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Name Bepotastine besilate;Betotastine besilate;TAU-284DS;TAU-284;Talion
Chemical Name (+)-(S)-4-[4-[1-(4-Chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]butyric acid monobenzenesulfonate
      (+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidin-1-yl]butyric acid monobenzenesulfonate
CAS 190786-44-8
Related CAS 190786-43-7 (free base), 125602-71-3 (free base undefined isomer)
Formula C27H31ClN2O6S
Structure
Formula Weight 547.07492
Stage 上市-2000
Company Ube (Originator), Senju (Licensee), Tanabe Seiyaku (Licensee)
Activity/Mechanism Allergic Skin Disorders, Treatment for, Antiallergic Ophthalmic Agents, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists
Syn. Route 2
Route 1
the reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (i) with ethyl 4-bromobutyrate (ii) by means of k2co3 in refluxing acetone gives the corresponding condensation product (iii), which is then hydrolyzed with naoh in ethanol/water yielding compound (iv).
List of intermediates No.
(6r,7s,9s,11r,12r,13s)-14-ethyl-9-fluoro-4,6,7,12,13-pentahydroxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione (ii)
(2s,3r,4s,6r)-4-(dimethylamino)-2-[((3r,5r,6r,7s,9r,11r,12r,13s,14r)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-7-[[(e)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-6-methyltetrahydro-2h-pyran-3-yl benzoate (i)
tert-butyl 2-[(z)-[4-(1,3-thiazol-2-yl)phenyl]methylidene]-1-hydrazinecarboxylate (iii)
tert-butyl 2-[4-(1,3-thiazol-2-yl)benzyl]-1-hydrazinecarboxylate (iv)
Reference 1:
    castaner, j.; graul, a.; betotastine besilate. drugs fut 1998, 23, 3, 256.
Reference 2:
    koda, a.; kuroki, y.; fujiwara, h.; takamura, s.; yamano, k. (ube industries, ltd.); piperidine and piperazine derivs., process for preparing the same and pharmaceutical compsns. containing them. ep 0335586; jp 1989242574; jp 1990025465; jp 1993294929; us 4929618 .

Route 2
a new synthesis of betotastine has been developed: the racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (i) is submitted to optical resolution with n-acyl amino acids such as n-acetyl-l-phenylalanine (preferred), n-acetyl-l-leucine, n-(benzyloxycarbonyl)-l-phenylalanine, n-(benzyloxycarbonyl)-l-valine, n-(benzyloxycarbonyl)-l-threonine, n-(benzyloxycarbonyl)-l-serine or with (2r,3r)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2r,3r)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (s)-isomer (ii). the condensation of (ii) with ethyl 4-bromobutyrate (iii) by means of a base such as na2co3, nahco3, k2co3 or khco3 gives the expected 4-(1-piperidinyl)butyric acid ester (iv), which is finally hydrolyzed with naoh or koh in aqueous ethanol or methanol.
List of intermediates No.
(6r,7s,9s,11r,12r,13s)-14-ethyl-9-fluoro-4,6,7,12,13-pentahydroxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione (iii)
(2s,3r,4s,6r)-4-(dimethylamino)-2-[((3r,5r,6r,7s,9r,11r,12r,13s,14r)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-7-[[(e)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-6-methyltetrahydro-2h-pyran-3-yl benzoate (i)
2-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]acetic acid (ii)
1-bromo-3,4-dihydro-1h-isochromene (iv)
Reference 1:
    kita, j.; yoshioka, r.; ozaki, y.; takemura, s.; fujiwara, h.; yamada, s. (tanabe seiyaku co., ltd.; ube industries, ltd.); acid-addition salts of optically active piperidine cpd. and process for producing the same. jp 1998237070; jp 2000198784; wo 9829409 .

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苯磺酸贝托司汀;英文名Bepotastine besilate;Betotastine besilate;TAU-284DS;TAU-284;Talion;CAS[190786-44-8]

 
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