DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

TELESCOPIC SYNTHESIS OF BRIVARACETAM

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Ground Floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a telescopic synthesis of brivaracetam of formula (1).

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyl pyrrolidinyl] butanamide, sold under the brand name Briviact among others, is a chemical analog of levetiracetam, is a racetam derivative with anticonvulsant (antiepileptic) properties. It is marketed by the pharmaceutical company UCB. On 14 January 2016, the European Commission, and on 18 February 2016, the U.S. Food and Drug Administration (FDA) approved brivaracetam under the trade name Briviact.

Brivaracetam is believed to act by binding to the ubiquitous synaptic vesicle glycoprotein 2A (SV2A), like levetiracetam, but with 20-fold greater affinity. There is some evidence that racetams including levetiracetam and brivaracetam access the luminal side of recycling synaptic vesicles during vesicular endocytosis. They may reduce excitatory neurotransmitter release and enhance synaptic depression during trains of high-frequency activity, such as is believed to occur during epileptic activity.

Brivaracetam was first disclosed in US6911461B2 and the process for the preparation of brivaracetam disclosed in this patent is as shown below:

The synthetic process for brivaracetam is reported in US ‘197, which comprises reacting 4-n-propyl-hydroxyfuranone with (S)-2-aminobutyramide in presence of toluene / H2O / AcOH and NaBH4 to obtain the compound of unsaturated pyrrolidone and it is followed by treated with HCOONH4 / Pd/C / H2O and preparative HPLC on chiral phase to obtain Brivaracetam.

US762947B2, US8076493B2 and US8338621B2 discloses the process for the preparation of brivaracetam.

All the prior-art processes disclose the preparation of the pure brivaracetam involving the separation of enantiomers of the brivaracetam using column chromatography, preparative HPLC which is difficult for bulk manufacturing as well as it affects the overall yield, making the process commercially not viable.

Therefore, there is a need in the prior art for an improved process for the preparation of brivaracetam. In view of the foregoing, the present invention provides as a result of number of experiments in the laboratory, a telescopic process of the preparation of brivaracetam. The advantage of the present invention is to offer better control over racemization and formation of enantiomers. The present invention provides a simple, cost effective process for preparation of brivaracetam, with high purity and good yield commercially.
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a telescopic method for the preparation of brivaracetam.
SUMMARY OF THE INVENTION
The problem addressed by the present invention is that of providing an improved, efficient, economic and an industrially viable telescopic process for preparation of brivaracetam (1).
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for describing the particular embodiments only and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials described within but similar, equivalent to those described herein can be used in the practice, or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further, the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
A telescopic process means a sequential one-pot synthesis with reagents added to a reactor one at a time and without work-up.
Accordingly, the present invention relates to a telescopic method for the preparation of brivaracetam (1),

comprising;
(a) reacting (R)-4-propyldihydrofuran-2(3H)-one (5) with HBr in Acetic Acid in a solvent to give (R)-3-(bromomethyl) hexanoic acid (6);
(b) reacting (R)-3-(bromomethyl) hexanoic acid (6) with a chlorinating agent in a solvent and presence of catalytic amount of DMF to give (R)-3-(bromomethyl)hexanoyl chloride (7);
(c) reacting (R)-3-(bromomethyl)hexanoyl chloride (7) with (S)-(+)-2-aminobutanamide hydrochloride (8) in presence of a catalyst and a base in a solvent to give a reaction mass;
(d) cooling the reaction mass of step (c) to -25 °C + 5°C with stirring.
(e) purging the reaction mass with carbon dioxide (CO2) till the pH is not more than (NMT) 8.0 to obtain brivaracetam.
(f) isolating brivaracetam (1) using a hydrocarbon solvent or alcohol solvent or mixture thereof.
The solvent used in step (a) is an acetic acid.
The chlorinating agent used in step (b) is selected from chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or pivaloyl chloride.
The solvent used in step (b) and step (c) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane (MDC), 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.
The base used in step (c) is selected from triethylamine, trimethylamine, dimethyl amine, tert-butyl amine, ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide or potassium tert- butoxide.
The catalyst used in step (c) is a phase transfer catalyst and is selected from tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide or ethyl triphenyl phosphonium bromide. More preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
The hydrocarbon solvent used in step (f) is toluene, xylene, cyclohexane, hexane, heptane or n-pentane.
The alcoholic solvent used in step (f) is methanol, ethanol, isopropyl alcohol (IPA), n-propanol or butanol.
In the isolation step (f) the volume ratio of IPA and n-heptane is 0.5:10.
The carbon dioxide used in step (e) is in the form of gas or dry ice.
According to another embodiment of the present invention, the process of step (b) can be carried out without isolating the intermediate compound 6 of step (a).
According to another embodiment of the present invention, the process of step (c) can be carried out without isolating the intermediate compound 7 of step (b).
According to another embodiment of the present invention, the process of step (d) can be carried out without isolating the intermediate compound 8 of step (c).

The complete synthetic scheme of preparation of brivaracetam of formula-1 according to the present invention can be represented as below:

According to the invention, the overall yield of compound of formula-1 as obtained by using the process of the present invention is with purity of at more than 99.0% by HPLC.

Thus, the present invention offers below advantages over previous methods reported in the literature include:
(i) during coupling reaction of (R)-3-(bromomethyl)hexanoyl chloride (7) with (S)-(+)-2-Aminobutanamide (8), the pH of the reaction mixture is highly alkaline (above 12) and to neutralize the pH in the prior-art large amount of inorganic acids were employed this affects chirality of the product and leads to the racemization of brivaracetam, while in the instant invention due to CO2 purging under conditions (-25 °C + 5°C), racemization of the product (1) gets controlled which helps to optimize the viability of the process at plant/commercial scale.
(ii) during coupling reaction of (R)-3-(bromomethyl)hexanoyl chloride (7) with (S)-(+)-2-Aminobutanamide (8), the pH of the reaction mixture is highly alkaline (above 12) which leads to generation of diastereomers while in the current invention due to CO2 purging under conditions (-25 °C + 5°C), the formation of diastereomers is well within control due to neutralization of the reaction mixture.
(iii) The combination of iso-propyl alcohol and n-heptane for final API purification in 0.5:10 proportion helps to control the polar and non-polar impurities as well as enantiomer and diastereomeric impurities.
(iv) Chiral purity of the final product obtained is more than 99.90%.
(v) Improved process Robustness and overall quality.

Thereby, the practicability of the reaction is greatly enhanced at both the laboratory scale and the industrial scale. The present invention results into purity of at least 99.0 % by HPLC, thereby, making the process ef?cient, economic and industrially viable.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1
Telescoping synthesis of brivaracetam
(a) Synthesis of (R)-3-(bromomethyl) hexanoic acid (6)
(200.0 mL) of Acetic Acid and (100.0 g) (R)-4-propyldihydrofuran were charged in (2L) jacketed reactor at 25-30°C and stirred for 5-10 min. To the obtained solution HBr in acetic acid was added and maintained for 5-6 h under heating. After completion of the reaction, reaction mixture was quenched with DM (demineralized water) water. Desired product was extracted with dichloromethane. Organic layer was washed with dilute Na-metabisulphite solution.
The layers were allowed to settle and separated. Organic layer was subjected to distillation and solvent was distilled under vacuum to obtain product (6), which was used in-situ for the next step (b).
Compound (6) was characterized at this stage via sampling but was not isolated from the reaction mixture.

(b) Synthesis of (R)-3-(bromomethyl)hexanoyl chloride (7)
MDC and DMF were added to the resulting mixture of step (a) at a temperature 25-30 °C and stirred for 5-10 min. To the obtained solution was added thionyl chloride at 25-35°C and stirred for 4-5 hrs. Reaction mixture was subjected to distillation and solvent was distilled under vacuum to obtain product (7), which was used in-situ for the next step (c).
Compound (7) was characterized at this stage via sampling but was not isolated from the reaction mixture

(c) Synthesis of crude/tech grade brivaracetam (1)
(S)-(+)-2-aminobutanamide hydrochloride dissolved in MDC having anhydrous sodium sulphate, and KOH powder (lot-1) was charged in 4 necked reactor at -10 to -5 °C and stirred for 20-30 mins. KOH powder lot-II and tetra butyl ammonium bromide were charged into the reaction mixture (RM). RM was cooled to -20 °C + 5°C and stirred for 20-30 min then resulting mixture of step (b) was added slowly in lot wise manner under cooling conditions (0-5°C) in MDC along with KOH. Reaction mixture was stirred for 5-6 h, at same conditions -20 °C to -15 °C. Carbon dioxide was purged into the reaction mixture till a pH of 7 - 8 (near to neutral) was obtained and DM water was added to it and stirred the reaction mass for 40-60 min. The reaction mass was filtered through celite bed and washed with MDC. After layers were separated, organic layer was subjected to distillation and solvent was distilled under vacuum. Product (1) was dissolved in DM water. The aqueous layer was subjected to treatment with charcoal followed by extraction in MDC. Further the organic layer was washed with sodium bicarbonate solution and aqueous HCl solution. Organic layer was subjected to distillation under vacuum to remove solvent. N-heptane was added to strip out MDC followed by isolation of the crude [technical grade brivaracetam (1)] using n-heptane. The isolated crude was used in step (d).

(d) Purification of brivaracetam
A solution of n-heptane and isopropyl alcohol were added to the crude (step c) and the reaction mixture was heated to 60- 650C and stirred to obtain clear solution. The resulting solution was gradually cooled to and precipitated solid was filtered, washed with n-heptane, sucked and dried under vacuum to afford pure Brivaracetam. [Yield = 35 - 100 g; Purity (HPLC) >99.00%; 2R,4S isomer: ND; 2R,4R isomer: ND; 2S,4S isomer: 0.05%].
ND: Not detected.
,CLAIMS:We claim:
1. A telescopic method for the preparation of brivaracetam (1),

comprising;
(g) reacting (R)-4-propyldihydrofuran-2(3H)-one (5) with HBr in Acetic Acid in a solvent to give (R)-3-(bromomethyl) hexanoic acid (6);
(h) reacting (R)-3-(bromomethyl) hexanoic acid (6) with a chlorinating agent in a solvent and presence of catalytic amount of DMF to give (R)-3-(bromomethyl)hexanoyl chloride (7);
(i) reacting (R)-3-(bromomethyl)hexanoyl chloride (7) with (S)-(+)-2-aminobutanamide hydrochloride (8) in presence of a catalyst and a base in a solvent to give a reaction mass;
(j) cooling the reaction mass of step (c) to -25 °C + 5°C with stirring.
(k) purging the reaction mass with carbon dioxide (CO2) till the pH is not more than (NMT) 8.0 to obtain brivaracetam.
(l) isolating brivaracetam (1) using a hydrocarbon solvent or alcohol solvent or mixture thereof.
wherein –
the process of step (b) can be carried out without isolating the intermediate compound 6 of step (a);
the process of step (c) can be carried out without isolating the intermediate compound 7 of step (b);
the process of step (d) can be carried out without isolating the reaction mass of step (c).

2. The telescopic process as claimed in claim 1, wherein the solvent used in step (a) is acetic acid.

3. The telescopic process as claimed in claim 1, wherein the chlorinating agent used in step (b) is selected from chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or pivaloyl chloride.

4. The telescopic process as claimed in claim 1, wherein the solvent used in step (b) and step (c) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane (MDC), 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

5. The telescopic process as claimed in claim 1, wherein the base used in step (c) is selected from triethylamine, trimethylamine, dimethyl amine, tert-butyl amine, ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide or potassium tert- butoxide.

6. The telescopic process as claimed in claim 1, wherein the catalyst used in step (c) is a phase transfer catalyst and is selected from tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide or ethyl triphenyl phosphonium bromide.

7. The telescopic process as claimed in claim 1, wherein the carbon dioxide used in step (e) is in the form of gas or dry ice.

8. The telescopic process as claimed in claim 1, wherein the hydrocarbon solvent used in step (f) is toluene, xylene, cyclohexane, hexane, heptane or n-pentane.

9. The telescopic process as claimed in claim 1, wherein the alcoholic solvent used in step (f) is methanol, ethanol, isopropyl alcohol (IPA), n-propanol or butanol.

10. The telescopic process as claimed in claim 1, wherein in step (f) the isolation of brivaracetam is carried out using a mixture of IPA and n-heptane used in the volume ratio of 0.5:10.