13-cis-retinoic acid, Isotretinoin, Ro-43780, Amnesteem, Claravis, Roacutan, Roaccutan, Roaccutane, Accutane, -Drug Synthesis Database

【结构式】

【药物名称】13-cis-retinoic acid, Isotretinoin, Ro-43780, Amnesteem, Claravis, Roacutan, Roaccutan, Roaccutane, Accutane

【化学名称】13-cis-Retinoic acid
　　　　　　cis-2-Vitamin A acid

【CA登记号】4759-48-2, 22232-80-0 (K salt), 13497-05-7 (Na salt)

【分子式】C₂₀H₂₈O₂

【分子量】300.44496

【开发单位】Roche (Originator), Bertek (Not Determined), Barr (Generic)

【药理作用】Acne Therapy, DERMATOLOGIC DRUGS, Retinoids

合成路线1 合成路线2

合成路线1

The reaction of vinyl-beta-ionol (I) with triphenylphosphonium bromide (II) in ethanol gives the corresponding phosphonium salt (III), which is condensed through a Wittig reaction with cis-beta-formylcrotonic acid (IV) by means of sodium ethoxide in ethanol to afford a mixture of cis-2-cis-4-vitamin A acid (V) and the desired product. Finally, compound (V) is isomerized bv irradiation with diffuse light in ether in the presence of iodine.

参考文献中间体

【1】 Garbers, C.F.; et al.; Synthesis of cis-2, cis-4-vitamin A by a Wittig condensation. J Chem Soc 1968, 16, 1982-83.
【2】 Castaner, J.; Serradell, M.N.; Hillier, K.; Blancafort, P.; Isotretinoin. Drugs Fut 1979, 4, 9, 651.

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)	33333	(2E,4E)-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadien-1-ol	3917-39-3	C₁₅H₂₄O	详情	详情
(III)	33334	[(2E,4E)-3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₃H₃₈BrP	详情	详情
(IV)	33335	(Z)-3-methyl-4-oxo-2-butenoic acid		C₅H₆O₃	详情	详情
(V)	32679	(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid; Retinoic acid	302-79-4	C₂₀H₂₈O₂	详情	详情

合成路线2

The formylation of the beta-ionone (I) with methyl formate and NaOMe gives the enol (II), which by reaction with methanol and H2SO4 yields the dimethylacetal (III). The reaction of (III) with methylenetriphenylphosphorane (IV) affords the methylene compound (V), which is treated with formic acid to provide the aldehyde (VI). The condensation of (VI) with isopropylidenemalonic acid dimethyl ester (VII) by means of NaOH gives the polyenic malonic acid (VIII) as a mixture of isomers that is separated by crystallization in ethyl ether to yield the desired all-trans-isomer (IX). Finally, this malonic acid is selectively monodecarboxylated by means of refluxing 2,6-dimethylpyridine to afford the target (E,E,E,Z)-isomer.

参考文献中间体

【1】 Valia, A.; et al.; Stereoselective synthesis of 13 E retinoic and 13 Z retinoic acids via a new intermediate compound, C-15 beta-methylenealdehyde. Tetrahedron 2000, 56, 37, 7211.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa),(IX)	49672	2-[(2E,4E,6E)-1,5-dimethyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-heptatrienylidene]malonic acid		C₂₁H₂₈O₄	详情	详情
(VIIb)	49673	2-[(2E,4Z,6E)-1,5-dimethyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-heptatrienylidene]malonic acid		C₂₁H₂₈O₄	详情	详情
(I)	39584	(E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one	14901-07-6	C₁₃H₂₀O	详情	详情
(II)	49667	(1E,4E)-1-hydroxy-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,4-pentadien-3-one		C₁₄H₂₀O₂	详情	详情
(III)	49668	(E)-5,5-dimethoxy-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-penten-3-one		C₁₆H₂₆O₃	详情	详情
(IV)	27301	methylene(triphenyl)phosphorane		C₁₉H₁₇P	详情	详情
(V)	49669	(E)-1-methoxy-3-methylene-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenyl methyl ether; 2-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-1,3,3-trimethyl-1-cyclohexene		C₁₇H₂₈O₂	详情	详情
(VI)	49670	(E)-3-methylene-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenal		C₁₅H₂₂O	详情	详情
(VII)	49671	dimethyl 2-(1-methylethylidene)malonate	22035-53-6	C₈H₁₂O₄	详情	详情

Extended Information