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WO2021161346A1 - Process for the preparation of gamma amino butyric acids and analogs thereof - Google Patents

Process for the preparation of gamma amino butyric acids and analogs thereof Download PDF

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Publication number
WO2021161346A1
WO2021161346A1 PCT/IN2021/050141 IN2021050141W WO2021161346A1 WO 2021161346 A1 WO2021161346 A1 WO 2021161346A1 IN 2021050141 W IN2021050141 W IN 2021050141W WO 2021161346 A1 WO2021161346 A1 WO 2021161346A1
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Prior art keywords
formula
compound
cycloalkyl
alkyl
ring
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PCT/IN2021/050141
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French (fr)
Inventor
Chada Raji REDDY
Amol Dnyandev PATIL
Muppidi SUBBARAO
Bodasu SRINIVAS
Genji SUKUMAR
Srivari CHANDRASEKHAR
Thennati Rajamannar
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Council Of Scientific And Industrial Research
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Priority to JP2022548730A priority Critical patent/JP7436689B2/en
Priority to EP21753915.4A priority patent/EP4103168A4/en
Publication of WO2021161346A1 publication Critical patent/WO2021161346A1/en

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    • 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

The present invention relates to a process for the preparation of gamma aminobutyric acid derivatives of formula I, in particular pregabalin, baclofen and analogs thereof. Further, this process is comprised of preparation protocol for compounds of formula I, involving Michael addition and Beckmann rearrangement strategy.

Description

PROCESS FOR THE PREPARATION OF GAMMA AMINO BUTYRIC ACIDS AND
ANALOGS THEREOF
FIELD OF THE INVENTION
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. Formula I is represented as:
Figure imgf000003_0001
wherein: X and Y are individually selected from H, C1-C12 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic rings (when n = 1, 2, 3 or 4 carbon atoms)
Ri is H and R2 is H.
BACKGROUND OF THE INVENTION
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.
Till date, several procedures on the synthesis and applications for the selective gamma aminobutyric acids, particularly pregabalin, baclofen and related analogs are reported in literature with varying levels of success. According to the inventor’s process, Knoevenagel condensation of isovelaraldehyde with active methylene group followed by the Michael addition (using cyanide group), hydrolysis and reduction led to the formation of core skeleton. After that several generic procedures has been developed to avoid the toxic potassium cyanide. The patent (W02012093411) reports that the preparation of ?-(-)- 3- (carbomoylmethyl)-5-Methylhexanoic acid from the hydrolysis of tetraester intermediate. Next, 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). According to the patent (US5616793), the Knoevenagel condensation was done with ethyl isocyanate followed by decarboxylation that gives key pregabalin intermediate 3- isobutylglutaric acid. Further, novel routes were developed for the synthesis of S-pregabalin starting from the diversified starting materials such as benzyloxy 5-chiral epoxide (US9422230), 4-methylvaleric acid (US6197819) and leucine (CN103833562). In addition, the asymmetric Michael addition of nitroalkene with diethyl malonate was developed in presence of thiourea catalyst for the synthesis of chiral pregabalin intermediate (Tetrahedron, 2011, 67, 636). A recyclable polymer bound phase transfer catalyst was utilized for the preparation of pregabalin in six steps with 54% overall yield (Organic Process Research & Development, 2015, 19, 1274). Palladium catalyzed direct C(sp3)-H carbonylation of alkylamines towards synthesis of g-lactams and g-amino acids has been developed, and this method was applied to the concise total synthesis of rac-Pregbalin (Organic Letters, 2015, 17, 3698). The flow reaction methods were also used for the preparation of Pregabalin starting from commercial isovaleraldehyde and methyl malonate in presence of heterogeneous catalysts (European Journal of Organic Chemistry, 2017, 44, 6491). Visible light-induced photoredox catalysed radical Michael addition of carboxylic acids was developed and this technology was applied to a three-step synthesis of the medicinal agent pregabalin (JACS, 2014, 136,10886).
Though, several of these methods and/or processes are practical at laboratory level, some of them are useful at industrial production. Reported methods results in low atom economy and further process requiring longer duration and higher temperature thus energy load. For example, reduction of cyano or nitro group under hydrogenation using metal catalysts; use of phosphonate in condensation reaction etc are needed. In some cases there are: (i) metal- mediated oxidation reactions involving carbon mononxide; (ii) isoxazole based nitro compound, (iii) catalytic hydrogenation of nitro functionality; (iv) use of heterogeneous catalysts for the reduction of nitro group; (v) usage of cyano functionality. OBJECTIVE OF THE INVENTION
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 .
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of g-aminobutyric acids derivatives, in particular pregabalin, baclofen and novel analogs thereof.
In an embodiment the present invention provides a process for the preparation of compounds of formula I
Figure imgf000005_0001
wherein: X and Y are individually selected from H, C1-C12 linear or branched alkyl, cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3 or 4 carbon atoms) wherein Ri and R2 are H, comprising the steps of:
(i) Michael addition reaction between compound of formula VI and methyl ketone compound of formula VII in presence of an amine base and an acid at a temperature range of 0-20°C, for 0.5-2 h, to give compounds of formula V;
Figure imgf000006_0001
wherein:
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl, cycloalkyl or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbons),
Ri and R2 are H,
A and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl, R3 is C1-C6 alkyl or cycloalkyl;
(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;
Figure imgf000006_0002
wherein:
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl, cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms) ,
Ri and R2 are H,
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;
(iii) Beckmann reaction 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
Figure imgf000007_0001
wherein;
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms)
Ri and R2 are H,
A and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl
R3 is C1-C6 alkyl or cycloalkyl,
(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;
Figure imgf000008_0001
wherein;
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms)
Ri and R2 are H;
(v) cleavage of cyclic amide intermediate compound of formula II, obtained in step-(iv) using an acid in a polar solvent a temperature range of 25-150 °C for 18-30 h to give the compound of formula I.
In another embodiment of the present invention, the amine base is selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives.
In another embodiment of the present invention, the acid is selected from the group consisting of mineral acids, trifluoroacetic acid, pTSA and mixtures thereof.
In another embodiment of the present invention, the oxyamine is hydroxylamine hydrochloride.
In an embodiment of the present invention, 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. In an embodiment of the present invention, the polar solvent is selected from the group consisting of water, alcohols, esters, dimethylformamide, dimethylsulfoxide, acetonitrile and mixtures thereof.
In an embodiment of the present invention, all steps of the process are carried out without isolation of intermediates. In an embodiment of the present invention, the compound of formula I is g-aminobutyric acid and stereoselective g-aminobutyric acid derivatives (enantiomers and diastereomers).
In another embodiment of the present invention the process is a continuous process.
In another embodiment of the present invention the process is carried out without a genotoxic chiral resolution agent towards chiral g-aminobutyric acid derivatives.
DETAILED DESCRIPTION OF DRAWINGS OF THE INVENTION
Scheme 1 provides a schematic representation of process for preparation of compounds of formula I
DETAILED DESCRIPTION OF THE INVENTION
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. This newly developed process starts from the compound of formula VI involving five step reaction sequences and comprises of the following simple and easy to replicate steps in large scale operations: Michael addition, oxime formation, Beckmann rearrangement, base-mediated cyclization and acid-mediated cleavage as illustrated in scheme 1 to give the desired compounds of formula I:
Figure imgf000009_0001
wherein:
X and Y are individually selected from H, C1-C12 linear or branched alkyl or cycloalkyl or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms) wherein Ri and R2 are H. In scheme 1, 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. Then, 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.
Further 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 present process for the preparation of g-aminobutyric acid derivatives, in particular, pregabalin, baclofen and intermediates, as illustrated in scheme 1 is described as follows. This process is the most convenient and feasible method involving five step reaction sequence employing simple key starting materials and reaction parameters comprising of following steps:
(i) 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;
Figure imgf000011_0001
wherein:
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl, cycloalkyl or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbons),
Ri and R2 are H,
A and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl,
R3 is C1-C6 alkyl or cycloalkyl.
(ii) 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).
Figure imgf000011_0002
wherein:
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl, cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms),
Ri and R2 are H,
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.
(iii) 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.
Figure imgf000012_0001
wherein:
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms)
Ri and R2 are H,
A and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl
R3 is C1-C6 alkyl or cycloalkyl.
(iv) 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.
Figure imgf000012_0002
wherein: X and Y are individually selected from H, C1-C12 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms)
Ri and R2 are H. (v) The fifth and final step in the process involves cleavage of the cyclic amide intermediate compound of formula II, using an acid in a polar solvent at a temperature range of 25°C for about 18hours to give the compound of formula I,
Figure imgf000013_0001
wherein: X and Y are individually selected from H, C1-C12 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3 or 4 carbon atoms)
Ri and R2 are H.
In another embodiment of the present invention, the amine base is selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives.
In another embodiment of the present invention, the acid is selected from the group consisting of mineral acids, trifluoroacetic acid, pTSA and mixtures thereof.
In another embodiment of the present invention, the oxyamine is hydroxylamine hydrochloride.
In an embodiment of the present invention, 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. In an embodiment of the present invention, the polar solvent is selected from the group consisting of water, alcohols, esters, dimethylformamide, dimethylsulfoxide, acetonitrile and mixtures thereof.
In an embodiment of the present invention, all steps of the process are carried out without isolation of intermediates.
In another embodiment of the present invention, the compound of formula I is g-aminobutyric acid and stereoselective g-aminobutyric acid derivatives (enantiomers and diastereomers).
In a preferred embodiment of the present invention, the process is a continuous process. In another embodiment of the present invention the process is a continuous process.
In another embodiment of the present invention the process is carried out without a genotoxic chiral resolution agent towards chiral g-aminobutyric acid derivatives. Following example is given by way of illustration and therefore should not be construed to limit the scope of the invention.
EXAMPLE
Figure imgf000014_0001
5 (formula IVa/IVb) E/Z mixture
Figure imgf000014_0002
6 (formula W) 7 (formula H)
Step 1
Preparation of compound of 4 (formula V): Acetone (200 mL, 4 vol, formula VII) was taken in round-bottom flask at 10 °C followed by addition of pyrrolidine (1 mol) at same temperature. Trifluroacetic acid (0.1 mol) was added to the reaction mixture at same temperature, then stirred for 30 min. Olefin compound 3 (50 g, 1 mol, formula VI) was dissolved in acetone and added to the reaction mixture and stirred for 30 min. The reaction mixture was diluted with water (5 vol) and ethyl acetate (5 vol), organic layer was separated and aqueous layer was extracted with ethyl acetate (2 vol x 1). Combined organic layer was washed with IN HC1 (3 vol x 2) and water (5 vol), organic layer was separated and washed with aq. saturated sodium bicarbonate solution (3 vol) and aq. saturated brine (5 vol). The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure to get crude compound V (4, 57 g, >95% purity). Mol. Formula CisHieOs; NMR (500 MHz, CDCb): ό 4.21 - 4.16 (m, 4H), 3.55 - 3.52 (m, 1H), 2.80-2.72 (m, 2H), 2.50 (td, / = 8.0, 3.0 Hz, 1H), 2.14 (s, 3H), 1.58-1.51 (m, 1H), 1.28- 1.24 (m, comprising of t, dd, dd, 8H), 0.91 (d, / = 6.6, Hz, 3H), 0.89 (d, /= 6.5, 3H); 13C NMR (126 MHz, CDCb): S 207.5, 169.0, 168.7, 61.2, 61.1, 53.9, 45.4, 41.4, 31.3, 30.3,
25.3, 22.7, 22.3, 14.1 (2C); HRMS (ESI): m/z calcd for CisHieOsNa (M+H)+: 309.1678, found: 309.1679.
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.
Step 2
Preparation of compound 5 (formula IVa and/or IVb): Compound 4 (1.0 mol) was taken in to the round-bottom flask in methanol (5 vol) and hydroxylamine hydrochloride was added (1.2 mol) followed by sodium acetate (1.6 mol) at ambient temperature. Reaction mixture was heated to 65°C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure at 50°C, diluted with water (3 vol) and ethyl acetate, and (5.0 vol) stirred for 15 min at room temperature. The layers were separated and aqueous layer was extracted with ethyl acetate (2 vol x 2). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound 5 (IVa and/or IVb). [50 g of compound 4 provided 45.7 g of 5, >94% purity, pale yellow oil].
Mol. Formula
Figure imgf000015_0001
4.16 (m, 4H), 3.49 (d, / = 5.1 Hz, 1H), 2.52-2.44 (m, 1H), 2.37 (dd, / = 24.4, 6.3 Hz, 1H), 2.22 (dd, / = 14.4, 7.2 Hz, 1H), 1.89 (s, 3H), 1.67-1.57 (m, 2H), 1.29-1.25 (m, 8H), 0.9 (d, J = 6.5 Hz, 3H); 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (126 MHz, CDCI3): S 168.9, 168.7, 157.0, 61.2 (2C), 54.6, 54.3, 40.7,
38.3, 33.1, 25.3, 22.7, 22.4, 14.1, 13.6; HRMS (ESI): m/z calcd for C15H28NO5 (M+H)+: 302.1967, found: 302.1967.
The step 2 is also carried out using the derivatives of hydroxylamine hydrochloride and other inorganic or organic bases thereof.
Step 3
Preparation of compound 6 (formula III): Compound 5 (1.0 mol) was dissolved in ethyl acetate (5 vol) taken in round-bottom flask at ambient temperature. Reaction mixture was cooled to 0°C, then drop-wise addition of thionyl chloride (1.0 mol) was carried out for 20 min, then the reaction mixture was allowed attain room temperature and stirred for 3 h. The Reaction mixture was cooled to 0°C, then quenched with aq. saturated sodium bicarbonate solution (drop-wise addition), the two layers were separated and aqueous layer was extracted with ethyl acetate (2 vol x 2). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound 6 (formula III). [45 g of compound 5 provided 32.8 g of 6, >95% purity, pale yellow oil]
Mol. Formula
Figure imgf000016_0001
6.14 (s, 1H), 4.25 - 4.11 (m, 4H), 3.44 (d, / = 5.7 Hz, 1H), 3.41 - 3.26 (m, 1H), 3.32 - 3.25 (m, 1H), 2.48-2.40 (m, 1H), 1.96 (s, 3H), 1.74 - 1.64 (m, 1H), 1.28 (td, 7 = 7.1, 1 Hz, 6H), 1.25-1.23 (m, 1H), 1.19-1.12 (m, 1H), 0.93 - 0.9 (t, /= 6.7 Hz, 6H); 13 C NMR (126 MHz, CDCI3): d 170.1, 169.3, 169.0, 61.6 (2C), 54.3, 40.7, 39.6, 36.2, 25.2, 23.3, 23.0, 22.0, 14.1 (2C); HRMS (ESI): m/z calcd for C15H28NO5 (M+H)+: 302.1967, found: 302.1965.
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.
Step 4
Preparation of compound 7 (formula II): Compound 6 (1.0 mol) was taken in to the round- bottom flask in water (10 vol) at room temperature. Potassium hydroxide (3.0 mol) was added to the reaction mixture at same temperature, heated to 100°C and stirred for 24 h. The Reaction mixture was cooled to 0°C and pH adjusted to 2 using 2N HC1. Reaction mixture was extracted with ethyl acetate (5.0 vol x 3), the combined organic layers were washed with saturated brine solution (5.0 vol), dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude compound 7 (formula II). [32 g of compound 6 provided 18.9 g of 7, >95% purity, Light brownish oil].
Mol. Formula
Figure imgf000016_0002
6.95 (s, 1H), 3.58 (t, / = 8.9 Hz, 1H), 3.07 - 3.01 (m, 2H), 2.94-2.84 (m, 1H), 1.70-1.54 (m, 2H), 1.41 - 1.35 (m, 1H), 0.93 (d, / = 6.4 Hz, 6H); 13 C NMR (101 MHz, CDCL): d 175.2, 171.6, 53.3, 47.1, 43.3, 36.7, 25.9, 22.9, 22.1; HRMS (ESI): m/z calcd for C9H16NO3 (M+H)+: 186.1130, found: 186.1128.
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 PH: 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 solid compound was dried over reduced pressure to get pure pregabalin (racemic mixture) compound 8 (formula I). [18 g of compound 7 provided 14. 2 g of 8, >99 % purity, overall yield 51% colour less solid, mp. 166-168 °C]
Mol. Formula CsHnNC H NMR (400 MHz, D20) S 2.95 (dd, / = 13.0 , 5.5 Hz, 1H); 2.89 (dd, / = 13.0, 6.7 Hz, 1H); 2.27 (dd, / =14.8, 6.0 Hz, 1H), 2.19 (dd, / =14.8, 7.2 Hz, 1H), 2.13-2.07 (m, 1H), 1.59 (m, 1H), 1.15 (dd=t, / = 7.1 Hz, 2H), 0.83 (d, 7 =5.2 Hz, 3H); 0.81 (d, / = 5.2 Hz, 3H); 13C NMR (126 MHz, D20) S 180.8, 43.7, 40.6, 40.4, 31.6, 24.4, 22.0, 21.5; HRMS (ESI): m/z calcd for C8Hi8N02 (M+H)+: 160.1338, found: 160.1343.
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.
Overall, the steps mentioned above are carried out using 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 Ac20). 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.
ADVANTAGES OF THE INVENTION
The various advantages of the present process are given below.
1. 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.
2. 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.
3. Another advantage of the present invention is that the process provides novel reaction steps and intermediate compounds.
4. Isolation and/or purification of the product/s are straight forward with high yields and purity.
5. This is an attractive and economic method for the production of gamma amino acid derivatives, in particular pregabalin, baclofen.
6. This process can be adopted to generate a large library of process intermediates and g- aminobutyric acid derivatives, in particular pregabalin, baclofen analogs.
7. Amenable for chiral synthesis or g-aminobutyric acid and derivatives of both enantiomers.
8. Yet another advantage is to adopt the process for a continues manufacturing process
9. Overall yield without isolation is 51%
10. Novel lactam intermediates, opens an avenue to make substituted and spiro-analogues

Claims

We claim:
1. A process for the preparation of compounds of formula I,
Figure imgf000019_0001
wherein: X and Y are individually selected from H, C1-C12 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3 or 4 carbon atoms)
Ri and R2 are H, comprising the steps of:
(i) Michael addition reaction between compound of formula VI and methyl ketone compound of formula VII in presence of an amine base and an acid at a temperature range of 0-20°C, for 0.5-2 hours, to give compounds of formula V;
Figure imgf000019_0002
wherein;
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl, cycloalkyl or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbons),
Ri and R2 are H,
A and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl,
R3 is C1-C6 alkyl or cycloalkyl; (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 hours, to give a compound of formula IVa and/or IVb;
Figure imgf000020_0001
wherein;
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl, cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms),
Ri and R2 are H,
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;
(iii) Beckmann reaction 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 hours, to obtain a compound of formula III;
Figure imgf000021_0001
wherein;
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms),
Ri and R2 are H,
A and B are individually selected from CN, COOR, wherein R is C1-C6 alkyl or cycloalkyl,
R3 is C1-C6 alkyl or cycloalkyl;
(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 hours, to obtain a cyclic amide intermediate compound of formula II;
Figure imgf000021_0002
wherein;
X and Y are individually selected from H, Cl -Cl 2 linear or branched alkyl or cycloalkyl, or X and Y may together form a ring M, wherein M is a monocyclic, bicyclic, polycylic ring (when n = 1, 2, 3, 4 carbon atoms),
Ri and R2 are H ;
(v) cleavage of the cyclic amide intermediate compound of formula II, obtained in step-(iv) using an acid in a polar solvent at a temperature range of 25-150°C for 18-30 hours to give the compound of formula I.
2. The process as claimed in claim 1, wherein the amine base is selected from the group consisting of secondary amine, tertiary amine, heterocyclic amine and their carbamate and urea derivatives.
3. The process as claimed in claim 1, wherein the acid is selected from the group consisting of mineral acids, trifluoroacetic acid, pTSA or a mixtures thereof.
4. The process as claimed in claim 1, wherein the oxyamine is hydroxylamine hydrochloride.
5. The process as claimed in claim 1, wherein 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 or mixtures thereof.
6. The process as claimed in claim 1, wherein the polar solvent is selected from the group consisting of water, alcohols, esters, dimethylformamide, dimethylsulfoxide, acetonitrile and mixtures thereof.
7. The process as claimed in claim 1, wherein all steps of the process are carried out without isolation of intermediates.
8. The process as claimed in any of the preceding claims, wherein the compound of formula I is g-aminobutyric acid and derivatives thereof.
9. The process as claimed in any of the preceding claims, wherein the process is a continuous process.
10. The process as claimed in any of the preceding claims, wherein the process is carried out without a genotoxic chiral resolution agent towards chiral g-aminobutyric acid derivatives.
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