EP4103168A1 - Procédé de préparation d'acides gamma-amino-butyriques et de leurs analogues - Google Patents

Procédé de préparation d'acides gamma-amino-butyriques et de leurs analogues

Info

Publication number
EP4103168A1
EP4103168A1 EP21753915.4A EP21753915A EP4103168A1 EP 4103168 A1 EP4103168 A1 EP 4103168A1 EP 21753915 A EP21753915 A EP 21753915A EP 4103168 A1 EP4103168 A1 EP 4103168A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
cycloalkyl
alkyl
ring
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
EP21753915.4A
Other languages
German (de)
English (en)
Other versions
EP4103168A4 (fr
Inventor
Chada Raji REDDY
Amol Dnyandev PATIL
Muppidi SUBBARAO
Bodasu SRINIVAS
Genji SUKUMAR
Srivari CHANDRASEKHAR
Thennati Rajamannar
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.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
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 Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Publication of EP4103168A1 publication Critical patent/EP4103168A1/fr
Publication of EP4103168A4 publication Critical patent/EP4103168A4/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds

Definitions

  • the present invention relates to a process for the preparation of compound of formula I.
  • the compound of formula I is g-aminobutyric acid (GABAs, 4-aminobutyric acid) and analogs, such as Pregabalin, Baclofen, 3,3-substituted GABA derivatives and like prepared by Michael addition and Beckmann rearrangement method.
  • GABAs g-aminobutyric acid
  • analogs such as Pregabalin, Baclofen, 3,3-substituted GABA derivatives and like prepared by Michael addition and Beckmann rearrangement method.
  • Ri is H and R2 is H.
  • Substituted g-amino acids play a pivotal role in drug discovery, lead to the development of several pharmaceuticals for epilepsy, neuropathic pain, spasticity etc. including many molecules in clinical pipeline.
  • the success rate in this area of research has been significant and there has been a great progress reported in identifying selective g-aminobutyric acids as drug candidates.
  • nitromethane was used as Michael donor for the 1,4-addition reaction in presence of DBU followed by reduction using ammonium formate Pd/C that provides 3-(aminomethyl)- 5-methylhex-4-enoic ester and hydrolysis of obtained compound furnished the 3- (aminomethyl)-5-methylhex-4-enoic acid intermediate (US20090137842; US20110144383).
  • the Knoevenagel condensation was done with ethyl isocyanate followed by decarboxylation that gives key pregabalin intermediate 3- isobutylglutaric acid.
  • the main objective of the present invention is to provide an efficient process for the preparation of g-aminobutyric acid derivatives, in particular pregabalin, baclofen and analogs thereof.
  • Another objective of the present invention is to provide a process, which could be carried out by employing Michael addition and Beckmann rearrangement strategy for the synthesis of a diverse library of the g-aminobutyric acids.
  • Another objective of the present invention is to provide a process for the preparation of chiral g-aminobutyric acids by employing a suitable chiral catalyst during Michael addition step, thus leading to the procedure for GABA analogues with chiral induction of either enantio selectivity .
  • the present invention provides a process for the preparation of g-aminobutyric acids derivatives, in particular pregabalin, baclofen and novel analogs thereof.
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl, R3 is C1-C6 alkyl or cycloalkyl;
  • step (ii) addition of an oxime moiety on the compound of formula V obtained in step (i) with an oxyamine compound of formula VIII using a basic reagent in a polar solvent at a temperature range of 30-75°C, for 1-4 h, to give a compound of formula IVa and/or IVb;
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl,
  • R3 is C1-C6 alkyl or cycloalkyl
  • R4 is H, alkyl, cycloalkyl, aryl or heteroaryl with one or more substitutions, wherein the E/Z oxime geometry ratio is >2 and up to 20;
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl
  • R3 is C1-C6 alkyl or cycloalkyl
  • step (iv) cyclization of the compound of formula III obtained in step (iii) using an inorganic base in a polar protic solvent at a temperature range of 25-120°C for 18-30 h, to obtain a cyclic amide intermediate compound of formula II;
  • Ri and R2 are H;
  • the amine base is selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives.
  • the acid is selected from the group consisting of mineral acids, trifluoroacetic acid, pTSA and mixtures thereof.
  • the oxyamine is hydroxylamine hydrochloride.
  • the basic reagent is an inorganic base selected from alkali and alkaline earth metal oxides, hydroxides, carbonates, bicarbonates, phosphates, preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate and mixtures thereof.
  • the polar solvent is selected from the group consisting of water, alcohols, esters, dimethylformamide, dimethylsulfoxide, acetonitrile and mixtures thereof.
  • the compound of formula I is g-aminobutyric acid and stereoselective g-aminobutyric acid derivatives (enantiomers and diastereomers).
  • the process is a continuous process.
  • the process is carried out without a genotoxic chiral resolution agent towards chiral g-aminobutyric acid derivatives.
  • Scheme 1 provides a schematic representation of process for preparation of compounds of formula I
  • the present invention provides an efficient and novel process for the preparation of g- aminobutyric acids derivatives, in particular pregabalin, baclofen and analogs thereof.
  • the present process can be operated by employing Michael addition and Beckmann rearrangement providing a novel strategy resulting in the desired analogs of a diverse library of the g-aminobutyric acid derivatives such as pregabalin, baclofen and analogs in high yields and purity and economical at industrial scale.
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl, R3 is C1-C6 alkyl or cycloalkyl, R4 is H, alkyl, cycloalkyl, aryl or heteroaryl with one or more substitutions.
  • the present process is performed very effectively in five overall steps with a short reaction time and is a highly viable strategy which could be most suitable for the industrial scale production of g-aminobutyric acid derivatives, in particular pregabalin, baclofen and analogs. Further, this process is most suitable for the generation of a large library of intermediates which may also find interesting properties.
  • the first step of this process involves Michael addition, wherein diverse functionalization is possible with the use of substrate screening methods. While, these Michael adducts could serve as valuable intermediates, to generate yet another library of oxime compounds upon treatment with oxy amines. Further, the Beckmann rearrangement could be performed using a wide variety of reagents to give the resultant rearrangement product in high yields.
  • the base mediated cyclization followed by acid- mediated amide cleavage could be performed in a polar solvent to generate and build a vast library of gamma-aminobutyric acid derivatives, in particular pregabalin, baclofen and analogs with diverse functional modifications. All the reaction steps involve purification and systematic characterization of the individual reaction product at each stage of the process, making it highly feasible for production scale.
  • the process is ideally suitable to perform on continuous mode, without isolating the intermediates in each step, due to inherent process advantage, i.e. homogenous reactions and capability to purge the impurities at the end of the process.
  • the first step of the process is Michael addition reaction between the compound of formula VI and methyl ketone compound of formula VII in presence of an amine base and an acid at a temperature range 0-20 °C, for 0.5-2 h, to give compounds of formula V;
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl,
  • R3 is C1-C6 alkyl or cycloalkyl.
  • the second step in the process is addition of oxime moiety on the compound of formula V obtained in step (i) with an oxyamine compound of formula VIII using a basic reagent in a polar solvent at a temperature range of 30-75 °C, for 1-4 h, to give compounds of formula IVa and/or IVb (wherein the E/Z oxime geometry ratio is >2 and up to 20).
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl, R3 is C1-C6 alkyl or cycloalkyl,
  • R4 is H, alkyl, cycloalkyl, aryl or heteroaryl with one or more substitutions.
  • the third step of the process is the Beckmann rearrangement of the compound of formula IVa and/or IVb obtained in step-(ii), using an acid reagent, in an aprotic solvent at a temperature range of 0-40 °C for 1-5 h, to obtain a compound of formula III.
  • a and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl
  • R3 is C1-C6 alkyl or cycloalkyl.
  • the fourth step of the process is cyclization of the compound of formula III using an inorganic base in a polar protic solvent at a temperature range of 25-120°C for 18-30 h, to obtain a cyclic amide intermediate compound of formula II.
  • Ri and R2 are H.
  • Ri and R2 are H.
  • the amine base is selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives.
  • the acid is selected from the group consisting of mineral acids, trifluoroacetic acid, pTSA and mixtures thereof.
  • the oxyamine is hydroxylamine hydrochloride.
  • the basic reagent is an inorganic base selected from alkali and alkaline earth metal oxides, hydroxides, carbonates, bicarbonates, phosphates, preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate and mixtures thereof.
  • the polar solvent is selected from the group consisting of water, alcohols, esters, dimethylformamide, dimethylsulfoxide, acetonitrile and mixtures thereof.
  • the compound of formula I is g-aminobutyric acid and stereoselective g-aminobutyric acid derivatives (enantiomers and diastereomers).
  • the process is a continuous process. In another embodiment of the present invention the process is a continuous process.
  • the process is carried out without a genotoxic chiral resolution agent towards chiral g-aminobutyric acid derivatives.
  • the step 1 is also carried out using other amine base selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives and other acid selected from the group consisting of mineral acids, pTSA or a mixture thereof.
  • other amine base selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives and other acid selected from the group consisting of mineral acids, pTSA or a mixture thereof.
  • the step 2 is also carried out using the derivatives of hydroxylamine hydrochloride and other inorganic or organic bases thereof.
  • the step 3 is also carried out using the other Lewis or Bronsted acids such as hydrochloric acid, sulfuric acid, phosphoric acids and their chlorides, metal halides or organic acids thereof.
  • Lewis or Bronsted acids such as hydrochloric acid, sulfuric acid, phosphoric acids and their chlorides, metal halides or organic acids thereof.
  • the step 3 is also carried out using the other inorganic bases such as hydroxides, carbonate, bicarbonate salts or organic bases such as amines and thereof.
  • Step 5 Preparation of compound 8 (formula I): Compound 7 was taken in to round-bottom flask in water (10 vol) and 6N HC1 (10 vol) at room temperature. Reaction mixture was heated to 120°C and stirred for 24 h. The reaction mixture was cooled to 25°C and washed with MTBE (3 vol x 3). The aqueous layer was concentrated under reduced pressure to get the crude compound. The crude compound was cooled to 0-5°C, acetone (5 vol) was added and stirred for 5 mins followed neutralization of the resulting mixture (upto P H : 6) using aq. ammonia solution, the solids were generated in the mixture. The solid compound was filtered off and washed with acetone (1.0 vol).
  • the step 5 is also carried out using the other Lewis or Bronsted acids such as hydrochloric acid, sulfuric acid, phosphoric acids and their chlorides, metal halides or organic acids thereof.
  • Lewis or Bronsted acids such as hydrochloric acid, sulfuric acid, phosphoric acids and their chlorides, metal halides or organic acids thereof.
  • inorganic base selected from alkali and alkaline earth metal oxides, hydroxides, carbonates, bicarbonates, phosphates, preferably potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate or a mixture thereof and polar solvent selected from the group consisting of water, alcohols, esters, dimethylformamide, dimethylsulfoxide, acetonitrile or a mixture thereof.
  • g-Aminobutyric acids are required in high volume for instance, gabapentin and Pregabalin are consumed in ton quantities. Therefore, an efficient process for their production in industrial scale is very important.
  • the existing scalable processes known in the art require toxic raw materials (eg. KCN or Ac 2 0). Further, majority of the known processes need longer reaction time as well as higher temperatures of about 140°C (energy intensified procedures) and require isolation of intermediates during the process. Hence the existing scalable processes known in the art are high energy intensive processes with longer reaction time.
  • the present process is carried out using inexpensive and less hazardous reagents. Further, the complete process of six steps is accomplished in three stages (without isolation of three intermediates in the process) using reactions carried out at low temperature and less reaction time. Overall, the present process is environmental-friendly with less energy and solvent consumption, which are attractive for the industrial manufacturing.
  • the present process serves as a highly efficient, scalable, commercially viable and with improved atom economy process for the preparation of gamma amino acid derivatives, in particular pregabalin, baclofen, that are FDA approved drugs for the treatment of epilepsy, neuropathic pain and spasticity in multiple sclerosis patients respectively.
  • the advantage of the present invention is that the process can be operated by engaging simple as well as requiring mild conditions and highly feasible protocols such as Michael addition and Beckmann rearrangement strategy using alkali and acid as reagents for transformation.
  • Another advantage of the present invention is that the process provides novel reaction steps and intermediate compounds.
  • This process can be adopted to generate a large library of process intermediates and g- aminobutyric acid derivatives, in particular pregabalin, baclofen analogs.
  • Novel lactam intermediates opens an avenue to make substituted and spiro-analogues

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de l'acide gamma aminobutyrique de formule I, en particulier la prégabaline, le baclofène et leurs analogues. En outre, ce procédé comprend un protocole de préparation pour des composés de formule I, impliquant une addition de Michael et une stratégie de réarrangement de Beckmann.
EP21753915.4A 2020-02-14 2021-02-13 Procédé de préparation d'acides gamma-amino-butyriques et de leurs analogues Pending EP4103168A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202011006475 2020-02-14
PCT/IN2021/050141 WO2021161346A1 (fr) 2020-02-14 2021-02-13 Procédé de préparation d'acides gamma-amino-butyriques et de leurs analogues

Publications (2)

Publication Number Publication Date
EP4103168A1 true EP4103168A1 (fr) 2022-12-21
EP4103168A4 EP4103168A4 (fr) 2024-04-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP21753915.4A Pending EP4103168A4 (fr) 2020-02-14 2021-02-13 Procédé de préparation d'acides gamma-amino-butyriques et de leurs analogues

Country Status (3)

Country Link
EP (1) EP4103168A4 (fr)
JP (1) JP7436689B2 (fr)
WO (1) WO2021161346A1 (fr)

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002241358A (ja) 2001-02-15 2002-08-28 Nippon Soda Co Ltd オキシム基を有する化合物及び殺虫・殺ダニ剤
JP4250887B2 (ja) 2001-10-22 2009-04-08 三菱化学株式会社 アミド化合物の製造方法
JP4562370B2 (ja) 2003-10-02 2010-10-13 独立行政法人科学技術振興機構 転位不飽和化合物の製造方法
AP2466A (en) 2004-06-21 2012-09-17 Warner Lambert Co Preparation of pregabalin and related compounds
WO2006110783A2 (fr) 2005-04-11 2006-10-19 Teva Pharmaceutical Industries Ltd. Procede de fabrication de (s)-pregabaline
US8293926B2 (en) 2005-12-09 2012-10-23 Sumitomo Chemical Company, Limited Method of producing optically active 4-amino-3-substituted phenylbutanoic acid
WO2008062460A2 (fr) 2006-10-06 2008-05-29 Cadila Healthcare Limited Formes cristallines de la prégabaline
CN102099482B (zh) 2008-05-21 2014-04-16 桑多斯股份公司 5-甲基-3-硝基甲基-己酸酯的立体选择性酶水解方法
WO2010061403A2 (fr) 2008-11-26 2010-06-03 Ind-Swift Laboratories Limited Procédé pour préparer de la (s)-prégabaline très pure
WO2012093411A2 (fr) 2011-01-07 2012-07-12 Dr Braja Sundar Pradhan Méthode de préparation d'acide r-(-)-3-(carbamoylméthyl)-5-méthylhexanoïque et de ses intermédiaires
US10023885B2 (en) * 2012-11-07 2018-07-17 Hikal Limited Process for the preparation of pregabalin
JP6724283B2 (ja) 2016-03-09 2020-07-15 国立大学法人 東京大学 光学活性の４−ニトロブタン酸エステル及びプレガバリンの製造方法

Also Published As

Publication number Publication date
JP7436689B2 (ja) 2024-02-22
EP4103168A4 (fr) 2024-04-24
WO2021161346A1 (fr) 2021-08-19
JP2023513330A (ja) 2023-03-30

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