WO2021260721A1 - A new cost effective and scalable process for synthesizing pure brivaracetam - Google Patents

A new cost effective and scalable process for synthesizing pure brivaracetam Download PDF

Info

Publication number
WO2021260721A1
WO2021260721A1 PCT/IN2021/050594 IN2021050594W WO2021260721A1 WO 2021260721 A1 WO2021260721 A1 WO 2021260721A1 IN 2021050594 W IN2021050594 W IN 2021050594W WO 2021260721 A1 WO2021260721 A1 WO 2021260721A1
Authority
WO
WIPO (PCT)
Prior art keywords
brivaracetam
formula
chiral purity
reacting
present
Prior art date
Application number
PCT/IN2021/050594
Other languages
French (fr)
Inventor
Angshuman GHOSH
Sarabindu Roy
Ramesh Dhondi KUBEER
Mutyala V. V. Vara PRASAD
Ramkrishna MIDYA
Amit Mondal
Animesh HALDAR
Ajay Kumar YADAW
Subho Roy
Original Assignee
Clininvent Research Pvt. Ltd.
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 Clininvent Research Pvt. Ltd. filed Critical Clininvent Research Pvt. Ltd.
Publication of WO2021260721A1 publication Critical patent/WO2021260721A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to the field of process development chemistry. Particularly, the present invention relates to an improved process for synthesizing Brivaracetam.
  • Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol- 1-yl] butanamide, having the chemical structure of formula 1 as below:
  • Brivaracetam is basically a chemical analogue of Levetiracetam, marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients at 16 years of age and older with epilepsy.
  • Brivaracetam has an advantage over Levetiracetam in that it gets into the brain "much more quickly," which means that "it could be used for status epilepticus, or acute seizures than cluster, or prolonged seizures".
  • Brivaracetam is considered as one of the most promising 3 rd generation antiepileptic drugs.
  • Brivaracetam molecule is first disclosed in patent publication WO2001062726, which describes 2-oxo-1 -pyrrolidine derivatives and methods for their preparation.
  • Kenda et al.: Journal of Medicinal Chemistry, 2004, 47, 530-549 further proposes selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83 ⁇ (ucb 34714; Brivaracetam) as the most interesting candidate showing 10 times more potency than Levetiracetam as an antiseizure agent in audiogenic seizure-prone mice.
  • This article further discloses methods for synthesizing the said compound Brivaracetam.
  • these compounds are synthesized as mixtures of stereoisomers (racemic or diastereoisomeric mixtures), separated by preparative HPLC on silica gel and/or chiral phases.
  • WO2016191435A1 (also as IN201717005820A) relates to a process for a scalable synthesis of enantiomerically pure Brivaracetam from an intermediate (4R)-4- Propyldihydrofuran-2(3H)-one (compound IV): , wherein, R is saturated or unsaturated C1-20 alkyl or C1 alkyl-unsubstituted or substituted aryl, comprising the steps of decarboxylation of the compound of formula IV to produce the compound of formula VI ring-opening of the compound of formula VI to produce the compound of formula VII , wherein Rl is saturated or unsaturated Cl-20 alkyl or Cl alkyl-unsubstituted or substituted aryl; and X is CI Br I OMs, OTs, ONs; or the compound of formula X reacting the compound of formula VI with (S)-2- aminobutanamide or its salt to
  • prior art IN201641030239A disclosed a process for the preparation of Brivaracetam of Formula (I) by means of converting enantiomerically pure compound of Formula VII to obtain enantiomerically pure compound of Formula XI: , wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR2; R2 is optionally substituted C1-C12 alkyl, aryl, alkyl aryl, aryl alkyl; such that the said process further comprises steps of: 1) cyclizing compound of formula VII to give enantiomerically pure compound of formula IX: , wherein R2 is optionally substituted C1-C12 alkyl, aryl, alkyl aryl or aryl alkyl; 2) converting the compound of formula IX to give a enantiomerically pure compound of formula X: , wherein X is halogen; 3) converting compound of formula X to give a enantiomer
  • CN108929289A discloses a process of reacting a compound represented by the formula IV with (S) -2-aminobutyramide in order to obtain Brivaracetam.
  • the synthetic route is as follows:
  • CN108689903B relates to a new preparation method of Brivaracetam that comprises steps of: a) subjecting a compound of formula III and (S) -2-aminobutanamide or salt thereof to condensation reaction, in the presence of a condensing agent, in order to obtain a compound shown in a formula IV, wherein the compound has two chiral centres; b) removal of the hydroxy-protecting group R1 to obtain a compound of formula V; and c) carrying out chlorination reaction on the compound shown in the formula V using a chlorination reagent to obtain a compound shown in the formula VI; and d) carrying out substitution reaction on the compound shown in the formula VI in the presence of an alkaline reagent, and closing a ring to obtain Briva
  • CN111196771A relates to a preparation method of Brivaracetam which comprises the steps of: 1) carrying out ring-opening reaction on a compound R-4- propyldihydrofuran-2-ketone in a formula II and a compound S-2-aminobutanamide in a formula III to obtain an intermediate compound in a formula I; 2) condensing the said intermediate compound of formula I is followed by cyclization to produce Brivaracetam
  • the ring-opening reaction in step 1 of this process essentially occurs under acidic conditions, specifically in presence of Lewis acids like tetra-isopropyl titanate, anhydrous aluminium trichloride, anhydrous zinc chloride, boron trifluoride diethyl etherate etc.; and also in presence of organic solvents chosen from one or more of anhydrous tetrahydrofuran, 2-methyltetrahydrofuran, acetone, dimethyl sulfoxide and N, N-dimethylformamide; which makes this
  • the present inventors have developed a cost effective, novel and efficient process for the preparation of Brivaracetam which essentially avoids all the drawbacks involved in prior art as mentioned above.
  • the currently developed process is advantageously capable of producing the key lactone intermediate with more than 80% ee applying transfer hydrogenation with a very simple operation in view of process perspective. Further, by means of using such chiral lactone with more than 80% ee, the currently developed process is also capable of delivering >99.9% chirally pure Brivaracetam with excellent yield.
  • An object of the invention is to overcome the disadvantages of the prior art.
  • Another object of the present invention is to provide a novel, green and economical process for the preparation of enantiomerically pure Brivaracetam that is (2S)-2-[(4R)-2- oxo-4- propylpyrrolidin-1-yl] butanamide from its chirally pure (R)-lactone intermediate that is (4R)-4-propyldihydrofuran-2(3H)-one
  • Another object of the present invention is to provide a new process for synthesizing enantiomerically pure Brivaracetam starting either from the (R)-lactone intermediate having approx 70-80% ee or from its further purified version that is the (R)-lactone intermediate having approx 99.99-100% ee.
  • Another object of the present invention is to provide a process for preparation of enantiomerically pure Brivaracetam that is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide via formation of an intermediate having the following structure, with chiral purity 97-100%:
  • Another object of the present invention is to provide a process for preparation of enantiomerically pure Brivaracetam that is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide via formation of an intermediate having the following structure, with chiral purity 99.9-100%:
  • Another object of the present invention is to provide a new industrially scalable process for the preparation of highly pure Brivaracetam that is (2S)-2-[(4R)-2-oxo-4- propylpyrrolidin-1-yl] butanamide having 99.9-100% chiral purity.
  • Another aspect of the present invention provides an alternative method for synthesizing Brivaracetam of formula 1 comprising steps of: (a) reacting (4R)-4-propyldihydrofuran-2(3H)-one having 99.99-100% ee with (S)-2- aminobutyramide in presence of a base to form Intermediate 7’ having chiral purity of 99-100%; (b) reacting said intermediate 7’ with a suitable reagent to form intermediate 8’ , wherein X is a leaving group selected from halides, or sulfonates; and (c) directly reacting the said intermediate 8’ with a suitable reagent to form Brivaracetam of formula 1 having chiral purity 99.9-100%.
  • Figure 1 graphically illustrates 1H NMR study results confirming formation of Intermediate 7 of the present invention
  • Figure 2 graphically illustrates LCMS data that further confirm formation of Intermediate 7
  • Figure 3 graphically illustrates HPLC data results that further confirm formation of Intermediate 7 having chiral purity of 97.38 %.
  • Figure 4 graphically illustrates 1H NMR study results confirming formation of Intermediate 8A of the present invention
  • Figures 5 (a, b) graphically illustrates LCMS data that further confirmed formation of Intermediate 8A
  • Figure 6 graphically illustrates Chiral HPLC data that confirms formation of purest form of Intermediate 8B having 100% chiral purity
  • Figure 7 graphically illustrates GLP-HPLC data that confirms formation of Intermediate 8B having 99.9% chemical purity
  • Figure 8 graphically illustrates chiral HPLC data result that confirms formation of Intermediate 7’ with a chiral purity 99.11%
  • Figure 9 graphically illustrates 1H NMR study results confirming formation of Intermediate 8’ of the present invention
  • Figure 10 graphically illustrate LCMS data that further confirmed formation of Intermediate 8’
  • Figure 11 graphically illustrates Chiral HPLC data that confirms formation of purest form of Intermediate 8’ having 100% chiral purity
  • Figure 12 graphically illustrates 1 H NMR study results that first confirms formation of Brivaracetam API of the present invention.
  • Figure 13 graphically illustrates LCMS data that further confirm formation of Brivaracetam API.
  • Figure 14 graphically illustrates Chiral HPLC data that confirms formation of purest form of Brivaracetam API having 99.93% chiral purity;
  • Figure 15 graphically illustrates GLP HPLC data that confirms formation of purest form of Brivaracetam API having 99.94% chemical purity.
  • the term “chirally pure” as used in the specification refers to synthesizing Brivaracetam with 99.9-100% chiral purity.
  • the terms“de and “ee” as used in the specification refer to‘diastereomeric excess’ and ‘enantiomeric excess’ respectively.
  • the present invention relates to a new, green and economical process for the preparation of enantiomerically pure Brivaracetam from its key R-lactone intermediate that is 4(R)- 4-propyldihydrofuran-2(3H)-one.
  • Such preparation method of Brivaracetam and intermediate compounds thereof as obtained during the process of the present invention is described below.
  • the currently developed process is embodied in many different forms and should not be construed as being limited to the description set forth herein.
  • An embodiment of the present invention provides a new, cost effective and easily scalable process for the preparation of Brivaracetam that is (2S)-2-[(4R)-2-oxo-4- propylpyrrolidin-1-yl] butanamide having 99.9-100% chiral purity.
  • the chirally pure R-lactone intermediate that is (4R)-4- propyldihydrofuran-2(3H)-one is synthesized by utilizing any one of the conventionally known methods in the art, preferably the one as disclosed in Clininvent’s prior filed patent WO2020148787A1 (also as IN201931002041) dated 17 th January 2019, which comprises of following steps: (a) condensing a pentanal with a glycoxylic acid in presence of a condensing agent to form Intermediate 1
  • Step 1 Ring opening of the R-lactone intermediate-3 that is (4R)-4-propyldihydrofuran- 2(3H)-one (70-80% ee) by means of reacting the same with (S)-2-aminobutyramide, in presence of a base without any additional solvent, forming an intermediate 7 that is (3R)- N-((S)-1-carbamoylpropyl)-3-(hydroxymethyl)hexanamide with 80-90 % yield and Chiral purity 97-100%;
  • Step 2 reacting the said intermediate 7 with a suitable reagent essentially comprising of a good leaving group, in presence of a base to form an intermediate 8A, having 75-80% yield, where X is a leaving group selected from halide ions, or sulfonates; Further purifying the said intermediate 8A by crystallization in order to form its chemically and chirally purified version, that is Intermediate 8B; Step 3: further reacting the said Intermediate 8B with a reagent selected from potassium tertiary butoxide, sodium tertiary butoxide, Lithium bis(trimethylsilyl)amide (LiHMDS), Potassium bis(trimethylsilyl)amide (KHMDS), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), or Lithium diisopropylamide (LDA) in a solvent such as tetrahydrofuran (THF), 2-Methyl THF, Acetonitrile, N-methyl-2-pyrroli
  • the key starting material can optionally be Intermediate-6 (99.99%-100% ee) which is a chirally purer version of Intermediate-3 (70-80%ee).
  • the key lactone intermediate i.e. Intermediate-6 is already taken in a chirally purer form having 99.99-100% ee; therefore, there remains no further requirement of the later step of purifying the subsequently formed Brivaracetam Intermediate 8A, thus rendering the process (as shown in below scheme B) economical.
  • the starting material as used in above scheme A i.e.
  • Step 1 Ring opening of the R-lactone of intermediate-6 that is (4R)-4- propyldihydrofuran-2(3H)-one (99.99-100% ee) by means of reacting the same with (S)- 2-aminobutyramide, in presence of a base without any additional solvent, forming an intermediate 7’ that is (3R)-N-((S)-1-carbamoylpropyl)-3-(hydroxymethyl)hexanamide with 90-100 % yield and with chiral purity 99-100%;
  • Step 2 reacting the said intermediate 7’ with a suitable reagent essentially comprising of a good leaving group , in presence of a base to form an intermediate 8’ having 80-90% yield, wherein X is a leaving group selected from halides, or sulfonates;
  • Step 3 reacting the said intermediate 8’ with a reagent selected from potassium tertiary butoxide, sodium tertiary butoxide, LiHMDS, KHMDS, DBU, or LDA in a solvent such as tetrahydrofuran (THF), 2-Methyl THF, Acetonitrile, N-Methyl 2-Pyrolliodone, Dimethyl Acetamide, or Dimethyl Formamide, in order to form the final Brivaracetam API with 80-90% yield and 99.9-100% chiral purity.
  • a solvent such as tetrahydrofuran (THF), 2-Methyl THF, Acetonitrile, N-Methyl 2-Pyrolliodone, Dimethyl Acetamide, or Dimethyl Formamide
  • the tertiary amine used as base is selected from triethyl amine, diisropropyl ethyl amine, or N-methyl morpholine, preferable triethyl amine.
  • the said reaction step 1 is advantageously conducted in absence of any further solvent than water, rendering the currently developed process a green one.
  • the reagent comprising of a good leaving group is essentially selected from a group consisting of SOCl 2 , POCl 3 , PCl 3 , MsCl, TsCl, Cyanuric Chloride, 1,3 dichloro-5,5-dimethyl hydantoin, and 1-Chloro-N,N,2-trimethyl-1-propenylamine.
  • scheme A of the present invention the purification of Intermediate 8A (respectively) is carried out by crystallization technique forming a purified version Intermediate 8B, wherein the said reaction comprises of: i) a suspension stirring method, ii) a heating lowering method, and iii) a volatilization method or an anti-solvent addition- precipitation method.
  • the choice of solvents is critical. For an effective crystallization to take place, often a binary or ternary solvent system is used, wherein set of solvent system is more polar in nature over the other set of solvent system.
  • Such solvent is selected from the group consisting of water, alcohol, ether, ketone, ester, a halogenated hydrocarbon, nitrile, an aliphatic hydrocarbon or a binary or ternary mixture of solvent system. Therefore, in the current purification process, the solvent is specifically selected from the group consisting of methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), heptane, dichloromethane (DCM), acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, ethyl acetate, isopropanol, ethanol and water.
  • MTBE methyl tert-butyl ether
  • DIPE diisopropyl ether
  • DCM dichloromethane
  • acetonitrile acetone
  • methyl isobutyl ketone isopropyl acetate
  • ethyl acetate isoprop
  • Brivaracetam API is produced having 99.9-100% chiral purity along with 75-90% yield.
  • the advantages of the present invention have been provided below: i.
  • the currently developed process for synthesizing Brivaracetam starting from its key lactone intermediate (Intermediate 3 or its chirally purer form Intermediate 6) is a novel, industrially scalable synthetic approach.
  • the key starting material (KSM) of the present invention is R-lactone that is Intermediate 3 which inspite of not being essentially chirally pure that is 70-80% ee is still capable of producing >99.9% chirally pure Brivaracetam.
  • KSM key starting material
  • the currently developed process is economical. iv.
  • EXAMPLE 1 Synthesis of (3R)-N-[(1S)-1-carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7 of scheme A of the present invention]
  • Example 1 illustrates one pot process for preparing purified (3R)-N-[(1S)-1- carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7] from Intermediate 3 (80% ee) as developed in step 1 of scheme A of the present invention.
  • EXAMPLE 2 Preparation of (3R)-N-(1S)-1-amino-1-oxobutan-2-yl)-3- (chloromethyl) hexanamide
  • Example 2 illustrates a process for preparing (3R)-N-(1S)-1-Amino-1-oxobutan-2-yl)-3- (chloromethyl) hexanamide [Intermediate 8A] from Intermediate 7 of example 1 above as developed in the present invention.
  • EXAMPLE 4 Synthesis of (3R)-N-[(1S)-1-carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7’ of scheme B of the present invention]
  • Example 4 illustrates one pot process for preparing purified (3R)-N-[(1S)-1- carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7’] from Intermediate 6 (99.99% ee) as developed in step-1 scheme B of the present invention.
  • Reaction mixture is then cooled to 0-10 °C and t-BuOK (1.5 eq) is added portion wise to the cooled solution over 1 h maintaining the temperature from - 0-10 °C to 25 °C under N 2 atm. Stirring is then continued for 2 h at -10 °C to 0 °C and then for 12 h at 15-25 °C under N 2 atm. Completion of reaction is monitored by TLC. After completion of reaction, the reaction mixture is quenched with addition of 1M HCl solution (pH ⁇ 6.5-7.0). The resulting mixture is extracted with i-PrOAc (2 L) and MTBE (1 L).

Landscapes

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

Abstract

The present invention relates to novel, economical processes for the preparation of enantiomerically pure Brivaracetam of Formula I having 99-100% diastereomeric excess (de) from its (R)-lactone intermediate that is (4R)-4-propyldihydrofuran-2(3H)-one.

Description

A NEW COST EFFECTIVE AND SCALABLE PROCESS FOR SYNTHESIZING PURE BRIVARACETAM FIELD OF INVENTION The present invention relates to the field of process development chemistry. Particularly, the present invention relates to an improved process for synthesizing Brivaracetam. BACKGROUND OF THE INVENTION AND PRIOR ART Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol- 1-yl] butanamide, having the chemical structure of formula 1 as below:
Figure imgf000002_0001
Brivaracetam is basically a chemical analogue of Levetiracetam, marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients at 16 years of age and older with epilepsy. Brivaracetam has an advantage over Levetiracetam in that it gets into the brain "much more quickly," which means that "it could be used for status epilepticus, or acute seizures than cluster, or prolonged seizures". From the Phase III trials, the self-reported rate of irritability with Brivaracetam was 2% for both drug doses (100 mg and 200 mg) vs 1% for placebo, which compares to as much as 10% for Levetiracetam in some post-marketing studies. With the improved safety profile and possibility to be used for wider range of epilepsy, Brivaracetam is considered as one of the most promising 3rd generation antiepileptic drugs. Brivaracetam molecule is first disclosed in patent publication WO2001062726, which describes 2-oxo-1 -pyrrolidine derivatives and methods for their preparation. This patent publication further discloses compound (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide which is known under the international non propriety name as Brivaracetam. As per Biopharmaceutics Classification System, Brivaracetam is a class I drug (high solubility and permeability). Some prior arts US6784197 and US7629474 disclose a process for synthesizing a diastereomeric mixture of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]-butanamide and (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]-butanamide (Brivaracetam) which is purified by chiral HPLC (Scheme-I & Scheme-II respectively, as provided below). This process used for chiral resolution makes it difficult for bulk manufacturing as well as it affects the overall yield making the process uneconomical. Scheme-I Synthesis of (2S)-2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide
Figure imgf000003_0001
[As disclosed in columns 37-38 of US 6784197 B2]
Scheme-II 1.1 Synthesis of (2S)-2-aminobutyramide-Free base
Figure imgf000004_0001
1.2 Synthesis of 5-hydroxy-4-n-propylfuran-2-one
Figure imgf000004_0002
1.3 Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide and (2S)-2-((4S)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide
Figure imgf000004_0003
[As disclosed in columns 6-7 of US 7629474 B2] Moreover, some prior arts such as US7122682B2, US8076493B2, US8338621B2 and US8957226B2 also describe processes for preparing Brivaracetam, wherein, the purifications are reportedly done by chiral HPLC methods resulting into similar shortcomings. Kenda et al.: Journal of Medicinal Chemistry, 2004, 47, 530-549 further proposes selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83α (ucb 34714; Brivaracetam) as the most interesting candidate showing 10 times more potency than Levetiracetam as an antiseizure agent in audiogenic seizure-prone mice. This article further discloses methods for synthesizing the said compound Brivaracetam. However, here too these compounds are synthesized as mixtures of stereoisomers (racemic or diastereoisomeric mixtures), separated by preparative HPLC on silica gel and/or chiral phases. All these processes for the preparation of Brivaracetam as described in the above- mentioned prior arts suffer from many disadvantages which includes difficulty in achieving desired chiral purity, tedious and cumbersome work up procedures, high temperature and longer time reaction, multiple crystallizations or isolation steps, use of excess reagents and solvents, column chromatographic separations & purifications etc. All these disadvantages affect the overall yield as well as the quality of the final product Brivaracetam and intermediates produced thereof; further, rendering such processes to be uneconomical and unsuitable for industrial scale-ups. As a result, enantioselective synthesis of Brivaracetam was perceived to be a possible way of overcoming such problems in view of the large-scale synthesis. However, very few prior arts have been found to report successful reduction of such concept into practice. WO2016191435A1 (also as IN201717005820A) relates to a process for a scalable synthesis of enantiomerically pure Brivaracetam from an intermediate (4R)-4- Propyldihydrofuran-2(3H)-one (compound IV):
Figure imgf000005_0001
, wherein, R is saturated or unsaturated C1-20 alkyl or C1 alkyl-unsubstituted or substituted aryl, comprising the steps of decarboxylation of the compound of formula IV
Figure imgf000005_0002
to produce the compound of formula VI
Figure imgf000005_0003
ring-opening of the compound of formula VI to produce the compound of formula VII
Figure imgf000006_0002
, wherein Rl is saturated or unsaturated Cl-20 alkyl or Cl alkyl-unsubstituted or substituted aryl; and X is CI Br I OMs, OTs, ONs; or the compound of formula X
Figure imgf000006_0001
reacting the compound of formula VI with (S)-2- aminobutanamide or its salt to produce the compound of formula XII in one step; or reacting the compound of formula VI with alkyl (S)-2- aminobutanoate to produce Xll-a , wherein R in the compound of formula Xll-a is a saturated or unsaturated C1-C20 alkoxyl; and then converting Xll-a to XII that is Brivaracetam by aminolysis and amide formation reaction. In above mentioned prior arts, the synthesis of chiral lactone which is the key starting material for making Brivaracetam involved Grignard addition, column chromatography and Krapcho decarboxylation techniques at high temperature, all of which are not at all recommendable in view of process perspective at industrial levels. Further the final step of the said reaction often involved cryogenic condition –30°C which is also difficult with respect to industrial scale up activities. Furthermore, prior art IN201641030239A disclosed a process for the preparation of Brivaracetam of Formula (I) by means of converting enantiomerically pure compound of Formula VII to obtain enantiomerically pure compound of Formula XI:
Figure imgf000007_0001
, wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR2; R2 is optionally substituted C1-C12 alkyl, aryl, alkyl aryl, aryl alkyl; such that the said process further comprises steps of: 1) cyclizing compound of formula VII to give enantiomerically pure compound of formula IX:
Figure imgf000007_0002
, wherein R2 is optionally substituted C1-C12 alkyl, aryl, alkyl aryl or aryl alkyl; 2) converting the compound of formula IX to give a enantiomerically pure compound of formula X:
Figure imgf000007_0003
, wherein X is halogen; 3) converting compound of formula X to give a enantiomerically pure compound of formula XI:
Figure imgf000007_0004
wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR2; R2 as defined above; followed by 4) treating the enantiomerically pure compound of formula XI with (S)- aminobutyramide of formula XII or its salt thereof to obtain Brivaracetam of Formula I.
Figure imgf000008_0001
However, this process suffered from drawbacks of handling acid chloride. Acid chlorides are unstable and storing a large amount of acid chloride is also not recommendable in view of safety and stability in industries. Moreover, this prior art process involves use of HBr in acetic acid, where HBr liberates Br that is hazardous and not recommendable for industrial scale-up activities in view of safety and handling. Some other prior arts such as CN108503573A, CN105646319A, CN106588740A, CN106588831A, CN108689903B and CN108929289A report various processes of synthesizing Brivaracetam from its lactone intermediate by various ring opening techniques. Among these, in particular CN108929289A discloses a process of reacting a compound represented by the formula IV with (S) -2-aminobutyramide in order to obtain Brivaracetam. The synthetic route is as follows:
Figure imgf000008_0002
Also, CN108689903B relates to a new preparation method of Brivaracetam that comprises steps of: a) subjecting a compound of formula III and (S) -2-aminobutanamide or salt thereof to condensation reaction, in the presence of a condensing agent, in order to obtain a compound shown in a formula IV, wherein the compound has two chiral centres; b) removal of the hydroxy-protecting group R1 to obtain a compound of formula V; and c) carrying out chlorination reaction on the compound shown in the formula V using a chlorination reagent to obtain a compound shown in the formula VI; and d) carrying out substitution reaction on the compound shown in the formula VI in the presence of an alkaline reagent, and closing a ring to obtain Brivaracetam of formula I having two chiral centres.
Figure imgf000009_0001
It has further been noted that although the above reaction goes through formation of intermediates V and/or VI; however, these intermediates are not essentially formed from the key lactone intermediate of Brivaracetam that is (4R)-4-propyldihydrofuran-2(3H)- one [or (R)-lactone]. Furthermore, CN111196771A relates to a preparation method of Brivaracetam which comprises the steps of: 1) carrying out ring-opening reaction on a compound R-4- propyldihydrofuran-2-ketone in a formula II and a compound S-2-aminobutanamide in a formula III to obtain an intermediate compound in a formula I; 2) condensing the said intermediate compound of formula I is followed by cyclization to produce Brivaracetam
Figure imgf000009_0002
However, the ring-opening reaction in step 1 of this process essentially occurs under acidic conditions, specifically in presence of Lewis acids like tetra-isopropyl titanate, anhydrous aluminium trichloride, anhydrous zinc chloride, boron trifluoride diethyl etherate etc.; and also in presence of organic solvents chosen from one or more of anhydrous tetrahydrofuran, 2-methyltetrahydrofuran, acetone, dimethyl sulfoxide and N, N-dimethylformamide; which makes this process both industrially non-scalable and environmentally unfriendly. The prior art Org. Process Res. Dev.2016. v 20. no 9. p 1566-1575 in its scheme 4, on page 17 also discloses a scheme for synthesizing Brivaracetam from its lactone intermediate:
Figure imgf000010_0001
Nevertheless, it has been noted that the process reported in this prior art provides Brivaracetam (API) with a very poor yield of ~30% and also having an inferior chiral purity of 95.9% ee, which does not even meet the ICH-specification for the Finished Product (API). Furthermore, a recently filed patent application WO2020148787A1 (also as IN201931002041) recites a new, improved and economical process for enantioselective synthesis and purification of a key intermediate of Brivaracetam that is the R-lactone, essentially utilizing a low chiral loading and without involving any chiral chromatographic resolution technique. Even though this prior art also discloses a process for the preparation of a chirally pure Brivaracetam of formula I utilizing the said intermediate; however, that process is mostly a conventional one. Accordingly, there is still a need in the art for a more economical and improved process for the synthesis of Brivaracetam with better purity and yield which overcomes the drawbacks of above prior arts. Therefore, the present inventors have developed a cost effective, novel and efficient process for the preparation of Brivaracetam which essentially avoids all the drawbacks involved in prior art as mentioned above. The currently developed process is advantageously capable of producing the key lactone intermediate with more than 80% ee applying transfer hydrogenation with a very simple operation in view of process perspective. Further, by means of using such chiral lactone with more than 80% ee, the currently developed process is also capable of delivering >99.9% chirally pure Brivaracetam with excellent yield. OBJECTS OF THE INVENTION: An object of the invention is to overcome the disadvantages of the prior art. Another object of the present invention is to provide a novel, green and economical process for the preparation of enantiomerically pure Brivaracetam that is (2S)-2-[(4R)-2- oxo-4- propylpyrrolidin-1-yl] butanamide from its chirally pure (R)-lactone intermediate that is (4R)-4-propyldihydrofuran-2(3H)-one
Figure imgf000011_0001
Another object of the present invention is to provide a new process for synthesizing enantiomerically pure Brivaracetam starting either from the (R)-lactone intermediate having approx 70-80% ee or from its further purified version that is the (R)-lactone intermediate having approx 99.99-100% ee. Another object of the present invention is to provide a process for preparation of enantiomerically pure Brivaracetam that is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide via formation of an intermediate having the following structure, with chiral purity 97-100%:
Figure imgf000012_0001
Another object of the present invention is to provide a process for preparation of enantiomerically pure Brivaracetam that is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide via formation of an intermediate having the following structure, with chiral purity 99.9-100%:
Figure imgf000012_0002
Another object of the present invention is to provide a new industrially scalable process for the preparation of highly pure Brivaracetam that is (2S)-2-[(4R)-2-oxo-4- propylpyrrolidin-1-yl] butanamide having 99.9-100% chiral purity. SUMMARY OF INVENTION One aspect of the present invention provides a process for synthesizing Brivaracetam of formula 1 and key intermediates thereof comprising steps of:
Figure imgf000013_0001
(a) reacting (4R)-4-propyldihydrofuran-2(3H)-one having 70-80% ee with (S)-2- aminobutyramide in presence of a base to form Intermediate 7 having chiral purity of 97-100%;
Figure imgf000013_0002
(b) reacting said intermediate 7 with a suitable reagent to form intermediate 8A
Figure imgf000013_0003
, wherein X is a leaving group selected from halide ions, or sulfonates, followed by, purifying the said intermediate 8A by crystallization in order to form its purified version that is Intermediate 8B having a chiral purity of 99.9- 100%
Figure imgf000014_0001
(c) reacting the said Intermediate 8B with a suitable reagent to form Brivaracetam of formula 1 having chiral purity of 99.9-100% . Another aspect of the present invention provides an alternative method for synthesizing Brivaracetam of formula 1 comprising steps of: (a) reacting (4R)-4-propyldihydrofuran-2(3H)-one having 99.99-100% ee with (S)-2- aminobutyramide in presence of a base to form Intermediate 7’ having chiral purity of 99-100%;
Figure imgf000014_0002
(b) reacting said intermediate 7’ with a suitable reagent to form intermediate 8’
Figure imgf000014_0003
, wherein X is a leaving group selected from halides, or sulfonates; and (c) directly reacting the said intermediate 8’ with a suitable reagent to form Brivaracetam of formula 1 having chiral purity 99.9-100%.
Figure imgf000015_0001
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS Figure 1 graphically illustrates 1H NMR study results confirming formation of Intermediate 7 of the present invention; Figure 2 graphically illustrates LCMS data that further confirm formation of Intermediate 7; Figure 3 graphically illustrates HPLC data results that further confirm formation of Intermediate 7 having chiral purity of 97.38 %. Figure 4 graphically illustrates 1H NMR study results confirming formation of Intermediate 8A of the present invention; Figures 5 (a, b) graphically illustrates LCMS data that further confirmed formation of Intermediate 8A; Figure 6 graphically illustrates Chiral HPLC data that confirms formation of purest form of Intermediate 8B having 100% chiral purity; Figure 7 graphically illustrates GLP-HPLC data that confirms formation of Intermediate 8B having 99.9% chemical purity; Figure 8 graphically illustrates chiral HPLC data result that confirms formation of Intermediate 7’ with a chiral purity 99.11%; Figure 9 graphically illustrates 1H NMR study results confirming formation of Intermediate 8’ of the present invention; Figure 10 graphically illustrate LCMS data that further confirmed formation of Intermediate 8’; Figure 11 graphically illustrates Chiral HPLC data that confirms formation of purest form of Intermediate 8’ having 100% chiral purity; Figure 12 graphically illustrates 1H NMR study results that first confirms formation of Brivaracetam API of the present invention. Figure 13 graphically illustrates LCMS data that further confirm formation of Brivaracetam API. Figure 14 graphically illustrates Chiral HPLC data that confirms formation of purest form of Brivaracetam API having 99.93% chiral purity; Figure 15 graphically illustrates GLP HPLC data that confirms formation of purest form of Brivaracetam API having 99.94% chemical purity. DETAILED DESCRIPTION OF THE INVENTION: The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness. The terms and words used in the following description and claims are not limited to bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their equivalents. It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments. It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. The term “cost-efficient or economical” as used in the specification refers to the cost of synthesizing Brivaracetam at a comparatively lesser due to mild reaction condition, involving cheaper reagents, less chemical steps with better yield; therefore making it suitable for industrial scale-ups. The term “chirally pure” as used in the specification refers to synthesizing Brivaracetam with 99.9-100% chiral purity. The terms“de and “ee” as used in the specification refer to‘diastereomeric excess’ and ‘enantiomeric excess’ respectively. The present invention relates to a new, green and economical process for the preparation of enantiomerically pure Brivaracetam from its key R-lactone intermediate that is 4(R)- 4-propyldihydrofuran-2(3H)-one.
Figure imgf000018_0002
Such preparation method of Brivaracetam and intermediate compounds thereof as obtained during the process of the present invention is described below. The currently developed process is embodied in many different forms and should not be construed as being limited to the description set forth herein. An embodiment of the present invention provides a new, cost effective and easily scalable process for the preparation of Brivaracetam that is (2S)-2-[(4R)-2-oxo-4- propylpyrrolidin-1-yl] butanamide having 99.9-100% chiral purity.
Figure imgf000018_0001
In the present invention, the chirally pure R-lactone intermediate that is (4R)-4- propyldihydrofuran-2(3H)-one is synthesized by utilizing any one of the conventionally known methods in the art, preferably the one as disclosed in Clininvent’s prior filed patent WO2020148787A1 (also as IN201931002041) dated 17th January 2019, which comprises of following steps: (a) condensing a pentanal with a glycoxylic acid in presence of a condensing agent to form Intermediate 1
Figure imgf000019_0001
(b) reducing said Intermediate 1 with a reducing agent to form Intermediate 2
Figure imgf000019_0002
; (c) treating said Intermediate 2 with 0.1-1 mol% of a chiral ligand in presence of a metal-based catalyst; followed by enantio-selectively reducing the unsaturated lactone of said Intermediate 2 in presence of a reductant and an additive in order to form Intermediate 3 (80% ee)
Figure imgf000019_0003
(d) chirally purifying the said Intermediate 3 with a chiral amine in a solvent to produce a diastereomeric mixture of Intermediate 4
Figure imgf000019_0004
wherein R1 is a substituted or unsubstituted aryl or heteroaryl; and R2 is a substituted or unsubstituted alkyl or cycloalkyl; (e) further purifying said Intermediate 4 by crystallization in order to form Intermediate 5 having 99.90-100% chiral purity
Figure imgf000020_0001
wherein R1 is a substituted or unsubstituted aryl or heteroaryl; and R2 is a substituted or unsubstituted alkyl or cycloalkyl; (f) cyclizing said Intermediate 5 with a cyclizing agent in order to form intermediate 6 having an enantiomeric purity of 99.90-100%
Figure imgf000020_0002
; In the present invention, a new process is developed for synthesizing the final API (active pharmaceutical ingredient) Brivaracetam with 99.9-100% chiral purity starting - either from the (R)-lactone Intermediate-3 having approx 80% ee; OR - from its further purified version that is the (R)-lactone Intermediate-6 having approx 99.99% ee, as mentioned in the above reported process. In a specific embodiment of the present invention, the parameters for each reaction step of the currently developed process have been provided in details below: Step 1: Ring opening of the R-lactone intermediate-3 that is (4R)-4-propyldihydrofuran- 2(3H)-one (70-80% ee) by means of reacting the same with (S)-2-aminobutyramide, in presence of a base without any additional solvent, forming an intermediate 7 that is (3R)- N-((S)-1-carbamoylpropyl)-3-(hydroxymethyl)hexanamide with 80-90 % yield and Chiral purity 97-100%;
Figure imgf000021_0001
Step 2: reacting the said intermediate 7 with a suitable reagent essentially comprising of a good leaving group, in presence of a base to form an intermediate 8A, having 75-80% yield, where X is a leaving group selected from halide ions, or sulfonates;
Figure imgf000021_0002
Further purifying the said intermediate 8A by crystallization in order to form its chemically and chirally purified version, that is Intermediate 8B;
Figure imgf000021_0003
Step 3: further reacting the said Intermediate 8B with a reagent selected from potassium tertiary butoxide, sodium tertiary butoxide, Lithium bis(trimethylsilyl)amide (LiHMDS), Potassium bis(trimethylsilyl)amide (KHMDS), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), or Lithium diisopropylamide (LDA) in a solvent such as tetrahydrofuran (THF), 2-Methyl THF, Acetonitrile, N-methyl-2-pyrrolidone, Dimethyl Acetamide, or Dimethyl Formamide, in order to form the final Brivaracetam API with 75-85% yield and 99.9- 100% chiral purity.
Figure imgf000022_0001
The above process of the present invention is schematically represented in Scheme A below:
Figure imgf000023_0001
Further, in the present invention, for synthesizing Brivaracetam, the key starting material can optionally be Intermediate-6 (99.99%-100% ee) which is a chirally purer version of Intermediate-3 (70-80%ee). In such a scenario, since, the key lactone intermediate i.e. Intermediate-6 is already taken in a chirally purer form having 99.99-100% ee; therefore, there remains no further requirement of the later step of purifying the subsequently formed Brivaracetam Intermediate 8A, thus rendering the process (as shown in below scheme B) economical. On the other hand, the starting material as used in above scheme A i.e. the R-lactone having a chiral purity of 80% ee costs around $260/KG, but its purified form as used in below scheme B i.e. the R-lactone intermediate having a chiral purity of 99.99-100% ee costs around $800/KG. Therefore, both processes for synthesizing Brivaracetam from R-lactone intermediate as depicted in scheme A or scheme B of the present invention are economically viable in their own rights; hence, both are suitable for industrial level scaling-up reactions. Accordingly, in another specific embodiment of the present invention, the reaction parameters for each step of the currently developed process have been provided in details below: Step 1: Ring opening of the R-lactone of intermediate-6 that is (4R)-4- propyldihydrofuran-2(3H)-one (99.99-100% ee) by means of reacting the same with (S)- 2-aminobutyramide, in presence of a base without any additional solvent, forming an intermediate 7’ that is (3R)-N-((S)-1-carbamoylpropyl)-3-(hydroxymethyl)hexanamide with 90-100 % yield and with chiral purity 99-100%;
Figure imgf000024_0001
Step 2: reacting the said intermediate 7’ with a suitable reagent essentially comprising of a good leaving group, in presence of a base to form an intermediate 8’ having 80-90% yield, wherein X is a leaving group selected from halides, or sulfonates;
Figure imgf000025_0001
Step 3: reacting the said intermediate 8’ with a reagent selected from potassium tertiary butoxide, sodium tertiary butoxide, LiHMDS, KHMDS, DBU, or LDA in a solvent such as tetrahydrofuran (THF), 2-Methyl THF, Acetonitrile, N-Methyl 2-Pyrolliodone, Dimethyl Acetamide, or Dimethyl Formamide, in order to form the final Brivaracetam API with 80-90% yield and 99.9-100% chiral purity.
Figure imgf000025_0002
The above process of the present invention is schematically represented in Scheme B below:
Figure imgf000026_0001
In accordance with the above reaction schemes A and/or B, in step 1, the tertiary amine used as base is selected from triethyl amine, diisropropyl ethyl amine, or N-methyl morpholine, preferable triethyl amine. The said reaction step 1 is advantageously conducted in absence of any further solvent than water, rendering the currently developed process a green one. Further, in step 2 of above scheme A and/or that of scheme B (formation of Intermediate 8A or 8’ respectively), the reagent comprising of a good leaving group is essentially selected from a group consisting of SOCl2, POCl3, PCl3, MsCl, TsCl, Cyanuric Chloride, 1,3 dichloro-5,5-dimethyl hydantoin, and 1-Chloro-N,N,2-trimethyl-1-propenylamine. Furthermore, scheme A of the present invention, the purification of Intermediate 8A (respectively) is carried out by crystallization technique forming a purified version Intermediate 8B, wherein the said reaction comprises of: i) a suspension stirring method, ii) a heating lowering method, and iii) a volatilization method or an anti-solvent addition- precipitation method. In such purification method as followed by the present invention, the choice of solvents is critical. For an effective crystallization to take place, often a binary or ternary solvent system is used, wherein set of solvent system is more polar in nature over the other set of solvent system. Such solvent is selected from the group consisting of water, alcohol, ether, ketone, ester, a halogenated hydrocarbon, nitrile, an aliphatic hydrocarbon or a binary or ternary mixture of solvent system. Therefore, in the current purification process, the solvent is specifically selected from the group consisting of methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), heptane, dichloromethane (DCM), acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, ethyl acetate, isopropanol, ethanol and water. In the final step 3 of above scheme A and/or scheme B above, Brivaracetam API is produced having 99.9-100% chiral purity along with 75-90% yield. ^ The advantages of the present invention have been provided below: i. The currently developed process for synthesizing Brivaracetam starting from its key lactone intermediate (Intermediate 3 or its chirally purer form Intermediate 6) is a novel, industrially scalable synthetic approach. ii. The key starting material (KSM) of the present invention is R-lactone that is Intermediate 3 which inspite of not being essentially chirally pure that is 70-80% ee is still capable of producing >99.9% chirally pure Brivaracetam. iii. The currently developed process is economical. iv. No hazardous chemicals have been used in the current process, rendering it environmentally friendly and suitable for industrial level scale-ups. v. The final step of cyclization forming Brivaracetam does not essentially demand any cryogenic condition. It works well at 0 ± 10 °C and yield is also quite good after crystallization (~80%). vi. The finished product (Brivaracetam) as obtained by means of the currently developed process is of 99.9-100% chiral purity along with >99% chemical purity. vii. On a whole, the currently developed process is industrially scalable, cost efficient and at the same time is capable of synthesizing Brivaracetam with best chirally purity (99.9-100%) and excellent yield (80-90%). The invention is now illustrated by way of non-limiting examples. The examples are intended to be purely exemplary of the invention, should therefore not be considered to limit the invention in any way. EXAMPLES: EXAMPLE 1: Synthesis of (3R)-N-[(1S)-1-carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7 of scheme A of the present invention] Example 1 illustrates one pot process for preparing purified (3R)-N-[(1S)-1- carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7] from Intermediate 3 (80% ee) as developed in step 1 of scheme A of the present invention.
Figure imgf000028_0001
Procedure: In the first step of scheme A of the present invention, a mixture of (R)/(S)-4- propyldihydrofuran-2(3H)-one (Intermediate 3, R: S isomer = 80: 20) (1 eq), (S)-2- aminobutanamide (1.1 eq), triethylamine (1.5 eq) is refluxed at a temperature of 95±5 °C for 24h. The mixture is then cooled to 60-65 °C, washed with a mixture of dichloromethane and diisopropyl ether (2.5 vol) in order to get Intermediate-7 [(3R)-N- [(1S)-1-carbamoyl-propyl]-3-(hydroxymethyl) hexanamide] (80% yield). Results: Formation of Intermediate 7 is confirmed further by following analytical studies: a) The 1H NMR analysis is conducted and the data as illustrated in accompanying figure 1 depicts: (400 MHz, DMSO-d6): δ 0.6 (t, J= Hz, 6H), 1.07-1.18 (m, 1H), 1.21-1.35 (m, 3H), 1.45-1.43 (m, 1H), 1.61-1.72 (m, 1H), 1.75-1.90 (m, 1H), 2.03 (dd, J=6.64 & 14.08 Hz, 1H), 2.18 (dd, J=7.0 & 14.08 Hz, 1H), 3.28 (t, J=5.36 Hz, 2H), 4.07-4.18 (m, 1H), 4.43 (t, J=5.2 Hz, 1H), 6.95 (s, 1H), 7.28 (s, 1H), 7.76 (d, J=8.08 Hz, 1H).; thus, confirming formation of Intermediate 7 of the present invention. b) The LCMS analysis is further conducted and the data as graphically illustrated in accompanying figure 2 provides a (M+H+) value of 231.0; thus, confirming formation of Intermediate 7 of the present invention. c) The HPLC study is also conducted and the data as graphically illustrated in accompanying figure 3 confirms formation of Intermediate 7 of the present invention with chiral purity of 97.38%
EXAMPLE 2: Preparation of (3R)-N-(1S)-1-amino-1-oxobutan-2-yl)-3- (chloromethyl) hexanamide [Intermediate 8A of scheme A of the present invention]: Example 2 illustrates a process for preparing (3R)-N-(1S)-1-Amino-1-oxobutan-2-yl)-3- (chloromethyl) hexanamide [Intermediate 8A] from Intermediate 7 of example 1 above as developed in the present invention.
Figure imgf000030_0001
Procedure: In second step of scheme A of the present invention, the said Intermediate 7 of example 1 above that is (3R)-N-(1S)-1-Amino-1-oxobutan-2-yl)-3-(hydroxymethyl) hexanamide (~98% Chemical purity and ~97% Chiral purity) (1736.86 mmol) is dissolved in DCM (1.2 L) at RT into a RBF under N2 atm. Then the solution is cooled to 10-20 C and Oxaloyl chloride (2605.29 mmol) is added to this cooled solution at 10-20 °C. The mixture is stirred for 24 h at 25-40 °C under N2 atm. Completion of the reaction is monitored by TLC. After completion of reaction, the solvent is distilled off and the residual mass is diluted with water (6 L), stirred at 30-50 °C for 4 h. Slurry mass is then filtered and washed with water (2×400 mL) followed by MTBE (800 mL). The solid is dried under vacuum at 50-55 °C for 4-5 h to afford Intermediate 8A that is (3R)-N-(1S)-1-Amino-1- oxobutan-2-yl)-3-(chloromethyl) hexanamide as a white solid (92% yield). Results: Formation of Intermediate 8A is confirmed further by following analytical studies: a) The 1H NMR analysis is conducted and the data as illustrated in accompanying figure 4 depicts: 1H NMR (400 MHz, DMSO-d6) : δ 0.83 (t, J=7.44 Hz, 3H), 0.85 (t, J=6.72 Hz, 3H), 1.20-1.40 (m, 4H), 1.43-1.56 (m, 1H), 2.08-2.18 (m, 1H), 2.20-2.28 (m, 2H), 3.61 (dd, J=4.6 & 10.8 Hz, 1 H), 3.67 (dd, J=4.6 & 10.8 Hz, 1H), 4.07-4.18 (m, 1H), 6.95 (s, 1H), 7.29 (s, 1H), 7.89 (d, J=8.12 Hz, 1H); thus confirming formation of Intermediate 8A of the present invention. b) The LCMS analysis is further conducted and the data as graphically illustrated in accompanying figure 5 (a, b) provides a (M+H+) value of 249.20; thus, confirming formation of Intermediate 8A of the present invention. EXAMPLE 3: Process for purification of Intermediate 8A forming Intermediate 8B Example 3 illustrates a process for purifying the said Intermediate 8A of example 2 above of the present invention. Procedure: The Intermediate 8A as obtained in example 2 above [that is (3R)-N-(1S)-1-Amino-1- oxobutan-2-yl)-3-(chloromethyl) hexanamide] is first dissolved in a polar solvent like Acetonitrile raising the temperature to 50 to 60 °C; followed by stirring and then addition of another solvent methyl tert-butyl ether (MTBE) which is less polar in nature. The mixture is then cooled down to 0°C, the filtered mass thus obtained is dried in order to obtain a white solid of Intermediate 8B. The material thus obtained is further dissolved in THF (5 vol) at 60 °C, cooled to 20-30°C, followed by addition of heptane (5 vol), stirred at 10°C to 30 °C for 1 h. The mass obtained is filtered and washed with heptane (2×1 vol), dried under vacuum at 50-55°C in order to afford formation of purer form of Intermediate 8A that is Intermediate 8B that is (3R)-N-(1S)-1-amino-1-oxobutan-2-yl)- 3-(chloromethyl) hexanamide as a white solid having a chemical purity of 99.9% along with a chiral purity of 100% (yield: 390 g). Results: The purification of Intermediate 8A is further confirmed by the following analytical test results: a) Chiral HPLC: A Chiral HPLC as illustrated in accompanying figure 6 confirmed formation of purest form of Intermediate 8B having 100% chiral purity [Peak 1; RT (min) = 6.244; %Area=100%]. b) GLP-HPLC: A GLP-HPLC as illustrated in accompanying figure 7 further confirmed formation of Intermediate 8B having 99.9% chemical purity [Peak 3; BRIV8; RT = 29.278; % Area=99.90%]. EXAMPLE 4: Synthesis of (3R)-N-[(1S)-1-carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7’ of scheme B of the present invention] Example 4 illustrates one pot process for preparing purified (3R)-N-[(1S)-1- carbamoylpropyl]-3-(hydroxymethyl) hexanamide [Intermediate 7’] from Intermediate 6 (99.99% ee) as developed in step-1 scheme B of the present invention. Procedure: In another method, in the first step of scheme B of the present invention, a mixture of (R)/(S)-4-propyldihydrofuran-2(3H)-one (Intermediate 6: S isomer = 99.99% : 0.1%) (1 eq), (S)-2-aminobutanamide (1.7 eq), triethylamine (5 eq) is refluxed at a temperature between 95±5 °C for 24 h. Then, the crude reaction mass is cooled and washed with dichloromethane and diisopropyl ether mixture (2.5 vol) in order to achieve Intermediate- 7’ of scheme B of the present invention [(3R)-N-[(1S)-1-carbamoylpropyl]-3- (hydroxymethyl) hexanamide] (90% yield). Results: The chiral purity of the formed Intermediate 7’ is analyzed by HPLC method and the data as graphically illustrated in accompanying figure 8 confirms formation of Intermediate 7’ of the present invention with chiral purity of 99.11% EXAMPLE 5: Preparation of (3R)-N-(1S)-1-amino-1-oxobutan-2-yl)-3- (chloromethyl) hexanamide [Intermediate 8’ of scheme B of present invention]: Example 5 illustrates a process for preparing purest form of (3R)-N-(1S)-1-amino-1- oxobutan-2-yl)-3-(chloromethyl) hexanamide [Intermediate 8’] from Intermediate 7’ of example 4 as developed in scheme B (step 2) of the present invention.
Figure imgf000033_0001
Procedure: In the second step of scheme B of the present invention, the intermediate 7’ of the above example 4 that is (3R)-N-(1S)-1-amino-1-oxobutan-2-yl)-3-(hydroxymethyl) hexanamide (98% Chemical purity and >99%Chiral purity) (1736.86 mmol) is dissolved in DCM (1.2 L) at RT in a round bottomed flask under N2 atm. Then the solution is cooled to 10-30 °C and 1-Chloro-N,N,2-trimethyl-1-propenylamine (2605.29 mmol) is added to this cooled solution at 10-30 °C. The mixture is stirred for 24 h at 25-40 °C under N2 atm. Completion of the reaction is monitored by TLC. After completion of the reaction, the solvent is distilled off and the residual mass is diluted with water (6 L), stirring at 30-50 °C for 4 h. The slurry mass thus obtained is then filtered and washed with water (2×400 mL) followed by methyl tert-buty ether (MTBE) (800 mL). The solid thus obtained is dried under vacuum at 50-55 °C for 4-5 h in order to afford formation of Intermediate 8’ that is (3R)-N-(1S)-1-amino-1-oxobutan-2-yl)-3-(chloromethyl) hexanamide as a white solid (92% yield). Results: Formation of Intermediate 8’ is confirmed further by following analytical studies: a) The 1H NMR analysis is conducted and the data as illustrated in accompanying figure 9 depicts: (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6) : δ 0.83 (t, J=7.44 Hz, 3H), 0.85 (t, J=6.72 Hz, 3H), 1.20-1.40 (m, 4H), 1.43-1.56 (m, 1H), 2.08-2.18 (m, 1H), 2.20-2.28 (m, 2H), 3.61 (dd, J=4.6 & 10.8 Hz, 1 H), 3.67 (dd, J=4.6 & 10.8 Hz, 1H), 4.07- 4.18 (m, 1H), 6.95 (s, 1H), 7.29 (s, 1H), 7.89 (d, J=8.12 Hz, 1H); thus, confirming formation of Intermediate 8’ of the present invention. b) The LCMS analysis is further conducted and the data as graphically illustrated in accompanying figure 10 provides a (M+H+) value of 249.1; thus, confirming formation of Intermediate 8’ of the present invention. c) The HPLC data as illustrated in accompanying figure 11 confirms 100% chiral purity of Intermediate 8’. EXAMPLE 6: Preparation of (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide [Brivaracetam-API]: Example 6 illustrates a process for preparing (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1- yl] butanamide [Brivaracetam API] from Intermediate 8B of example 3 or from Intermediate 8’ of example 5 as developed in step 3 of scheme A or scheme B of the present invention respectively.
Figure imgf000035_0001
Procedure: In the final step of scheme A or scheme B of the present invention, the intermediate 8B of example 3 or intermediate 8’ of example 5 above that is (3R)-N-((1S)-1-Amino-1- oxobutan-2-yl)-3-(chloromethyl) hexanamide (1608.04 mmol) is dissolved in dimethyl acetamide (0.5 vol) and isopropylacetate (2 L) into a RBF at 25-30 °C under N2 atm. Then 18-Crown-6 (160.79 mmol) is added into the solution and stirred at RT for 30 min. Reaction mixture is then cooled to 0-10 °C and t-BuOK (1.5 eq) is added portion wise to the cooled solution over 1 h maintaining the temperature from - 0-10 °C to 25 °C under N2 atm. Stirring is then continued for 2 h at -10 °C to 0 °C and then for 12 h at 15-25 °C under N2 atm. Completion of reaction is monitored by TLC. After completion of reaction, the reaction mixture is quenched with addition of 1M HCl solution (pH~6.5-7.0). The resulting mixture is extracted with i-PrOAc (2 L) and MTBE (1 L). Water (0.5 L) is added to the combined organic extract and then filtered through celite bed, washed the bed with MTBE-i-PrOAc (1:1) (400 mL). The organic part is separated and the aqueous part is re- extracted with i-PrOAc-MTBE (1:1) (2 ×0.8 L). The combined organic phases are washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum under a rotary evaporator to afford crude API. Distillation of dimethylacetamide solvent from the crude is then done at high vacuum pressure (0.05 mm Hg) at 70 °C. Crude product is then dissolved in isopropyl acetate (1.6 L) and treated with activated charcoal (7% w/w) to afford a tech-grade crude of Brivaracetam API as a white solid (yield: 90%) with 97.82% chemical purity. Results: Formation of Brivaracetam API is confirmed further by following analytical studies: a) The 1H NMR analysis is conducted and the data as illustrated in accompanying figure 12 depicts: 1H NMR (400 MHz, DMSO-d6) : δ 0.77 (t, J=7.32 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H), 1.21-1.31 (m, 2H), 1.33-1.43 (m, 2H), 1.50-1.62 (m, 1H), 1.73-1.84 (m, 1H), 1.97 (dd, J=8.0 & 16.12 Hz, 1H), 2.18-2.28 (m, 1H), 2.37 (dd, J=8.4 & 16.14 Hz, 1H), 3.11 (dd, J=7.16 & 9.44 Hz, 1H), 3.36 (dd, J=9.2 & 17.5 Hz, 1H), 4.30 dd, J=5.44 & 10.28 Hz, 1H), 6.98 (s, 1H), 7.32 (s, 1H); thus, confirming formation of Brivaracetam API of the present invention. b) The LCMS analysis is further conducted and the data as graphically illustrated in accompanying figure 13 provides a (M+H+) value of 213.0; thus, confirming formation of Brivaracetam API of the present invention. ^ Purification of Brivaracetam API: The Brivaracetam thus formed above is further purified by means of dissolving the said material (307 g) in 30% i-PrOAc -MTBE (1 vol) at 55-60 °C, cool to 20-30°C. A mixture of Heptane and MTBE and DIPE (2:2:1) is added, stirred at 10 °C to 30°C for 1 h. The obtained mass is filtered and washed with heptane, which is subsequently dried under vacuum at 40-45 °C to afford (3R)-N-((1S)-1-amino-1-oxobutan-2-yl)-3-(chloromethyl) hexanamide as a white solid (yield: 80%, chiral purity 99.93% and chemical purity 99.94%). Results: a) Chiral HPLC: A Chiral HPLC as illustrated in accompanying figure 14 confirmed formation of purest form of Brivaracetam API having 99.93% chiral purity [Peak 2; RT (min) = 9.45; %Area=99.93%]. b) GLP-HPLC: A GLP-HPLC as illustrated in accompanying figure 15 further confirmed formation of Brivaracetam API having 99.9% chemical purity [Peak 2; RT = 21.138; % Area=99.94%].

Claims

CLAIM: 1. A process for synthesizing Brivaracetam of formula 1 comprising steps of: (a) reacting (4R)-4-propyldihydrofuran-2(3H)-one having 70-80% ee with (S)-2- aminobutyramide in presence of a base to form Intermediate 7 having chiral purity of 97-100%;
Figure imgf000037_0001
(b) reacting said intermediate 7 with a suitable reagent to form intermediate 8A
Figure imgf000037_0002
wherein X is a leaving group selected from halide ions, or sulfonates; followed by, purifying the said intermediate 8A by crystallization in order to form its purified version that is Intermediate 8B having a chiral purity of 99.9-100%
Figure imgf000037_0003
(c) reacting the said Intermediate 8B with a suitable reagent to form Brivaracetam of formula 1 having chiral purity of 99.9-100% .
Figure imgf000038_0001
2. A process for synthesizing Brivaracetam of Formula 1 comprising steps of: (a) reacting (4R)-4-propyldihydrofuran-2(3H)-one having 99.99-100% ee with (S)-2- aminobutyramide in presence of a base to form Intermediate 7’ having chiral purity of 99-100% ;
Figure imgf000038_0002
(b) reacting said intermediate 7’ with a suitable reagent to form intermediate 8’
Figure imgf000038_0003
, wherein X is a leaving group selected from halides, or sulfonates; and (c) directly reacting the said intermediate 8’ with a suitable reagent to form Brivaracetam of formula 1 having chiral purity 99.9-100%.
Figure imgf000039_0001
3. The process as claimed in claim 1 or claim 2, wherein the said base in respective step (a) is a tertiary amine selected from a group consisting of triethyl amine, diisropropyl ethyl amine, and N-methyl morpholine.
4. The process as claimed in claim 1 or claim 2, wherein the said step (a) is carried out without any additional solvent. 5. The process as claimed in claim 1 or claim 2, wherein the said reagent of step (c) of claim 1 or step (b) of claim 2 is selected from a group consisting of SOCl2, POCl3, PCl3, MsCl, TsCl, cyanuric chloride, 1,3 dichloro-5,
5-dimethyl hydantoin and 1-Chloro- N,N,2-trimethyl-1-propenylamine.
6. The process as claimed in claim 1 or 2, wherein the said reagent of step (d) of claim 1 or step (c) of claim 2 is selected from a group consisting of potassium tertiary butoxide, sodium tertiary butoxide, Lithium bis(trimethylsilyl)amide (LiHMDS), Potassium bis(trimethylsilyl)amide (KHMDS), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and Lithium diisopropylamide (LDA) in a solvent such as tetrahydrofuran (THF), 2-Methyl THF, Acetonitrile, isopropyl acetate N-methyl-2-pyrrolidone, Dimethyl Acetamide and Dimethyl Formamide.
7. The process as claimed in claim 6 is conducted at a temperature ranging between 0 and 10 °C.
8. The process as claimed in any of the preceding claims provides Brivaracetam with 75-90% yield.
9. The process as claimed in any of the preceding claims provides Brivaracetam with a chiral purity 99.9-100%.
PCT/IN2021/050594 2020-06-23 2021-06-19 A new cost effective and scalable process for synthesizing pure brivaracetam WO2021260721A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202031026414 2020-06-23
IN202031026414 2020-06-23

Publications (1)

Publication Number Publication Date
WO2021260721A1 true WO2021260721A1 (en) 2021-12-30

Family

ID=79282643

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2021/050594 WO2021260721A1 (en) 2020-06-23 2021-06-19 A new cost effective and scalable process for synthesizing pure brivaracetam

Country Status (1)

Country Link
WO (1) WO2021260721A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180155284A1 (en) * 2015-05-25 2018-06-07 ESTEVE QUIMlCA S.A. Processes to produce brivaracetam
CN106365986B (en) * 2015-07-21 2019-01-08 苏州鹏旭医药科技有限公司 Compound and preparation method thereof and the purposes in synthesis Bu Waxitan

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180155284A1 (en) * 2015-05-25 2018-06-07 ESTEVE QUIMlCA S.A. Processes to produce brivaracetam
CN106365986B (en) * 2015-07-21 2019-01-08 苏州鹏旭医药科技有限公司 Compound and preparation method thereof and the purposes in synthesis Bu Waxitan

Similar Documents

Publication Publication Date Title
US20240199541A9 (en) Processes to produce brivaracetam
WO2017006968A1 (en) Method for producing 7h-pyrrolo[2, 3-d]pyrimidine derivative and intermediate thereof
US10858324B2 (en) Processes for the preparation of pyrimidinylcyclopentane compounds
US20150011755A1 (en) Amine salts of prostaglandin analogs
CN110300756B (en) Process for preparing 7H-pyrrolo [2,3-d ] pyrimidine derivatives and synthetic intermediates therefor
DE60102825T2 (en) KINETIC RACEMATING OF CHIRALER 2 AND 3 SUBSTITUTED CARBOXYLIC ACIDS
CN108285436B (en) Preparation process of AE-active ester
WO2021260721A1 (en) A new cost effective and scalable process for synthesizing pure brivaracetam
CN112218853B (en) Process for the stereoselective preparation of chiral 2- [ (hetero) aralkylthio ] pyrimidines and products obtainable therefrom
US20220064111A1 (en) Enantioselective synthesis of brivaracetam and intermediates thereof
US20070129443A1 (en) Production method of aminochlorohydrin sulfate
JP3598277B2 (en) Method for producing ethanesulfonylpiperidine derivative
US20040176637A1 (en) Process for preparation of 2-chlorophenylglycine derivatives and enantiomerically separation
EP3230258B1 (en) Process for the preparation of (1s,2r)-milnacipran
CN113045468A (en) Preparation method of brivaracetam intermediate
Ammazzalorso et al. Synthesis of diastereomerically enriched 2‐bromoesters and their reaction with nucleophiles
HUE027145T2 (en) A process for the preparation of benzyl [(3as,4r,6s,6ar)-6-hydroxy-2,2- dimethyltetrahydro-3ah-cyclopenta[d][1,3]dioxol]-4-yl]carbamate and intermediates in the process
US20020151744A1 (en) Kinetic resolutions of chiral 2-and-3-substituted carboxylic acids
KR20040047870A (en) Process and Compositions for the Production of Chiral Amino-Nitriles
WO2016147133A1 (en) Process for the preparation of droxidopa
US20030236226A1 (en) Catalytic asymmetric cyanosilylation of ketones, aldehydes, thioketones, thioaldehydes, imines and hydrazones
CN114671915A (en) Preparation method of high diastereoisomer phosphonyl chloride
JP2010527975A (en) Process for the preparation of enantiomerically enriched N-carboxylic anhydrides

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: 21829564

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21829564

Country of ref document: EP

Kind code of ref document: A1