WO2009125426A2 - NOUVEAU PROCÉDÉ DE PRODUCTION D'HYDROBROMURE DE (3SM-[2-(2 J-DIHYDRO-5- BENZOFURANYL)ÉTHYL]-α.α -DIPHÉNYL-3-PYRROLIDINEACÉTAMIDE - Google Patents

NOUVEAU PROCÉDÉ DE PRODUCTION D'HYDROBROMURE DE (3SM-[2-(2 J-DIHYDRO-5- BENZOFURANYL)ÉTHYL]-α.α -DIPHÉNYL-3-PYRROLIDINEACÉTAMIDE Download PDF

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Publication number
WO2009125426A2
WO2009125426A2 PCT/IN2009/000088 IN2009000088W WO2009125426A2 WO 2009125426 A2 WO2009125426 A2 WO 2009125426A2 IN 2009000088 W IN2009000088 W IN 2009000088W WO 2009125426 A2 WO2009125426 A2 WO 2009125426A2
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WO
WIPO (PCT)
Prior art keywords
formula
ethyl
dihydro
benzofuran
compound
Prior art date
Application number
PCT/IN2009/000088
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English (en)
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WO2009125426A3 (fr
Inventor
Arul Ramakrishnan
S. Kapkoti Gobind
Arshad Moosa Hashmi
Aliva Sahoo
Original Assignee
Neuland Laboratories Ltd
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Publication date
Application filed by Neuland Laboratories Ltd filed Critical Neuland Laboratories Ltd
Publication of WO2009125426A2 publication Critical patent/WO2009125426A2/fr
Publication of WO2009125426A3 publication Critical patent/WO2009125426A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This compound of formula IV was reacted with methyl p-toluenesulphonate in presence of triphenylphosphine and diethylazodicarboxylate to furnish l-tosyl-3-(S)- tosyloxypyrrolidine a compound of formula V which was condensed with diphenylacetonitrile in the presence of sodium hydride to afford 3-(R 5 S)-(I -cyano- l,l-diphenylmethyl)l-tosylpyrrolidine a compound of formula VI which underwent deprotection in the presence of aqueous hydrobromic acid to afford 3-(R,S)-(l-cyano-l,l-diphenylmethyl)pyrrolidine a compound of formula VII.
  • the present invention further provides a process for the preparation of (3S)-3-substituted-l-[2-(2,3- dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine of Formula XXVII, in a single step by the reaction of (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV with a halogenating agent, like thonyl chloride, oxalyl chloride, phosphorous oxychloride preferably thionyl chloride in the presence of catalytic amount of N,
  • a halogenating agent like thonyl chloride, oxalyl chloride, phosphorous oxychloride preferably thionyl chloride in the presence of catalytic amount of N
  • the present invention further provides a process for the preparation of N-(ethyl-2,3- dihydrobenzofuran)-3-substituted-pyrrolidine of Formula XXVII, in a single step by the reaction of N- (ethyl-2,3-dihydrobenzofuran)-3-hydroxypyrrolidine of Formula XXV with a halogenating agent, like thonyl chloride, oxalyl chloride, phosphorous oxychloride preferably thionyl chloride in the presence of catalytic amount of N,N-dimethylformamide in presence of hydrocarbon solvent such as toluene, xylene, n- heptane, n-hexane, cyclohexane, methylcyclohexane and or chlorinated solvents such as dichloromethane, ethylene chloride, chloroform, methylene chloride and a mixture thereof.
  • the preferred solvent is methylene dichloride.
  • Inversion of configuration for (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5-yl)ethyl]pyrrolidin-3-ol of Formula XXV is conducted by a in situ reaction consisting of Mitsunobu reaction followed by the hydrolysis of the ester to give the inverted alcohol.
  • the Mitsunobu reaction was performed using a reagent selected from either diethylazodicarboxylate or diisopropylazodicarboxylate or Di-p- chlorobenzylazodiacrboxylate, more preferably diethylazodicarboxylate along with triphenyl phosphine.
  • the hydrolysis of the crude product was performed using a suitable alkali metal hydroxide, selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, more preferably lithium hydroxide.
  • phase transfer catalyst selected from tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimethyl benzyl ammonium chloride more preferably tetra-n-butyl ammonium bromide, in the presence of a base selected from potassium or sodium hydroxide, more preferably potassium hydroxide, in a suitable alcoholic solvent such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert butanol, more preferably n- butanol .
  • phase transfer catalyst selected from tetra-n-butyl ammonium bromide, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimethyl benzyl ammonium chloride more preferably tetra-n-butyl ammonium bromide,
  • the compound (3S)-3-substituted-l-[2-(2,3-dihydro-l-benzofuran-5-yl)ethyl] pyrrolidine of Formula XXVII could also be prepared from (3R)-l-[2-(2,3-Dihydro-l-benzofuran-5- yl)ethyl]pyrrolidin-3-ol of Formula XXV, by an SN 2 reaction , where the preferred substituent is the chloro group.
  • the preferred mode of reaction being the addition of a catalytic amount of aprotic solvent selected from N,N-Dimethylformamide, N,N-Dimethylavetamide, N,N-Dimethylsulfoxide, preferably, N,N-Dimethylformamide along with a chlorinated solvent followed by the addition of the halogenating agent, preferably thionyl chloride.
  • aprotic solvent selected from N,N-Dimethylformamide, N,N-Dimethylavetamide, N,N-Dimethylsulfoxide, preferably, N,N-Dimethylformamide along with a chlorinated solvent followed by the addition of the halogenating agent, preferably thionyl chloride.
  • the solution was stirred at a temperature of about 35°C to 50 0 C for a period of 2 to 5 hours.
  • Darifenacin hydrobromide of Formula I as obtained by this process has HPLC purity of more than 99.5 % and having other isomer less than 0.5 % of (3R)l-[2-(2,3-Dihydro-5-benzofuranyl)ethyl]- ⁇ , ⁇ - diphenyl-3-pyrrolidineacetamide.
  • Darifenacin hydrobromide prepared as in the present invention and as described in Example 6 hereafter, has the characteristic XRPD peak values as shown in Table 1 below.
  • the X-ray powder diffractogram is depicted in Figure I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé, à viabilité industrielle et rentable, de production d'hydrobromure de (3S)- 1-[2-(2,3-dihydro-5- benzofuranyl)éthyl]-α.α -diphényl-3-pyrrolidineacétamide également connu sous le nom d'hydrobromure de darifénacine.
PCT/IN2009/000088 2008-02-08 2009-02-09 NOUVEAU PROCÉDÉ DE PRODUCTION D'HYDROBROMURE DE (3SM-[2-(2 J-DIHYDRO-5- BENZOFURANYL)ÉTHYL]-α.α -DIPHÉNYL-3-PYRROLIDINEACÉTAMIDE WO2009125426A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN330CH2008 2008-02-08
IN330/CHE/2008 2008-02-08

Publications (2)

Publication Number Publication Date
WO2009125426A2 true WO2009125426A2 (fr) 2009-10-15
WO2009125426A3 WO2009125426A3 (fr) 2010-04-29

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PCT/IN2009/000088 WO2009125426A2 (fr) 2008-02-08 2009-02-09 NOUVEAU PROCÉDÉ DE PRODUCTION D'HYDROBROMURE DE (3SM-[2-(2 J-DIHYDRO-5- BENZOFURANYL)ÉTHYL]-α.α -DIPHÉNYL-3-PYRROLIDINEACÉTAMIDE

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030191176A1 (en) * 2002-03-26 2003-10-09 Pfizer Inc. Stable hydrate of a muscarinic receptor antagonist
WO2008000418A2 (fr) * 2006-06-27 2008-01-03 Sandoz Ag Nouveau procédé de préparation de sel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030191176A1 (en) * 2002-03-26 2003-10-09 Pfizer Inc. Stable hydrate of a muscarinic receptor antagonist
WO2008000418A2 (fr) * 2006-06-27 2008-01-03 Sandoz Ag Nouveau procédé de préparation de sel

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WO2009125426A3 (fr) 2010-04-29

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