DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL COMPOUNDS AND THEIR USE IN THE PREPARATION OF ANTIEPILEPTIC AGENT

We, Stereokem Pvt. Ltd.,
a company incorporated under the companies act, 1956 having address at
Plot No. 36/A, IDA Uppal, Hyderabad-500039, Telangana,
INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to process for the preparation of and antiepileptic agent and it novel intermediates.

The present invention particularly relates to a process for preparing Brivaracetam of formulae (I).

The present invention also relates to novel intermediate compounds and the process for the preparation of the novel intermediates.

BACKGROUND OF THE INVENTION
Brivaracetam is an antiepileptic drug for the treatment of partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. Brivaracetam is approved by USFDA in May 2016.

Brivaracetam is a racetam derivative with anticonvulsant properties and is 4-n-propyl analog of Levetiracetam. Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl] butanamide. Its empirical formula is C11H20N2O2 and the molecular weight is 212.29. The structural formula is:

Brivaracetam was first disclosed in US 6,911,461 B2 and the process for the preparation of Brivaracetam disclosed in this patent is as shown below:

US 7,122,682 discloses a process for preparation of (4S) isomer of Brivaracetam which is shown in the scheme given below :

US 7,676.474 discloses a process for preparing Brivaracetam using separation of 2 diastereomers which shown below

US 8,076,493 discloses a process for preparing Brivaracetam by decaboxylation or decarbalkoxylation of the following formula

US 8,957,226 discloses a process for preparing Brivaracetam by separation of 2 diastereomers which is shown below :

CN 106748950 A assigned to Chengdu Meiyuan Pharmaceutical Co Ltd, filed on January 13, 2017 discloses a process for the preparation of Brivaracetam by separation of diastereomeric mixture using phenethylamine and is shown below :

WO 2016/191435 A1 discloses a process for the Brivaracetam which is shown in the schemes given below :

Scheme-1

Scheme-2

WO 2017/076737 A1 assigned to UCB Biopharma discloses different processes for the preparation of Brivaracetam which is shown in the scheme given below :

WO 2017/076738 A1 assigned to UCB Biopharma discloses different processes for the preparation of Brivaracetam which is shown in the scheme given below :

A bio-catalytic route for the preparation of Brivaracetam is disclosed in Organic Process research and development 20(9), 1566-1575, 2016.

Scheme-1:

Scheme-2:
Scheme-3:

As can be seen from the above, most of the prior art process reported involves chiral separation of two diastereomers. Chiral separation using column chemistry is not a commercially viable process in industrial scale. The Bioctalytic route to Brivaracetam suffers from low yields during the last two steps. The resolution method to Brivaracetam suffers from the inability to recycle the undesired diastereomer.

In view of the importance of anitepileptic agents such as Brivaracetam, there is a need for developing a relatively simple, commercially feasible process which involves use of inexpensive, chiral, environmental friendly reagents which are easily available or prepared from commercially available sources easily. Further, there is a need for a process for the preparation of alkyl amines which yields the compound with high chemical purity and chiral purity with high enantiomeric excess.

The present inventors have invented novel compounds which can be used as intermediates in the preparation of Brivaracetam. Brivaracetam as prepared according to the present invention is of high purity and with high enantiomeric excess.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis of Brivaracetam with a commercially acceptable yield and high purity and with high enantiomeric excess.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for the preparation of Brivaracetam.

Another objective of the present invention is to provide novel intermediate compounds and the process for the preparation of the novel intermediates.

In a more preferred objective of the present invention is to provide an improved process for the preparation of Brivaracetam, which is commercially feasible / industrially scalable.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis of Brivaracetam with a commercially acceptable yield and high purity.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of compound of Formula (I)

Formula (I)
or its salts which comprises dehydroxylating a compound of formula (II)

Formula (II)
wherein R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl, using a Lewis acid to produce Brivaracetam of compound of Formula I or its salts and if required converting compound of Formula when R1 is OR2 to amine group.

In yet another preferred embodiment, the present invention provides a process for the preparation of compound of Formula (II)

Formula (II)
wherein R1 is as defined above or its salts, which comprises cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (III)

Formula (III)
wherein R1 is as defined above or its salts, which comprises:
a) reducing compound of Formula (IV)

Formula (IV)
wherein X1 and X2 is selected from oxygen, sulfur with a proviso that both X1 and X2 are same at any single point; R is same or different which is selected form hydrogen, alkyl, aryl, heteroaryl; R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl; R3 is selected from alkyl, aryl, aralkyl or its salts using a reducing agent to give compound of Formula (III) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts, which comprises reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above; R4 is selected from any carboxylic protecting group; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula IV or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts, which comprises reacting compound of Formula (VI)

Formula (VI)
wherein, X1, X2, R and R3 are as defined above; with an alkylating agent to give compound of Formula V or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
wherein, X1, X2, R and R3 are as defined above; or its salts, which comprises reacting compound of Formula (VII)

Formula (VII)
wherein X1, X2, R and R3 are as defined above; or its salts with compound of Formula (VIII)

Formula (VIII) or succinic anhydride
wherein L is selected from halogen or any suitable leaving group; or its salts to produce compound of Formula (VI), or its salts using a base by peptide coupling reaction.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) converting a compound of Formula (IX)

Formula (IX)
where R4 is defined above or its salts to produce compound of Formula (I) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IX)

Formula (IX)
where R4 is defined above or its salts, which comprises converting compound of Formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above or its salts using a base.

In yet another embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
b) dehydroxylating pyrrolidinone derivatives of formula (II) using a Lewis acid to produce Brivaracetam of compound of Formula (I) or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reducing a compound of Formula (IV)

Formula (IV)
wherein X1 and X2 is selected from oxygen, sulfur with a proviso that both X1 and X2 are same at any single point; R is same or different which is selected form hydrogen, alkyl, aryl, heteroaryl; R3 is selected from alkyl, aryl, aralkyl or its salts using a reducing agent to give compound of Formula (III) or its salts,
b) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
c) dehydroxylating pyrrolidinone derivatives of formula (II) using a Lewis acid to produce Brivaracetam of compound of Formula I or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula IV or its salts,
b) reducing a compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts to produce compound of Formula (III) or its salts,
c) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
wherein R1 is as defined above,
d) dehydroxylating pyrrolidinone derivatives of formula (II) using a Lewis acid to produce Brivaracetam of compound of Formula I or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reacting compound of Formula (VI)

Formula (VI)

wherein, X1, X2, R and R3 are as defined above with an alkylating agent to produce Compound of Formula (V) or its salts,
b) reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula (IV) or its salts,
c) reducing a compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts to produce compound of Formula (III) or its salts,
d) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
e) dehydroxylating pyrrolidinone derivatives of formula (II) using Lewis acid to produce Brivaracetam of compound of Formula I or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reacting compound of Formula (VII)

Formula (VII)
or its, with a compound of Formula (VIII)

Formula (VIII)
or succinic anhydride
wherein L is selected from halogen or any suitable leaving group; or its salts to produce compound of Formula (VI), or its salts, using a base by peptide coupling reaction,

b) reacting compound of Formula (VI)

Formula (VI)
with an alkylating agent to produce Compound of Formula (V) or its salts,
c) reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula (IV) or its salts,
d) reducing a compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts to produce compound of Formula (III) or its salts,
e) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
f) dehydroxylating pyrrolidinone derivatives of formula (II) using Lewis acid to produce Brivaracetam of compound of Formula I or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) converting a compound of Formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above; R4 is selected from any carboxylic protecting group; or its salts to produce Compound of Formula (IX) or its salts,
b) converting a compound of Formula (IX)

Formula (IX)
wherein R4 is as defined above or its salts to produce compound of Formula (I) or its salts.

The present invention also relates to novel intermediates of formula (II), (III), (IV), (V), (VI), and (IX).

In yet another preferred aspect, the present invention provides use of compounds of Formulae (II), (III), (IV), (V), (VI), and (IX) in the preparation of compound of Formula (I) or its salts.

DETAILED DESCRIPTION OF THE INVENTION
The group R as used herein and not limited to hydrogen, (C1-C6) alkyl group, aryl group, heteroaryl group.

The group R3 as used herein and not limited to alkyl, aryl, aralkyl group

Alkyl group as used herein is a straight or branched, substituted or unsubstituted alkyl. The substituents on alkyl group are selected from halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, 6 to 10 member aryl ring such as phenyl, napthyl.

Aryl group as used herein is substituted or unsubstituted phenyl, napthyl. The substituents on aryl group are selected from halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, cyano, amino.

Heteroaryl group as used herein refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl group is substituted or unsubstituted monocyclic and fused heterocycles selected from furan, thiofuran, oxazole, thiazole, pyrrole, imidazole, pyrazole, benzimidazole, benzthiazole, benzoxazole,. The substituents on heteroaryl group are selected from halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, (C1-C6) alkyl group, which may further be substituted; alkoxyalkyl; 6 to 10 member aryl ring such as phenyl, napthyl.

The group L as defined herein is selected from chloro, bromo and iodo, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl) sulfonyloxy, (4-rertbutyl-phenyl)sulfonyloxy and (4-methoxy-phenyl)sulfonyloxy. Preferably, L is selected from the group comprising iodo, bromo, chloro, mesyloxy, tosyloxy, (4-nitro-phenyl)sulfonyloxy and (2-nitro-phenyl)sulfonyloxy.

In another embodiment the compound of formula (II) is converted to compound of Formula (I)

Formula (I)
or its salts by a process which comprises:
a) protecting a compound of formula (II)

Formula (II)
wherein R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl using a Lewis acid to produce compound of formula (IIa)

Formula (IIa)
b) dehydroxylating the compound of formula (IIa) to produce Brivaracetam of compound of Formula I or its salts and if required converting compound of Formula when R1 is OR2 to amine group.

In another embodiment the compound of Formula (III)

Formula (III)
or its salts, is prepared by a process which comprises:
a) hydrolysing a compound of Formula (IV)

Formula (IV)
using a base reducing agent to give compound of Formula (IVa) or its salts

Formula (IVa)
b) converting the acid compound of formula (IVa) into a mixed anhydride followed by reduction to give compound of Formula (III) or its salts.

In yet another embodiment, the compound of formula (V) is first deprotected using a strong acid

Formula (V)
to produce a compound of formula (Va)

Formula (Va)
which is in turn is reacted with 2-aminobutanamide by using a peptide coupling reagent to produce compound of Formula (IV)

Formula (IV)
wherein X and R are as defined above; or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reducing the compound of Formula (IX)

Formula (IX)
wherein R4 is as defined above using a reducing agent followed by protecting the alcohol group to give a compound of formula (X)

Formula (X)
wherein Pg is a conventional alcohol protecting group,
b) deprotecting acid protecting group / removing R4 to give an acid of formula (XI)

Formula (XI)
c) reacting a compound of formula (XI) with 2-aminobutanamide followed by deprotection, oxidation and cyclization to produce compound of Formula (I) or its salts.

In yet another preferred embodiment, the present invention provides a process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reducing the compound of Formula (IX)

Formula (IX)
wherein R4 is as defined above using a reducing agent to give a compound of formula (XII),

Formula (XII)

b) oxidizing the compound of formula (XII) to give an aldehyde of formula (XIII)

Formula (XIII)
c) protecting the aldehyde functional group in compound of formula (XIII) to give compound of formula (XIV)

Formula (XIV)
wherein R5 is an alkyl group or aralkyl group or taken together form a aldehyde protecting group,
d) cyclizing a compound of formula (XIV) using a Lewis acid to produce a compound of formula (XV)

Formula (XV)
e) reacting a compound of formula (XV) with SOCl2 or oxalyl chloride, coupling with 2-aminobutanamide followed by deoxygenation using an appropriate combination of Lewis acid produce compound of Formula (I) or its salts.

The present invention provides novel intermediate of formula (II)

Formula (II)
wherein R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl group.

The present invention provides the use of novel intermediate of formula (II)

Formula (II)
wherein R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl group in the preparation of Brivaracetam of Formula (I).

The present invention provides novel intermediate of formula (III).

Formula (III)
The present invention provides the use of novel intermediate of formula (III)

Formula (III)
in the preparation of Brivaracetam of Formula (I).

The present invention provides novel intermediate of formula (IV)

Formula (IV)
wherein X1 and X2 is selected from oxygen, sulfur with a proviso that both X1 and X2 are same at any single point; R is same or different which is selected form hydrogen, alkyl, aryl, heteroaryl; R3 is selected from alkyl, aryl, aralkyl or its salts.

The present invention provides the use of novel intermediate of formula (IV)

Formula (IV)
wherein X1 and X2 is selected from oxygen, sulfur with a proviso that both X1 and X2 are same at any single point; R is same or different which is selected form hydrogen, alkyl, aryl, heteroaryl; R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl; R3 is selected from alkyl, aryl, aralkyl or its salts in the preparation of Brivaracetam of Formula (I).

The present invention provides novel intermediate of formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above; R4 is selected from any carboxylic protecting group; or its salts.

The present invention provides the use of novel intermediate of formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above; R4 is selected from any carboxylic protecting group; or its salts in the preparation of Brivaracetam of Formula (I).

The present invention provides novel intermediate of formula (VI)

Formula (VI)
wherein, X1, X2, R and R3 are as defined above or its salts.

The present invention provides the use of novel intermediate of formula (VI)

Formula (VI)
wherein, X1, X2, R and R3 are as defined above or its salts in the preparation of Brivaracetam of Formula (I).

The present invention provides novel intermediate of formula (IX)

Formula (IX)
where R4 is defined above with the proviso that R4 is not t-butyl or its salts.

The present invention provides use of novel intermediate of formula (IX)

Formula (IX)
where R4 is defined above in the preparation of Brivaracetam of Formula (I).

The dehydroxylation of compound of Formula (I) is carried out using a lewis acid which is selected from BF3, BCl3, BBr3, BI3, SbF5, AlCl3, AlBr3, TiBr4, TiCl4, TiCl3, ZrCl4, PF5, FeCl3, FeBr3, ZnCl2, TES, BF3(OEt)2, TES/TFA, Titanium tetraisopropoxide, and a halide or a trifluoromethanesulfonate of a transition metal of the lanthanide series.

Cyclization reaction of a compound of formula (III) to compound of formula (II) is carried out using an oxidizing agent as used herein is selected from MnO2, 2-iodoxybenzoic acid, Dess-Martin oxidation, Potassium dichromate, Pyridinium chlorochromate (PCC), pyridine sulphur trioxide, Swern oxidation, TEMPO, Ruthenium oxide mono hydrate and the like.

The compound of formula (III) is first converted to an aldehyde which is not stable and is converted into compound of Formula (II) immediately.

The compound of formula (VI) is converted to compound of Formula (V) using a non-nucleophlic base and alkylating agent. The non-nucleophlic base as used herein is selected from LDA, LIHMDS, NaHMDS, KHMDS, LiTMP. Alkylating agent as used herein is selected from alkyl ester such as alkyl (straight chain or branched), aryl or aralkyl esters_t-butyl esters, benzoyl esters or alkyl nitriles such as haloacetonitrile, (Cl, Br, I). When the alkylating agent used is alkyl nitriles, the nitrile group is converted into a carboxylic acid which is subsequently protected to produce compound of formula (V).

The reducing agent as used herein is selected from borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, alkyl and dialkyl cyanoborohydrides, lithium borohydride, potassium borohydride, zinc borohydride, and lithium tri-sec-butyl borohydride; Sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al), hydride such as lithium hydride and lithium aluminium hydride or mixtures thereof.

The peptide coupling reagents are selected from /\/,/\/'-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), /\/-(3-dimethylaminopropyl)-/\/-ethylcarbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 6-chloro-1-hydroxybenzotriazol (HOBt), tetramethyluroniumhexafluorophosphate (HATU), O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and mixtures thereof

In yet another embodiment is carried out using suitable acid selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, pivalic acid, acetic acid, formic acid and the like. In particular hydrobromic acid may be used. The embodiments of the process comprises use of hydrobromic acid in form of its isopropanolic solution, hydrobromic acid gas or its solution in suitable solvent like acetone, ethyl acetate etc. More particularly, the isopropanolic hydrobromide solution may be used

The conversion of aldehyde to acetal is conventionally carried out using an alcohol or diol in the presence of a strong acid and a solvent. The strong acid may be selected from p-toluene sulfonic acid, trifluoromethanesulfonic acid , perchloric acid, trialkyl orthoformate etc.
The intermediates formed in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain compound of formula (I) or its intermediates. The above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.

Any of the reagents as used herein can be used catalytically or stoichiometrically. Preferably, the reagents are used in an amount from 1 to 10 equivalents.

The reactions in any of the steps of the present invention are carried out in the absence or presence of a solvent. The volumes of the solvents as used herein as taken appropriately based on the quantities of the reactants and reagents.

Any of the reactions as referred herein may be carried out at a temperature in the range 0 °C to 120 °C, preferably at reflux temperature of the solvent used therein.

In yet another embodiment, solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

In yet another preferred embodiment base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; alkyl metals such as n-butyl lithium or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

Acids used in hydrogenation herein is and not limited to inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, poly phosphoric acid, Conc. H2SO4; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid.

The present invention is illustrated by the following examples which are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES
Example 1:
Preparation of (S)-methyl 2-amino-2-phenylacetate hydrochloride:
To a stirred solution of L-PheGly (200 g, 1.32 mol) in MeOH (1.5 L) was added SOCl2 (288 mL, 3.97 mol) at 0 °C and stirred at RT for 16h. Methanol was evaporated completely to obtain compound 1(266 g, quantitative) as a white solid.

Example 2:
Preparation of tert-butyl (S)-(methoxycarbonyl)(phenyl)methylcarbamate:
To a stirred solution of L-PheGlyOMe.HCl (266.8 g, 1.32 mol) in CH2Cl2 (500 mL)was added NEt3 (368 mL, 2.64 mol ), (Boc)2O (334 ml, 1.45 mol) and stirred at RT for 16h. The RM was diluted with CH2Cl2 (300 mL)and washed with water (2 x 100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain compound 2as a white solid (325 g, 92.8 %).

Example 3:
Preparation of tert-butyl (S)-2-hydroxy-2-methyl-1-phenylpropylcarbamate:
A stirred solution of N-Boc-L-PheOMe (90 g, 0.33mol) in THF (1.2 L) was cooled to 0 °C and MeMgCl (3.0 M soln in THF) (566 ml, 1.69 mol) was added drop wise at same temperature (during addition the temp rose to about 15 °C). After addition, the reaction was maintained between 0-10 °C for 1h and then slowly warmed to RT and stirred for 16h. After completion of the reaction, the RM was cooled to 0 °C and quenched with saturated NH4Cl solution (1.5 Lt ) and stirred for 1h. The layers were separated and extracted with EtOAc(3 x 200 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain 80 g of crude product which was used directly for the next step without further purification.

Example 4:
Preparation of (S)-5,5-dimethyl-4-phenyloxazolidin-2-one:
A solution of compound 3 (80 g, 0.30mol) in THF was cooled to 0°C and KOtBu (40.5 g, 0.362mol) was added portion wise (during addition the temp of the RM rose to 15 °C). At the end of addition, the RM turned into a thick slurry. The thick RM was allowed to RT and stirred for 20h while monitoring the reaction by TLC. The RM was cooled to 0°C and slowly quenched with sat. NH4Cl solution (300 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain (72 g, 90 %) of compound 4 as a cream color solid.

Example 5:
Preparation of (S)-5,5-dimethyl-3-pentanoyl-4-phenyloxazolidin-2-one:
A stirred suspension of compound 4 (80 g, 0.42 mol) in THF was cooled to -78 °C and nBuLi(1.6 M in THF) (340 mL, 0.54mol) was added drop wise over a period of 30 min. After addition the RM was stirred at the same temperature for 30 min and added valeroyl chloride (75.4 g, 0.63 mol) drop wise while maintaining the temp below -70 °C. The RM was stirred at this temperature for 1h and slowly warmed to RT and maintained for 4h. The RM was then cooled to 0 °C, quenched with sat. NH4Cl solution (300 mL) and extracted with EtoAc (3x 200 mL). The organic layer was washed with water, dried over Na2SO4 and evaporated under reduced pressure to obtain (92 g, 80 %) of compound 5.
KEM12-21-79
1H NMR (500 MHz, CDCl3): d 7.38 -7.30 (m, 3H), 7.14 - 7.12 (m, 2H), 3.03 - 2.91 (m, 2H), 1.63 - 1.53 (m, 6H), 1.37 - 1.30 (m, 2H), 0.98 (s, 3H), 0.9 (t, J = 8.0 Hz, 3H).

Example 6:
Preparation of Step-6:
A suspension of compound 5 (90 g, 0.32 mol) in THF was cooled to -78 °C and LiHMDS (1.0 M in THF) (426 mL, 0.43mol) was added drop wise over a period of 30 min. After addition the RM was stirred at the same temperature for 1h and added tert butyl bromoacetate(64 ml, 0.43 mol) drop wise while maintaining the temp below -70 °C. The RM was stirred at this temperature for 3h while monitoring the progress of the reaction by HPLC. The RM was then cooled to 0 °C, quenched with sat. NH4Cl solution (300 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was washed with water, dried over Na2SO4 and evaporated under reduced pressure to obtain (102 g, 80 %) of compound 6 as off white solid.
KEM12-21-169
1H NMR (500 MHz, CDCl3): d 7.36-7.20 (m, 5H), 5.04 (s, 1H), 4.35 -4.32 (m, 1H), 2.69 – 2.63 (m, 1H), 2.36 – 2.32 (m, 1H), 1.61 (s, 3H), 1.47 – 1.35 (m, 4H), 1.30 (s, 9H), 0.99 (s, 3H), 0.92 (t, 3H).

Example 7:
Preparation of (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid:
To a stirred solution of compound 6 (170 g, 0.44 mol) in THF: H2O (1:1) was added LiOH (27.5 g, 0.65 mol) at 0?C and stirred at RT for 16h. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with EtOAc (2 x 300 mL). The aqueous layer was cooled and acidified with saturated citric acid solution to pH 3.0 and extracted with EtOAc (3 X300 mL). The combined organic layer was washed with water, dried over Na2SO4 and evaporated to obtain compound 7 (80 g, 85 % based on chiral auxiliary recovery) as a straw yellow oil.
1H NMR (CDCl3, 400 MHz): d 4.42 (dd, J = 8.0Hz, 1 H) 3.93 (dd, J = 8.0 Hz, 1 H) 2.65-2.54 (m, 2 H) 2.19 (dd, J = 16.3, 7.3 Hz, 1 H) 1.48-1.44 (m, 2 H) 1.40-1.30 (m, 2 H) 0.95 (t, J = 7.1 Hz, 3 H).

Example 8:
Preparation of (R)-dihydro-4-propylfuran-2(3H)-one:
A 20 L double jacketed reactor equipped with a mechanical stirrer and a condenser is charged with 6 (67 g, 0.31mol, 1.0 eq) and toluene (670mL). The solution is cooled to -5°C under nitrogen flow. Triethylamine (52.0mL, 0.37mol, 1.2 eq) is added maintaining the temperature between -6.0 °C and -5.0 °C over a period of 30 min. Ethyl chloroformate (32.5mL, 0.34mol, 1.1 eq) is added maintaining the temperature between -7 °C and -4 °C over a period of 30 min. The heterogeneous reaction mixture is stirred for 1 hour at -5 °C. Then the reaction mixture is warmed to 20 °C and filtered to remove the triethylammonium chloride salt.
The cake is washed with toluene (100 mL) at 20 °C. The filtrate is transferred into the reactor and the solution is cooled to -20.0 °C. Under nitrogen flow, powdered sodium borohydride (23.5 g, 0.62 mol, 2.0eq) is added one pot at -18.0 °C. Then methanol (134mL) is transferred drop wise in order to maintain the temperature below -18 °C and to limit the formation of foaming. The reaction mixture is stirred for 1 hour at -20 °C. At -20.0 °C, under nitrogen flow, saturated NH4Cl solution (200 mL) is added dropwise in order to maintain the temperature below -18 °C and to limit the formation of foaming. Then the reaction mixture is warmed to 20 °C. Water (250mL) is added until dissolution of salts and the aqueous layer is discarded. An additional water wash (100 mL) is done. At 25 °C, trifluoroacetic acid 95% v/v (7.1 mL, 0.093 mol) is added one pot and the reaction mixture is stirred until the completion of the reaction (~1 h). The organic layer is washed with water (2 x 3 L, 2 x 3 L/kg) then evaporated to give 8(38 g, GC purity 90 %).
1H NMR (400 MHz, CDCl3): d 4.42 (1H, dd), 3.92 (1H, dd), 2.65-2.52 (m, 2H), 2.18 (dd, 1H), 1.47-1.40 (m, 2H), 1.47-1.40 (m, 2H), 1.39-1.27 (m, 2H), 0.94 (t, 3H).

Example 9:
Preparation of (R)-3-(chloromethyl)hexanoyl chloride:
A solution of thionyl chloride (76 ml, 1.05 mol), anhydrous ZnCl2 (4.0 g) and compound 8 (38 g, 0.3 mol) was heated to 85 °C. After completion of the reaction, the solvents were evaporated under vacuo. The crude compound was vacuum distilled to obtain compound 9 (38 g, 70 %).
1H NMR (400 MHz, CDCl3):d 3.67 (dd, 1H), 3.59 (dd, 1H), 2.58 (dd, 1H), 2.40 (dd, 1H), 2.20-2.31 (m, 1H), 1.25 – 1.53 (m, 4H), 0.93 (t, 3H).

Example 10:
Preparation of (3R)-N-((S)-1-carbamoylpropyl)-3-(chloromethyl) hexanamide:
To a mixture of (S)-2-aminobutyramide.HCl (20.0 g, 0.14 mol) and K2CO3 (36.3 g, 0.26 mol) in ACN (240 ml) was added compound 9 (24.0 g, 0.13 mol) at -10 ?C and stirred for 16 h at RT. After the reaction was completed, K2CO3 was filtered off and the cake was washed thoroughly with ACN. Most of the solvent was evaporated under reduced pressure and the residue was diluted with EtOAc (500 ml). The organic layer was washed with water, brine, dried over Na2SO4 and evaporated to obtain crude compound 10. Recrystallization of the crude compound afforded pure 10(22.8 g, 70 %).1H NMR (400 MHz, CDCl3+ DMSO-d6): d 6.45 (d, J = 7.5 Hz, 1H), 6.44 (bs, 1H), 5.70 (bs, 1H), 4.45 – 4.44 (m, 1H), 3.62 (d, J = 4.0 Hz, 2H), 2.37 – 2.24 (m, 3H), 1.93 – 1.89 (m, 1H), 1.70 – 1.66 (m, 1H), 1.36 - 1.31 (m, 4H), 0.97 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H).

Example 11:
Preparation of Brivaracetam:
To a solution of compound 10 (15 g) in anhydrous DMF (50 ml), KOH was added portion wise (5.08 g) at -15 °C. After the reaction was complete by HPLC, the reaction was quenched with 1N HCl and brine was added. The mixture was then extracted with MTBE (4x ml).The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Filtration and evaporation of the solvent yielded crude Brivaracetam, which was recrystallized to afford pure compound.
1H NMR (500 MHz, CDCl3): d 6.44 (bs, 1H), 5.86 (bs, 1H), 4.46 (dd, J = 8.75 Hz and J = 6.75 Hz, 1H), 3.49 (dd, J = 9.75 Hz and J = 8.5 Hz, 1H), 3.07 – 3.05 (m, 1H), 2.58 – 2.55 (m, 1H), 2.34 – 2.31 (m, 1H), 2.11 – 2.05 (m, 1H), 1.95 -1.90 (m, 1H), 1.70 – 1.67 (m, 1H), 1.42 – 1.39 (m, 2H), 1.35 – 1.33 (m, 2H), 0.93 – 0.88 (m, 6H).
,CLAIMS:We Claim:
1. A process for the preparation of compound of Formula (I)

Formula (I)
or its salts which comprises dehydroxylating a compound of formula (II)

Formula (II)
wherein R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl, using a Lewis acid to produce Brivaracetam of compound of Formula (I) or its salts and if required converting compound of Formula when R1 is OR2 to amine group.
2. The process for the preparation of compound of Formula (I) as claimed in claim 1, wherein the compound of Formula (II)

Formula (II)
wherein R1 is as defined above or its salts, is prepared by cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II).
3. The process for the preparation of compound of Formula (II) as claimed in claim 2, wherein the compound of Formula (III)

Formula (III)
wherein R1 is as defined above or its salts, is prepared by reducing compound of Formula (IV)

Formula (IV)
wherein X1 and X2 is selected from oxygen, sulfur with a proviso that both X1 and X2 are same at any single point; R is same or different which is selected form hydrogen, alkyl, aryl, heteroaryl; R1 is an amine group or OR2, the R2 is selected from an substituted or unsubstituted alkyl, aryl; R3 is selected from alkyl, aryl, aralkyl or its salts using a reducing agent to give compound of Formula (III) or its salts.
4. The process for the preparation of compound of Formula (III) as claimed in claim 3, wherein the compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts, is prepared by reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above; R4 is selected from any carboxylic protecting group; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula IV or its salts.

5. The process for the preparation of compound of Formula (IV) as claimed claim 4, wherein the compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts, is prepared by reacting compound of Formula (VI)

Formula (VI)
wherein, X1, X2, R and R3 are as defined above; with an alkylating agent to give compound of Formula V or its salts.
6. The process for the preparation of compound of Formula (V) as claimed claim 5, wherein the compound of Formula (VI)

Formula (VI)
wherein, X1, X2, R and R3 are as defined above; or its salts, is prepared by reacting compound of Formula (VII)

Formula (VII)
wherein X1, X2, R and R3 are as defined above; or its salts with compound of Formula (VIII)

Formula (VIII) or succinic anhydride
wherein L is selected from halogen or any suitable leaving group; or its salts to produce compound of Formula (VI), or its salts using a base by peptide coupling reaction.
7. The process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts which comprises converting a compound of Formula (IX)

Formula (IX)
where R4 is defined above or its salts to produce compound of Formula (I) or its salts.
8. The process for the preparation Brivaracetam of Formula (I) as claimed in claim 7, wherein the compound of Formula (IX) or its salts, is prepared by converting compound of Formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above or its salts using a base.
9. The process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts which comprises
a) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
b) dehydroxylating pyrrolidinone derivatives of formula (II) using a Lewis acid to produce Brivaracetam of compound of Formula (I) or its salts.
10. A process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts thereof which comprises
a) reducing a compound of Formula (IV)

Formula (IV)
wherein X1 and X2 is selected from oxygen, sulfur with a proviso that both X1 and X2 are same at any single point; R is same or different which is selected form hydrogen, alkyl, aryl, heteroaryl; R3 is selected from alkyl, aryl, aralkyl or its salts using a reducing agent to give compound of Formula (III) or its salts,
b) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
c) dehydroxylating pyrrolidinone derivatives of formula (II) using a Lewis acid to produce Brivaracetam of compound of Formula I or its salts.
11. The process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts which comprises
a) reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula IV or its salts,
b) reducing a compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts to produce compound of Formula (III) or its salts,
c) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
wherein R1 is as defined above,
d) dehydroxylating pyrrolidinone derivatives of formula (II) using a Lewis acid to produce Brivaracetam of compound of Formula I or its salts.
12. The process for preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts which comprises
a) reacting compound of Formula (VI)

Formula (VI)

wherein, X1, X2, R and R3 are as defined above with an alkylating agent to produce Compound of Formula (V) or its salts,
b) reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula (IV) or its salts,
c) reducing a compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts to produce compound of Formula (III) or its salts,
d) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
e) dehydroxylating pyrrolidinone derivatives of formula (II) using Lewis acid to produce Brivaracetam of compound of Formula I or its salts.
13. The process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts which comprises
a) reacting compound of Formula (VII)

Formula (VII)
or its, with a compound of Formula (VIII)

Formula (VIII)
or succinic anhydride
wherein L is selected from halogen or any suitable leaving group; or its salts to produce compound of Formula (VI), or its salts, using a base by peptide coupling reaction,

b) reacting compound of Formula (VI)

Formula (VI)
with an alkylating agent to produce Compound of Formula (V) or its salts,
c) reacting compound of Formula (V)

Formula (V)
wherein X1, X2, R, R3 and R4 are as defined above; or its salts with 2-aminobutanamide or its derivative to produce Compound of Formula (IV) or its salts,
d) reducing a compound of Formula (IV)

Formula (IV)
wherein X1, X2, R, R1, R3 are as defined above; or its salts to produce compound of Formula (III) or its salts,
e) cyclizing a compound of formula (III)

Formula (III)
wherein R1 is as defined above using an oxidizing agent to produce pyrrolidinone derivatives of formula (II),

Formula (II)
f) dehydroxylating pyrrolidinone derivatives of formula (II) using Lewis acid to produce Brivaracetam of compound of Formula I or its salts.
14. The process for the preparation of Brivaracetam of Formula (I)

Formula (I)
or its salts which comprises
a) converting a compound of Formula (V)

Formula (V)
wherein X1, X2, R and R3 are as defined above; R4 is selected from any carboxylic protecting group; or its salts to produce Compound of Formula (IX) or its salts,
b) converting a compound of Formula (IX)

Formula (IX)
wherein R4 is as defined above or its salts to produce compound of Formula (I) or its salts.
15. Novel intermediates of compound of Formulae

Formula (II)

Formula (III)

Formula (IV)

Formula (V)

Formula (VI)


Formula (IX)

16. The process as claimed in claim 1, claims 9-13 wherein the lewis acid in the dehydroxylation as used herein is selected from BF3, BCl3, BBr3, BI3, SbF5, AlCl3, AlBr3, TiBr4, TiCl4, TiCl3, ZrCl4, PF5, FeCl3, FeBr3, ZnCl2, TES, BF3(OEt)2, TES/TFA, Titanium tetraisopropoxide, and a halide or a trifluoromethanesulfonate of a transition metal of the lanthanide series.
17. The process as claimed in claim 2, claims 9-13, wherein an oxidizing agent in the cyclization reaction as used herein is selected from MnO2, 2-iodoxybenzoic acid, Dess-Martin oxidation, Potassium dichromate, Pyridinium chlorochromate (PCC), pyridine sulphur trioxide, Swern oxidation, TEMPO, Ruthenium oxide mono hydrate and the like.
18. The process as claimed in claim 3, claims 10-13 wherein the reducing agent as used herein is selected from borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, alkyl and dialkyl cyanoborohydrides, lithium borohydride, potassium borohydride, zinc borohydride, and lithium tri-sec-butyl borohydride; Sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al), hydride such as lithium hydride and lithium aluminium hydride or mixtures thereof.
19. The process as claimed in claim 5, claims 12-13, wherein the alkylating agent used is alkyl nitriles, the nitrile group is converted into a carboxylic acid which is subsequently protected to produce compound of formula (V).
20. The process as claimed in claim 6 and claim 13 wherein the peptide coupling reagents are selected from /\/,/\/'-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), /\/-(3-dimethylaminopropyl)-/\/-ethylcarbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 6-chloro-1-hydroxybenzotriazol (HOBt), tetramethyluroniumhexafluorophosphate (HATU), O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and mixtures thereof.
21. The process as claimed in any of the claims 1-14, wherein reaction is carried out in the presence or absence of the solvent selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

22. The process as claimed in claim 6, claim 8 and claim 13, wherein base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; alkyl metals such as n-butyl lithium or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like, and non-nucleophlic base as used herein is selected from LDA, LIHMDS, NaHMDS, KHMDS, LiTMP.
23. Use of compounds of Formula (II), (III), (IV), (V), (VI), and (IX) in the preparation of compound of Formula (I) or its salts.

Dated this Ninth (09th) day of August, 2018.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883