WO2024251812A1 - Procédé de préparation d'un intermédiaire de bromure d'uméclidinium - Google Patents

Procédé de préparation d'un intermédiaire de bromure d'uméclidinium Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
process according
ethanol
piperidine
anyone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/065458
Other languages
English (en)
Inventor
Ester Masllorens Llinas
Sridhar Pratha
Kollapudi CHANDRABABU
Subhash YENUPURI
Divakara LAXMAN SOMAYAJULU NORI
Hari PRASAD VEERA VENKATA NACHARLA
Pradeep MAVUDURU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmazell GmbH
Original Assignee
Pharmazell GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmazell GmbH filed Critical Pharmazell GmbH
Publication of WO2024251812A1 publication Critical patent/WO2024251812A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne le procédé de préparation de bromure d'uméclidinium et le procédé de préparation d'intermédiaires utilisés dans la préparation de bromure d'uméclidinium.
PCT/EP2024/065458 2023-06-07 2024-06-05 Procédé de préparation d'un intermédiaire de bromure d'uméclidinium Pending WO2024251812A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202341039125 2023-06-07
IN202341039125 2023-06-07

Publications (1)

Publication Number Publication Date
WO2024251812A1 true WO2024251812A1 (fr) 2024-12-12

Family

ID=91470068

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/065458 Pending WO2024251812A1 (fr) 2023-06-07 2024-06-05 Procédé de préparation d'un intermédiaire de bromure d'uméclidinium

Country Status (1)

Country Link
WO (1) WO2024251812A1 (fr)

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 (fr) 2004-04-27 2005-11-10 Glaxo Group Limited Antagonistes des récepteurs muscariniques de l'acétylcholine
WO2014027045A1 (fr) 2012-08-15 2014-02-20 Glaxo Group Limited Processus chimique
WO2016071792A1 (fr) 2014-11-03 2016-05-12 Laboratorio Chimico Internazionale S.P.A. Procédé de préparation d'esters éthyliques de l'acide 1-(2-halogène-éthyl)-4 pipéridine carboxylique
CN107935917A (zh) * 2017-10-30 2018-04-20 广东莱佛士制药技术有限公司 一种1‑(2‑氯乙基)‑4‑哌啶甲酸酯的合成方法
CN114736201B (zh) * 2022-06-13 2022-09-02 奥锐特药业(天津)有限公司 芜地溴铵中间体的制备方法

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 (fr) 2004-04-27 2005-11-10 Glaxo Group Limited Antagonistes des récepteurs muscariniques de l'acétylcholine
WO2014027045A1 (fr) 2012-08-15 2014-02-20 Glaxo Group Limited Processus chimique
WO2016071792A1 (fr) 2014-11-03 2016-05-12 Laboratorio Chimico Internazionale S.P.A. Procédé de préparation d'esters éthyliques de l'acide 1-(2-halogène-éthyl)-4 pipéridine carboxylique
CN107935917A (zh) * 2017-10-30 2018-04-20 广东莱佛士制药技术有限公司 一种1‑(2‑氯乙基)‑4‑哌啶甲酸酯的合成方法
CN114736201B (zh) * 2022-06-13 2022-09-02 奥锐特药业(天津)有限公司 芜地溴铵中间体的制备方法

Similar Documents

Publication Publication Date Title
KR101458369B1 (ko) 트리틸 올메사탄 메독소밀 및 올메사탄 메독소밀의 제조방법
US8188285B2 (en) Purification process of Montelukast and its amine salts
CN115819400A (zh) 合成增加血红蛋白氧亲和力的化合物的方法
KR20070026300A (ko) 펙소페나딘 다형 및 그 제조방법
CA2710523A1 (fr) Procede de preparation d'esters de scopine
US9388168B2 (en) Process for the preparation of 1-([1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine
EP2268634A2 (fr) Procédés de préparation de bosentan et de composés apparentés à l'aide de nouveaux intermédiaires
US20150141449A1 (en) Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
US9006443B2 (en) Process for preparing quinoline-3-carboxamide derivatives
US7534885B2 (en) Process and intermediates for preparing emtricitabine
US20100029945A1 (en) Process for the purification of Montelukast
WO2024251812A1 (fr) Procédé de préparation d'un intermédiaire de bromure d'uméclidinium
US20220340532A1 (en) Processes for the preparation of roxadustat and intermediates thereof
WO2022149161A1 (fr) Procédé de préparation d'acide bempédoïque et de ses intermédiaires
US11453698B2 (en) Preparation method of vascular leakage blockers with a high yield
US20090281323A1 (en) Process for the manufacture of montelukast sodium
US8772491B2 (en) Process for the preparation of solifenacin succinate
US20130072688A1 (en) Method for preparing an intermediate of pitavastatin or of the salt thereof
US6956121B2 (en) Preparation of paroxetine involving novel intermediates
US10562834B2 (en) Process for preparing substituted crotonic acids
WO2007135693A2 (fr) Intermédiaires utiles pour la préparation d'un dérivé de la pipéridine antihistaminique
JP2006512278A (ja) アルコキシ不純物を実質的に含有しないパロキセチンの製造方法
EP2686301B1 (fr) Sel d'acide camphresulfonique d'intermédiaire du montélukast
US20250145651A1 (en) Method of preparation of 1-(n-(quinolin-2-yl)-(phenylamino)-1-deoxy-beta-d-glucopyranuronic acid derivatives
US20170247359A1 (en) Process for the preparation of canagliflozin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24732181

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE