WO2016162878A1 - Procédé avantageux de préparation de bromure de 1-azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thiénylacétyl)oxy]-1-(3-phénoxypropyle), (3r)- et de sa nouvelle forme cristalline i - Google Patents

Procédé avantageux de préparation de bromure de 1-azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thiénylacétyl)oxy]-1-(3-phénoxypropyle), (3r)- et de sa nouvelle forme cristalline i Download PDF

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Publication number
WO2016162878A1
WO2016162878A1 PCT/IN2015/000331 IN2015000331W WO2016162878A1 WO 2016162878 A1 WO2016162878 A1 WO 2016162878A1 IN 2015000331 W IN2015000331 W IN 2015000331W WO 2016162878 A1 WO2016162878 A1 WO 2016162878A1
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WO
WIPO (PCT)
Prior art keywords
solvent
octane
bromide
azoniabicyclo
hydroxydi
Prior art date
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PCT/IN2015/000331
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English (en)
Inventor
Vijay Trimbak KADAM
Dhananjay Uddhavrao Edaki
Nagaraju Oruganti
Harpreet Singh Minhas
Gurpreet Singh Minhas
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Harman Finochem Limited
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Publication of WO2016162878A1 publication Critical patent/WO2016162878A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine

Definitions

  • the present invention relates to an industrially feasible process for preparation of 1- Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-'phenoxypropyl)-, bromide, (3R)- and its novel crystalline form-I.
  • ⁇ - Azoniabicyclo [2.2.2] octane,3 - [(hydroxy di-2-thienylacetyl)oxy] - 1 -(3phenoxypropyl)-, bromide, (3R)- , quaternary ammonium compound, is s an anticholinergic agent with specificity for muscarinic receptors and prescribed for treatment for chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • example- 37 describes the process for preparing 1- Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]- 1 -(3-phenoxypropyl)-, bromide, (3R)- according to methods c and a.
  • reaction of (Furan-2-yl)-hydroxy-phenylacetic acid methyl ester with 3-(R)-hydroxy-l-azabicyclo[2.2.2]octane in presence of sodium hydride (60% dispersion in mineral oil), toluene to obtain mixture of diasteroisomers which is further crystallized about four times with acetonitrile to get pure (Furan-2- yl)hydroxyphenylacetic acid l-azabicyclo[2.2.2]oct-3(R)-yl ester is described.
  • the main object of the present invention is to provide a process that does not involve highly flammable compounds which are difficult to handle.
  • the process disclosed in the current invention involves cheaper reactants, solvents as compared to prior art which makes the process cost effective. More over the process does not involve more than one time purification and the purification process does not involve any costly technique/equipment, however, carried out with solvents which are industrially feasible. Due to less crystallization steps and higher solubility of reactants in organic solvents the present invention results in the product with higher yield and purity over prior art.
  • the present invention provides the process for preparation of 1- Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- (Formula-I) and its novel crystalline form-I.
  • the present invention describes the process for purification of intermediate methyl hydroxyl (dithiophen-2-yl) acetate which comprises;
  • the instant invention discloses the process for preparing (R)-l- azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate from Methyl hydroxy (dithiophen-2-yl) acetate which comprises;
  • the present invention discloses the process for preparing 1- Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- from (R)-l-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate which comprises, (a) Reacting l-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate with 1- bromo phenoxy propane in presence of mixture of polar-aprotic solvent and non- polar solvent and
  • the present invention provides the process for purification of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- which comprises; ,
  • the instant invention provides process for purification of 1- Azoniabicyclo [2.2.2] octane,3 - [(hydroxy di-2-thienylacetyl)oxy] - 1 -(3 -phenoxypropyl)-, bromide, (3R)- which comprises;
  • the instant invention provides process for purification of 1- Azoniabicyclo [2.2.2] octane,3 - [(hydroxy di-2-thienylacetyl)oxy] - 1 -(3 -phenoxypropyl)-, bromide, (3R)- which comprises;
  • the present invention provides the process for preparing novel crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l- (3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • the instant invention provides process for preparing novel crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l- (3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • the instant invention provides process for preparing novel crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l- (3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • the present invention discloses the process for preparing impurity, i.e. s- isomer of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3- phenoxypropyl)-, bromide, (3R)- (formulaTVI) and its intermediate- (S)-l- azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl) (formula-VII) which comprises;
  • Fig.l shows the XPRD pattern of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in Methanol, prepared as per example 17
  • Fig.2 shows the XPRD pattern of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DMF/IPA prepared as per example 15
  • Fig.3 shows the XPRD pattern of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3 )- crystalline form-I in DMF/ Acetone prepared as per example 12
  • Fig.4 shows the XPRD pattern of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DM Ac/ Acetone prepared as per example 14
  • Fig.5 shows the XPRD pattern of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in EA/Methanolprepared as per example 13
  • Fig.6 shows the XPRD pattern of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- crystalline form-I in DMSO/Acetoneprepared as per example 16
  • the instant invention provides an efficient, advantageous and economical process for preparing 1 -Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]- 1 -(3- phenoxypropyl)-, bromide, (3R)- (Formula-I)and its novel crystalline form-I.
  • the present invention describes the process for purification of intermediate methyl hydroxyl (dithiophen-2-yl) acetatewhich comprises;
  • the non-polar solvent is selected from the group consisting of Toluene, cyclohexane, Dichloromethane, Hexane, 1,4-Dioxane, Chloroform, Diethyl ether.
  • the heating temperature is 50-55°C.
  • the instant invention discloses the process for preparing(R)-l- azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl)acetate from Methyl hydroxy (dithiophen-2-yl) acetate which comprises;
  • metalalkoxide refers to sodiummethoxide (sodium methylate).
  • solvent refers to linear or cycloalkane is selected from the group consisting of pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane.
  • the reaction is carried out at 80 to 85°C.
  • methanol layer is separated which can be discarded easily, the removal of which helps to protect the reaction from hydrolysis of Methylhydroxy (dithiophen-2-yl) acetate.
  • the present invention discloses the process for preparing 1- Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- of formula I from (R)-l-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2- yl)acetate which comprises,
  • the polar-aprotic solvent is selected from the group consisting of acetonitrile,dimethylsulfoxide, dimethylformamide, acetone, ethyl acetate, tetrahydrofuran.
  • the non-polar solvent is selected from the group consisting of Chloroform,Dichloromethane, Toluene, Hexane, 1 ,4-Dioxane, Diethyl ether. According to above process the reaction temperature is 25 to 30°C.
  • the present invention provides the process for purification of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • polar aprotic solvent is selected from the group consisting of dimethylformamide, acetone, acetonitrile,dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetate.
  • the heating temperature is 70-80°C and cooling temperature ranges from 0-5°C.
  • the instant invention provides process for purification of 1 - Azoniabicyclo[2.2.2]octane,3 - [(hydroxy di-2-thienylacetyl)oxy] - 1 -(3 -phenoxypropyl)-, bromide, (3R)- which comprises;
  • the polar aprotic solvent is selected from the group consisting of ethyl acetate, dimethylformamide, acetone," acetonitrile,dimethyl sulfoxide, ,tetrahydrofuran.
  • the polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water.
  • the heating temperature is 60- 75°C and cooling temperature ranges from 0-5°C.
  • the instant invention provides process for purification of 1- Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • the polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water.
  • the heating temperature is 60-65°C and cooling temperature ranges from 0-5°C.
  • the invention further encompasses a novel crystalline form, which is designated herein below as Form-1 and process for preparation thereof.
  • the present invention provides the process for preparing novel crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • polar aprotic solvent is selected from the group consisting of dimethylformamide, acetone, acetonitrile,dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetate.
  • the heating temperature is 70-80°C and cooling temperature ranges from 0-5°C.
  • the instant invention provides process for preparing novel crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l- (3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • the polar aprotic solvent is selected from the group consisting of ethyl acetate, dimethylformamide, acetone, acetonitrile ,dimethyl sulfoxide, tetrahydrofuran.
  • the polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water.
  • the heating temperature is 60- 75°C and cooling temperature ranges from 0-5°C.
  • the instant invention provides process for preparing novel crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l- (3-phenoxypropyl)-, bromide, (3R)- which comprises;
  • the polar protic solvent is selected from the group consisting of methanol, ethanol, nitromethane, isopropanol, n-butanol, formic acid, Acetic acid, Water.
  • the heating temperature is 60-65°C and cooling temperature ranges from 0-5°C.
  • novel crystalline form-I according to the present invention is characterised by PXRD with peaks at 2 ⁇ values by at least one characteristic peak (expressed in 2 ⁇ ) at 7.88, 13.28, 13.95, 14.03, 20.77, 21.09, 23.34, 24.49, 25.97, 26.37, 29.49, 31.21 ⁇ 0.2.
  • the present invention discloses the process for preparing impurity, i.e. s- isomer of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thienylacetyl)oxy]-l-(3- phenoxypropyl)-, bromide, (3R)- (formula- VI) and its intermediate- (S)-l- azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2-yl) (formula-VII) which comprises;
  • metal alkoxide refers to sodium methoxide (sodium methylate).
  • solvent refers to linear or cyclo alkane is selected from the group consisting of pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane. According to above process, the reaction is carried out at 80 to 85°C.
  • the polar-aprotic solvent is selected from the group consisting of acetonitrile,dimethyl sulfoxide, dimethylformamide, acetone, ethyl acetate, tetrahydrofuran.
  • the non-polar solvent is selected from the group consisting of Chloroform, Dichloromethane, Toluene, Hexane, 1,4-Dioxane, Diethyl ether. According to above process the reaction temperature is 25 to 30°C.
  • Example-1 Purification of Methyl hydroxy (dithiophen-2-yl) acetate
  • Example-2 Preparation of l-azabicyclo[2.2.2]oct-3-ylhydroxy(dithiophen-2- yl)acetate
  • Example-4 Purification of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-
  • Example 5 Purification of 1-Azoniabicyclo [2.2.2] octane,3-[(hydroxydi-2- thienylaceryl)oxy]-l-(3-phenoxypropyI)-, bromide, (3R)-
  • Example 6 Purification of 1-Azoniabicyclo [2.2.2] octane,3-[(hy droxydi-2- thieny!acetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-
  • Example 7 Purification of l-Azoniabicyclo(2.2.2]octane,3-[(hydroxydi-2- thienylacetyl)oxy]-l-(3-phenoxypropyI)-, bromide, (3R)-
  • Example 8 Purification of l-Azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2- thienylacety oxyj-l-p- henoxypropyl)-, bromide, (3R)-
  • Example-12 Preparation of crystalline form -I of 1-Azoniabicyclo [2.2.2] octane,3- [(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-
  • Example 13 Preparation of crystalline form-I of l-AzoniabicycIo[2.2.2]octane,3- [(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-
  • Example 14 Preparation of crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3- [(hydroxydi-2-thienylacetyI)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-
  • Example 15 Preparation of crystalline form-I of l-Azoniabicydo[2.2.2]octane,3- [(hydroxydi-2-thienylacetyl)oxy]-l-(3-phenoxypropyI)-, bromide, (3R)-
  • Example 16 Preparation of crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3- [(hydroxydi-2-thienyIacetyl)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-
  • Example 17 Preparation of crystalline form-I of l-Azoniabicyclo[2.2.2]octane,3- [(hydroxydi-2-thienylacetyI)oxy]-l-(3-phenoxypropyl)-, bromide, (3R)-

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

Abstract

La présente invention concerne un procédé de préparation de bromure de 1-azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thiénylacétyl)oxy]-1-(3-phénoxypropyle)-, (3R)- et de sa nouvelle forme cristalline I.
PCT/IN2015/000331 2015-04-04 2015-08-24 Procédé avantageux de préparation de bromure de 1-azoniabicyclo[2.2.2]octane,3-[(hydroxydi-2-thiénylacétyl)oxy]-1-(3-phénoxypropyle), (3r)- et de sa nouvelle forme cristalline i WO2016162878A1 (fr)

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IN1423/MUM/2015 2015-04-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019129801A1 (fr) 2017-12-28 2019-07-04 Linnea S.A. Procédé de purification du methyl-2,2-dithiénylglycolate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004118A2 (fr) * 1999-07-14 2001-01-18 Almirall Prodesfarma S.A. Nouveaux derives de quinuclidine et compositions medicales les contenant
WO2008009397A1 (fr) * 2006-07-21 2008-01-24 Laboratorios Almirall, S.A. Procédé de préparation de bromure de 3(r)-(2-hydroxy-2,2-dithièn-2-ylacétoxy)-1-(3- phénoxypropyl)-1 -azoniabicyclo[2.2.2]octane

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004118A2 (fr) * 1999-07-14 2001-01-18 Almirall Prodesfarma S.A. Nouveaux derives de quinuclidine et compositions medicales les contenant
WO2008009397A1 (fr) * 2006-07-21 2008-01-24 Laboratorios Almirall, S.A. Procédé de préparation de bromure de 3(r)-(2-hydroxy-2,2-dithièn-2-ylacétoxy)-1-(3- phénoxypropyl)-1 -azoniabicyclo[2.2.2]octane

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019129801A1 (fr) 2017-12-28 2019-07-04 Linnea S.A. Procédé de purification du methyl-2,2-dithiénylglycolate

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