WO2024134671A1

WO2024134671A1 - Preparation of 3-ethylbicyclo[3.2.0]hept-3-en-6-one

Info

Publication number: WO2024134671A1
Application number: PCT/IN2023/051150
Authority: WO
Inventors: Swapnil Sonawane; Nilima SONAWANE
Original assignee: Bhisaj Pharmaceuticals Pvt Ltd
Current assignee: Bhisaj Pharmaceuticals Pvt Ltd
Priority date: 2022-12-21
Filing date: 2023-12-09
Publication date: 2024-06-27
Anticipated expiration: 2025-06-21

Abstract

The present invention relates to an industrially feasible, robust, and economically viable process for preparation of 3-ethylbicyclo [3.2.0] hept-3-en-6-one (7). The process produces compound (7) having chiral purity >99%.

Description

“PREPARATION OF 3-ETHYLBICYCLO[3.2.0]HEPT-3-EN-6-ONE”

FIELD OF THE INVENTION

The present invention relates to a process for preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one (7).

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.

Compound of formula (7) is chemically known as 3-ethylbicyclo[3.2.0]hept-3-en- 6-one and is represent by the following structural formula:

The intermediate compound of formula 7, as an optically active compound, which is used in the preparation of a bicyclic y-amino tetrazole derivative of formula (1). Structurally the compound of formula (1) is shown below:

The compound of formula (1) is a medication developed by Daiichi Sankyo, a gabapentinoid. Gabapentin and pregabalin are belongs to members of this class. It binds to the a25 subunit of voltage-gated calcium channel (1 and 2), but compound of formula 1 has significantly higher potency than pregabalin. It has shown promising results in Phase II clinical trials for the treatment of diabetic peripheral neuropathic pain.

The process for preparing intermediate compound of formula (7) is disclosed in US9162971B2, US8324425B2 and US10150723B2. The present inventors, after analysing the reported methods, have assumed that a more efficient production method would be established for isolating optically active compound of formula (7) in an economical and more robust manner. The prior art separation technologies, uses expensive solvent and reagent combinations for the isolation of compound of formula (6), however, the present inventors have come up with superior method for producing optically active compound of formula 6 with desirable chiral purity.

SUMMARY OF THE INVENTION

The present invention relates to provide a method of preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one of formula (7).

Further invention relates to provide a method for preparation of racemic mixture of compound of formula (7) and compound of formula (8). 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 the purpose of 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 similar or 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.

The term “about,” as used herein, is intended to qualify the numerical values, which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, considering significant figures. The term “heating”, as used herein, is heating the solution gradually to a temperature in the range of 40°C -150°C.

As used herein, in any embodiment of the invention, the term “chiral auxiliary” refers to a chemical compound or unit that is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of one of two enantiomers. Chiral auxiliaries are optically active compounds and introduce chirality in otherwise racemic compounds.

According to one of the embodiments, the present invention provides an improved process for preparation of racemic mixture of compound of formula (7) and compound of formula (8), comprising; a) reacting butanal of formula (2) with allyl alcohol of formula (3) in a solvent and in presence of a catalyst to provide l,l-bis(allyloxy)butane of formula (4);

b) heating the l,l-bis(allyloxy)butane of formula (4) in presence of an acid anhydride and an acid in a solvent to provide 2-ethylpent-4-enal of formula (5);

c) heating 2-ethylpent-4-enal of formula (5) with malonic acid in a presence of base or a mixture of bases in a solvent to provide (2E)-4-Methylhepta- 2,6-dienoic acid of formula (6);

(5) (6) d) heating (2E)-4-Methylhepta-2,6-dienoic acid of formula (6) in a solvent and in presence of acid anhydride and a base to provide racemic mixture of compound of formula (7) and the compound of formula (8);

Solvent

The solvent used in step (a), step (b) , step (c) and step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2 -methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4- bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); 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 catalyst used in step (a) is magnesium sulfate.

The step (b) is performed in by heating to approximately 100° C to 130° C. The acid anhydride used in step (b) and step (d) is selected from acetic anhydride, propionic anhydride, butanoic anhydride, succinic anhydride, more preferably acetic anhydride.

The acid used in step (b) as a catalyst is preferably a carboxylic acid, more preferably maleic acid. The addition of an acid in a catalytic amount can promote the reaction.

The base used in step (c) and step (d) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid selected from sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines selected from diethylamine, triethylamine, di-n-propyl amine, diisopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-diazabicyclo[4.3.0]non-5-ene (DBN). The most preferred base used in step (c) is a mixture of morpholine and pyridine.

The step (c) is performed in by heating at 70° C to 80° C.

The step (d) reaction proceeds by heating. The reaction temperature is preferably 100° C to 120° C.

According to one of the embodiments, the present invention provides a process for preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one of formula (7), comprising; a) reacting the racemic mixture of the compound of formula (7) and the compound of formula (8) with an aromatic aldehyde in presence of a base and optionally in presence of a chiral auxiliary compound of formula (9) to provide reaction mixture having compound of formula (7); and

Aromatic aldehyde

Base

Optional Chiral auxiliary(9)

b) stir reaction mixture having compound of formula (7) at 70-80°C then treating this mixture with di-polar solvent to provide compound of formula (7) having chiral purity more than 99%.

The aromatic aldehyde used in step (a) is selected from 4-formyl benzoic acid, 1,2-benzenedicarboxaldehyde, 1,3-benzenedicarboxaldehyde, 1,4- benzenedicarbox-aldehyde or 2-hydroxybenzene- 1 ,3 ,5 -tricarbaldehyde .

The base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid selected from sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines selected from diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, N,N-diisopropylethylamine, pyridine, 4- dimethyl aminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5- diazabicyclo [4.3.0] non-5 -ene (DBN) .

The dipolar solvent used in step (b) is selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), N-ethyl -2- pyrrolidone (NEP), Dimethylacetamide (DMAc or DMA), acetonitrile (CHsCN), acetone or tetrahydrofuran (THF).

The chiral auxiliary used in step (a) is a compound of formula (9) is structurally shown as: Free base or acid addition salt selected from hydrochloride, sulfate, acetate, formate etc.

wherein

X = OH, F, Cl, Br, I or any group selected from alkyl, aryl, aromatic, substituted aromatic, diphenyl alkyl or substituted diphenyl alkyl;

Y = any salt such as HC1, HBr, HI. The chiral auxiliary used in step (a) is (R)-2-(diphenylmethyl)pyrrolidine hydrochloride or (S)-3 -hydroxypyrrolidine HC1 of formula (9).

The details of the present invention are described in the Examples given below which are provided to illustrate the invention and therefore should not be construed to limit the scope of the present invention.

Examples of the invention

Example 1:

Preparation of l,l-bis(allyloxy)butane [4] Butanal of formula (2) (100 g, 1.38 mol) and allyl alcohol of formula (3) (161 g, 2.77 mol) were dissolved in cyclohexane (500 mL) under a nitrogen atmosphere. To the solution, magnesium sulfate (103.7 g, 0.86 mol) was added, and the mixture was stirred. This mixture was cooled to 10° C. or lower, and p-toluenesulfonic acid monohydrate (4.06 g, 0.021 mol) was added thereto. The reaction mixture was stirred at 15° C. or lower for 1 hour and warmed to room temperature (approximately 25° C ), followed by further stirring for approximately 2.5 hours. The reaction mixture was cooled again to 10° C. or lower, and potassium carbonate (2.38 g) and water (400 mL) were added thereto in this order. The mixture was stirred until insoluble matter was dissolved. The organic layer was separated and then washed with water (100 mL). The obtained organic layer was concentrated under reduced pressure, to provide the title compound (217 g, yield: 91%, oil substance).

Example 2:

Preparation of 2-ethylpent-4-enal (5) l,l-Bis(allyloxy)butane (4) (102.15 g, 0.60 mol) was dissolved in N,N- dimethylacetamide (306 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (170 mL, 1.80 mol) and maleic acid (3.48 g, 0.03 mol) were added, and the mixture was stirred. The reaction mixture was warmed to 120 to 125° C., stirred at this temperature for 24 hours, and then cooled to 10° C. or lower. To the reaction mixture, toluene (410 mL) and water (410 mL) were added, and a 25% aqueous sodium hydroxide solution (586 mL) was slowly added with stirring to separate an organic layer. The aqueous layer was subjected to extraction with toluene (210 mL), and the extract was combined with the organic layer and then washed with water (102 mL) and 20% saline (102 mL) in this order. The organic layer was fdtered to remove insoluble matter. Then, the obtained product was used in the next step without being concentrated or purified. The solution of the crude product, it is taken for the next step.

Example -3:

Preparation of (2E)-4-Ethylhepta-2,6-dienoic acid [6]

Malonic acid (93.88 g, 0.90 mol), morpholine (26 mL, 0.30 mol), and pyridine (97 mL, 1.20 mol) were added in this order to the solution of 2-ethylpent-4-enal (5) (58.44 g) in toluene obtained by the method described above under a nitrogen atmosphere, and the mixture was slowly warmed to approximately 80° C. over approximately 1 hour. After stirring at approximately 80° C. for about 24 hours. To the reaction mixture, water (408 mL) was added, and concentrated hydrochloric acid (130 mL) was added at room temperature to separate an organic layer. The aqueous layer was subjected to extraction with toluene (153 mL), and the extract was combined with the organic layer, followed by two extractions of the compound of interest into aqueous layers using a 2 M aqueous NaOH solution (360 mfx 1 and 90 mfx 1). The aqueous layers were combined and then adjusted to be acidic by the addition of concentrated hydrochloric acid (80 mL), followed by two extractions with toluene (each with 204 mL). The organic layers were combined and then washed with water (102 mL). The organic layer was concentrated under reduced pressure to provide the title compound (72 g, oil substance).

Example-4:

Preparation of racemic mixture of compound-7 and Compound-8

(2E)-4-Ethylhepta-2,6-dienoic acid (6) (145 g) obtained by the method described above was dissolved in N,N-dimethylacetamide (367.6 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (167 g) and triethylamine (114 mL) were added. The reaction mixture was warmed and stirred at 115 to 117° C. for 5 - 6 hours. The reaction mixture was cooled to room temperature, and n-hexane (510 mL) and water (714 mL) were added thereto to separate an organic layer. The aqueous layer was subjected to two extractions with hexane (each with 255 mL), and all the organic layers were combined and then washed with a 5% aqueous sodium bicarbonate solution (102 mL) and water (102 mL) in this order. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled to provide the title compound (100 g, oil substance).

Example-5:

Preparation of racemic mixture of compound-7 and Compound-8

(2E)-4-Ethylhepta-2,6-dienoic acid (6) (14.5 g) obtained by the method described above was dissolved in N,N-dimethylacetamide (36.76 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (16.7 g) and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) (12.36 g) were added. The reaction mixture was warmed and stirred at 115 to 117° C. for 5 -6 hours. The reaction mixture was cooled to room temperature, and n-hexane (51 mL) and water (71.4 mL) were added thereto to separate an organic layer. The aqueous layer was subjected to two extractions with hexane (each with 25.5 mL), and all the organic layers were combined and then washed with a 5% aqueous sodium bicarbonate solution (10.2 mL) and water (10.2 mL) in this order. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled to provide the title compound (10g, oil substance)

Example-6:

Preparation of racemic mixture of compound-7 and Compound-8

(2E)-4-Ethylhepta-2,6-dienoic acid (6) (14.5 g) obtained by the method described above was dissolved in acetic anhydride (100 mL) under a nitrogen atmosphere. To the solution, potassium acetate (23.07 g) was added and stirred at room temperature. The reaction mixture was warmed and stirred at 110 to 120° C. The reaction mixture was cooled to room temperature and poured over ice water & extracted with n- hexane. The hexane layer was washed with IN aqueous NaOH, and saturated sodium chloride solution. The hexane layer was distilled under reduced pressure to provide the title compound (8g, oil substance).

Example-7:

Preparation of compound 7

To a stirred solution of 4-formyl benzoic acid (11 g) and triethyl amine (30 mL) was added a racemic mixture of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one (7+8 mixture) (10 g). The mixture was stirred at 40° C. The reaction mixture was allowed to cool to room temperature and added mixture of water (20 mL) & Con HC1 (23 mL). The combined mixture was fdtered and extracted with methyl tert-butyl ether (MTBE). The combined MTBE layer was washed with 5% sodium bicarbonate solution and distilled under reduced pressure to provide enantio-enriched (1R,5S)- 3 -ethylbicyclo [3.2.0]hept-3-en-6-one (7) (2.5 g,) as an oil.

Example-8:

Preparation of compound 7

To a stirred solution of 4-formyl benzoic acid (11 g) and triethyl amine (30 m ) was added a racemic mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one (7+8) (10 g), followed by (S)-3 -hydroxypyrrolidine HC1 (0.9 g). The mixture was stirred at 40° C. The reaction mixture was allowed to cool to room temperature and added mixture of water (20 m ) & Con HC1 (23 mb). The combined mixture was fdtered and extracted with methyl tert-butyl ether (MTBE). The combined MTBE layer was washed with 5% sodium bicarbonate solution and distilled under reduced pressure to provide enantio-enriched (lR,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (7) (2.5 g,) as an oil.

Example-9:

Preparation of compound 7

To a stirred solution of 4-formyl benzoic acid (1.1 Kg) and N,N- diisopropylethylamine (2L) was added a racemic mixture of 3- ethylbicyclo[3.2.0]hept-3-en-6-one (7+8) (l.OKg), followed by (R)-diphenyl methyl pyrrolidine. HC1 (0.21Kg). The mixture was stirred at 70-80° C. After completion of reaction N-Methyl-2- pyrrolidone (NMP), (3L) was added at room temperature. Add methyl tert-butyl ether (MTBE, 5L). Add solution of cone. HC1 (1.14 L) in water (10.26 L). Separate the MTBE layer and extract the acidic layer with MTBE. Wash the combined MTBE layer with aqueous sodium carbonate or bicarbonate solution and distilled under reduced pressure followed by fractional distillation under high vacuum to provide enantio-enriched (lR,5S)-3- ethylbicyclo[3.2.0]hept-3-en-6-one (7) (0.35Kg,) as an oil. The chiral purity is > 99% and chemical purity is >99%.

Claims

WE CLAIM:

1. A process for preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one of formula (7), comprising; a) reacting the racemic mixture of the compound of formula (7) and the compound of formula (8) with an aromatic aldehyde in presence of a base and optionally in presence of a chiral auxiliary compound of formula (9) to provide compound of formula (7); and

Aromatic aldehyde

Base

Optional Chiral auxiliary(9)

b) stir reaction mixture having compound of formula (7) at 70-80°C then treating this mixture with di-polar solvent to provide compound of formula (7) having chiral purity >99%.

2. The process as claimed in claim 1, wherein the aromatic aldehyde used in step (a) is selected from 4-formyl benzoic acid, 1,2-benzenedicarboxaldehyde, 1,3- benzenedicarboxaldehyde, 1,4-benzenedicarbox-aldehyde or 2- hydroxybenzene- 1,3,5 -tricarbaldehyde .

3. The process as claimed in claim 1, wherein the base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid selected from sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines selected from diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-diazabicyclo[4.3.0]non-5-ene (DBN).

4. The process as claimed in claim 1, wherein the dipolar solvent used in step (b) is selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N- methyl-2-pyrrolidinone (NMP), N-ethyl -2- pyrrolidone (NEP), Dimethylacetamide (DMAc or DMA), acetonitrile (CHsCN), acetone or tetrahydrofuran (THF).

5. The process as claimed in claim 1, wherein the chiral auxiliary used in step (a) is selected from (R)-2-(diphenylmethyl)pyrrolidine hydrochloride or (S)-3- hydroxypyrrolidine HC1.

6. A process for preparation of compound of formula (7), comprising; a) reacting the racemic mixture of the compound of formula (7) and the compound of formula (8) with 4-formyl benzoic acid in the presence of N,N-diisopropylethylamine and (R)-2-(diphenylmethyl)pyrrolidine hydrochloride (9) to provide reaction mixture having compound of formula (7) having chiral purity more than 99%; and b) stir reaction mixture having compound of formula (7) at 70-80°C then treating this mixture with N-Methyl -2- pyrrolidone (NMP) to provide compound of formula (7).

7. The process as claimed in claim 1, wherein the preparation of racemic mixture of compound of formula (7) and compound of formula (8), comprising; a) reacting butanal of formula (2) with allyl alcohol of formula (3) in a solvent and in presence of a catalyst to provide l,l-bis(allyloxy)butane of formula (4);

(2) (3) (4) b) heating l,l-bis(allyloxy)butane of formula (4) in presence of an acid anhydride and an acid in a solvent to provide 2-ethylpent-4-enal of formula (5);

(4) (5) c) heating 2-ethylpent-4-enal of formula (5) with malonic acid in a presence of base or a mixture of bases in a solvent to provide (2E)-4-Methylhepta- 2,6-dienoic acid of formula (6);

d) heating (2E)-4-Methylhepta-2,6-dienoic acid of formula (6) in a solvent and in presence of an acid anhydride and a base to provide racemic mixture of compound of formula (7) and the compound of formula (8); Solvent

8. The process as claimed in claim 7, wherein, in step (a) the solvent used in step (a), step (b) , step (c) and step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2- methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3- dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); 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; in step (a) the catalyst used is magnesium sulfate; in step (b) and step (d) the acid anhydride used in is selected from acetic anhydride, propionic anhydride, butanoic anhydride or succinic anhydride; in step (b) the acid used as a catalyst is carboxylic acid selected from maleic acid; in step (c) the base used is a mixture of morpholine and pyridine; and in step (d) the base is selected from triethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium acetate.

9. The process as claimed in claim 7, wherein, step (b) is performed at a temperature of 100 °C to 130 °C; step (c) is performed at a temperature of 70 °C to 80 °C; and step (d) is performed at a temperature of 100 °C to 120 °C.

10. A process for preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one of formula (7), comprising; a) reacting the racemic mixture of the compound of formula (7) and the compound of formula (8) with 4-formyl benzoic acid in presence of N,N- diisopropylethylamine and (R)-diphenyl methyl pyrrolidine. HC1 of formula (9) to provide compound of formula (7); and

Aromatic aldehyde

b) stir reaction mixture having compound of formula (7) at 70-80°C then treating this mixture with N-Methyl-2- pyrrolidone (NMP) to provide compound of formula (7) having chiral purity >99%.