyl (3R,4S,5R)-5-azido-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate		C₁₄H₂₃N₃O₄	详情	详情
(XI)	29904	ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate		C₁₄H₂₃NO₃	详情	详情
(XII)	29905	ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate		C₁₄H₂₄N₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

A new industrial synthesis of (3R,4S,5S)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester, a key intermediate in the synthesis of the oseltamivir phosphate has been developed: The esterification of (-)-shikimic acid (I) with SOCl2 and ethanol gives the expected ethyl ester (II), which is treated with 2,2-dimethoxypropane and p-toluenesulfonic acid in ethyl acetate to yield the acetonide (III). Mesylation of (III) with mesyl chloride and triethylamine in ethyl acetate affords mesylate (IV), which is trans-ketalized with 3-pentanone and trifluoromethanesulfonic acid giving the pentylidene ketal (V). Reductive opening of the ketal ring of (V) with triethylsilane and TiCl4 in dichloromethane gives the hydroxyether (VI), which is converted into the target epoxide by a treatment with NaHCO3 in ethanol/water. Another route to pentylidene ketal (V) has also been developed: The direct ketalization of ester (II) with 3-pentanone and trifluoromethanesulfonic acid gives the pentylidene ketal (VIII), which is then mesylated with mesyl chloride and triethylamine as before yielding the alredy described mesylate (V). From the above two routes, the route through the mesylate (IV) is preferred even though it is one step longer. Compound (IV) is a highly crystalline compound which can be purified efficiently. In contrast, intermediates (VIII) and (V) are oils and cannot be purified easily and often, the resulting epoxide (VII) obtained through pentylidene ketal (VIII) do not meet the quality requirements and may be reprocessed.

参考文献中间体

合成目标

【1】 Fischer, R.; Henning, M.; Federspiel, M.; et al.; Industrial synthesis of the key precursor in the synthesis of the anti-influenza drug oseltamivir phosphate (Ro 64-0796/002, GS-4104-02): Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate. Org Process Res Dev 1999, 3, 4, 266.

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)	29907	(3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid	138-59-0	C₇H₁₀O₅	详情	详情
(II)	41701	ethyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate		C₉H₁₄O₅	详情	详情
(III)	41702	ethyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate		C₁₂H₁₈O₅	详情	详情
(IV)	29899	ethyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate		C₁₃H₂₀O₇S	详情	详情
(V)	29900	ethyl (3aR,7R,7aR)-2,2-diethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate		C₁₅H₂₄O₇S	详情	详情
(VI)	29901	ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate		C₁₅H₂₆O₇S	详情	详情
(VII)	29902	ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate		C₁₄H₂₂O₄	详情	详情
(VIII)	41703	ethyl (3aR,7R,7aS)-2,2-diethyl-7-hydroxy-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate		C₁₄H₂₂O₅	详情	详情

Extended Information