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Name Rosiglitazone maleate;SB-206846((-)-enantiomer;free base);SB-210232((+)-enantiomer;free base);BRL-49653C;Venvia;Nyracta;Avandia
Chemical Name (±)-5-[4-[2-[N-Methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate
CAS 155141-29-0
Related CAS 122320-73-4 (free base)
Formula C22H23N3O7S
Structure
Formula Weight 473.50851
Stage 上市-1999
Company GlaxoSmithKline (Originator), Bristol-Myers Squibb (Licensee), Asahi Kasei (Distributor)
Activity/Mechanism Alzheimers Dementia, Treatment of , Antidiabetic Drugs, Antipsoriatics, Cognition Disorders, Treatment of, DERMATOLOGIC DRUGS, ENDOCRINE DRUGS, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, NEUROLOGIC DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARgamma Agonists, Thiazolidinediones (Glitazones)
Syn. Route 3
Route 1
the reaction of 2-chloropyridine (i) with 2-(methyl-amino)ethanol (ii) by heating at 150 c gives 2-[n-methyl-n-(2-pyridyl)amino]ethanol (iii), which is condensed with 4-fluorobenzaldehyde (iv) by means of nah in dmf, yielding 4-[2-[n-methyl-n-(2-pyridyl)amino]-ethoxy]benzaldehyde (v) (1-3). the reaction of (v) with thiazolidine-2,4-dione (vi) by means of piperidinium acetate in refluxing toluene affords 5-[4-[2-[n-methyl-n-(2-pyridyl)- amino]ethoxy]benzylidene]thiazolidine-2,4-dione (vii). finally, this compound is reduced with h2 over pd/c (1), mg in methanol (2,3) or biocatalytically by incubation with whole cells of the yeast rhodotorula rubra cbs 6469 at ph 7.5-8.0 (4-6). under acidic conditions, ph 3.0-5.0, this microbial biotransformation is enantioselective, giving the (+)-(r)-enantiomer of rosiglitazone.
List of intermediates No.
6-bromo-2-methylquinoline (vi)
methyl (1r,2s,3r)-3-acetyl-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylate (iv)
tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11h-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate (ii)
ethyl (3ar,5r,7r,7as)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate (i)
ethyl (3ar,7r,7ar)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate (iii)
ethyl (3r,4r,5r)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate (v)
ethyl (3r,4s,5r)-5-azido-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate (vii)
Reference 1:
    jones, j.j.; verrall, m.s.; heath, c.m.; imrie, r.c.; rees, m.j.; robins, k.g.; whole cell biotransformation of 5-(4-(2-(2-pyridyl)methylamino)ethoxy)benzylidenethiazolidine-2,4-dione to its benzyl derivative using a yeast reductase. j chem tech biotech 1997, 68, 324-30.
Reference 2:
    cantello, b.c.c.; haigh, d.; eggleston, d.s.; jennings, k.r.; heath, c.m.; sime, j.t.; haltiwanger, r.c.; woroniecki, s.r.; hindley, r.m.; facile biocatalytic reduction of the carbon-carbon double bond of 5-benzylidenethiazolidine-2,4-diones. synthesis of (?-5-(4-(2-[methyl(2-pyridyl)amino]ethoxy)benzyl)-thiazolidine-2,4-dione (brl 49653), its (r)-(?-enantiomer and analogues. j chem soc - perkins trans i 1994, 22, 22, 3319-24.
Reference 3:
    thurlby, p.l.; lister, c.a.; duff, p.t.; hindley, r.m.; cottam, g.p.; haigh, d.; smith, s.a.; cantello, bb.c.c.; cawthorne, m.a.; [[*-(heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. j med chem 1994, 37, 23, 3977-85.
Reference 4:
    sorbera, l.a.; rabasseda, x.; leeson,p.a.; rosiglitazone maleate. drugs fut 1998, 23, 9, 977.
Reference 5:
    hindley, r.m. (smithkline beecham plc); substd. thiazolidine-dione derivs. au 8821738; ep 0306228; ep 0842925; jp 1989131169; jp 1997183726; jp 1997183771; jp 1997183772; jp 1998194970; jp 1998194971; us 5002953; us 5194443; us 5232925; us 5646169 .
Reference 6:
    hindley, r.m.; woroniecki, s.r. (smithkline beecham plc); process for the preparation of pharmaceutically active thiazolidine or oxazolidine cpds. by a yeast reductase. wo 9310254 .
Reference 7:
    vyas, s.k. (torrent pharmaceuticals ltd.); process for the preparation of rosiglitazone maleate. us 2002115866; us 6515132; wo 0251823 .
Reference 8:
    smith, s.a.; thurlby, p.l.; cantello, b.c.c.; haigh, d.; cawthorne, m.a.; hindley, r.m.; the synthesis of brl 49653 - a novel and potent antihyperglycaemic agent. bioorg med chem lett 1994, 4, 10, 1181-4.

Route 2
the bromination of rosiglitazone (i) with nbs in hot acetic acid gives the dibromo compound (ii), which is the hydrogenated with tritium over pd/baso4 in dmf/tea to yield the target labeled compound.
List of intermediates No.
Reference 1:
    kirefu, t.; landwater, s.w.; latter, a.j.; lawrie, k.w.m.; morecombe, d.j.; willcocks, k.; rosiglitazone maleate (brl 49653-c); the preparation of [14c] and [3h] isotopomers. j label compd radiopharm 2001, 44, 5, 329.

Route 3
the reaction of 4-fluoroiodobenzene (i) with 14c-kcn and cui in refluxing dmf gives 4-fluorobenzonitrile (ii), which is reduced with hco2h and rani in dmf to yield 4-fluorobenzaldehyde (iii). the condensation of (iii) with the substituted ethanolamine (iv) by means of tbu-ok in dmf affords 4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzaldehyde (v), which is condensed with thiazolidine-2,4-dione (vi) by means of piperidine acetate in refluxing toluene to provide the benzylidene-thiazolidinedione (vii). finally this compound is hydrogenated with h2 over pd/c in dmf to furnish the target labeled compound.
List of intermediates No.
6-bromo-2-methylquinoline (vi)
ethyl (3ar,7r,7ar)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate (iv)
Reference 1:
    kirefu, t.; landwater, s.w.; latter, a.j.; lawrie, k.w.m.; morecombe, d.j.; willcocks, k.; rosiglitazone maleate (brl 49653-c); the preparation of [14c] and [3h] isotopomers. j label compd radiopharm 2001, 44, 5, 329.

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马来酸罗格列酮;英文名Rosiglitazone maleate;SB-206846((-)-enantiomer;free base);SB-210232((+)-enantiomer;free base);BRL-49653C;Venvia;Nyracta;Avandia;CAS[155141-29-0]

 
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