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药物详细合成路线

Name Canthaxanthin;RO-19915
Chemical Name beta-Carotene-4-4-dione
CAS 514-78-3
Related CAS
Formula C40H52O2
Structure
Formula Weight 564.85924
Stage 生物学测试
Company LOreal (Originator)
Activity/Mechanism Acne Therapy, DERMATOLOGIC DRUGS
Syn. Route 5
Route 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.
List of intermediates No.
1-[(2r,4s,5r)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1h,3h)-pyrimidinedione (ii)
methyl (2r,3r)-3-hydroxy-2-isobutyl-4-methylpentanoate (i)
(2r,3r)-3-hydroxy-2-isobutyl-4-methylpentanoic acid (iii)
2-(aminooxy)tetrahydro-2h-pyran; o-tetrahydro-2h-pyran-2-ylhydroxylamine (iv)
(2r,3r)-3-hydroxy-2-isobutyl-4-methyl-n-(tetrahydro-2h-pyran-2-yloxy)pentanamide (v)
(3r,4s)-3-isobutyl-4-isopropyl-1-(tetrahydro-2h-pyran-2-yloxy)-2-azetidinone (vi)
(2r,3s)-2-isobutyl-4-methyl-3-[(tetrahydro-2h-pyran-2-yloxy)amino]pentanoic acid (vii)
(2r,3s)-3-[formyl(tetrahydro-2h-pyran-2-yloxy)amino]-2-isobutyl-4-methylpentanoic acid (viii)
tert-butyl (1s,2s)-2-methyl-1-[(2-pyridinylamino)carbonyl]butylcarbamate (ix)
Reference 1:
    serradell, m.n.; blancafort, p.; castaner, j.; hillier, k.; canthazanthin. drugs fut 1979, 4, 7, 477.
Reference 2:
    rosenberg, m.; us 4000198 .
Reference 3:
    rigassi, n.; schwieter, u.; de 2037935 .

Route 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.
List of intermediates No.
benzhydryl (6r,7r)-7-[((2r,3s)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (b)
methyl (2r)-2-[(tert-butoxycarbonyl)amino]-3-[3-[(diethoxyphosphoryl)methyl]-6,7-dimethyl-2-quinolinyl]propanoate (a)
(2r,3s)-3-[formyl(tetrahydro-2h-pyran-2-yloxy)amino]-2-isobutyl-4-methylpentanoic acid (viii)
tert-butyl (1s,2s)-2-methyl-1-[(2-pyridinylamino)carbonyl]butylcarbamate (ix)
(2s,3s)-2-amino-3-methyl-n-(2-pyridinyl)pentanamide (x)
(2r,3s)-3-[formyl(tetrahydro-2h-pyran-2-yloxy)amino]-2-isobutyl-4-methyl-n-[(1s,2s)-2-methyl-1-[(2-pyridinylamino)carbonyl]butyl]pentanamide (xi)
2-hydroxy-3,4-bis(4-methoxyphenyl)-4-oxobutyric acid (xii)
4-hydroxy-5,6-bis(4-methoxyphenyl)-4,5-dihydro-3(2h)-pyridazinone (xiii)
5,6-bis(4-methoxyphenyl)-3(2h)-pyridazinone (xiv)
1-chloro-4-[(e)-3-chloro-1-propenyl]benzene (c)
Reference 1:
    rosenberg, m.; us 4000198 .
Reference 2:
    serradell, m.n.; blancafort, p.; castaner, j.; hillier, k.; canthazanthin. drugs fut 1979, 4, 7, 477.
Reference 3:
    rigassi, n.; schwieter, u.; de 2037935 .

Route 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.
List of intermediates No.
uvic acid; tartaric acid; dihydroxysuccinic acid; 2,3-dihydroxybutanedioic acid (xv)
6-ethoxy-1,3-benzothiazol-2-ylamine; 6-ethoxy-1,3-benzothiazol-2-amine (xvi)
chlorosulfonylacetyl chloride (xvii)
2-[[(6-ethoxy-1,3-benzothiazol-2-yl)amino]sulfonyl]acetyl chloride (xviii)
8-ethoxy-4-hydroxy-2h-2lambda(6)-[1,2,4]thiadiazino[3,4-b][1,3]benzothiazole-2,2-dione (xix)
Reference 1:
    surmatis, j.d.; et al.; synthesis of oxygenated carotenoids. helv chim acta 1970, 53, 5, 974-990.
Reference 2:
    surmatis, j.d.; us 3311656 .
Reference 3:
    serradell, m.n.; blancafort, p.; castaner, j.; hillier, k.; canthazanthin. drugs fut 1979, 4, 7, 477.

Route 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).
List of intermediates No.
uvic acid; tartaric acid; dihydroxysuccinic acid; 2,3-dihydroxybutanedioic acid (xv)
6-ethoxy-1,3-benzothiazol-2-ylamine; 6-ethoxy-1,3-benzothiazol-2-amine (xvi)
[3-(methoxymethoxy)phenoxy]methyl methyl ether; 1,3-bis(methoxymethoxy)benzene (xx)
1-[2,6-bis(methoxymethoxy)phenyl]-1-ethanone (xxi)
ethyl 2-(2-acetyl-3-hydroxyphenoxy)acetate (xxii)
ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate (xxiii)
Reference 1:
    surmatis, j.d.; et al.; synthesis of oxygenated carotenoids. helv chim acta 1970, 53, 5, 974-990.
Reference 2:
    serradell, m.n.; blancafort, p.; castaner, j.; hillier, k.; canthazanthin. drugs fut 1979, 4, 7, 477.

Route 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).
List of intermediates No.
8-ethoxy-4-hydroxy-2h-2lambda(6)-[1,2,4]thiadiazino[3,4-b][1,3]benzothiazole-2,2-dione (xix)
ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate (xxiii)
Reference 1:
    serradell, m.n.; blancafort, p.; castaner, j.; hillier, k.; canthazanthin. drugs fut 1979, 4, 7, 477.
Reference 2:
    surmatis, j.d.; et al.; synthesis of oxygenated carotenoids. helv chim acta 1970, 53, 5, 974-990.

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角黄素;英文名Canthaxanthin;RO-19915;CAS[514-78-3]

 
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