Canthaxanthin, RO-19915, -Drug Synthesis Database

【结构式】

【药物名称】Canthaxanthin, RO-19915

【化学名称】beta-Carotene-4-4'-dione

【CA登记号】514-78-3

【分子式】C₄₀H₅₂O₂

【分子量】564.85924

【开发单位】L'Oreal (Originator)

【药理作用】Acne Therapy, DERMATOLOGIC DRUGS

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

The reaction of 3-methyl-2-trans-penten-4-yn-1-ol (I) with ethyl vinyl ether (II) by means of p-toluenesulfonic acid gives 1-(1-ethoxyethoxy)-3-methyl-4-trans-penten-1-yne (III), which is condensed with 2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1-one (IV) by means of butyllithium in ether at -60 C to afford 5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol (V). The reduction of (V) with H2 over a Lindlar catalyst in toluene yields 5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-pentadien-1-ol (VI), which is converted into the corresponding pentadienyl bromide (VII) by reaction with PBr3 in ether. The reaction of (VII) with triphenylphosphine in refluxing benzene affords 5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-pentadien-1-triphenylphosphonium bromide (VIII) , which is finally condensed in a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (IX) by means of sodium methoxide in dichloromethane.

参考文献中间体

【1】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Canthazanthin. Drugs Fut 1979, 4, 7, 477.
【2】 Rosenberg, M.; US 4000198 .
【3】 Rigassi, N.; Schwieter, U.; DE 2037935 .

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)	39576	(E)-3-methyl-2-penten-4-yn-1-ol	6153-06-6	C₆H₈O	详情	详情
(II)	18762	1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene	109-92-2	C₄H₈O	详情	详情
(III)	39577	5-(1-ethoxyethoxy)-3-methyl-1-penten-4-yne; 1-ethoxyethyl 3-methyl-4-penten-1-ynyl ether		C₁₀H₁₆O₂	详情	详情
(IV)	39578	3-isobutoxy-2,6,6-trimethyl-2-cyclohexen-1-one		C₁₃H₂₂O₂	详情	详情
(V)	39579	3-[(E)-5-hydroxy-3-methyl-3-penten-1-ynyl]-2,4,4-trimethyl-2-cyclohexen-1-one		C₁₅H₂₀O₂	详情	详情
(VI)	39580	3-[(1E,3E)-5-hydroxy-3-methyl-1,3-pentadienyl]-2,4,4-trimethyl-2-cyclohexen-1-one	29538-78-1	C₁₅H₂₂O₂	详情	详情
(VII)	39581	3-[(1E,3E)-5-bromo-3-methyl-1,3-pentadienyl]-2,4,4-trimethyl-2-cyclohexen-1-one		C₁₅H₂₁BrO	详情	详情
(VIII)	39582	[(2E,4E)-3-methyl-5-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₃H₃₆BrOP	详情	详情
(IX)	39583	(2E,4E,6E)-2,7-dimethyl-2,4,6-octatrienedial		C₁₀H₁₂O₂	详情	详情

合成路线2

The reaction of beta-ionon (X) with triethyl orthoformate (A) by means of H2SO4 in dioxane gives beta-ionon enolether (XI), which by reaction with NBS in CCl4 and hydrolysis with acetic acid is converted into 4-acetoxyonon (XII). The Grignard reaction of (XII) with vinylmagnesium bromide (B) in THF and hydrolysis with KOH in methanol gives 5-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIII), which is oxidized with MnO2 in methylene chloride yielding 5-(3-oxo-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIV). Finally, this compound by reaction with triphenylphosphonium bromide (C) in DMF is converted into the phosphonium salt (VIII), which is finally condensed in a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (IX) by means of sodium methoxide in dichloromethane.

参考文献中间体

【1】 Rosenberg, M.; US 4000198 .
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Canthazanthin. Drugs Fut 1979, 4, 7, 477.
【3】 Rigassi, N.; Schwieter, U.; DE 2037935 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(A)	21304	Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether	122-51-0	C₇H₁₆O₃	详情	详情
(VIII)	39582	[(2E,4E)-3-methyl-5-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₃H₃₆BrOP	详情	详情
(IX)	39583	(2E,4E,6E)-2,7-dimethyl-2,4,6-octatrienedial		C₁₀H₁₂O₂	详情	详情
(X)	39584	(E)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-one	14901-07-6	C₁₃H₂₀O	详情	详情
(XI)	39585	6-[(Z,2Z)-3-methoxy-2-butenylidene]-1,5,5-trimethyl-1-cyclohexene; methyl (Z)-1-methyl-3-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-1-propenyl ether		C₁₄H₂₂O	详情	详情
(XII)	39586	2,4,4-trimethyl-3-[(E)-3-oxo-1-butenyl]-2-cyclohexen-1-yl acetate		C₁₅H₂₂O₃	详情	详情
(XIII)	39587	3-[(1E)-3-hydroxy-3-methyl-1,4-pentadienyl]-2,4,4-trimethyl-2-cyclohexen-1-ol		C₁₅H₂₄O₂	详情	详情
(XIV)	39588	3-[(1E)-3-hydroxy-3-methyl-1,4-pentadienyl]-2,4,4-trimethyl-2-cyclohexen-1-one		C₁₅H₂₂O₂	详情	详情
(C)	39589	triphenylphosphonium bromide	6399-81-1	C₁₈H₁₆BrP	详情	详情

合成路线3

The reaction of vitamin A aldehyde (retinene) (XV) with NBS and acetic acid - acetic anhydride in CHCl3 gives 3-acetoxyretinene (XVI), which is reduced with NaBH4 in methanol to yield 3-acetoxyretinol (XVII). The reaction of (XVII) with triphenylphosphine and HCl in methanol affords 3-acetoxyretinyltriphenylphosphonium chloride (XVIII), which is condensed through a Wittig reaction with aldehyde (XVI) by means of sodium methoxide in isopropanol giving trans-isozeaxanthin (XIX). Finally, this compound is oxidized with aluminum isopropoxide in refluxing benzene - acetone.

参考文献中间体

【1】 Surmatis, J.D.; et al.; Synthesis of oxygenated carotenoids. Helv Chim Acta 1970, 53, 5, 974-990.
【2】 Surmatis, J.D.; US 3311656 .
【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Canthazanthin. Drugs Fut 1979, 4, 7, 477.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XV)	39590	(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenal	C₂₀H₂₈O	详情	详情
(XVI)	39591	3-[(1E,3E,5E,7E)-3,7-dimethyl-9-oxo-1,3,5,7-nonatetraenyl]-2,4,4-trimethyl-2-cyclohexen-1-yl acetate	C₂₂H₃₀O₃	详情	详情
(XVII)	39592	3-[(1E,3E,5E,7E)-9-hydroxy-3,7-dimethyl-1,3,5,7-nonatetraenyl]-2,4,4-trimethyl-2-cyclohexen-1-yl acetate	C₂₂H₃₂O₃	详情	详情
(XVIII)	39593	[(2E,4E,6E,8E)-9-[3-(acetoxy)-2,6,6-trimethyl-1-cyclohexen-1-yl]-3,7-dimethyl-2,4,6,8-nonatetraenyl](triphenyl)phosphonium chloride	C₄₀H₄₆ClO₂P	详情	详情
(XIX)	39594	3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-18-(3-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyl-1,3,5,7,9,11,13,15,17-octadecanonaenyl]-2,4,4-trimethyl-2-cyclohexen-1-ol	C₄₀H₅₆O₂	详情	详情

合成路线4

The reduction of retinene (XV) with NaBH4 in methanol gives retinol (XX), which by reaction with triphenylphosphine and H2SO4 is converted into retinyltriphenylphosphonium sulfate (XXI). The Wittig reaction of (XXI) with aldehyde (XVI) by means of sodium methoxide in benzene - methanol yields 3-acetylisocryptoxanthin (XXII), which by reaction with aqueous 68% HBr in methylene chloride, followed by a treatment with Na2CO3 affords dehydro-retro-carotene (XXIII).

参考文献中间体

【1】 Surmatis, J.D.; et al.; Synthesis of oxygenated carotenoids. Helv Chim Acta 1970, 53, 5, 974-990.
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Canthazanthin. Drugs Fut 1979, 4, 7, 477.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	39590	(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenal		C₂₀H₂₈O	详情	详情
(XVI)	39591	3-[(1E,3E,5E,7E)-3,7-dimethyl-9-oxo-1,3,5,7-nonatetraenyl]-2,4,4-trimethyl-2-cyclohexen-1-yl acetate		C₂₂H₃₀O₃	详情	详情
(XX)	39595	(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ol	68-26-8	C₂₀H₃₀O	详情	详情
(XXI)	39596	[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenyl](triphenyl)phosphonium hydrogen sulfate		C₃₈H₄₅O₄PS	详情	详情
(XXII)	39597	2,4,4-trimethyl-3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-3,7,12,16-tetramethyl-18-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5,7,9,11,13,15,17-octadecanonaenyl]-2-cyclohexen-1-yl acetate		C₄₂H₅₈O₂	详情	详情
(XXIII)	39598	1,5,5-trimethyl-6-[(Z,2E,4E,6E,8E,10E,12E,14E,16E)-3,7,12,16-tetramethyl-18-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-2,4,6,8,10,12,14,16-octadecaoctaenylidene]-1-cyclohexene		C₄₀H₅₄	详情	详情

合成路线5

Finally, compound (XXIII) by reaction with NBS and acetic acid in CHCl3, followed by a treatment with KOH in methanol, is converted into the previously obtained diol (XIX).

参考文献中间体

【1】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Hillier, K.; Canthazanthin. Drugs Fut 1979, 4, 7, 477.
【2】 Surmatis, J.D.; et al.; Synthesis of oxygenated carotenoids. Helv Chim Acta 1970, 53, 5, 974-990.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	39594	3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-18-(3-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyl-1,3,5,7,9,11,13,15,17-octadecanonaenyl]-2,4,4-trimethyl-2-cyclohexen-1-ol		C₄₀H₅₆O₂	详情	详情
(XXIII)	39598	1,5,5-trimethyl-6-[(Z,2E,4E,6E,8E,10E,12E,14E,16E)-3,7,12,16-tetramethyl-18-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-2,4,6,8,10,12,14,16-octadecaoctaenylidene]-1-cyclohexene		C₄₀H₅₄	详情	详情

Extended Information