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. |
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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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