DESC:“A PROCESS FOR THE PREPARATION OF 3-ETHYLBICYCLO[3.2.0]HEPT-3-EN-6-ONE”

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one with high yield and purity, which is key intermediate for the preparation of Mirogabalin Besylate.

BACKGROUND OF THE INVENTION
Mirogabalin Besylate is a medication developed by Daiichi Sankyo. This drug is a therapeutic agent for neuropathic pain that binds to the voltage-gated calcium channel a2d-1 subunit and exerts an analgesic effect in Japan, the company submitted a marketing application for treatment of peripheral neuropathic pain. The medication was approved for neuropathic pain and postherpetic neuralgia in Japan in January 2019.

3-Ethylbicyclo[3.2.0]hept-3-en-6-one as a key intermediate for the preparation of therapeutic agent for neuropathic pain, this intermediate is also used in the preparation of Mirogabalin, which is treated of neuropathic pain that binds to the voltage-gated calcium channel a2d-1 subunit and exerts an analgesic effect. 3-Ethylbicyclo[3.2.0]hept-3-en-6-one, is represented by structural Formula (I).

3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), which is a key intermediate for the preparation of Mirogabalin Besylate.

US 9162971 discloses a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), which comprises compound of formula (VI) is reacted with compound of formula (VII) in presence of hexane/magnesium sulfate (MgSO4)/p-toluenesulfonic acid monohydrate (PTSA.H2O)/potassium carbonate (K2CO3) and water to obtain the compound of formula (VIII). The compound of formula (VIII) is reacted with acetic anhydride (Ac2O) and maleic acid in presence of N,N-dimethylacetamide (DMAC)/ toluene/water/NaOH to obtain the compound of formula (III). The compound of formula (III) is reacted with malonic acid in presence of acetonitrile /morpholine/ pyridine/toluene to obtain the compound of formula (II). The compound of formula (II) is reacted with acetic anhydride (Ac2O) in presence of N,N-dimethylacetamide (DMAC) and triethylamine (TEA) to obtain the compound of formula (I). The process is schematically shown as below:

US 9206104 discloses a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), which comprises compound of formula (VI) is reacted with compound of formula (IX) in presence of toluene to obtain the compound of formula (X). The compound of formula (X) is reacted with allyl bromide in presence of acetonitrile to obtain the compound of formula (XI). The compound of formula (XI) is reacted with malonic acid in presence of piperidine to obtain the compound of formula (II). The compound of formula (II) is reacted with acetic anhydride (Ac2O) in presence of N,N-dimethylacetamide (DMAC) and triethylamine (TEA) to obtain the compound of formula (I).
The process is schematically shown as below:

The above processes disclose the preparation of the 3-Ethylbicyclo[3.2.0]hept-3-en-6-one is difficult for bulk manufacturing process commercially. Impurities are generated in the preparation process of the 3-Ethylbicyclo[3.2.0]hept-3-en-6-one and the impurities affect the purity of the Mirogabalin.
Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed a method for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one. The present invention is providing a simple, cost effective, high pure, good yield and industrial applicable process.

OBJECT OF THE INVENTION
The objective of the invention relates to a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one with high yield and purity.

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one with high yield and purity, which is key intermediate for the preparation of Mirogabalin Besylate.

In one embodiment of the present invention provides, a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), comprising the steps of;
a) reacting the compound of formula (VI) with compound of formula (V) in presence of acid and solvent to obtain compound of formula (IV),

b) reacting the compound of formula (IV) with allyl bromide in presence of base and solvent to obtain compound of formula (III),

c) reacting the compound of formula (III) with dimethyl malonate in presence of base and solvent to obtain compound of formula (II), and

d) reacting the compound of formula (II) with acetic anhydride (Ac2O) in presence of base and solvent to obtain compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one with high yield and purity.

In one embodiment of the present invention provides, a process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), comprising the steps of;
a) reacting the compound of formula (VI) with compound of formula (V) in presence of acid and solvent to obtain compound of formula (IV),

b) reacting the compound of formula (IV) with allyl bromide in presence of base and solvent to obtain compound of formula (III),

c) reacting the compound of formula (III) with dimethyl malonate in presence of base and solvent to obtain compound of formula (II), and

d) reacting the compound of formula (II) with acetic anhydride (Ac2O) in presence of base and solvent to obtain compound of formula (I).

According to embodiment of the present invention, reacting the compound of formula (VI) with compound of formula (V) in presence of acid and solvent and the reaction is carried out at reflux temperature for 2-8 hours to obtain the compound of formula (IV).

According to embodiment of the present invention, reacting the compound of formula (IV) with allyl bromide in presence of base and solvent and the reaction is carried out at reflux temperature for 1-4 hours to obtain the compound of formula (III).

According to embodiment of the present invention, reacting the compound of formula (III) with dimethyl malonate in presence of base and solvent and the reaction is carried out at 70 to 80°C for 15-16 hours to obtain the compound of formula (II).

According to embodiment of the present invention, reacting the compound of formula (II) with acetic anhydride (Ac2O) in presence of base and solvent and the reaction is carried out at 105 to 115°C for 6-8 hours to obtain the compound of formula (I).

According to an embodiment of the present invention provides 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I) having HPLC purity = 99.5%.

According to an embodiment of the present invention, wherein the acid is selected from inorganic acid or organic acid; inorganic acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid and nitric acid; organic acid is selected from para-toluene sulfonic acid, formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, trifluoroacetic acid and methane sulfonic acid.

According to an embodiment of the present invention, wherein the base is selected from inorganic base or organic base; inorganic base is selected from 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; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; ammonia; sodium sulphite; organic base is selected from morpholine, pyridine, triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine and 4-dimethylaminopyridine (DMAP).

According to an embodiment of the present invention, the reaction carried out suitable solvent is selected from tetrahydrofuran, methyl tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, 2-propanol, 2-butanol, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone (MIBK), cyclohexanone, n-hexane, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, chloroform, carbon tetrachloride and chloroform, methyl tert-butyl ether (MTBE) and/or mixtures thereof.

According to an embodiment of the present invention provides 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), which is key intermediate for the preparation of Mirogabalin Besylate.

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

EXAMPLES

Example 1:
Synthesis of 2-propyl-1,3-dioxolane (IV)
Butyraldehyde (118g), 1,2-ethanediol (82g), toluene (250 ml) and p-toluenesulfonic acid (0.05 g) were added into round-bottomed flask at 25-30°C. The reaction mass heated to reflux (110-115°C) and stir for 4-6 hours at same temperature. After complete of the reaction, the reaction mixture was cooled to room temperature and add 10% potassium carbonate solution (200 ml). The obtained layers were separated, the organic layer was distilled to obtain 2-propyl-1,3-dioxolane (IV).
Yield: 86.80% (165g)
HPLC Purity: = 99.0%.

Example 2:
Synthesis of 2-ethylpent-4-enal (III)
2-Propyl-1,3-dioxolane (IV) (72g) was dissolved in acetonitrile (200ml) at 25-30°C and reaction mass heated to 80-90°C, then added sodium hydride (5g) at 80-90°C for 1 hour, and allyl bromide (150g) was added dropwise. The obtained reaction mass was stirred for 1-4 hours at reflux temperature, then cooled the reaction mass to 0-5°C. The reaction mass quench with dilute hydrochloric acid solution, add toluene (500 ml) at 25-30°C and stir for 1 hour. The obtained organic layer separate, the aqueous layer was extracted with Toluene (150ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain 2-ethylpent-4-enal (III).
Yield: 90.61% (63g)
HPLC Purity: = 99.2%.

Example 3:
Synthesis of (2E)-4-Ethylhepta-2,6-dienoic acid (II)
Dimethyl malonate (100g), acetonitrile (250 ml) and pyridine (80 ml) were added into the solution of 2-ethylpent-4-enal (III) (60g) in acetonitrile at under a nitrogen atmosphere at 25-30°C and the mixture was slowly heated to approximately 80°C. The reaction mass was stirred for 15-16 hours at same temperature. After completion of the reaction, reaction mass was cooled to room temperature. The obtained reaction mixture was added sodium hydroxide solution (530 ml) and separate an organic layer. The obtained organic layer was vacuum distilled to obtain the (2E)-4-Ethylhepta-2,6-dienoic acid (II).
Yield: 90.92% (75g).
HPLC Purity: = 99.2%.

Example 4:
Synthesis of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I)
((2E)-4-Ethylhepta-2,6-dienoic acid (II) (40 g) was dissolved in N,N-dimethylacetamide (100 ml) under the nitrogen atmosphere at 25-30°C. To the solution, acetic anhydride (40 ml) and triethylamine (30 ml) were added at 25-30°C. The reaction mixture was warmed and stirred at 105°C to 115°C for 6-8 hours. The reaction mixture was cooled to room temperature, and water (200 ml) was added thereto, followed by extractions with n-hexane (600ml). All the extracted organic layers were combined and then washed with a saturated aqueous solution of sodium bicarbonate (50 ml) and water (50 ml) in this order. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain the 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I).

Yield: 86.33% (30.5g)
HPLC Purity: = 99.50%.
,CLAIMS:WE CLAIM:

1. A process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), comprising the steps of;
a) reacting the compound of formula (VI) with compound of formula (V) in presence of acid and solvent to obtain compound of formula (IV),

b) reacting the compound of formula (IV) with allyl bromide in presence of base and solvent to obtain compound of formula (III),

c) reacting the compound of formula (III) with dimethyl malonate in presence of base and solvent to obtain compound of formula (II), and

d) reacting the compound of formula (II) with acetic anhydride (Ac2O) in presence of base and solvent to obtain compound of formula (I).

2. The process as claimed in claim 1, wherein the acid is selected from inorganic acid or organic acid; inorganic acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid and nitric acid; organic acid is selected from para-toluene sulfonic acid, formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, trifluoroacetic acid and methane sulfonic acid.

3. The process as claimed in claim 1, wherein the base is selected from inorganic base or organic base; inorganic base is selected from 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; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; ammonia; sodium sulphite; organic base is selected from morpholine, pyridine, triethylamine, triethanolamine, diisopropylethylamine, di-n-propylamine and 4-dimethylaminopyridine (DMAP).

4. The process as claimed in claim 1, wherein the reaction carried out suitable solvent is selected from tetrahydrofuran, methyl tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, 2-propanol, 2-butanol, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone (MIBK), cyclohexanone, n-hexane, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, dichloromethane (MDC), dichloroethane, chloroform, carbon tetrachloride and chloroform, methyl tert-butyl ether (MTBE) and/or mixtures thereof.

5. The process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), as claimed in claim 1, having HPLC purity = 99.5%.

6. The process for the preparation of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one (I), as claimed in claim 1, which is key intermediate for the preparation of Mirogabalin Besylate.