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药物详细合成路线

Name Etretinate;Ro-10-9359;Tegison
Chemical Name (all-E)-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester
CAS 54350-48-0
Related CAS
Formula C23H30O3
Structure
Formula Weight 354.49375
Stage 撤市
Company Roche (Originator)
Activity/Mechanism Antipsoriatics, DERMATOLOGIC DRUGS, Retinoids
Syn. Route 2
Route 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.
List of intermediates No.
5-methoxy-2-(2-nitrophenoxy)benzaldehyde (i)
5-methoxy-2-(2-nitrophenoxy)benzoic acid (ii)
3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid (iii)
3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-12,16-heptadecadienoic acid (iv)
3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-12,16-heptadecadienoic acid (a)
Reference 1:
    castaner, j.; thorpe, p.; ro 10/9359. drugs fut 1977, 2, 3, 199.
Reference 2:
    bollag, w. et al.; polyene derivatives. de 2414619; es 424750; fr 2223037; gb 1468401; gb 1468402 .

Route 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).
List of intermediates No.
3-(3-iodopropyl)phenyl phenyl ether; 1-(3-iodopropyl)-3-phenoxybenzene (c)
2-[[([(2s,3s,5r)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(oxo)phosphoranyl]oxy]-1-[(palmitoyloxy)methyl]ethyl palmitate (v)
5-methoxy-2-(2-nitrophenoxy)benzaldehyde (i)
5-methoxy-2-(2-nitrophenoxy)benzoic acid (ii)
2-(2-aminophenoxy)-5-methoxybenzoic acid (b)
2-methoxydibenzo[b,f][1,4]oxazepin-11(10h)-one (vi)
2-hydroxydibenzo[b,f][1,4]oxazepin-11(10h)-one (vii)
11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl trifluoromethanesulfonate (viii)
11-chlorodibenzo[b,f][1,4]oxazepin-2-yl trifluoromethanesulfonate (ix)
4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate (d)
Reference 1:
    bollag, w. et al.; polyene derivatives. de 2414619; es 424750; fr 2223037; gb 1468401; gb 1468402 .
Reference 2:
    castaner, j.; thorpe, p.; ro 10/9359. drugs fut 1977, 2, 3, 199.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名依曲替酯;英文名Etretinate;Ro-10-9359;Tegison;CAS[54350-48-0]

 
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