DESC:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

“An improved process for the preparation of Brivaracetam intermediates”

Vimal Drugs Private Limited
Plot no: - 39/B, Road no: 1, JN Parma city
Parawada, Visakhapatnam, Andhra Pradesh
Pin code: 531021. India
sm@vimaldrugs.com

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

“An improved process for the preparation of Brivaracetam intermediates”

Field of the Invention:
The Present invention relates to an improved process for the preparation of (R)-4-Propyldihydrofuran-2(3H)-one.

Background of the Invention:
R)-4-Propyldihydrofuran-2(3H)-one is a key intermediate in the synthesis of a new antiepileptic drug Brivaracetam. At present, there have been more literature reports on the synthesis method of this compound. The synthetic method was first seen in Journal of American Chemical Society, 1985, 107, 4088-4090. There have been literature reports on synthesis methods (for example: Journal of American Chemical Society, 2003, 125, 11253 -11258), the cost is high, and there is no industrial value.
Benoit M. (J. Med. Chem. 2004, 47, 530-549) reported that (5H)-furanone reacts with propyl magnesium bromide to obtain -4-propyl-dihydrofuran-2-one, which is then further synthesized, the reaction route of Brivaracetam, but this synthetic route produces racemates, and the final product needs to be prepared and separated by chirality, and the cost is relatively high.

Arnaud S. (Org. Process Res.Dev.2016,20,9,1566-1575) etc. reported the preparation of (R)-4-propyl from diethyl propyl malonate as a raw material and through enzymatic catalysis and other steps. The reaction route for further synthesizing Brivaracetam with the base-dihydrofuran-2-one. The route uses enzymes to resolve the isomers, and the efficiency is not high.

CN106008411A discloses a compound of formula IV prepared by using n-valeric acid and oxazolidinone as starting materials through condensation, alkylation, hydrolysis, reduction, and ring closure. The hydrogen peroxide and borane two are used in the reaction process. Inflammable and explosive reagents such as dimethyl sulfide have greatly restricted the application of this route in the industrial production process.

There are several methods for preparing chiral 4-substituent dihydrofuran-2(3H)-one in the prior art, but these methods more or less have some disadvantages and are not suitable for industrial application. The existing methods for preparing chiral 4-substituent dihydrofuran-2(3H)-one mainly includes the following:
Method 1: The paper (Journal of Organic Chemistry, 65(18), 5623-5631, 2000) discloses a method for preparing chiral 4-substituent dihydrofuran-2(3H)-one. This method mainly has the following shortcomings: (1R, 2S, 5R)-(-)-menthol (S)-p-toluenesulfinate is used as the starting material in the first step, which has no suppliers in the market. And the preparation cost is high, the process is difficult; the noble metal rhodium catalyst used is RhCl(PPh) 3 It is expensive; the last step requires tributyltin hydride, which is a highly toxic liquid with a very unpleasant odor. Therefore, considering the cost of raw materials, the operability of the process, and the safety of the human environment of the raw materials used, this method is difficult to apply to industrial production.
Method 2: The paper (Journal of the Chemical Society, Perkin Transactions 1:
Organic and Bio-Organic Chemistry (1972-1999), (5), 935-43, 1989) discloses a method for preparing chiral 4-substituent dihydro Furan-2(3H)-one method. This method has the following shortcomings: the starting material (1R, 2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine for the first step is expensive, and allyl dichloride There is no supplier in the phosphine market; ozone is needed in the third step. Ozone has strong oxidizing properties and high risk, which requires very high production equipment and is extremely expensive. Therefore, considering the cost of the raw materials, the operability of the process, and the safety of the human environment of the raw materials used, although this method can finally obtain (R)-4-propyldihydrofuran-2(3H)-one with high optical purity, However, its application is still at the level of academic research, and it is difficult to apply to industrial production.
Method 3: Thesis [1. Journal of Organic Chemistry, 52(5), 719-28, 1987; 2. e-EROS Encyclopedia of Reagents for Organic Synthesis, no pp. given, 2001; 3. Journal of the American Chemical Society, 107 (13), 4088-90; 1985] discloses a method for preparing enantiomerically pure 4-substituent dihydrofuran-2(3H)-one. This method has the following shortcomings: the starting material 2(5H)-furanone for the first step of the method is expensive; the starting material allyl p-toluene sulfinate has no supplier in the market. If you prepare it yourself, the preparation cost is high, the process is complicated, and the nature is unstable, and it needs to be made and used now, which brings uncertainty to the production. Therefore, considering the cost of raw materials and the operations of the process, although this method can finally obtain high optical purity (R)-4-propyldihydrofuran-2(3H)-one, its application is still in academic research. At the higher scale level, it is difficult to apply to industrial production.
In order to solve the above technical problems and the drawbacks in the above listed prior arts, the inventors of the present application attempted purpose to provide a method for preparing chiral 4-substituent dihydrofuran-2(3H)-one which is a suitable for industrial production in an affordable cost.
Therefore, there is an unmet need in the market for the manufacture and a method for preparing chiral 4-substituent dihydrofuran-2(3H)-one, which is low-cost, highly maneuverable, and suitable for industrial production.
At the same time, surprisingly our inventors of the present application have found an economical way of manufacturing the product, which is industrially scalable, affordable and with a highest possible purity and finally with an improved yield.

Summary of the invention:
An embodiment of the present invention is to provide a shortest synthetic route, easy-to-obtain raw materials, simple process, and therefore has low cost and is suitable for industrial production.
One aspect of the present invention provides an improved process for the synthesis of compound of formula I, it is a key intermediate of Brivaracetam.
4-Propyldihydrofuran-2(3H)-one compound of the present invention can be used as an active compound or an important pharmaceutical intermediate, as shown in formula I:

The configuration shown by the * position is R-type
Another aspect of the present invention adopts the following technical solutions: A preparation method of chiral 4-substituent dihydrofuran-2(3H)-one includes the following steps:

1) Compound of the formula XI reacted with compound of formula X in presence of coupling agent and base to give compound of formula IX.

2) Without isolating compound of formula IX reacted with compound of formula VIII, in presence of a strong base gives compound of formula VII

3) Without isolating compound of formula VII in presence of oxidizing agent, gives compound of formula VI.

4) Compound of formula VI without isolating in presence of base to give compound of formula V.

5) Compound of formula V with salt in presence of acid, gives compound of formula IV.

6) Compound formula IV without isolating in presence of acid it gives compound of formula III.

7) Compound of formula III in presence of reducing agent gives compound of formula II.

8) Compound of formula II under cyclization gives compound of formula I.

Detailed description:
The present invention relates to an improved, economical process for the preparation of enantiomerically pure -(R)-4-Propyldihydrofuran-2(3H)-one without Involving any chiral chromatographic resolution technique.
An embodiment of the present invention provides improved, cost effective and easily scalable process for the preparation of (R)-4-Propyldihydrofuran-2(3H)-one with 99-100% chiral purity.

In a further specific embodiment, the reaction conditions for each reaction step of the present invention are detailed below:
In one embodiment, Valeryl Chloride reacted with (S)-4-b-benzyl-2-oxazolidinone in presence of base and dehydrating agent to form (S)-4-benzyl-3-valeryl-oxazolidin-2-one. It is forming in in-situ.

Base selected from the group of sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate. Most preferably Sodium bicarbonate.
Coupling agent selected from the group of DCC, DIC, EDC HCl, BOP, HATU, HBTU, HCTU, TATU, TBTU. Most preferably DCC.
In second embodiment, the compound (S)-4-benzyl-3-valeryl-oxazolidin-2-one is not isolated in stage-1. Without isolating it is reacted with tert-butyl Bromoacetate in presence of Base, formed (R)-tert-butyl-3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl) hexanoate. The compound is not isolating.

Base is selected from the group of Lithium hexamethyldisilazide (LiHMDS), Sodium hexamethyldisilazide (NaHMDS), Potassium hexamethyldisilazide (KHMDS), n-butyl lithium, tert-butyl lithium, sodium tert-butoxide, sodium methoxide, sodium hydroxide, potassium hydroxide. Most preferably base used is Sodium hexamethyldisilazide.
The solvent is selected from Tetrahydrofuran, Acetonitrile, N, N-dimethyl formamide, N-methyl pyrrolidone, 1,4-dioxane, dichloromethane, chloroform, methyl tert-butyl ether. Among them the most preferable solvent is Tetrahydrofuran.
In third embodiment, the compound (R)-tert-butyl-3-((S)-4-benzyl-2-oxooxazolidine-3-carboxyl) hexanoate in presence of oxidizing agent, sodium hydroxide under hydrolysis formed (R)-2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid. The compound is not isolating.

Base is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, Lithium hydroxide. Preferably sodium hydroxide. Oxidizing agent is hydrogen peroxide.
Solvent is selected from tetrahydrofuran, methylene dichloride, diethyl ether, methyl tert-butyl ether. Preferable solvent is tetrahydrofuran.
In fourth embodiment, compound (R)-2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid without isolating in presence of salt forming agents, isolated as (R)-2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid with amine salt. The compound is isolating with amine salt.

Salt forming agents are Ethanolamine, Triethanolamine, Tris (Hydroxyethyl) amino methane. Solvent is Ethyl acetate.
Obtained salt compound in presence of acid converted into (R )-2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid but it should not be isolated and not detected in reaction. It is further reacted with chlorinating agent and alcohol solvent obtained 4-tert-butyl-1-methyl-2-propyl succinate.

Chlorinating agent is thionyl chloride, alcohol solvent is Methanol.
In further embodiment, compound 4-tert-butyl-1-methyl-2-propyl succinate under reduction obtained tert-Butyl-(R)-3-(hydroxymethyl) hexanoate.

The Reducing agent is selected from Sodium borohydride, lithium borohydride, and lithium tetrahydroaluminum, diborane, most preferably sodium borohydride. Solvent is methanol.
In another embodiment, tert-butyl-(R)-3-hydroxymethyl) hexanoate in presence of HCl, methyl tertiary butyl ether under cyclization gives (R)-4-Propyldihydrofuran-2(3H)-one.

The above process of the present invention is schematically represented in Scheme below.
SCHEME

EXAMPLES:
Example-1: Preparation of (S)-4-benzyl-3-pentanoyloxazolidin-2-one (Compound-IX):

To the mixture of Pentanoyl chloride (compound-XI) (150 Gm, 1.1 eq.), methylene dichloride (1000 mL) and Dicyclohexylcarbodiimide (300.0 Gm) in Tetrahydrofuarn (400 mL) add (S)-(+)-4-Phenyl-2-oxazolidinone (compound-X) (200 Gm, 1.0 eq) at 10-15°C and stirred for 15 Hrs. After reaction complies, cooled to 0-5°C and washed the reaction mass with Hydrochloric acid solution, Aq. sodium bicarbonate solution followed by water. The obtained organic layer was concentrated to get title compound as crude (270.0 Gm). The obtained crude is gone for next stage without isolation.
Example-2: Preparation of tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl) hexanoate (Compound-VII):

To a solution of (S)-4-benzyl-3-pentanoyloxazolidin-2-one (Compound-IX) (270 Gm, 1.0eq.) in Tetrahydrofuran (540 mL), sodium hexamethyldisilazide 40% in Tetrahydrofuran (680 mL) was added about -80°C to -70°C over a period of 60-90 minutes, and then maintained for 2-3 Hours at same temperature. Tert-butyl 2-bromoacetate (Compound-VIII) (265 Gm, 1.32 eq.) was added to the reaction mass at about -80°C to -70°C for 60-90 minutes and maintained for 2-3 Hrs. On completion of reaction, temperature raised to -10°C to -5°C and quenched in saturated ammonium chloride solution and then temperature raised to 25-35°C and extracted the mass with Ethyl acetate (1000 mL) followed by 20% sodium chloride solution. Total organic layer concentrated under reduced pressure to obtain the title compound as crude (300.0 Gm). The obtained crude is gone for next stage without isolation.

Example-3: Preparation of 2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid (Compound-VI):

To a solution of pre-cooled (0-5°C) sodium hydroxide solution (50 Gm in 300 mL Water) and Tetrahydrofuran (600 mL), Hydrogen peroxide (43 Gm) was added and stirred for 30 minutes. To this solution, Compound-VII (300 Gm, 1.0 eq.) obtained from Example-2 was added at 0-5°C and stirred for 2-3 Hrs. Above mass quenched into Aq. Sodium sulphite solution and raise the reaction mass temperature to 25-35°C. Wash the product layer with methylene dichloride and adjust the Aq. Layer pH to acidic by using Hydrochloric acid. Extracted the mass with Ethyl acetate (600 mL), concentrated to obtain the title compound as crude (105.0 Gm). The obtained crude is gone for next stage without isolation.
Example-4: Preparation of 2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid in salt form (Compound-V):

Example-4A: Preparation of tert-butyl 3-((2-hydroxyethyl) carbamoyl) hexanoate
Ethanolamine (30 Gm, 1.07 eq.) was added slowly to a solution of 2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid (Compound-VI) (100 Gm, 1.0 eq.) obtained from Example-3 in Ethyl acetate was heated to 50-55°C and cooled to 0-5°C, stirred for 60-90 minutes and filtered off to get title compound (100 Gm).
Example-4B: Preparation of tert-butyl 3-((1,5-dihydroxy-3-(2-hydroxyethyl) pentan-3-yl) carbamoyl) hexanoate.
Tris(hydroxyethyl)amino methane (82.5 Gm, 1.10 eq.) was added slowly to a solution of 2-(2-(tert-butoxy)-2-oxoethyl) pentanoic acid (Compound-VI) (100 Gm) obtained from Example-3 in Ethyl acetate was heated to 50-55°C and cooled to 0-5°C, stirred for 60-90 minutes and filtered off to get title compound (140 Gm).
Example-5: Preparation of (R)-tert-butyl 3-(hydroxymethyl) hexanoate (Compound-II):

The above wet material obtained from Example-4A (compound-V) (100 Gm, 1.0 eq.) was added into mixture of Water and methylene dichloride and adjusted the pH acidic by using Hydrochloric acid and then separated both organic and aqueous layer. The organic layer is distilled and charged methanol. Cooled to 0-5°C, added Thionyl chloride (70 Gm, 1.64 eq.) into the mass and raised the temperature to reflux. On completion distilled the solvent completely under reduced pressure to get compound-III. The obtained crude dissolved in methanol and was added to a sodium borohydride (15 Gm, 1.03eq.) solution and maintained for 2-3 Hrs. On completion, quench the reaction mass into water and neutralize with hydrochloric acid. Extracted with ethyl acetate and concentrated to get title compound as crude (60.0 Gm). The obtained crude is used for next stage without purification.
Example-6: Preparation of (R)-4-propyldihydrofuran-2(3H)-one (Compound-I):

To a solution of crude (60 Gm, 1.0 eq.) obtained from Example-5(compound-11) in Methyl-tert-butyl ether added Hydrochloric acid (43.85 Gm, 1.61 eq.) and heated to 60-65°C, stirred for 3-4 Hrs. on completion, separated both organic and aqueous layers. Organic layer washed with 20% sodium chloride solution followed by distillation to get the title compound (30 Gm).

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.
While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein may be interpreted as mere illustrative of the invention and not in a limiting sense.
,CLAIMS:We Claim:
Claim 1:
1. An improved process for the preparation of (R)-4-Propyldihydrofuran-2(3H)-one formula I

Formula I
comprising the steps of:
a) Reacting valeryl chloride with (S)-4-b-benzyl-2-oxazolidinone in presence of dehydrating agent to obtain (S)-4-benzyl-3-valeryl-oxazolidin-2-one of formula IX, which is not isolating.

XI X IX
b) Reacting (S)-4-benzyl-3-valeryl-oxazolidin-2-one of formula IX with tertiary butyl bromo acetate in presence of base to obtain (R)-tert-butyl-3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl) hexanoate of formula VII, which is not isolating.

IX VIII VII
c) Conversion of compound of formula VII in presence of oxidizing agent and suitable solvent to obtain compound of formula VI, which is not isolating.

VII VI

d) Salt formation of compound of formula VI with amine to obtain compound of formula V.

VI V
e) Conversion of above obtained salt of formula V into compound of formula III without isolating compound of formula IV.

V IV III
f) Conversion of formula III to compound of formula II by reduction in presence of suitable solvent.

III II
g) Cyclization of compound of formula II in presence of an acid and solvent to obtain compound (R)-4-Propyldihydrofuran-2(3H)-one of formula I having
more than 99%.

II I
Claim 2: The process as claimed in claim 1 wherein step a) dehydrating agent
is dicyclohexylcarbodiimide and solvent is methylene dichloride. Reaction
carried out at 10-15°C.

Claim 3: The process as claimed in claim 1 wherein step b) base is sodium
hexamethyldisilazide and solvent is tetrahydrofuran. Reaction carried out
at -80°C to -70°C.

Claim 4: The process as claimed in claim 1 wherein step c) oxidizing agent is
hydrogen peroxide and solvent is tetrahydrofuran. Reaction carried out at
0-5°C.

Claim 5: The process as claimed in claim 1 wherein step d) reaction carried
out in presence of Ethanolamine or Tris(hydroxyethyl)amino methane and solvent
is ethyl acetate. Reaction carried out at 0°C to 5°C.

Claim 6: The process as claimed in claim 1 wherein step e) the reagent used
in conversion of salt to free base is HCl. Solvent used is methylene dichloride
or water or mixture thereof.

Claim 7: The process as claimed in claim 1 wherein step e) chlorinating agent
is thionyl chloride and the solvent is methanol.

Claim 8: The process as claimed in claim 1 wherein step f) the reducing agent used
is sodium borohydride. Solvent is methanol.

Claim 9: The process as claimed in claim 1 wherein step g) wherein acid
is hydrochloric acid, and solvent methyl tertiary butyl ether, wherein reaction
carried out at 60-65°C.

Dated this 8th day of October 2022


Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636
VP, Legal/IPR/Portfolio Management
Vimal Drugs Private Limited
RK Pharma Group and subsidiaries