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藥物詳細合成路線

Name Trimexolone;Rimexolone;Org-6216;Rimexel;Vexol
Chemical Name 11beta-Hydroxy-16alpha,17alpha,21-trimethylpregna-1,4-dien-3,20-dione
      11beta-Hydroxy-16alpha,17alpha-dimethyl-17beta-propionylandrosta-1,4-dien-3-one
CAS 49697-38-3
Related CAS
Formula C24H34O3
Structure
Formula Weight 370.53678
Stage 上市-1995
Company Organon (Originator), Alcon (Licensee)
Activity/Mechanism Antiinflammatory Ophthalmic Agents, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Corticosteroids
Syn. Route 3
Route 1
a new synthesis of rimexolone from prednisolone has been described:the reaction of prednisolone (i) with tosyl chloride in pyridine gave the 21-tosylate (ii), which was treated with sodium iodide in acetone to yield the 21-iodo derivative (iii). the deiodination of (iii) with refluxing acetic acid afforded 21-deoxyprednisolone (iv), which was dehydrated with semicarbazide in water at 80-5 c yielding the trienone (v). the silylation of (v) with tms-cl and pyridine gave the protected compound (vi), which was methylated with methyl iodide and lithium bis(trimethylsilyl)amide to the 21-methyl derivative (vii). a new methylation of (vii) with me2cu(cn)li2 followed by silylation with tms-cl afforded the silylated dimethyl enol ether (viii), which was submitted to a third methylation with methyl iodide and benzyltrimethylammonium fluoride in thf giving the silylated 16,17,21-trimethyl derivative (ix). finally, this compound is desilylated to rimexolone with 6m hcl in methanol.
List of intermediates No.
7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5h)-one (i)
2-chloro-4-nitrobenzoic acid (ii)
2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-4-nitrobenzoic acid (iii)
2-(carboxymethyl)-4-nitrobenzoic acid (v)
6-nitro-1h-isochromene-1,3(4h)-dione (vi)
2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol (vii)
2-[5-amino-2-(hydroxymethyl)phenyl]-1-ethanol (viii)
4-(trifluoromethyl)[1,1-biphenyl]-2-carboxylic acid (ix)
4-(trifluoromethyl)[1,1-biphenyl]-2-carbonyl chloride (iv)
Reference 1:
    conrow, r.e.; synthesis of the 16alpha,17alpha,21-trimethyl corticosteroid rimexolone from prednisolone. j org chem 1999, 64, 3, 1042.

Route 2
the methylation of 11-acetoxy-3-tetrahydropyranyloxy-16alpha,17-alpha-dimethyl-5alpha-pregnane-20-one (ia) with lithium diisopropylamide and methyl iodide in thf gives 11beta-acetoxy-3beta-hydroxy-16alpha,17alpha,21-trimethyl-5alpha-pregnane-20-one (iia), which is oxidized with chromic acid in acetone yielding 11beta-acetoxy-16alpha,17alpha,21-trimethylpregnane-3,20-dione (iiia). this compound is dehydrogenated with dichlorodicyanobenzoquinone (a) in refluxing toluene affording 11beta-acetoxy-16alpha,17alpha,21-trimethyl-delta1,4-pregnadiene-3,20-dione (iva), which is finally hydrolyzed with koh in methanol. this sequence can also be perfomed with the 11beta-propoxy, 11beta-isobutyroxy derivatives of (ib-c, iib-c, iiib-c and ivb-c).
List of intermediates No.
diethyl 2-[[4-(2-propynylamino)benzoyl]amino]pentanedioate (a)
5-fluoro-1,3-dihydro-2h-inden-2-one (ia)
ethyl 2-(5-fluoro-1h-inden-2-yl)acetate (ib)
2-(5-fluoro-1h-inden-2-yl)acetaldehyde (ic)
2-amino-3-(5-fluoro-1h-inden-2-yl)propanenitrile (iia)
3-(5-fluoro-1h-inden-2-yl)-1,2-propanediamine; 2-amino-1-[(5-fluoro-1h-inden-2-yl)methyl]ethylamine (iib)
4-[(5-fluoro-1h-inden-2-yl)methyl]-4,5-dihydro-1h-imidazole (iic)
(iiia)
(2s)-2-amino-5-[((1r)-1-[(benzylsulfanyl)methyl]-2-[[(r)-carboxy(phenyl)methyl]amino]-2-oxoethyl)amino]-5-oxopentanoic acid (iiib)
(2s)-2-amino-5-[[(1r)-2-[[(r)-carboxy(phenyl)methyl]amino]-2-oxo-1-(sulfanylmethyl)ethyl]amino]-5-oxopentanoic acid (iiic)
(10r,15s)-15-amino-4-[bis(2-chloroethyl)amino]-10-([[(r)-carboxy(phenyl)methyl]amino]carbonyl)-1-chloro-3-(2-chloroethyl)-4,12-dioxo-5-oxa-8-thia-3,11-diaza-4lambda(5)-phosphahexadecan-16-oic acid (iva)
2-(2,6-difluorophenyl)acetonitrile (ivb)
2-(2,6-difluorophenyl)-1-ethanamine; 2,6-difluorophenethylamine (ivc)
Reference 1:
    woods, g.f.; et al.; alkylated 3,20-diketo-steroids of the pregnane series. de 2301317; fr 2168006; gb 1416427; jp 50004060; us 3862194 .
Reference 2:
    hillier, k.; castaner, j.; trimexolone. drugs fut 1977, 2, 10, 695.

Route 3
the methylation of 3beta-tetrahydropyranyloxy-16alpha,17alpha-dimethyl-delta9(11)-5alpha-pregnene-20-one (v) with lithium diisopropylamide and methyl iodide in thf gives 3beta-hydroxy-16alpha,17alpha,21-trimethyl-delta[9(11)]-5alpha-pregnene-20-one (vi), which is then oxidized with chromic acid in acetone yielding 16alpha,17alpha,21-trimethyl-delta[9(11)]-5alpha-pregnene-3,20-dione (vii). this compound is dehydrogenated as before affording 16alpha,17alpha,21-trimethyl-delta[1,4,9(11)]-pregnatriene-3,20-dione (viii), which is finally hydroxylated by treatment first with nbs and then with butanethiol and chromous acetate in dmso.the pregnene (vii) can also be obtained by methylation of 3-dimethyl-ketal-16alpha,17alpha-dimethyl-delta[9(11)]-5alpha-pregnene-3,20-dione (ix) with lithium diisopropylamide and methyl iodide in thf.the pregnatriene (viii) can also be obtained by dehydrogenation of 16alpha,17alpha,21-trimethyl-delta[1,4,9(11)]-pregnatriene-3,20-dione (x), which is with br2 in acetic acid and dehydrobromination with caco3 and libr in dimethylacetamide.
List of intermediates No.
diethyl 2-[[4-(2-propynylamino)benzoyl]amino]pentanedioate (a)
n-(2,6-difluorophenethyl)-1h-imidazole-1-carbothioamide (v)
(2r,3r)-3,5,7-trihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydro-4h-chromen-4-one (vi)
3,5,7-trihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-4h-chromen-4-one (vii)
6-[(2e)-3,7-dimethyl-2,6-octadienyl]-3,5,7-trihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-4h-chromen-4-one (ix)
1-(3,4-dichlorophenyl)-1-ethanone (viii)
1,21-dibromohenicosane (x)
Reference 1:
    woods, g.f.; et al.; alkylated 3,20-diketo-steroids of the pregnane series. de 2301317; fr 2168006; gb 1416427; jp 50004060; us 3862194 .
Reference 2:
    hillier, k.; castaner, j.; trimexolone. drugs fut 1977, 2, 10, 695.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名瑞美松龍;英文名Trimexolone;Rimexolone;Org-6216;Rimexel;Vexol;CAS[49697-38-3]

 
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