Etretinate, Ro-10-9359, Tegison, -Drug Synthesis Database

【结构式】

【药物名称】Etretinate, Ro-10-9359, Tegison

【化学名称】(all-E)-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester

【CA登记号】54350-48-0

【分子式】C₂₃H₃₀O₃

【分子量】354.49375

【开发单位】Roche (Originator)

【药理作用】Antipsoriatics, DERMATOLOGIC DRUGS, Retinoids

合成路线1 合成路线2

合成路线1

The chloromethylation of 2,3,5-trimethylanisole (II) [prepared by alkylation of 2,3,5-trimethylphenol (I) with methyl iodide] with formaldehyde and HCl gives 4-chloromethyl-2,3,5-trimethylanisole (III), which by reaction with triphenylphosphine in refluxing toluene affords 4-methoxy-2,3,6-trimethylbenzyltriphenylphosphonium chloride (IV). The Wittig reaction of (IV) with ethyl 7-formyl-3-methylocta-2,4,6-trien-1-oate (A) affords the desired compound.

参考文献中间体

【1】 Castaner, J.; Thorpe, P.; RO 10/9359. Drugs Fut 1977, 2, 3, 199.
【2】 Bollag, W. et al.; Polyene derivatives. DE 2414619; ES 424750; FR 2223037; GB 1468401; GB 1468402 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	40060	ethyl (2E,4E,6E)-3,7-dimethyl-8-oxo-2,4,6-octatrienoate		C₁₂H₁₆O₃	详情	详情
(I)	33479	2,3,5-trimethylphenol	697-82-5	C₉H₁₂O	详情	详情
(II)	33480	1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether	20469-61-8	C₁₀H₁₄O	详情	详情
(III)	40058	4-(chloromethyl)-2,3,5-trimethylphenyl methyl ether; 2-(chloromethyl)-5-methoxy-1,3,4-trimethylbenzene		C₁₁H₁₅ClO	详情	详情
(IV)	40059	(4-methoxy-2,3,6-trimethylbenzyl)(triphenyl)phosphonium chloride		C₂₉H₃₀ClOP	详情	详情

合成路线2

The reaction of 2,3,5-trimethylanisole (II) [prepared by alkylation of 2,3,5-trimethylphenol (I) with methyl iodide] with DMF and POCl3 affords 4-(4-methoxy-2,3,6-trimethylbenzaldehyde (V), which is condensed with propanone (B) in aqueous NaOH giving 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (VI). The Grignard reaction of (VI) with ethynylmagnesium bromide (C) in THF yields 5-(4-methoxy-2,3,6-trimethylphe-nyl)-3-methyl-3-hydroxypenta-4-en-1-yne (VII), which is partially hydrogenated with H2 over deactivated Pd in hexane to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxypenta-1,4-diene (VIII). The reaction of (VIII) with triphenylphosphonium hydrobromide in benzene affords 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (IX). Finally, this compound is submitted to a Wittig reaction with ethyl 3,4-formylcrotonate (D) in DMF (NaH is used as base).

参考文献中间体

【1】 Bollag, W. et al.; Polyene derivatives. DE 2414619; ES 424750; FR 2223037; GB 1468401; GB 1468402 .
【2】 Castaner, J.; Thorpe, P.; RO 10/9359. Drugs Fut 1977, 2, 3, 199.

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)	33481	4-methoxy-2,3,6-trimethylbenzaldehyde		C₁₁H₁₄O₂	详情	详情
(D)	40061	ethyl (E)-3-methyl-4-oxo-2-butenoate	62054-49-3	C₇H₁₀O₃	详情	详情
(I)	33479	2,3,5-trimethylphenol	697-82-5	C₉H₁₂O	详情	详情
(II)	33480	1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether	20469-61-8	C₁₀H₁₄O	详情	详情
(V)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(VI)	33482	(E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one	54757-47-0	C₁₄H₁₈O₂	详情	详情
(VII)	33483	(E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol		C₁₆H₂₀O₂	详情	详情
(VIII)	33484	(1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol		C₁₆H₂₂O₂	详情	详情
(IX)	33485	[(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide		C₃₄H₃₆BrOP	详情	详情
(C)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情

Extended Information