WO2024251812A1 - A process for the preparation of umeclidinium bromide intermediate - Google Patents

A process for the preparation of umeclidinium bromide intermediate Download PDF

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WO2024251812A1
WO2024251812A1 PCT/EP2024/065458 EP2024065458W WO2024251812A1 WO 2024251812 A1 WO2024251812 A1 WO 2024251812A1 EP 2024065458 W EP2024065458 W EP 2024065458W WO 2024251812 A1 WO2024251812 A1 WO 2024251812A1
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solvent
process according
ethanol
piperidine
anyone
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Inventor
Ester Masllorens Llinas
Sridhar Pratha
Kollapudi CHANDRABABU
Subhash YENUPURI
Divakara LAXMAN SOMAYAJULU NORI
Hari PRASAD VEERA VENKATA NACHARLA
Pradeep MAVUDURU
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Pharmazell GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

  • the present invention relates to a process for the preparation of ethyl 1-(2-chloroethyl)piperidine- 4-carboxylate (IV).
  • the present invention also relates to a process for the preparation of Umeclidinium Bromide (I).
  • Umeclidinium bromide (I) is chemically known as 4-[hydroxy(diphenyl)methyl]-1-[2- (phenylmethyl)oxy]ethyl]-1- azoniabicyclo[2.2.2.]octane bromide.
  • Umeclidinium bromide (I) is an effective anticholinergic agent and has been used in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary diseases (COPD).
  • the chemical structure of the drug is represented by formula (I).
  • Umeclidinium is a long-acting muscarinic antagonist (LAMA) used as maintenance treatment for symptoms of chronic obstructive pulmonary disease (COPD). It is used as an inhalation monotherapy or as a fixed-dose combination product with the long-acting beta2-agonist vilanterol.
  • LAMA long-acting muscarinic antagonist
  • COPD chronic obstructive pulmonary disease
  • COPD is a progressive obstructive lung disease characterized by shortness of breath, cough, sputum production, and chronically poor airflow with a forced expiratory volume in 1 second (FEV1) of less than 80%.
  • FEV1 forced expiratory volume in 1 second
  • Umeclidinium bromide is claimed in WO 2005/104745 A2.
  • WO 745 A2 also discloses a process for the preparation of Umeclidinium bromide as follows.
  • ethyl 1-(2-chloroethyl)piperidine-4-carboxylate of formula (IV) is synthesized by reacting 1-bromo-2-chloroethane and ethyl isonipecotate (V) in the presence of potassium carbonate in acetone.
  • the compound of formula (IV) is prepared in very low yields (40%), due to the formation of a dimer by-product, diethyl 1 , 1 '-(ethane-1 ,2-diyl)bis(piperidine-4- carboxylate) (IV-A), which must be separated from the primary compound by chromatographic techniques.
  • WO 2014/027045 A1 claims an alternative two-step process for the preparation of the compound of formula (IV) in better yield (80%) as follows: Ethy p per ne- - carboxylate
  • WO 2016/071792 A1 claims a one-step process for the preparation of compound of formula (IV) which comprises the reaction of ethyl isonipecotate (V) with halogenated acetaldehyde in a mixture of methanol: acetic acid together with a reducing agent as follows:
  • Umeclidinium bromide intermediate (IV) becomes difficult on commercial scale via routes of synthesis disclosed in art.
  • an object of the present invention is to provide a process to overcome aforesaid problems and to provide simple, cost effective and industrially feasible processes for manufacture of Umeclidinium bromide and intermediates thereof.
  • the main objective of the present invention is to provide a process for the preparation of Umeclidinium bromide and its intermediates with high purity and good yield, on commercial scale and substantially free of impurities.
  • the principle object of the present invention is to provide a process for the preparation of ethyl 1- (2-chloroethyl)piperidine-4-carboxylate (IV), which comprises: a) reacting isonipecotic acid of formula (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; and b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
  • Another object of the present invention is to provide a process for the preparation of Umeclidinium bromide, which involves the steps of: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV); c) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV) with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); d) reacting ethyl
  • the present invention provides a process for the preparation of ethyl 1-(2- chloroethyl)piperidine-4-carboxylate (IV), which comprises: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; and b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
  • the reaction comprises, reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent at a temperature between 20-50°C to form 1-(2-hydroxyethyl)piperidine-4- carboxylic acid (VI).
  • a base and a solvent at a temperature between 20-50°C
  • a solvent at a temperature between 20-50°C
  • removing salt by conventional techniques and isolating the product 1-(2-hydroxyethyl)piperidine-4-carboxylic acid by adjusting the pH with con.
  • HCI is performed.
  • the 2-halo ethanol is selected from 2-bromo ethanol or 2-chloro ethanol.
  • the reaction is carried out at a temperature of 30-60°C, preferably 45°C.
  • the reaction is carried out in presence of an inorganic bases such as preferably selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate or mixtures thereof; in an solvent selected from alcohols, as for example methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably methanol.
  • an inorganic bases such as preferably selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caes
  • reaction comprises, reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and solvent to form ethyl 1-(2-chloroethyl)piperidine-4- carboxylate (IV).
  • the reaction is carried out at a temperature of 30-70°C, preferably 55°C.
  • the reaction is carried out in presence of a reagent such as selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
  • a reagent such as selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
  • the reagent is thionyl chloride.
  • the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably ethanol.
  • the present invention provides a process for the preparation of Umeclidinium bromide, which involves the steps of: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV); c) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV) with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); d) reacting ethyl 1-aza
  • Step a) of the above process of the present invention is carried out reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent at a temperature between 30-60°C to form 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI).
  • VI 1-(2-hydroxyethyl)piperidine-4-carboxylic acid
  • Step a) of the above process of the present invention is carried out reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent at a temperature between 30-60°C to form 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI).
  • removing salt by conventional techniques and isolating the product 1-(2-hydroxyethyl)piperidine-4-carboxylic acid by adjusting the pH with Con HCI.
  • the 2-halo ethanol is selected from 2-bromo ethanol or 2-chloro ethanol.
  • the reaction is carried out at a temperature of 30-60°C, preferably 45°C.
  • the reaction is carried out in presence of an in-organic bases such as preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate or mixtures thereof; in an solvent selected from alcohols for example methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably methanol.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate
  • alkali metal bicarbonates
  • Step b) of the above process of the present invention is carried out reacting 1-(2- hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
  • the reaction is carried out at a temperature of 30-70°C, preferably 55°C.
  • the reaction is carried out in the presence of a reagent such as selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
  • a reagent such as selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
  • the reagent is thionyl chloride.
  • the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably ethanol.
  • Step c) of the above process of the present invention is carried out by reacting ethyl 1-(2- chloroethyl)piperidine-4-carboxylate (IV) with suitable base and solvent at a temperature between 30-60°C to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III).
  • the solvent used in step c) may be selected from the group consisting of cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; ethers such as dibutyl ether; cyclohexane and mixtures thereof.
  • the base used in step c) is selected from KHMDS, LiHMDS and NaHMDS.
  • Step d) of the above process of the present invention is carried out by reacting ethyl 1- azabicyclo[2.2.2]octane-4-carboxylate (III) with phenyl magnesium bromide in the presence of solvent at a temperature between 20-80°C to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (II).
  • the solvent used in step d) may be selected from the group consisting of cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; or mixtures thereof.
  • the most preferred solvent is toluene.
  • the product can be isolated by conventional known techniques like filtration and dried preferably under vacuum with a purity of > 99.0%.
  • Step e) of the above process of the present invention is carried out by reacting a compound of formula (II) with ((2-bromoethoxy)methyl)benzene in the presence of an alcoholic solvent at a temperature of 40-80°C, preferably 60°C to form Umeclidinium bromide and isolation is carried out in the presence of an ester solvent.
  • the alcoholic solvents are selected from methanol, ethanol and isolation is carried out by addition of ester solvent.
  • ester solvent is selected from ethyl acetate, isopropyl acetate, n-butyl acetate etc., preferably ethyl acetate.
  • Step f) of the above process of the present invention is carried out in the presence of an alcoholic solvent or mixture of alcoholic solvent, water and final purification with water.
  • Umeclidinium bromide is carried out by using an alcoholic solvent at a temperature of 40-80°C, preferably 60°C, and preferably cooling the reaction mixture temperature between about 0-25°C, preferably stirring the reaction mass at a temperature between 0-25°C for about 2 hours. Thereafter, the resulting product can be isolated, preferably by filtration.
  • Umeclidinium bromide is carried out by using an alcoholic solvent at a temperature of 40-80°C, preferably 60°C, and preferably adding water to the reaction mixture at a temperature of 40-80°C, preferably 60°C, preferably cooling the reaction mixture at a temperature between about 0-25°C, preferably stirring the reaction mass at a temperature between 0-25°C for about 2 hours. Thereafter, the resulting product can be isolated, preferably by filtration.
  • the alcoholic solvent is selected from methanol or ethanol.
  • the purified product is treated with water by heating the reaction mixture to 40-80°C, preferably 60°C, preferably by cooling the reaction mixture at a temperature between about 0-25°C, preferably by stirring the reaction mass at a temperature between 0-25°C for about 2 hours.
  • the product can be isolated, preferably by filtration and then be dried at a temperature between 35- 55°C, preferably under vacuum, with a purity of > 99.0% by HPLC.
  • Example-1 Process for the preparation of 1-(2-hydroxyethyl) piperidine-4-carboxylic acid hydrochloride (VI)
  • Example-2 Process for the preparation of 1-(2-hydroxyethyl) piperidine-4-carboxylic acid hydrochloride (VI)
  • the toluene layer was concentrated under vacuum, and dissolved in IPA (0.7 volumes) and added IPA. HCI (1.7 volumes) were added at RT. The reaction mixture was heated to 70-80°C and cooled to 0-5°C. The material was filtered under vacuum and washed with IPA (0.7 volumes). The material was dried in an oven under vacuum.
  • Phenyl Magnesium bromide 1 M solution in THF (4.0 moles) was added to a mixture of ethyl quinuclidine-4-carboxylate hydrochloride (1 mole), toluene (5 volumes) at 25-35°C.
  • the reaction mixture was heated to 60-65°C and maintained for 2 hours.
  • the reaction mass was cooled to 20- 30°C and quenched with 26% ammonium chloride solution (28 volumes).
  • the reaction mass was distilled to remove THF, the solid material was filtered and washed with toluene (2 volumes).
  • Ethyl acetate (6 volumes) was charged to the solid material and the mixture was heated to 40-50°C, stirred for few minutes, cooled to 25-30°C and filtered. 10% potassium carbonate solution (18 volumes) was charged to the filtered solid material and stirred for 30-45 minutes. The material was filtered and washed with water (2 volumes). The material was dried in oven under vacuum. Yield: 80%, Purity by HP
  • Phenyl magnesium bromide (1 M solution in THF;4.0 moles) was added to a mixture of ethyl quinuclidine-4-carboxylate hydrochloride (1 mole), toluene (5 volumes) at 25-35°C.
  • the reaction mixture was heated to 60-65°C and maintained for 2 hours.
  • the reaction mass was cooled to 20- 30°C and quenched with 26% ammonium chloride solution (28 volumes).
  • the reaction mass was distilled to remove THF, the solid material was filtered and washed with toluene (2 volumes).
  • Ethyl acetate (6 volumes) was charged to the solid material and the mixture was heated to 50-60°C, stirred for few minutes, cooled to 25-30°C and filtered.

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Abstract

The present invention relates to the process for the preparation of Umeclidinium bromide and to the process for the preparation of intermediates used in the preparation of Umeclidinium bromide.

Description

A PROCESS FOR THE PREPARATION OF UMECLIDINIUM BROMIDE INTERMEDIATE
FIELD OF INVENTION:
The present invention relates to a process for the preparation of ethyl 1-(2-chloroethyl)piperidine- 4-carboxylate (IV).
Figure imgf000002_0001
The present invention also relates to a process for the preparation of Umeclidinium Bromide (I).
Figure imgf000002_0002
BACKGROUND OF THE INVENTION
Umeclidinium bromide (I) is chemically known as 4-[hydroxy(diphenyl)methyl]-1-[2- (phenylmethyl)oxy]ethyl]-1- azoniabicyclo[2.2.2.]octane bromide.
Umeclidinium bromide (I), is an effective anticholinergic agent and has been used in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary diseases (COPD). The chemical structure of the drug is represented by formula (I).
Figure imgf000003_0001
Umeclidinium is a long-acting muscarinic antagonist (LAMA) used as maintenance treatment for symptoms of chronic obstructive pulmonary disease (COPD). It is used as an inhalation monotherapy or as a fixed-dose combination product with the long-acting beta2-agonist vilanterol.
COPD is a progressive obstructive lung disease characterized by shortness of breath, cough, sputum production, and chronically poor airflow with a forced expiratory volume in 1 second (FEV1) of less than 80%. By blocking the M3 muscarinic receptor which is highly expressed in airway smooth muscle of the lungs, Umeclidinium inhibits the binding of acetylcholine and thereby opens up the airways by preventing bronchoconstriction. Its use has been shown to provide clinically significant, sustained improvements in lung function.
Umeclidinium bromide is claimed in WO 2005/104745 A2. WO 745 A2 also discloses a process for the preparation of Umeclidinium bromide as follows.
Figure imgf000004_0001
Umeclidinium bromide
The key intermediate ethyl 1-(2-chloroethyl)piperidine-4-carboxylate of formula (IV) is synthesized by reacting 1-bromo-2-chloroethane and ethyl isonipecotate (V) in the presence of potassium carbonate in acetone. However, the compound of formula (IV) is prepared in very low yields (40%), due to the formation of a dimer by-product, diethyl 1 , 1 '-(ethane-1 ,2-diyl)bis(piperidine-4- carboxylate) (IV-A), which must be separated from the primary compound by chromatographic techniques.
Figure imgf000004_0002
Diethyl l,l’-(ethane-l,2-diyl) bis(piperidine-4-carboxylate)
(IV-A)
WO 2014/027045 A1 claims an alternative two-step process for the preparation of the compound of formula (IV) in better yield (80%) as follows: Ethy
Figure imgf000005_0004
p per ne- -
Figure imgf000005_0001
carboxylate
Figure imgf000005_0002
Ethyl 1 -(2 -chloroethyl) piperidine-4 -carboxylate
Alternatively, WO 2016/071792 A1 claims a one-step process for the preparation of compound of formula (IV) which comprises the reaction of ethyl isonipecotate (V) with halogenated acetaldehyde in a mixture of methanol: acetic acid together with a reducing agent as follows:
Ethy
Figure imgf000005_0005
p per ne- 4-carboxylate
Figure imgf000005_0003
Ethyl 1 -(2 -chloroethyl) piperidine-4 -carboxylate
The preparation of Umeclidinium bromide intermediate (IV) becomes difficult on commercial scale via routes of synthesis disclosed in art.
Accordingly, there is need of a synthetic, eco-friendly, non- hazardous and cost-effective process for the preparation of Umeclidinium bromide and intermediates with high yield and purity thereof that overcomes the above-mentioned drawbacks of the prior art.
Thus, an object of the present invention is to provide a process to overcome aforesaid problems and to provide simple, cost effective and industrially feasible processes for manufacture of Umeclidinium bromide and intermediates thereof.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for the preparation of Umeclidinium bromide and its intermediates with high purity and good yield, on commercial scale and substantially free of impurities. SUMMARY OF THE INVENTION
The principle object of the present invention is to provide a process for the preparation of ethyl 1- (2-chloroethyl)piperidine-4-carboxylate (IV),
Figure imgf000006_0001
which comprises: a) reacting isonipecotic acid of formula (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; and b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
Another object of the present invention is to provide a process for the preparation of Umeclidinium bromide, which involves the steps of: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV); c) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV) with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); d) reacting ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III) with phenyl magnesium bromide in the presence of solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (II); e) reacting compound of formula (II) with ((2-bromoethoxy)methyl)benzene in presence of an alcoholic solvent to form Umeclidinium bromide and isolation is carried out in the presence of an ester solvent; and f) optional recrystallisation of Umeclidinium bromide is carried out in the presence of an alcoholic solvent or mixture of alcoholic solvent, water, and final purification with water.
DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a process for the preparation of ethyl 1-(2- chloroethyl)piperidine-4-carboxylate (IV),
Figure imgf000007_0001
which comprises: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; and b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
The route of synthesis is shown in scheme I:
Isonip
Figure imgf000007_0003
Figure imgf000007_0002
1 -(2-Hydroxyethyl)piperidine- 4-carboxylic acid Ethyl 1 -(2 -chloroethyl) (VI) pi perid ine-4 -carboxylate (IV)
The reaction comprises, reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent at a temperature between 20-50°C to form 1-(2-hydroxyethyl)piperidine-4- carboxylic acid (VI). Optionally thereafter removing salt by conventional techniques and isolating the product 1-(2-hydroxyethyl)piperidine-4-carboxylic acid by adjusting the pH with con. HCI is performed.
Preferably, the 2-halo ethanol is selected from 2-bromo ethanol or 2-chloro ethanol.
The reaction is carried out at a temperature of 30-60°C, preferably 45°C. The reaction is carried out in presence of an inorganic bases such as preferably selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate or mixtures thereof; in an solvent selected from alcohols, as for example methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably methanol.
Further, the reaction comprises, reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and solvent to form ethyl 1-(2-chloroethyl)piperidine-4- carboxylate (IV).
The reaction is carried out at a temperature of 30-70°C, preferably 55°C. The reaction is carried out in presence of a reagent such as selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides. Preferably, the reagent is thionyl chloride.
Further, the acid chloride compound is reacted with an alcoholic solvent to form ethyl 1-(2- chloroethyl)piperidine-4-carboxylate (IV).
The alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably ethanol.
In another aspect, the present invention provides a process for the preparation of Umeclidinium bromide, which involves the steps of: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof; b) reacting 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV); c) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV) with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); d) reacting ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (Illi) with phenyl magnesium bromide in the presence of solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (II); e) reacting compound of formula (II) with ((2-bromoethoxy)methyl)benzene in presence of an alcoholic solvent to form Umeclidinium bromide and isolation is carried out in the presence of an ester solvent.; and f) optional recrystallisation of Umeclidinium bromide is carried out in the presence of an alcoholic solvent or mixture of alcoholic solvent, water, and final purification with water.
Step a) of the above process of the present invention is carried out reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent at a temperature between 30-60°C to form 1-(2-hydroxyethyl)piperidine-4-carboxylic acid (VI). Optionally thereafter removing salt by conventional techniques and isolating the product 1-(2-hydroxyethyl)piperidine-4-carboxylic acid by adjusting the pH with Con HCI.
Wherein the 2-halo ethanol is selected from 2-bromo ethanol or 2-chloro ethanol.
The reaction is carried out at a temperature of 30-60°C, preferably 45°C. The reaction is carried out in presence of an in-organic bases such as preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate or mixtures thereof; in an solvent selected from alcohols for example methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably methanol.
Step b) of the above process of the present invention is carried out reacting 1-(2- hydroxyethyl)piperidine-4-carboxylic acid (VI) or a salt thereof with a suitable reagent and solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
The reaction is carried out at a temperature of 30-70°C, preferably 55°C. The reaction is carried out in the presence of a reagent such as selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides. Preferably the reagent is thionyl chloride.
Further, the acid chloride compound is reacted with an alcoholic solvent to form ethyl 1-(2- chloroethyl)piperidine-4-carboxylate (IV).
The alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably ethanol. Step c) of the above process of the present invention is carried out by reacting ethyl 1-(2- chloroethyl)piperidine-4-carboxylate (IV) with suitable base and solvent at a temperature between 30-60°C to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III).
The solvent used in step c) may be selected from the group consisting of cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; ethers such as dibutyl ether; cyclohexane and mixtures thereof.
The base used in step c) is selected from KHMDS, LiHMDS and NaHMDS.
Step d) of the above process of the present invention is carried out by reacting ethyl 1- azabicyclo[2.2.2]octane-4-carboxylate (III) with phenyl magnesium bromide in the presence of solvent at a temperature between 20-80°C to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (II).
The solvent used in step d) may be selected from the group consisting of cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; or mixtures thereof. The most preferred solvent is toluene. The product can be isolated by conventional known techniques like filtration and dried preferably under vacuum with a purity of > 99.0%.
Step e) of the above process of the present invention is carried out by reacting a compound of formula (II) with ((2-bromoethoxy)methyl)benzene in the presence of an alcoholic solvent at a temperature of 40-80°C, preferably 60°C to form Umeclidinium bromide and isolation is carried out in the presence of an ester solvent.
Therein the alcoholic solvents are selected from methanol, ethanol and isolation is carried out by addition of ester solvent. Therein the ester solvent is selected from ethyl acetate, isopropyl acetate, n-butyl acetate etc., preferably ethyl acetate.
Step f) of the above process of the present invention is carried out in the presence of an alcoholic solvent or mixture of alcoholic solvent, water and final purification with water.
The purification of Umeclidinium bromide is carried out by using an alcoholic solvent at a temperature of 40-80°C, preferably 60°C, and preferably cooling the reaction mixture temperature between about 0-25°C, preferably stirring the reaction mass at a temperature between 0-25°C for about 2 hours. Thereafter, the resulting product can be isolated, preferably by filtration. In another way the purification of Umeclidinium bromide is carried out by using an alcoholic solvent at a temperature of 40-80°C, preferably 60°C, and preferably adding water to the reaction mixture at a temperature of 40-80°C, preferably 60°C, preferably cooling the reaction mixture at a temperature between about 0-25°C, preferably stirring the reaction mass at a temperature between 0-25°C for about 2 hours. Thereafter, the resulting product can be isolated, preferably by filtration.
Therein the alcoholic solvent is selected from methanol or ethanol.
The purified product is treated with water by heating the reaction mixture to 40-80°C, preferably 60°C, preferably by cooling the reaction mixture at a temperature between about 0-25°C, preferably by stirring the reaction mass at a temperature between 0-25°C for about 2 hours. The product can be isolated, preferably by filtration and then be dried at a temperature between 35- 55°C, preferably under vacuum, with a purity of > 99.0% by HPLC.
The route of synthesis is shown in scheme-ll:
Reagent Base Solvent Solvent
Figure imgf000011_0001
Figure imgf000011_0002
H Ethyl quinuclidine-4- Isonipecotic acid
Figure imgf000011_0003
Figure imgf000011_0004
carboxylate (VII) Cl
1-(2-Hydroxyethyl)piperidine- Eth , ^-chloroethyl) (I") 4-carboxylic acid pjperidine-4-carboxylate
(VI) (IV)
Phenyl magnesium bromide
Figure imgf000011_0005
The following examples illustrate the nature of the invention, and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
10
SUBSTITUTE SHEET (RULE 26) EXAMPLES:
Example-1 : Process for the preparation of 1-(2-hydroxyethyl) piperidine-4-carboxylic acid hydrochloride (VI)
2-Bromoethanol (1.2 moles) was added to a mixture of isonipecotic acid (10 g), 20% aqueous ethanol (5 volumes) and potassium hydroxide (2.5 moles) at 25-35°C. The reaction mixture was heated to 45-50°C and stirred for 6-8 hours. The reaction mass pH was adjusted to 2-3 with cone. HCI, the salts were filtered and washed with ethanol (2 volumes). The filtrate was concentrated under vacuum and co-distilled with ethanol (3 volumes). The crude material was dissolved in methanol (10 volumes) and the solution was filtered to remove salts. The filtrate was concentrated under vacuum and isolated by ethanol (3 volumes). The isolated material was dried under vacuum.
Yield: 70%, Purity by HPLC: 98%
Example-2: Process for the preparation of 1-(2-hydroxyethyl) piperidine-4-carboxylic acid hydrochloride (VI)
2-Bromoethanol (1.2 moles) was added to a mixture of isonipecotic acid (10 g), methanol (5 volumes), potassium hydroxide (2.5 moles) at 25-35°C. The reaction mixture to 45-50°C was heated and stirred for 6-8 hours. The salts was filtered and the pH of the filtrate was adjusted to 2-3 with cone. HCI and washed with methanol (2 volumes). The reaction mass was filtered again to remove salts and the filtrate was concentrated. The product was isolated by using ethanol (5 volumes). The isolated material was dried under vacuum.
Yield: 81 %, Purity by HPLC: 98%
Example-3: Process for the preparation of Ethyl 1-(2-chloroethyl) piperidine-4-carboxylate (IV)
A mixture of 1-(2-hydroxyethyl) piperidine-4-carboxylic acid hydrochloride (1 mole) and thionyl chloride (2 volumes) were heated to 50-60°C and maintained for 2 hours. The reaction mass was distilled under vacuum and the reaction mass was co-distilled with toluene (4 volumes). Ethanol (2 volumes) was charged and stirred for few minutes at 45-50°C. The reaction mass was concentrated under vacuum and charged with toluene (8 volumes). The Toluene layer was washed with 10% sodium carbonate solution (7 volumes), water (2 volumes) and concentrated under vacuum to obtain the product.
Yield: 90%, Purity by GC: 97%
Example-4: Process for the preparation of Ethyl Quinuclidine-4-carboxylate hydrochloride (I")
11
SUBSTITUTE SHEET (RULE 26) 1 M KHMDS solution (1.6 moles) was added to the mixture of ethyl 1 -(2 -chloroethyl) piperidine-4- carboxylate (1 mole), toluene (8 volumes) at 40-50°C and the reaction mass was maintained for 2 hours. The reaction mass was quenched by addition of ethanol (1.3 volumes) and acetic acid (1 .4 Volumes) at 0-10°C. The reaction mass was maintained for 2 hours at 40-45°C and charged with 25% potassium carbonate solution (13 volumes) at RT. The aqueous layer was extracted with toluene (5 volumes) and the combined organic layers were washed with water. The toluene layer was concentrated under vacuum, and dissolved in IPA (0.7 volumes) and added IPA. HCI (1.7 volumes) were added at RT. The reaction mixture was heated to 70-80°C and cooled to 0-5°C. The material was filtered under vacuum and washed with IPA (0.7 volumes). The material was dried in an oven under vacuum.
Yield: 55%, Purity by GC: 99.0%
Example-5: Process for the preparation of Diphenyl (Quinuclidine-4-yl) methanol (II)
Phenyl Magnesium bromide 1 M solution in THF (4.0 moles) was added toa mixture of ethyl quinuclidine-4-carboxylate hydrochloride (1 mole), toluene (5 volumes) at 25-35°C. The reaction mixture was heated to 60-65°C and maintained for 2 hours. The reaction mass was cooled to 20- 30°C and quenched with 26% ammonium chloride solution (28 volumes). The reaction mass was distilled to remove THF, the solid material was filtered and washed with toluene (2 volumes). Ethyl acetate (6 volumes) was charged to the solid material and the mixture was heated to 40-50°C, stirred for few minutes, cooled to 25-30°C and filtered. 10% potassium carbonate solution (18 volumes) was charged to the filtered solid material and stirred for 30-45 minutes. The material was filtered and washed with water (2 volumes). The material was dried in oven under vacuum. Yield: 80%, Purity by HPLC: 99.0%
Example-6: Process for the preparation of Diphenyl (Quinuclidine-4-yl) methanol (II)
Phenyl magnesium bromide (1 M solution in THF;4.0 moles) was added to a mixture of ethyl quinuclidine-4-carboxylate hydrochloride (1 mole), toluene (5 volumes) at 25-35°C. The reaction mixture was heated to 60-65°C and maintained for 2 hours. The reaction mass was cooled to 20- 30°C and quenched with 26% ammonium chloride solution (28 volumes). The reaction mass was distilled to remove THF, the solid material was filtered and washed with toluene (2 volumes). Ethyl acetate (6 volumes) was charged to the solid material and the mixture was heated to 50-60°C, stirred for few minutes, cooled to 25-30°C and filtered. 15% potassium carbonate solution (10 volumes) was charged to the filtered solid material and stirred for 30-45 minutes. The material was filtered and washed with water (2 volumes) twice and finally washed with ethyl acetate (1 volume). The material was dried in oven under vacuum.
12
SUBSTITUTE SHEET (RULE 26) Yield: 86%, Purity by HPLC: 99.5%
Example-7: Process for the preparation of Umeclidinium bromide (I)
A mixture of diphenyl (quinuclidine-4-yl) methanol (1 mole), ((2-bromoethoxy) methyl) benzene (1.2 moles), methanol (10 volumes) was heated to 60-65°C for 10 hours. The reaction mixture was concentrated and charged with ethyl acetate (10 volumes). The contents were stirred at 45- 50°C and filtered by cooling to 25-30°C. Methanol (13 volumes) was charged to the solid material and the mixture heated to 60-65°C. The mixture was cooled to 0-10°C and filtered. Water (13 volumes) was charged to the solid material and heated to 45-50°C. The mixture was cooled to 0- 10°C and filtered. The material was dried under vacuum.
Yield: 70%, Purity by HPLC: 99.5%
Example-8: Process for the preparation of Umeclidinium bromide (I)
Amixture of diphenyl (quinuclidine-4-yl) methanol (1 mole), ((2-bromoethoxy) methyl) benzene (1.2 moles), methanol (10 volumes) was heated to 60-65°C for 10 hours. The reaction mixture was concentrated and charged with 25% methanol in ethyl acetate (5 volumes). The contents were stirred at 60-65°C and filtered by cooling to 25-30°C. Methanol (13 volumes) was charged to the solid material, heated the mixture to 60-65°C and then purified water (13 volumes) was added. The mixture was cooled to 0-10°C and filtered. Water (13 volumes) was charged to the solid material and heated to 50-55°C. The mixture was cooled to 0-10°C and filtered. The material was dried under vacuum.
Yield: 85%, Purity by HPLC: 99.9%
The invention has been described as detailed above but various embodiments and variations are possible beyond the preferred embodiments disclosed in this document. All such variations and modifications as obvious to the skilled person are within the scope of this invention. The applicant intends to rely upon the provisional specification.
13
SUBSTITUTE SHEET (RULE 26)

Claims

1 . A process for the preparation of ethyl 1-(2-chloroethyl)piperidine-4-carboxylate of formula (IV)
Figure imgf000015_0001
Formula IV which comprises: a) reacting isonipecotic acid of formula (VII)
Figure imgf000015_0002
Formula VII with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl) piperidine-4-carboxylic acid (VI) or a salt thereof. its salt
Figure imgf000015_0003
Formula VI b) reacting 1-(2-hydroxyethyl) piperidine-4-carboxylic acid (VI) ora salt thereof with a suitable reagent and a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (IV).
2. The process according to claim 1 , wherein the 2-halo ethanol is selected from 2-bromo ethanol or 2-chloro ethanol.
3. The process according to claim 1 or 2, wherein the base used in step a) is selected from in-organic bases such as preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate or mixtures thereof.
4. The process according to anyone of the preceding claims , wherein the solvent used in step a) is selected from alcohols preferably methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably methanol.
5. The process according anyone of the preceding claims, wherein the reagent used in step b) is selected from thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
6. The process according anyone of the preceding claims, wherein the solvent used in step b) is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof.
7. A process for the preparation of Umeclidinium bromide which comprises: a) reacting isonipecotic acid (VII) with 2-halo ethanol in the presence of a base and a solvent to form ethyl 1-(2-hydroxyethyl) piperidine-4-carboxylic acid (VI) or a salt thereof. b) reacting 1-(2-hydroxyethyl) piperidine-4-carboxylic acid (VI) ora salt thereof with a suitable reagent and a solvent to form ethyl 1 -(2 -chloroethyl) piperidine-4-carboxylate (IV): c) reacting ethyl 1-(2-chloroethyl) piperidine-4-carboxylate (IV) with a base in the presence of solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); d) reacting ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (Illi) with phenyl magnesium bromide in the presence of solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (II); e) reacting compound of formula (II) with ((2-bromoethoxy)methyl)benzene in presence of an alcoholic solvent to form Umeclidinium bromide and isolation is carried out in the presence of an ester solvent. f) optionally recrystallisation of Umeclidinium bromide is carried out in presence of an alcoholic solvent or mixture of alcoholic solvent, water, and final purification with water.
8. The process according to claim 7, wherein the base used in step a) is selected from inorganic bases such as preferably from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal acetates such as sodium acetate and potassium acetate or mixtures thereof.
9. The process according to anyone of the claims 7 and 8, wherein the solvent used in step a) is selected from alcohols preferably methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof, and most preferably methanol.
10. The process according to anyone of the claims 7 to 98, wherein the suitable reagent used in step b) is selected from thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
11 . The process according to anyone of the claims 7 to 10, wherein the solvent used in step b) is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol or mixtures thereof.
12. The process according to anyone of the claims 7 to 11 , wherein the solvent used in step c) is selected from cyclic ethers such as tetrahydrofuran; aromatic solvents such as toluene; ethers such as dibutyl ether; cyclohexane and mixtures thereof.
13. The process according to anyone of the claims 7 to 12, wherein the base used in step c) is selected from KHMDS, LiHMDS and NaHMDS.
14. The process according to anyone of the claims 7 to 13, wherein the solvent used in step d) is selected from tetrahydrofuran; aromatic solvents such as toluene; or mixtures thereof. The most preferred solvent is toluene.
15. The process according to anyone of the claims 7 to 14, wherein the alcoholic solvent used in step e) is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tertbutanol or mixtures thereof.
16. The process according to anyone of the claims 7 to 15, wherein the ester solvent used in step e) is selected from ethyl acetate, isopropyl acetate, n-butyl acetate etc. preferably ethyl acetate.
17. The process according to anyone of the claims 7 to 16, wherein the alcoholic solvent used in step f) is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tertbutanol or mixtures thereof.
18. The process according to anyone of the claims 7 to 17, wherein umeclidinium bromide is obtained with a purity greater than 99%.
Y1
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3317546A (en) * 1964-04-10 1967-05-02 Reilly Tar & Chem Corp N-hydroxyalkyl-piperidine carboxylic acids
WO2005104745A2 (en) 2004-04-27 2005-11-10 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
WO2014027045A1 (en) 2012-08-15 2014-02-20 Glaxo Group Limited Chemical process
WO2016071792A1 (en) 2014-11-03 2016-05-12 Laboratorio Chimico Internazionale S.P.A. Method for the preparation of 1-(2-halogen-ethyl)-4 piperidine-carboxylic acid ethyl esters
CN107935917A (en) * 2017-10-30 2018-04-20 广东莱佛士制药技术有限公司 A kind of synthetic method of 1 (2 chloroethyl) 4 piperidinecarboxylic acid ester
CN114736201B (en) * 2022-06-13 2022-09-02 奥锐特药业(天津)有限公司 Preparation method of umeclidinium bromide intermediate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3317546A (en) * 1964-04-10 1967-05-02 Reilly Tar & Chem Corp N-hydroxyalkyl-piperidine carboxylic acids
WO2005104745A2 (en) 2004-04-27 2005-11-10 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
WO2014027045A1 (en) 2012-08-15 2014-02-20 Glaxo Group Limited Chemical process
WO2016071792A1 (en) 2014-11-03 2016-05-12 Laboratorio Chimico Internazionale S.P.A. Method for the preparation of 1-(2-halogen-ethyl)-4 piperidine-carboxylic acid ethyl esters
CN107935917A (en) * 2017-10-30 2018-04-20 广东莱佛士制药技术有限公司 A kind of synthetic method of 1 (2 chloroethyl) 4 piperidinecarboxylic acid ester
CN114736201B (en) * 2022-06-13 2022-09-02 奥锐特药业(天津)有限公司 Preparation method of umeclidinium bromide intermediate

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