RU2812607C1 - Method of preparing 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione, its racemic mixture and s-enantiomer - Google Patents

Abstract

FIELD: pharmacology and medicine.

SUBSTANCE: invention relates to a method of the synthesis of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione in the form of a racemate or its S-enantiomer, which can be used to make medicinal products for the treatment of motor neuron disease. The preparation method includes the following: (a) reacting 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the form of a racemic mixture or enantiomerically pure (S)-form with (carbethoxymethylene)triphenylphosphorane to obtain ethyl-5-(3,5- bis(trifluoromethyl)phenoxy)hex-3-enoate as, respectively, a racemic mixture or enantiomerically pure (S)-form and (b) reaction of the resulting ethyl 5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate with tert-butylacetoacetate and potassium tert-butoxide to obtain the target compound as a racemate or its enantiomerically pure (S)-form, according to the diagram:

EFFECT: provision of a production method with accelerated synthesis and increased yield of the target product.

9 cl, 1 dwg, 1 ex

Description

Field of technology

The invention relates to the field of organic chemistry, pharmacology and medicine and concerns a new method for the synthesis of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione and its S-enantiomer, which can be used for the manufacture of drugs for the treatment of motor neuron disease.

State of the art

Motor neuron disease (MND) is a group of degenerative diseases of the central nervous system that damage both upper (motor cortex) and lower (anterior horn of the spinal cord and cranial nerve nuclei) motor neurons. The death of cells in the nervous system leads to paralysis and subsequent muscle atrophy. The forms of the disease (amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy) differ in the rate of progression and different types of damage to motor neurons.

It is known that the destruction of motor neurons in MND can be caused by improper coagulation of the mSOD1 protein and the accumulation of pathological TDP-43 protein in nerve tissues. This accumulation of proteins prevents neurons from working; transport nutrients into them, damages mitochondria, disrupts protein synthesis. As a result of this process, neurons are destroyed and do not transmit information to the muscles, which leads to their paralysis and atrophy.

A study of the biological activity of 5-(1-(3,5-bis(trifluoromethyl)phenoxy) ethyl)cyclohexane-1,3-dione, developed by researchers from the USA (WO2011059821A2, [1]), showed its ability to reduce the toxicity of mSOD1 and restore mitochondria and the endoplasmic reticulum of neuronal cells, where protein synthesis and transport occurs, ultimately improving the functioning of motor neurons. Studies have shown that 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione is able to reverse neuronal degeneration and is superior to existing drugs approved for the treatment of MND (Genç B. et al. Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology // Clin Transl Med. 2021 Feb;11(2):e336. doi: 10.1002/ctm2.336, [ 2]).

According to [1] (Schemes 4 and 5), when preparing the compound 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione at the first stage from 3,5-bis(trifluoromethyl )phenol under the influence of an alkylating agent produces the corresponding ethyl ester, which is then reduced in the presence of a suitable reducing agent (eg, a metal hydride such as LiAIH ₄ ) to the corresponding alcohol. Its further acylation and saponification followed by oxidation provides the final product.

The article by Zhang Y. et al. Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS // ACS medicinal chemistry letters. - 2012. T.3. No. 7 pp 584-587 ([3]) the authors of the invention [1] proposed an alternative method for the synthesis of chiral cyclohexane-1,3-diones, including 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl) cyclohexane-1,3-dione, which is the closest analogue of the present invention. The starting components for the synthesis were ethyl lactate and 3,5-ditrifluoromethyl phenol, from which the ester was obtained by the Mitsunobu reaction. The aldehyde, enone, and final dione were subsequently obtained through conjugated Michael addition. This solution has some disadvantages, namely: low yield of the final product (53%) and long duration of certain stages of synthesis.

Disclosure of the Invention

The objective of the invention is to develop a method for the production of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione and its S-enantiomer, which ensures accelerated production and increased yield of the target product.

The problem is solved by developing a method for producing 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione, having the structural formula

its ramemic mixture or enantiomerically pure (S)-form, including the following steps:

(a) reacting 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the form of a racemic mixture or enantiomerically pure (S)-form with (carbethoxymethylene)triphenylphosphorane to give ethyl 5-(3,5-bis(trifluoromethyl) phenoxy)hex-3-enoate in the form of a racemic mixture or enantiomerically pure (S)-form, respectively;

(b) reacting the resulting ethyl 5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate with tert-butylacetoacetate and potassium tert-butoxide to obtain the target compound in the form of, respectively, the racemate or its enantiomerically pure (S )-forms,

according to the diagram:

.

In some embodiments of the invention, to obtain the enantiomerically pure (S)-form of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione, it is isolated from the resulting racemate 5-(1-( 3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione.

In particular embodiments of the invention, the isolation of the enantiomerically pure (S)-form of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione is carried out by chiral high-performance liquid chromatography (HPLC) using the racemate conversion method into a mixture of diastereomers or by kinetic resolution. In preferred embodiments, isolation of the enantiomerically pure (S)-form is accomplished by chiral HPLC.

In preferred embodiments of the invention, the reactions in steps (a) and (b) are carried out in a polar aprotic solvent.

In some embodiments, the racemic or enantiomerically pure (S)-form 2-(3,5-bis(trifluoromethyl)phenoxy)propanal used in step (a) is prepared by

reaction in the first (1) stage of 3,5-bis(trifluoromethyl)phenol with ethyl lactate in the form of a racemic mixture or enantiomerically pure (S)-form to obtain ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate by the reaction Mitsunobu in the form, respectively, of a racemic mixture or enantiomerically pure (S)-form;

carrying out at the second (2) stage of the reaction the reduction of the resulting ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate to obtain 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the form, respectively, of a racemic mixture or enantiomerically pure (S)-form,

according to the diagram:

.

In preferred embodiments of the invention, in step (1), the reaction of 3,5-bis(trifluoromethyl)phenol with ethyl lactate is carried out in the presence of triphenylphosphine in a polar aprotic solvent.

In preferred embodiments of the invention, in step (2), the reduction reaction is carried out in a polar aprotic solvent, and diisobutylaluminum hydride is used as the reducing agent.

In particular embodiments of the invention, the polar aprotic solvent is independently selected and is tetrahydrofuran, 1,4-dioxane or dimethyl sulfoxide.

In particular embodiments of the invention, the purification of the intermediate and target product at each of stages (a), (b) and (1) is carried out using flash chromatography.

As a result of the invention, the following technical results are achieved:

• a new method has been developed for the preparation of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione and its S-enantiomer, a compound potentially highly effective for the treatment of motor neuron disease, including amyotrophic lateral sclerosis, - by changing the synthesis path of raw material-ether-aldehyde-ketone-product to raw material-ether-aldehyde-ether-product;

• the developed method ensures an increase in the yield of the target product to more than 80%;

• the developed method provides a significant acceleration of the synthesis of the target compound.

Brief description of the drawings

Figure 1 NMR spectrum of the synthesized compound ((S)-(5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione).

Terms and Definitions

Unless otherwise specified, all technical and scientific terms used in this application have the same meaning as understood by those skilled in the art. References to techniques used in the description of this invention refer to well known techniques, including modifications of these techniques and replacement thereof with equivalent techniques known to those skilled in the art.

As used herein, the terms “includes,” “including,” and the like, as well as “comprises,” “comprising,” and the like are used herein. are interpreted to mean “includes, but is not limited to” (or “contains, among other things”). These terms are not intended to be construed as “consisting only of.”

The term “and/or” means one, more, or all of the above.

The term "optional" or "optional" or "optional" or "optional" as used herein means that the event or circumstance subsequently described may, but is not required to, occur and that the description includes instances in which the event or circumstance occurs and cases in which it does not occur.

The term "enantiomerically pure" means compounds having an enantiomeric excess of at least 95% (i.e., a minimum of 95% of one enantiomer and a maximum of 5% of the other enantiomer) to an enantiomeric excess of 100% (i.e., 100% of one enantiomer and zero of the other) in particular, compounds having an enantiomeric excess of 96 to 100% and especially an enantiomeric excess of 98 to 100%. Enantiomerically pure forms of compounds can be readily prepared from enantiomerically pure isomeric forms of starting materials, provided that subsequent reactions proceed stereospecifically; or can be obtained by resolution of the racemate.

The term "enantiomerically pure (S)-form" means an excess of the (S)-form of the enantiomer (S-enantiomer).

The terms “racemic mixture” and “racemate”, “(±)” - denote an equimolar mixture of two enantiomeric molecules that does not have optical activity.

Unless otherwise defined, technical and scientific terms in this application have their standard meanings commonly accepted in the scientific and technical literature.

Detailed Description of the Invention

The compound (±)-5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione, and to a greater extent its S-enantiomer, i.e. (S)-5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione

is aimed at treating motor neuron diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy. The ability to cross the blood-brain barrier, low toxicity and high efficiency in stopping the degradation of motor neurons are strong prerequisites for the promising use of this compound in medicine and use for the manufacture of drugs for the treatment of motor neuron disease.

The present invention is aimed at developing a new method for the preparation of (±)-5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione and its S-enantiomer.

The proposed method includes the following stages:

(a) reacting 2-(3,5-bis(trifluoromethyl)phenoxy)propanal with (carbethoxymethylene)triphenylphosphorane to produce ethyl 5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate;

(b) reacting the resulting ethyl 5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate with tert-butylacetoacetate and potassium tert-butoxide to obtain the target compound.

The synthesis of the enantiomerically pure (S)-form is carried out using 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the enantiomerically pure (S)-form as the starting component in step (a), all further reactions proceed stereospecifically .

The starting compound 2-(3,5-bis(trifluoromethyl)phenoxy)propanal can be prepared by any known methods. In some preferred embodiments of the invention, 2-(3,5-bis(trifluoromethyl)phenoxy)propanal can be prepared according to the method described in document [3], as follows:

(1) reacting 3,5-bis(trifluoromethyl)phenol with ethyl lactate to produce ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate via the Mitsunobu reaction;

(2) reducing the resulting ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate to produce 2-(3,5-bis(trifluoromethyl)phenoxy)propanal.

The synthesis of the enantiomerically pure (S)-form is carried out using ethyl lactate in the enantiomerically pure (S)-form as the starting component in step (1), all further reactions proceed stereospecifically.

Thus, in preferred embodiments, the proposed method includes the following steps:

1. reaction of 3,5-bis(trifluoromethyl)phenol with ethyl lactate to obtain ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate via the Mitsunobu reaction;

2. reduction reaction of the resulting ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate to obtain 2-(3,5-bis(trifluoromethyl)phenoxy)propanal;

3. reaction of 2-(3,5-bis(trifluoromethyl)phenoxy)propanal with (carbethoxymethylene)triphenylphosphorane to produce ethyl 5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate;

4. reacting (±)-ethyl-5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate with tert-butylacetoacetate and potassium tert-butoxide in tetrahydrofuran as a solvent to obtain the target compound.

As shown in the diagram below:

The synthesis of the enantiomerically pure (S)-form is carried out using ethyl lactate in the enantiomerically pure (S)-form as a starting component in the first stage, all further reactions proceed stereospecifically.

When compounds in the form of a racemic mixture are used as starting components, the synthesis is not stereospecific. As a result of this synthesis, the racemate of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione is obtained. Although the racemate has the necessary properties for its use in the treatment of MND, as shown by studies (see, for example, WO2023056307A1), the S-enantiomer is more promising for use in medicine. The S-enantiomer can be isolated from the resulting racemate by any means well known to those skilled in the art (eg, chiral HPLC, conversion of the racemate to a mixture of diastereomers, kinetic resolution, etc.).

Thus, the present invention makes it possible to simplify and improve the existing procedure for the synthesis of the racemate 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione and obtaining its enantiomerically pure (S)-form.

The main differences between the method according to the invention and the known technique described in [3] are as follows:

• According to the procedure described in [3], the synthesis route is raw material-ether-aldehyde-ketone-product. In the process of the invention, the third step (aldehyde-ketone) was changed to an aldehyde-ester step. The result was an ester ((±)-ethyl-5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate) instead of a ketone. This is achieved by replacing 1-triphenylphosphoranylidene-2-propanone with (carbethoxymethylene)triphenylphosphorane, which is due to the need to obtain an ether for the subsequent stage.

• The fourth stage (ketone-product) was changed in the process of the invention to an ether-product stage. To do this, in the fourth stage, instead of diethyl malonate, sodium ethoxide and ethanol, tert-butylacetoacetate, tetrahydrofuran and potassium tert-butoxide were used. This made it possible to reduce the duration of the stage from 12 hours to 1 hour. At the same time, the yield of the finished product was 83% instead of 53% according to the known method.

The proposed method for preparing 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione is described in more detail below in the examples section. It should be understood that the listed methods and techniques are not exhaustive and allow for the introduction of reasonable modifications. These reactions must be carried out using suitable solvents and materials. It should also be understood that the examples given in the application materials are not limiting and are provided only to illustrate the present invention.

Example 1. Preparation of enantiomerically pure (S)-form of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione.

Stage 1.

Preparation of ester - (S)-ethyl-2-(3,5-bis(trifluoromethyl)phenoxy)propionate, M=330 g/mol (Mitsunobu reaction).

118 g (0.45 mol) of triphenylphosphine are loaded into a jacketed glass reactor in 750 ml of a polar aprotic solvent (tetrahydrofuran (THF)), 92 g (0.4 mol) of the original 3,5-bis(trifluoromethyl)phenol are added successively with stirring and 48 g (0.4 mol) of starting (S)-ethyl lactate.

The mixture is then cooled to 0°C (using a cryostat) and 70 ml of diethyl azodicarboxylate (DEAD) is added dropwise at a dosing rate of 2 drops/sec.

Reaction medium 24 hours at +20°C in an inert atmosphere (argon).

The solvent is then distilled off from the reaction system using a rotary evaporator (60 rpm, full vacuum, bath temperature +50°C) until a dry solid precipitate is obtained.

Next, add 200 ml of diethyl ether (+4°C) and stir vigorously, the resulting precipitate is filtered using a Schott funnel fixed in a 1000 ml Bunsen flask. The remaining solution is evaporated by 50% in a rotary evaporator and placed in the refrigerator at -20°C for 1 hour. The resulting precipitate is filtered again under the same conditions. The procedure is repeated (3-4 times) until a homogeneous solution without sediment is obtained.

The resulting homogeneous solution is evaporated using a rotary evaporator until the solvent is completely distilled off.

Next, flash chromatography is performed. Silica gel for chromatography (0.060-0.200 mm, 60 A) in hexane is wet applied to a Schott funnel fixed in a Bunsen flask. The resulting ether is dissolved in hexane in a ratio of 1:2 and applied on top of the filter through a layer of glass wool. Wait until the solvent passes through the filter into the Bunsen flask.

Next, flash chromatography is carried out using hexane-ethyl acetate as an eluent in a ratio of 10:1. Fractions with a volume of 100 ml each are selected. Each fraction is analyzed using thin layer chromatography (hereinafter referred to as TLC) on Sorbifil PTSH-AF-A plates in the hexane:ethyl acetate system - 5:1. Collect fractions until the product spot is no longer visible on thin layer chromatography.

The resulting fractions are combined and co-evaporated using a rotary evaporator. Yield: 126 g (95%)

Stage 2.

Preparation of aldehyde - (S)-2-(3,5-bis(trifluoromethyl)phenoxy)propanal, M=286 g/mol.

A solution of 126 g of the ether obtained in the first stage in 450 ml of a polar aprotic solvent (THF) is loaded into a jacketed glass reactor. The solution is cooled to minus -78°C and a solution of 51.5 ml of diisobutylaluminum hydride (DIBAL) in 120 ml of a polar aprotic solvent (THF) is added dropwise with constant stirring over 2 hours. The solution is stirred for an additional 60 minutes while strictly maintaining the temperature at -78°C.

Sample preparation for thin layer chromatography (TLC) on Sorbifil PTSH-AF-A plates in the hexane:ethyl acetate system - 5:1. To do this, take 0.75 ml of the reaction mixture into an Eppendorf, add 2 drops of diisopropylethylamine (hereinafter referred to as DIPEA), 0.75 ml of distilled water and shake. The upper (aqueous) phase is selected with a Pasteur pipette for TLC on Sorbifil PTSH-AF-A plates in the hexane:ethyl acetate system - 5:1. Based on the TLC result, it is judged that the characteristic alcohol spot has disappeared; otherwise, the reaction mixture is stirred further and TLC is repeated.

Next, the reaction mixture is allowed to warm up to 0°C, then washed twice in portions in a separating funnel with a 1M HCl solution (400 ml) cooled to +5-8°C, and the organic phase is collected. The collected organic phase is washed with a saturated NaCl solution until the pH of the aqueous phase is no more than 6.

The organic phase is dried in a desiccator over anhydrous magnesium sulfate for 12 hours. Next, the solvent is distilled off in a rotary evaporator to obtain the desired aldehyde. The liquid is then removed and allowed to cool to room temperature, whereby crystallization occurs into a dry product. Yield: 122 g (97%).

Stage 3.

Preparation of the ester - (S)-ethyl-5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate. M=356 g/mol.

122 g of the aldehyde obtained at stage 3 are loaded into a glass reactor in 150 ml of a polar aprotic solvent (dry THF), and 165 g of (carbethoxymethylene)triphenylphosphorane (C ₂₂ H ₂₁ O ₂ P) are added. The mixture is stirred at +20°C for 12 hours. The reaction progress is monitored by TLC (the reaction mass is compared with the starting aldehyde) on Sorbifil PTSH-AF-A plates in the hexane:ethyl acetate system - 5:1.

The solvent is then completely evaporated using a rotary evaporator and 500 ml of cold diethyl ether is added to allow a precipitate to form. The precipitate is filtered using a Schott filter and a Bunsen flask.

Next, flash chromatography is performed. Silica gel for chromatography (0.060-0.200 mm, 60 A) in hexane is wet applied to a fine-porous Schott filter, fixed in a Bunsen flask, so that the height of the silica gel layer is 8 cm. 8 g of the product, dissolved, is applied on top of the filter on a layer of glass wool in hexane in a ratio of 1:2.

Chromatography of the resulting solution is carried out using the eluent hexane: ethyl acetate = 10:1 with a volume of 1000 ml; by-products come out - the top spot (control by TLC on Sorbifil PTSH-AF-A plates in the hexane: ethyl acetate system - 5: 1), then apply eluent hexane:ethyl acetate 7:1 with a volume of 3000 ml and the product is isolated (control by TLC on Sorbifil PTSH-AF-A plates in the system hexane:ethyl acetate = 5:1). The resulting fraction is evaporated using a rotary evaporator. Yield: 110 g (90%).

Stage 4.

Preparation of diketone - (S)-5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione. M=368 g/mol.

A jacketed glass reactor was charged with 67.2 g (0.6 mol, 2 eq.) of tert-butyl acetoacetate in 450 ml of a polar aprotic solvent (THF). The suspension is cooled to 0°C and 65 g (0.3 mol, 1 eq.) of potassium tert-butoxide are added slowly. The suspension is vigorously stirred for 30 minutes at 0°C. Then add 110 g (0.3 mol) of the starting compound (ether obtained at stage 3) and stir for 20 minutes at room temperature (TLC control on Sorbifil PTSH-AF-A plates, eluent - methylene chloride). Afterwards, 200 ml of distilled water and 18% hydrochloric acid solution are added to the reaction mixture while cooling (0°C) until pH = 4.

The above-described stage 4 of the method according to the invention takes 1 hour, while in the analogue the reaction time at stage 4 (ketone product) was 12 hours, with a product yield of 53%.

The mixture is extracted with ethyl acetate (3×200 ml), then dried in a desiccator over anhydrous magnesium sulfate for 12 hours.

The solvent is distilled off in a rotary evaporator.

The resulting intermediate is diluted with a 2N sodium hydroxide solution (5 equiv.) and heated in a 1000 ml flask to +40°C. The mixture is stirred on a magnetic stirrer for 4 hours at a temperature of +40 °C, then a concentrated solution of 1N hydrochloric acid is added dropwise to pH = 1 and heated to 90 °C. The mixture is stirred for 2 hours at 90°C, then cooled to a temperature of +20°C, diluted with 1000 ml of ethyl acetate and extracted portionwise in a separating funnel. Collect the organic layer from the funnel and dry it in a desiccator over anhydrous magnesium sulfate for 12 hours.

The solvent is distilled off in a rotary evaporator.

In flash chromatography, a solution of the product in methylene chloride (1:10) is applied. The product is eluted with a solvent mixture of methylene chloride: methanol in a ratio of 200:1, volume 1000 ml, then 100:1 - 1000 ml and 50:1 - 1000 ml. From the last fraction, a substance is isolated that is enriched with the target product with a purity of 99%. The purity of the product was confirmed by HPLC-TOFMS (m/z = 369.09275 [M+H] ⁺ ; m/z = 391.07476 [M+Na] ⁺ ) and NMR (see Fig. .1). The substance studied was represented by the S-isomer with a purity of 107.4%. The amount of impurity was less than 1%, and the impurity was not an R-isomer. The mass-charge ratio for the impurity was estimated to be 378.0649. Yield: 91 g (83%).

Although the invention has been described with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments detailed are provided for purposes of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be understood that various modifications can be made without departing from the spirit of the present invention.

Claims (19)

1. Method for preparing 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione of the formula in the form of its racemate or enantiomerically pure (S)-form, including the following steps: (a) reacting 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the form of a racemic mixture or enantiomerically pure (S)-form with (carbethoxymethylene)triphenylphosphorane to give ethyl 5-(3,5-bis(trifluoromethyl) phenoxy)hex-3-enoate in the form of a racemic mixture or enantiomerically pure (S)-form, respectively; (b) reacting the resulting ethyl 5-(3,5-bis(trifluoromethyl)phenoxy)hex-3-enoate with tert-butylacetoacetate and potassium tert-butoxide to obtain the target compound in the form of, respectively, the racemate or its enantiomerically pure (S )-forms, according to the diagram: 2. The method according to claim 1, in which to obtain the enantiomerically pure (S)-form of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione, it is isolated from the resulting racemate 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione. 3. The method according to claim 2, in which the isolation of the enantiomerically pure (S)-form of 5-(1-(3,5-bis(trifluoromethyl)phenoxy)ethyl)cyclohexane-1,3-dione is carried out by the chiral HPLC method, by the conversion method racemate into a mixture of diastereomers or by kinetic resolution. 4. The method according to claim 1, in which the reactions in stages (a) and (b) are carried out in a polar aprotic solvent. 5. The method according to claim 1, in which 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the form of a racemic mixture or enantiomerically pure (S)-form is obtained by reaction in the first (1) stage of 3,5-bis(trifluoromethyl)phenol with ethyl lactate in the form of a racemic mixture or enantiomerically pure (S)-form to obtain ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate by the reaction Mitsunobu in the form, respectively, of a racemic mixture or enantiomerically pure (S)-form; carrying out at the second (2) stage of the reaction the reduction of the resulting ethyl 2-(3,5-bis(trifluoromethyl)phenoxy)propionate to obtain 2-(3,5-bis(trifluoromethyl)phenoxy)propanal in the form, respectively, of a racemic mixture or enantiomerically pure (S)-form, according to the diagram: 6. The method according to claim 5, in which in step (1) the reaction of 3,5-bis(trifluoromethyl)phenol with ethyl lactate is carried out in the presence of triphenylphosphine in a polar aprotic solvent. 7. The method according to claim 5, in which in step (2) the reduction reaction is carried out in a polar aprotic solvent, and diisobutylaluminum hydride is used as a reducing agent. 8. The method according to any one of claims 4, 6 or 7, wherein the polar aprotic solvent is independently selected and is tetrahydrofuran, 1,4-dioxane or dimethyl sulfoxide. 9. The method according to any one of claims 1 to 7, in which the purification of the intermediate and target product at each of stages (a), (b) and (1) is carried out using flash chromatography.