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药物详细合成路线

Name Alclometasone dipropionate;Sch-22219;Aclosone;Legederm;Aclovate;Almeta;Vaderm;Modrasone;Delonal
Chemical Name (7alpha,11beta,16alpha)-7-Chloro-11-hydroxy-16-methyl-17,21-bis(1-oxopropoxy)pregna-1,4-diene-3,20-dione
CAS 66734-13-2
Related CAS 67452-97-5 (free base)
Formula C28H37ClO7
Structure
Formula Weight 521.05589
Stage 上市-1982
Company Essex (Originator), Kirby-Warrick (Originator), Schering-Plough (Originator), Dominion Pharma (Not Determined), GlaxoSmithKline (Not Determined), Shionogi (Licensee), Elan (Distributor)
Activity/Mechanism DERMATOLOGIC DRUGS, Antiinflammatory Drugs, Corticosteroids
Syn. Route 2
Route 1
the dehydrogenation of 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione-21-acetate (i) with dichlorodicyanobenzoquinone (ii) in dioxane hcl gives 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-21-acetate (iii), which is hydrolyzed with aqueous nahco3 to the corresponding free triol (iv). the reaction of (iv) with triethyl orthopropionate (a) by means of p-toluenesulfonic acid in dmso yields 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-ethylorthopropionate (v), which is hydrolyzed partially with acetic acid to 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17-propionate (vi). the acylation of (vi) with propionic anhydride affords 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-dipropionate (vii), which is finally treated with dry hcl in dioxane.
List of intermediates No.
4-phenylnicotinic acid (a)
methyl 2-(4-[2-[(tert-butoxycarbonyl)amino]ethoxy]phenyl)acetate
diethyl 2-[[4-(2-propynylamino)benzoyl]amino]pentanedioate (ii)
(i)
(iii)
4-amino-2-hydroxybenzoic acid (iv)
methyl 4-amino-2-methoxybenzoate (v)
methyl 4-(acetamido)-2-methoxybenzoate (vi)
methyl 4-(acetamido)-5-chloro-2-methoxybenzoate (vii)
Reference 1:
    green, m.j.; et al. (schering corp.); 7alpha-halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor. us 4124707 .
Reference 2:
    green, m.j.; et al. (schering corp.); process for the preparation of 7{60 -halogeno-3-oxo-4-dehydro steroids and novel 7{60 -halogeno derivatives produced thereby. ca 1099254; us 4076708 .
Reference 3:
    van wagenen, b.c.; barmore, r.m. (nps pharmaceuticals, inc.); chiral reductions of imines leading to the syntheses of optically active amines. wo 9711934 .

Route 2
the dehydrogenation of 16alpha-methyl-17alpha,21-dihydroxypregna-1,4-diene-3,11,20-trione-21-acetate (viii) with (ii) in dioxane-hcl gives 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-21-acetate (ix), which is hydrolyzed with aqueous nahco3 to the corresponding free diol (x). the reaction of (x) with triethyl orthopropionate (a) as before yields 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-17,21-ethylorthopropionate (xi), which is hydrolyzed partially with acetic acid to 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-17-propionate (xii). the acylation of (xii) with propionic anhydride yields the corresponding dipropionate (xiii), which is treated with dry hcl in dioxane to afford 16alpha-methyl-17alpha,21-dihydroxy-7alpha-chloropregna-1,4-diene-3,11,20-trione 17,21-dipropionate (xiv). finally, this compound is reduced with nash4 in methanol - thf.
List of intermediates No.
4-phenylnicotinic acid (a)
methyl 2-(4-[2-[(tert-butoxycarbonyl)amino]ethoxy]phenyl)acetate
diethyl 2-[[4-(2-propynylamino)benzoyl]amino]pentanedioate (ii)
4-amino-5-chloro-2-methoxybenzoic acid (viii)
4-amino-5-chloro-n-[2-(diethylamino)ethyl]-2-methoxybenzamide (ix)
sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate (x)
4-amino-5-chloro-n-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide (xi)
2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(fluoromethoxy)imino]acetic acid (xii)
2-[ethyl(methyl)amino]acetonitrile (xiii)
2-[ethyl(methyl)amino]acetamide (xiv)
Reference 1:
    green, m.j.; et al. (schering corp.); 7alpha-halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor. us 4124707 .
Reference 2:
    green, m.j.; et al. (schering corp.); process for the preparation of 7{60 -halogeno-3-oxo-4-dehydro steroids and novel 7{60 -halogeno derivatives produced thereby. ca 1099254; us 4076708 .
Reference 3:
    van wagenen, b.c.; barmore, r.m. (nps pharmaceuticals, inc.); chiral reductions of imines leading to the syntheses of optically active amines. wo 9711934 .

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阿氯米松双丙酸酯;英文名Alclometasone dipropionate;Sch-22219;Aclosone;Legederm;Aclovate;Almeta;Vaderm;Modrasone;Delonal;CAS[66734-13-2]

 
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