RU2296116C2 - Method for preparing esters and derivatives of cyclopropyl carboxylic acid - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method for synthesis of some cyclopropyl carboxylic acid esters and other derivatives of cyclopropyl carboxylic acid of the general formula: (I):

. Also, invention relates to a novel method for synthesis of dimethylsulfoxonium methylide and dimethylsulfonium methylide, using some cyclopropyl carboxylic acid esters, to a method for synthesis of intermediate compounds that can be used in synthesis of pharmaceutically active compounds and some intermediate compounds synthesized by these methods.

EFFECT: improved method of synthesis.

15 cl, 13 ex

Description

FIELD OF THE INVENTION

The present invention relates to a new method for producing certain cyclopropylcarboxylic acid esters and other cyclopropylcarboxylic acid derivatives; a new method for producing dimethylsulfoxonium methylide and dimethylsulfonium methylide; the use of certain cyclopropylcarboxylic acid esters in a process for the preparation of intermediates that can be used in the synthesis of pharmaceutically active compounds, and for certain intermediates obtained by these methods. Said pharmaceutically active compounds may have useful pharmacological properties as, for example, cardiovascular preparations. Specifically, compounds that are antagonists of P ₂ T receptors and useful as antithrombotic agents can be prepared from these intermediates.

DESCRIPTION OF THE INVENTION

Thus, in a first aspect of the invention, there is provided a process for preparing a compound of formula (I):

wherein:

R represents phenyl substituted with one or more halogens;

Y represents OR ¹ , where R ¹ represents normal alkyl, branched alkyl, cycloalkyl or substituted bicycloheptyl (e.g., bornyl), which includes reacting a compound of formula (II):

where R and Y are as defined above, with dimethyl sulfoxonium methylide in the presence of a solvent.

In a convenient case, the solvent is a polar solvent, preferably dimethyl sulfoxide. Accordingly, the reaction is carried out at -10 ° C to 90 ° C, preferably at 25 ° C.

Dimethyl sulfoxonium methylide can be prepared by reacting the trimethyl sulfoxonium salt with a solid strong base, preferably in solid form, in dimethyl sulfoxide at room or elevated temperature. In a convenient case, the base is a metal hydroxide, for example NaOH, LiOH, or an alkali metal hydride, for example NaH. Preferably, the base is sodium hydroxide.

Preferably, trimethyl sulfoxonium iodide is mixed with powdered sodium hydroxide in dimethyl sulfoxide (in the absence of a phase transfer catalyst), optionally in a nitrogen atmosphere, at 20-25 ° C for 90 minutes. Alternatively, dimethyl sulfoxonium methylide can be prepared from a trimethyl sulfoxonium salt (preferably iodide or chloride) using sodium hydroxide in dimethyl sulfoxide with an interfacial catalyst, for example tetrabutyl n-ammonium bromide or with other strong bases such as alkali metal hydrides in dimethyl sulfoxide.

A compound of formula (II) can be prepared by reacting a compound of formula (III):

in which R is as defined above, with a suitable chlorinating agent in the presence of an inert solvent and an optional catalyst at a temperature of 0-200 ° C. Preferably, Y is OR ¹ , the chlorinating reagent is thionyl chloride, the inert solvent is toluene, and the catalyst is pyridine. In a convenient case, the reaction temperature is 70 ° C. Then, the obtained acid chloride reacts with YH or Y ^- (where Y ^- represents anionic particles of Y), Y has the meanings defined above, optionally at an elevated temperature such as 100 ° C.

The compound of formula (III) can be obtained using conventional chemical operations, for example by reacting a compound of formula (IV):

where R is as defined above, with malonic acid in the presence of pyridine and piperidine at an elevated temperature, preferably 50-90 ° C.

The compound of formula (I) can be hydrolyzed using basic hydrolysis to give a compound of formula (V):

where R has the meanings defined above. For example, ether groups are preferably removed by basic hydrolysis using an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxide in a solvent such as water, aqueous alcohol or aqueous tetrahydrofuran, at a temperature in the range of 10-100 ° C. Most preferably, the base is sodium hydroxide, the solvent is ethanol, and the reaction temperature is 50 ° C.

The compound of formula (V) can be used to obtain the compounds of formula (VI):

where R is as defined above, by reaction with thionyl chloride or another suitable chlorinating agent in the presence of toluene or another suitable solvent and, optionally, a catalyst, preferably pyridine, at 0-200 ° C. Preferably, the temperature is 65-70 ° C.

The compound of formula (VI) can be used in the synthesis of the compounds of formula (VII):

where R is as defined above, by reacting an alkali metal azide (preferably sodium azide) in the presence of an interfacial catalyst (preferably tetra-n-butylammonium bromide), an aqueous solution of potassium carbonate and an inert solvent (preferably toluene). Preferably, the reaction temperature is 0-10 ° C.

The compound of formula (VII) can be used in the synthesis of the compounds of formula (VIII):

where R has the meanings given above, by rearrangement in toluene at a temperature ranging from 0 ° C to 200 ° C, preferably at a reaction temperature of 90-100 ° C, after which the isocyanate intermediate reacts with hydrochloric acid at an elevated temperature, preferably 85 - 90 ° C.

Unprotonated starting amine (free base) of the formula (IX):

where R has the meanings given above, can be distinguished by adjusting the pH of an aqueous solution of a salt of a compound of formula (VIII) to 10 or higher. It can then be converted into other salts of organic acids or inorganic acids, preferably mandelic acid. A salt of R - (-) - mandelic acid and a compound of formula (IX) can be prepared by adding R - (-) - mandelic acid at room or elevated temperature to a solution of a compound of formula (IX) in a solvent, preferably ethyl acetate. Preferably, the temperature is 20 ° C.

R is conveniently phenyl optionally substituted with one or more halogen atoms. Preferably R is phenyl substituted with one or more fluorine atoms. More preferably, R is 4-fluorophenyl or 3,4-difluorophenyl.

Preferably, Y is D-menthoxy, or more preferably L-menthoxy.

The compounds of formulas (I) to (IX) can exist in various isomeric forms (such as cis / trans, enantiomers or diastereoisomers). The method according to this invention includes all such isomeric forms and mixtures thereof in all ratios.

Where Y is chiral, the compound of formula (I) will be a mixture of diastereoisomers and can be separated by crystallization or chromatographic methods to obtain a diastereoisomerically enriched compound of formula (Ia):

where R and Y are as defined above. Preferably, the crystallization is carried out in situ after synthesis of the compound of formula (I) described above by heating the crude reaction mixture until complete or almost complete dissolution is achieved, then cooling at an appropriate rate until a sufficient number of crystals of the desired quality are formed. Then the crystals are collected by filtration. Alternatively, the separation can be carried out in any other suitable solvent such as a hydrocarbon, for example heptane, by extracting the compound of formula (I) with an appropriate amount of solvent, heating the extracts until complete dissolution is achieved, then cooling at the appropriate speed until a sufficient number of crystals of the desired quality. Optionally, the organic extracts can be washed with water, dried over magnesium sulfate and filtered before crystallization is described above.

The compound of formula (Ia) can be hydrolyzed to give a compound of formula (Va):

where R has the meanings defined above, using the method described above for the hydrolysis of a compound of formula (I) to obtain a compound of formula (V).

The compound of formula (Va) can be used to obtain the compounds of formula (VIa):

where R has the meanings defined above, using the method described above for converting a compound of formula (V) to obtain a compound of formula (VI).

The compound of formula (VIa) can be used in the synthesis of the compounds of formula (VIIa):

where R has the meanings given above, using the method described above for converting a compound of formula (VI) to obtain a compound of formula (VII).

The compound of formula (VIIa) can be used in the synthesis of the compounds of formula (VIIIa):

where R has the meanings given above, using the method described above for converting a compound of formula (VII) to obtain a compound of formula (VIII).

The compound of formula (VIIIa) can be used in the synthesis of the compounds of formula (IXa):

where R has the meanings given above, using the method described above for converting a compound of formula (VIII) to obtain a compound of formula (IX).

A salt of R - (-) - mandelic acid and a compound of formula (IXa) can be obtained using the method described above to obtain a salt of mandelic acid and a compound of formula (IX).

New compounds form an additional aspect of the invention. Therefore, in an additional aspect of the invention, there are provided compounds of formulas (I), (Ia), (II), (III), (V), (Va), (VI), (VIa), (VII), (VIIa), ( VIII), (VIIIa), (IX) and (IXa) as defined above.

Particularly preferred compounds include:

((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate;

((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylate;

((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) - (E) -3- (3,4-difluorophenyl) -2-propenoate;

(E) -3- (3,4-difluorophenyl) -2-propenoic acid;

(E) -3- (3,4-difluorophenyl) -2-propenoyl chloride;

trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid;

trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride;

trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonylazide;

trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine;

and trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropanamine (2R) -2-hydroxy-2-phenylethanoate.

Examples

The invention is illustrated by the following non-limiting examples.

Example 1

This example shows the preparation of (E) -3- (3,4-difluorophenyl) -2-propenoic acid.

A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) was heated to 90 ° C. Malonic acid (17.6 kg) was added, followed by slow addition of 3,4-difluorobenzaldehyde (12.0 kg) over 50 minutes. The reaction mixture was stirred at 90 ° C for another 4 hours 36 minutes. Water (58.5 kg) was added and then 32 L of the pyridine / water mixture was evaporated from the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) for 40 min, then cooled to 25 ° C with vigorous stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 L per serving), once with water (61 L), and then the liquid was carefully removed by passing through a filter. Then the product was dried under vacuum at 40 ° C for 24 h 40 min to obtain 13.7 kg of crystalline product.

Example 2

An example shows the preparation of (E) -3- (3,4-difluorophenyl) -2-propenoyl chloride.

A stirred mixture of (E) -3- (3,4-difluorophenyl) -2-propenoic acid (8.2 kg), toluene (7.4 kg) and pyridine (0.18 kg) was heated at 65 ° C and then added thionyl chloride (7.4 kg) for 30 minutes The reaction mixture was stirred for another 2 hours 15 minutes after completion of the addition, then diluted with toluene (8.7 kg). An excess of thionyl chloride, sulfur dioxide and hydrogen chloride was then distilled off with toluene (10 L) under reduced pressure to obtain a solution of (E) -3- (3,4-difluorophenyl) -2-propenoyl chloride (about 9 kg) in toluene.

Example 3

This example shows the preparation of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl (E) -3- (3,4-difluorophenyl) -2-propenoate.

A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over 20 minutes to a solution of (E) -3- (3,4-difluorophenyl) -2-propenoyl chloride (obtained in Example 2) and pyridine (0.18 kg, 2.28 mmol), stirring at 65 ° C. The reaction mixture was stirred at 65 ° C for another 4 h 40 min after the addition was completed, then cooled to 25 ° C and stirred for 14 h. The solution was diluted with toluene (16 kg), washed with 5% aqueous sodium chloride (6.4 kg), then 6% sodium bicarbonate (6.47 kg), then water (6.1 kg). The solution was azeotropically dried by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure to obtain 47.3 kg of a solution of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl (E) -3- (3,4-difluorophenyl) -2-propenoate (approximately 13.3 kg) in dimethyl sulfoxide.

Example 4

This example shows a method for producing dimethylsulfoxonium methylide (dimethyl (methylene) oxo-λ ⁶ -sulfane).

Powdered sodium hydroxide (1.2 kg) obtained by grinding granules of sodium hydroxide in a rotary mill with a 1 mm metal sieve and trimethyl sulfoxonium iodide (6.2 kg) were stirred in dimethyl sulfoxide (25.2 kg) in a nitrogen atmosphere at 25 ° C in within 90 minutes The solution was directly used to prepare (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate.

Example 5

This example shows a method for producing dimethylsulfonium methylide (dimethyl (methylene) -λ ⁴ -sulfane).

Powdered sodium hydroxide (970 mg) obtained by grinding granules of sodium hydroxide in a rotary mill with a 1 mm metal sieve, and trimethylsulfonium iodide (4.66 g) were stirred in dimethyl sulfoxide (17 ml) under nitrogen at 20 - 25 ° C for 10 min The solution was directly used to prepare (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate.

Example 6

This example shows the preparation of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate.

A solution of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl (3,4-difluorophenyl) -2-propenoate (approximately 8.6 kg) in dimethyl sulfoxide (approximately 27.9 kg) was added with stirring over 20 minutes to a mixture of dimethyl sulfoxonium methylide (about 2.6 kg, obtained as described above), sodium iodide ((E-3) about 4.2 kg), water (about 500 g) and sodium hydroxide (about 56 g) in dimethyl sulfoxide ( 27.7 kg) at 25 ° C. The reaction mixture was stirred for another 2 h 50 min at 25 ° C, then directly used to obtain (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1R, 2R) -2- (3,4 difluorophenyl) cyclopropanecarboxylate.

Example 7

This example shows the preparation of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylate.

The crude solution of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate obtained as described in example 6 was heated with stirring from 25 ° C to 50 ° C for 1 h and the temperature was maintained for another hour. The mixture was then cooled with stirring from 50 ° C to 35 ° C for 4 hours, kept at 35 ° C for 1 hour, then cooled to 26 ° C for 4 hours, kept at 26 ° C for 1 hour, then cooled to 19 ° C for 3 h and kept at 19 ° C for 5 h 10 min. The product was crystallized and collected by filtration to obtain a crystalline solid (2.7 kg), which was shown to include a mixture of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1R, 2R) -2 - (3,4-difluorophenyl) cyclopropanecarboxylate (1.99 kg) and (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl trans- (1S, 2S) -2- (3,4-difluorophenyl) cyclopropanecarboxylate (85 g).

Example 8

This example shows an alternative method for the preparation of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylate.

n-Heptane (82.5 L) was distilled off under reduced pressure from a solution of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate (14.3 kg, 44 , 4 mol) in heptane (128.6 L). The mixture was then cooled from 34 ° C to 24 ° C for 3 hours 20 minutes. Then, seed crystals of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylate were introduced and the mixture was cooled to 0 ° C for 5 h 50 min Filtration gave the product as a crystalline, solvent-containing solid (7.05 kg), which was shown to contain a mixture of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1R, 2R) - 2- (3,4-difluorophenyl) cyclopropanecarboxylate (4.7 kg) and (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1S, 2S) -2- (3,4-difluorophenyl) cyclopropanecarboxylate (1.1 kg).

Example 9

This example shows a method for producing trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid.

(1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl-trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylate (9.6 kg, 91.8% excess diastereoisomer) was dissolved in ethanol (13.8 kg) and heated with stirring to 46 ° C. A 45% aqueous sodium hydroxide solution (3.1 kg) was added over 20 minutes and the mixture was stirred for another 2 hours 27 minutes. The solvent (28 L) was distilled off from the mixture under reduced pressure, then the mixture was cooled to 24 ° C and diluted with water (29.3 kg), after which the released menthol was extracted with toluene (3 portions of 3.3 kg each). The remaining aqueous substance was acidified to pH 2 with 37% hydrochloric acid (3.3 L) and the product was extracted with toluene (8.6 kg, 2 portions of 4.2 kg and 4.3 kg). The combined toluene extracts were washed with 1% hydrochloric acid (4.9 L), then diluted with more toluene (4.2 kg) and dried by azeotropic distillation of the solvent (25 L) under reduced pressure. After final dilution with toluene (24.2 kg), the solvent was distilled off under reduced pressure (10 L) to obtain a solution containing trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (about 3.45 kg) suitable for the preparation of trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride.

Example 10

This example shows a method for producing trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride.

Pyridine (70 ml) was added to a solution of trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (about 3.45 kg) in toluene (about 12-15 kg), prepared as described above, and then the mixture was heated to 65 ° C. Thionyl chloride (2.3 kg) was added over 1 hour and the mixture was stirred at 70 ° C. for 3 hours. Thionyl chloride (0.5 kg) was added and the mixture was stirred for another 2 hours at 70 ° C. A final portion of thionyl chloride (0.5 kg) was added and the reaction mixture was stirred for 1 h at 70 ° C, then cooled to 40 ° C. During the distillation of the solvent (approximately 60 L) from the mixture under reduced pressure, toluene (45 kg, 3 applications of 15 kg each) was added periodically, then a solution of trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride (about 3.8 kg) in toluene (about 6-9 l) were cooled to 20 ° C.

Example 11

This example shows a method for producing trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonylazide.

A solution of trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonyl chloride (about 3.8 kg) in toluene (about 6-9 L) at 1 ° C was added over a period of 74 minutes to a mixture of sodium azide (1 , 24 kg), tetrabutylammonium bromide (56 g) and sodium carbonate (922 g) in water (6.2 kg) with stirring at 1.5 ° C. The mixture was stirred at 0 ° C for 1 h 55 min, then the aqueous layer was diluted with cold water (3.8 kg), stirred quickly, then separated. The toluene layer was washed again at 0 ° C. with water (3.8 kg), then with a 20% aqueous solution of sodium chloride (3.8 L), then stored at 3 ° C. for further use.

Example 12

This example shows a method for producing trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine.

A cold solution of trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarbonylazide prepared as described in Example 11 was added over 41 minutes to toluene (6.0 kg) while stirring at 100 ° C. The mixture was stirred for another 55 minutes at 100 ° C, then cooled to 20 ° C and added over 2 hours 15 minutes to hydrochloric acid (3 M, 18.2 kg), stirring at 80 ° C. After 65 minutes, the solution was diluted with water (34 kg) and cooled to 25 ° C. The toluene layer was removed and the aqueous layer was basified to pH 12 with a 45% sodium hydroxide solution (3.8 kg), and then the product was extracted with ethyl acetate (31 kg) and washed twice with water (13.7 kg per serving) to obtain a solution containing trans- ( 1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (2.6 kg, 91.8% excess of ethanethiomer) in ethyl acetate (29.5 L).

Example 13

This example shows a process for the preparation of trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropanamine (2R) -2-hydroxy-2-phenylethanoate.

R - (-) mandelic acid (2.26 kg) was added to a solution containing trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (2.6 kg, more than 91.8% excess enantiomer) while stirring at 17 ° C in ethyl acetate (45.3 L). The mixture was stirred at 25 ° C for 3 hours 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg in total). The crystalline product was dried at 40 ° C. under reduced pressure for 23 hours to obtain trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropanamine (2R) -2-hydroxy-2-phenylethanoate (4.45 kg )

Claims (15)

1. The method of obtaining the compounds of formula (I)

wherein R represents phenyl substituted with one or more halogens; Y represents OR ¹ , where R ¹ represents linear alkyl, branched alkyl, cycloalkyl or substituted bicycloheptyl, which includes the interaction of the salt of trimethyl sulfoxonium with solid metal hydroxide in dimethyl sulfoxide at room or elevated temperature to obtain dimethyl sulfoxonium methylide; the interaction of the compounds of formula (II)

where R and Y are as defined above, with dimethyl sulfoxonium methylide in the presence of a solvent at a temperature in the range of 10-90 ° C. 2. The method of obtaining the compounds of formula (I)

wherein R represents phenyl substituted with one or more halogens; Y represents OR ¹ , where R ¹ represents linear alkyl, branched alkyl, cycloalkyl or substituted bicycloheptyl, which includes a) chlorination of the compounds of formula (III)

where R and Y have the meanings defined above, by reacting with a chlorinating reagent in the presence of an inert solvent and catalyst at a temperature in the range of 0-200 ° C, and then reacting the resulting solution with YH or Y ^- , where Y has the meanings given above, when elevated temperature to obtain a compound of formula (II)

where R and Y are as defined above; b) the interaction of the salt of trimethyl sulfoxonium with solid metal hydroxide in dimethyl sulfoxide at room or elevated temperature to obtain dimethyl sulfoxonium methylide; and C) the interaction of the compounds of formula (II) with dimethyl sulfoxonium methylide in the presence of a solvent at a temperature in the range of 10-90 ° C. 3. The method according to claim 1 or 2, in which the metal hydroxide is sodium hydroxide. 4. The method according to claim 1, in which the compound of formula (III) interacts with thionyl chloride in the presence of an inert solvent and pyridine at a temperature in the range of 0-200 ° C, then the resulting solution interacts with YH or Y ^- , where Y has the meanings defined in claim 1, at elevated temperature. 5. The method according to any one of the preceding paragraphs, in which YH is L-menthol. 6. The method according to any one of claims 1 to 5, in which the compound of formula (III) is obtained by reacting a compound of formula (IV)

where R has the meanings defined in claim 1, with malonic acid in the presence of pyridine and piperidine at elevated temperature. 7. The method according to any one of the preceding paragraphs, in which R represents phenyl substituted with one or more fluorine atoms. 8. The method according to claim 7, in which R is 3,4-difluorophenyl. 9. The method according to any one of the preceding paragraphs, in which Y is chiral. 10. The method according to claim 9, in which Y is L-menthoxy. 11. The method according to any one of claims 1 to 10, in which the compound of formula (I) is separated to obtain a compound of formula (Ia):

where R and Y are as defined in claim 1, by crystallization or chromatographic methods. 12. The method according to claim 11, in which the separation is carried out by extraction of the compounds of formula (I) with heptane and then crystallization from heptane extracts. 13. An intermediate compound which is (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans-2- (3,4-difluorophenyl) cyclopropanecarboxylate. 14. An intermediate compound which is (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-trans- (1R, 2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylate. 15. An intermediate compound which is (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl- (E) -3- (3,4-difluorophenyl) -2-propenoate.