DESC: PROCESS FOR (R)-4-PROPYLDIHYDROFURAN-2(3H)-ONE

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of (R)-4-propyldihydrofuran-2(3H)-one (I), which is a key intermediate for the preparation of Brivaracetam. The present invention is also relating to a commercially viable and cost effective process of (R)-4-propyl dihydrofuran-2(3H)-one (I) with high yield and high purity.

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-npropyl analogue of Levetiracetam. Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyl pyrrolidinyl] butanamide. Its empirical formula is C11H20N2O2 and the molecular weight is 212.29. The structural formula is:

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.
The present invention explains improved process for the preparation of (R)-4-propyl dihydro furan-2(3H)-one (I), which is a key intermediate for the preparation of Brivaracetam. The structural formula is

Brivaracetam was first disclosed in US 6911461 and the process for the preparation of Brivaracetam, which comprises 4-n-propyl-hydroxyfuranone is reacted with (S)-2-aminobutyramide in presence of toluene /H2O/AcOH and NaBH4 to obtain the compound of unsaturated pyrrolidone and its followed treated with HCOONH4/Pd/C and water to obtain Brivaracetam.
The above process is schematically shown as below:

US ‘461 not explain the process for the preparation of (R)-4-propyldihydrofuran-2(3H)-one (I).

US 10221134 discloses a process for the preparation of (R)-4-propyl dihydrofuran-2(3H)-one (I), which comprises (R)-epichlorohydrin is reacted with diethyl malonate in presence of NaOMe and ethanol to obtain (1S,5R)-ethyl 2-oxo-3-oxabicyclo [3.1.0] hexane-1-carboxylate (II). The compound of formula (II) is reacted with EtMgBr in presence of CuI and THF to obtain (4R)-ethyl-4-propyl-2-oxotetrahydrofuran-3-carboxylate (III). The compound of formula (III) converts into (R)-4-propyl dihydrofuran-2(3H)-one (I) in presence of LiCl / H2O and DMSO.
The above process is schematically shown as below:

The main drawback of the prior art process is using solvents are having high boiling point, the reaction is carried out at high temperature (140°C), time taking process (18 hours) and less chiral purity and very less yield, which is not suitable for large scale industrial production.

CN105837535 discloses a process for the preparation of (R)-4-propyl dihydrofuran-2(3H)-one (I), which comprises n-valeryl chloride is reacted with (R)-4-benzyl-oxazolidin-2-one (IV) in presence of tert-butyl lithium / THF / n-hexane and NH4Cl to obtain (R)-4-benzyl-3-pentanoyl oxazoline-2-one (V). The compound of formula (V) is reacted with tert-butyl 2-bromoacetate in presence of THF / LiHMDS and NH4Cl to obtain (R)-3-((R)-4-tert-butyl benzyl-2- oxazoline-3-formyl) hexanoate (VI). The compound of formula (VI) converts into (R)-3-(hydroxymethyl) tert-butyl hexanoate (VII) in presence of LiBH4/ / THF / MTBE / MeOH and NaOH. The compound of formula (VII) converts into (R)-4-propyldihydrofuran -2(3H)-one (I) in presence of MDC / TFA and MeOH.

The above process is schematically shown as below:

The prior art process involves conversion of (R)-3-(hydroxymethyl) tert-butyl hexanoate (VII) to (R)-4-propyl dihydrofuran-2(3H)-one (I) in presence of chlorinated organic solvent, which is a highly expensive and time taking process.

The advantage of the present invention is process for the preparation of (R)-4-propyl dihydrofuran-2(3H)-one (I) with high chiral purity, high yield and the reaction is carried out at medium temperatures and a cost effective process.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of (R)-4-propyldihydrofuran-2(3H)-one (I), which is a key intermediate for the preparation of Brivaracetam. The present invention is also relating to an improved and commercially viable and cost effective process of (R)-4-propyl dihydrofuran-2(3H)-one (I) with high yield and high purity.

The present invention provides an improved process for the preparation of (R)-4-propyl dihydrofuran-2(3H)-one (I), comprising the steps of;

a) (R)-epichlorohydrin is reacted with diethyl malonate in presence of strong inorganic base and organic solvent to obtain (1S,5R)-ethyl 2-oxo-3-oxabicyclo [3.1.0] hexane-1-carboxylate (II),

b) The compound of formula (II) is reacted with grignard reagent in presence of Cu catalyst and organic solvent to obtain (4R)-ethyl-4-propyl-2-oxotetrahydrofuran-3-carboxylate (III),

c) The compound of formula (III) is reacted with (S)-1-Phenylethylamine in presence of organic base to obtain 2-((R)-1-hydroxypentan-2-yl)-N1, N3-bis((S)-1-phenylethyl) malonamide (VIII), and

d) The compound of formula (VIII) converts into (R)-4-propyl dihydrofuran-2(3H)-one (I) in presence of acid and absence of solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of (R)-4-propyldihydrofuran-2(3H)-one (I), which is a key intermediate for the preparation of Brivaracetam. The present invention is also relating to an improved and commercially viable and cost effective process of (R)-4-propyl dihydrofuran-2(3H)-one (I) with high yield and high purity.

The present invention provides an improved process for the preparation of (R)-4-propyl dihydrofuran-2(3H)-one (I), comprising the steps of;
a) (R)-epichlorohydrin is reacted with diethyl malonate in presence of strong inorganic base and organic solvent to obtain (1S,5R)-ethyl 2-oxo-3-oxabicyclo [3.1.0] hexane-1-carboxylate (II),

b) The compound of formula (II) is reacted with grignard reagent in presence of Cu catalyst and organic solvent to obtain (4R)-ethyl-4-propyl-2-oxotetrahydrofuran-3-carboxylate (III),

c) The compound of formula (III) is reacted with (S)-1-Phenylethylamine in presence of organic base to obtain 2-((R)-1-hydroxypentan-2-yl)-N1,N3-bis((S)-1-phenylethyl) malonamide (VIII), and

d) The compound of formula (VIII) converts into (R)-4-propyl dihydrofuran-2(3H)-one (I) in presence of acid and absence of solvent.

In an embodiment of the present invention, (R)-epichlorohydrin is reacted with diethyl malonate in presence of sodium ethoxide and ethanol to obtain (1S,5R)-ethyl 2-oxo-3-oxabicyclo [3.1.0] hexane-1-carboxylate (II) and the reaction is carried out at 45-75°C for 16-18 hours. The compound of formula (II) is reacted with ethyl magnesium chloride in presence of copper chloride, toluene, add 20% ammonium chloride to the reaction mixture and separate organic layer, which is concentrated under reduced pressure to obtain (4R)-ethyl-4-propyl-2-oxotetra hydro furan-3-carboxylate (III). The compound of formula (III) is reacted with (S)-1- phenylethylamine in presence of organic base to obtain 2-((R)-1-hydroxypentan-2-yl)-N1,N3-bis((S)-1-phenylethyl) malonamide (VIII) and the reaction is carried out at 75-100°C for 10-12 hours. The compound of formula (VIII) converts into (R)-4-propyl dihydrofuran-2(3H)-one (I) in presence of acid and absence of solvent and the reaction is carried out at 95-100°C for 15-18 hours.

According to an embodiment of the present invention, (1S,5R)-ethyl 2-oxo-3-oxabicyclo [3.1.0] hexane-1-carboxylate (II) liquid material (Purity by GC is 90% and enantiomeric purity by GC is 98%) is treated with methyl tert-butyl ether and cool to 0 to -5°C. The obtained precipitated solid material is filtered at 0 to -5°C to get pure (1S,5R)-ethyl 2-oxo-3-oxa-bicyclo [3.1.0] hexane-1-carboxylate solid (Purity by GC is 99%, enantiomeric purity by GC is 99.9%).

According to an embodiment of the present invention, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl tert-butyl ether (MTBE), methyl isobutyl ketone, cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform and/or mixtures thereof.

According to an embodiment of the present invention, wherein the inorganic base is selected from sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, lithium hydroxide, barium hydroxide, calcium hyrdroxide, cesium hydroxide and potassium hydroxide.

According to an embodiment of the present invention, wherein the organic base is selected from triethyl amine, diisopropyl ethylamine, ethyl amine, methyl amine.

According to an embodiment of the present invention, wherein the grignard reagent is selected from methyl magnesium bromide, methyl magnesium chloride, phenyl magnesium chloride, phenyl magnesium bromide, ethyl magnesium bromide and ethyl magnesium chloride.

According to an embodiment of the present invention, wherein the copper (Cu) catalyst is selected from copper oxide (CuO), copper chloride (CuCl), copper iodide (CuI) and copper bromide (CuBr).

According to an embodiment of the present invention, wherein the acid is selected from 20% sulfuric acid, con hydrochloric acid, hydrobromic acid, acetic acid and methanesulfonic acid.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example-1:
Preparation of (1S,5R)-ethyl 2-oxo-3-oxa-bicyclo [3.1.0] hexane-1-carboxylate:

Charge 100 g (1.08 mole) of R-Epichlorohydrin, ethanol (1000 ml) into flask and cool to 0-5°C. Add 73g (1.073 mole) of sodium ethoxide portion wise to the reaction mixture at 0-5°C and maintain for 30min, followed by 208 g (1.298 mole) of diethylmalonate is added dropwise to the mixture at 10-15°C and maintain for 30 min. The resultant reaction mass temperature raised to 55-60°C and maintain for 18 hr. After completion of the reaction, solvent is removed under reduced pressure at below 60°C and the obtained residue is diluted with water (1000 ml) at 20-30°C. The obtained residue is extracted with toluene (900 ml) and the organic layer is concentrated under reduced pressure to get crude material. The obtained crude material is distilled at 110°C/730mmhg to get liquid material (Purity by GC is 90% and enantiomeric purity by GC is 98%). The obtained liquid material with methyl tert-butyl ether (60 ml) and cool to 0 to -5°C. The precipitated solid material is filtered at 0 to -5°C to get pure (1S,5R)-ethyl 2-oxo-3-oxa-bicyclo[3.1.0] hexane-1-carboxylate solid (Purity by GC is 99%, enantiomeric purity by GC is 99.9%).
Yield: 40%

Example-2:

Preparation of (4R)-ethyl 2-oxo-4-propyltetrahydro furan-3-carboxylate:

Charge 116 g (1.174 mole) of copper (I) chloride, toluene (400 ml) into RB flask and cool to
-40 to -30°C. Add 600 ml (1.174 mole) of ethyl magnesium chloride in THF (2.0 M) in to flask at -40 to -30°C, stir for 2 hr and followed by dropwise addition of (100 g, 0.587 mole) (1S,5R)-ethyl 2-oxo-3-oxa-bicyclo[3.1.0] hexane-1-carboxylate in toluene (300 ml) into the flask at -40 to -30°C for 1 hr and maintain for 1hr at same temperature. After completion of the reaction, the reaction mass is quenched with 20% ammonium chloride solution (1200 ml) and separate two layers. Take the organic layer, washed with water (200 ml) and dried over sodium sulphate. The obtained product concentrated under reduced pressure to get (4R)-ethyl 2-oxo-4-propyltetrahydro furan-3-carboxylate (Purity by GC is 88%)

Yield: 85%

Example-3:

Preparation of (4R)-ethyl 2-oxo-4-propyltetrahydro furan-3-carboxylate

Charge 116 g (1.174 mole) copper (I) chloride, THF (300ml) into RB flask and cool to -40 to -30°C. Add 600 ml (1.174 mole) of ethyl magnesium chloride in THF (2.0 M) in to flask at -40 to -30°C, stir for 2hr and followed by dropwise addition of (100 g, 0.587 mole) (1S,5R)-ethyl 2-oxo-3-oxa-bicyclo [3.1.0] hexane-1-carboxylate in THF (200 ml) into the flask at -40 to -30°C for 1hr and maintain for 1hr at same temperature. After completion of the reaction, the reaction mass is quenched with 20% ammonium chloride solution (1200 ml) and the obtained product is extracted with toluene (600 ml), separate two layers. Take the organic layer, washed with water (200 ml) and dried over sodium sulphate. The obtained product concentrated under reduced pressure to get (4R)-ethyl 2-oxo-4-propyltetrahydro furan-3-carboxylate (Purity by GC is 82%).

Yield: 80%

Example-4:
Preparation of 2-((R)-1-hydroxypentan-2-yl)-N1,N3-bis((S)-1-phenylethyl)malonamide:

Charge 100 g (0.499 mole) of (4R)-ethyl 2-oxo-4-propyltetrahydro furan-3-carboxylate, 121g (0.998 mole) of (S)-1-phenyl ethylamine and 101 g (0.998 mole) of triethylamine into RB flask at 25-30°C. The reaction mass raised temperature to 60-70°C and stir 5hr at 60-70°C. After completion of the reaction, reaction mass was cooled to room temperature and water is added to dilute the reaction mass. The obtained product is extracted with dichloromethane (600 ml), separate two layers. Take the organic layer, washed with water (200 ml) and then concentrated under reduced pressure to get crude material. The obtained crude material is recrystallized from di-n-butyl ether (1500 ml) to get pure 2-((R)-1-hydroxypentan-2-yl)-N1,N3-bis((S)-1-phenylethyl)malonamide (Purity by HPLC is 98% and enantiomeric purity by HPLC is 99.9%).
Yield: 75%

Example-5:
Preparation of (R)-4-propyldihydrofuran-2(3H)-one

Charge 100 g (0.252 mole) of 2-((R)-1-hydroxypentan-2-yl)-N1,N3-bis((S)-1-phenylethyl) malonamide, 20% sulfuric acid (500 ml) into RB flask at 25-30°C. The reaction mass raised temperature to 95-100°C. The resultant reaction mass stir for 6 hr at 95-100°C. After completion of the reaction, reaction mass is cooled to room temperature and product is extracted with dichloromethane (600 ml) separate two layers. Take the organic layer, washed with water (200 ml) and concentrated under reduced pressure to get (R)-4-propyldihydrofuran-2(3H)-one. (Purity by GC is 98% and enantiomeric purity by GC is 99.9%).

Yield: 70%

,CLAIMS:WE CL AIM:

1. An improved process for the preparation of (R)-4-propyl dihydrofuran-2(3H)-one (I), comprising the steps of;

a) (R)-epichlorohydrin is reacted with diethyl malonate in presence of strong inorganic base and organic solvent to obtain (1S,5R)-ethyl 2-oxo-3-oxabicyclo [3.1.0] hexane-1-carboxylate (II),

b) The compound of formula (II) is reacted with grignard reagent in presence of Cu catalyst and organic solvent to obtain (4R)-ethyl-4-propyl-2-oxotetrahydrofuran-3-carboxylate (III),

c) The compound of formula (III) is reacted with (S)-1-Phenylethylamine in presence of organic base to obtain 2-((R)-1-hydroxypentan-2-yl)-N1, N3-bis((S)-1-phenylethyl) malonamide (VIII), and

d) The compound of formula (VIII) converts into (R)-4-propyl dihydrofuran-2(3H)-one (I) in presence of acid and absence of solvent.

2. The process as claimed in claim 1, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl tert-butyl ether (MTBE), methyl isobutyl ketone, cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform and/or mixtures thereof.

3. The process as claimed in claim 1, wherein the inorganic base is selected from sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, lithium hydroxide, barium hydroxide, calcium hyrdroxide, cesium hydroxide and potassium hydroxide.

4. The process as claimed in claim 1, wherein the organic base is selected from triethyl amine, diisopropyl ethylamine, ethyl amine, methyl amine.

5. The process as claimed in claim 1, wherein the grignard reagent is selected from methyl magnesium bromide, methyl magnesium chloride, phenyl magnesium chloride, phenyl magnesium bromide, ethyl magnesium bromide and ethyl magnesium chloride.

6. The process as claimed in claim 1, wherein the copper (Cu) catalyst is selected from copper oxide (CuO), copper chloride (CuCl), copper iodide (CuI) and copper bromide (CuBr).

7. The process as claimed in claim 1, wherein the acid is selected from 20% sulfuric acid, con hydrochloric acid, hydrobromic acid, acetic acid and methanesulfonic acid.

8. The process for preparing Brivaracetam comprising the process for preparing compound of Formula (I) as claimed in any of claims 1-7.