A method for the resolution of stereoisomers of 4-(trifluoromethyl)cyclohexan-1-ol

Abstract

This invention discloses a method for resolving the stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol, comprising first dissolving a mixture of stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol and an acyl donor in an organic solvent, and then reacting in the presence of Candida antarcticis lipase B to obtain trans-4-(trifluoromethyl)cyclohexane-1-ol and a cis-esterified product. This invention achieves the resolution of trans-4-(trifluoromethyl)cyclohexol from a mixture of 4-(trifluoromethyl)cyclohexol stereoisomers, and further obtains the cis-esterified product. The Candida antarcticis lipase B used in this invention is a more environmentally friendly biological enzyme with high product yield and mild reaction conditions. When used in immobilized form, Candida antarcticis lipase B is also easy to recover and reuse, which helps reduce production costs and has high production utilization value.

Description

Technical Field

[0001] This invention relates to the field of stereoisomer resolution technology, and particularly to a method for resolving the stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol. Background Technology

[0002] Due to the unique properties of the trifluoromethyl and cyclohexanol groups, 4-(trifluoromethyl)cyclohexanol has significant applications as an intermediate in medicinal chemistry, materials science, and fine chemicals. Trifluoromethyl (CF3) is a strong electron-withdrawing group that can significantly alter the chemical properties of molecules, improving compound stability and hydrophobicity, and is frequently used in drug design and development. Cyclohexanol can participate in various chemical reactions, such as redox reactions and esterification reactions, providing a structural basis for the synthesis of complex molecules. Cis-trans isomerism can significantly affect the physicochemical properties of compounds. In biological systems, one isomer may be physiologically active, while another may be inactive or have different activities. Cis-trans isomers may also differ in reactivity due to their different spatial configurations. For example, patent WO2021 / 97110AO reports the synthesis of a target compound using trans-4-(trifluoromethyl)cyclohexane-1-ol as an intermediate, which has potential significance for treating diseases or conditions mediated by TEAD activity in mammals. John PA Harrity et al. reported that cis-4-(trifluoromethyl)cyclohexane-1-ol can be used as a GPCR ligand side chain to improve affinity and selectivity. Therefore, obtaining high-purity 4-(trifluoromethyl)cyclohexanol isomers is of great significance and has enormous potential.

[0003] The preparation of 4-(trifluoromethyl)cyclohexanol is mainly achieved through catalytic hydrogenation. Patent US05209868A reports the preparation of a mixture of 4-(trifluoromethyl)cyclohexanol isomers via rhodium-carbon catalytic reduction of 4-trifluoromethylphenol, with a cis / trans ratio of 30% / 70%. Patent US20090256137A1_0092 reports the preparation of a mixture of 4-(trifluoromethyl)cyclohexanol isomers via rhodium-alumina catalytic reduction of 4-trifluoromethylphenol; patent CN110330400A reports the preparation of a mixture of 4-(trifluoromethyl)cyclohexanol isomers via carbene rhodium complex catalyst catalytic reduction of 4-trifluoromethylphenol, with a cis / trans ratio of 75% / 25%. Although one isomer dominates in the catalytic reduction process, the purity of these isomers still cannot meet the requirements of actual production. However, there is very little research on the separation of 4-(trifluoromethyl)cyclohexanol isomers, and there is an urgent need for a green and efficient separation method. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for resolving the stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol, which can separate trans-4-(trifluoromethyl)cyclohexane-1-ol and cis-I compound from a mixture.

[0005] To solve the above-mentioned technical problems, the present invention provides a method for resolving the stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol, comprising the following steps: S1. Dissolve the stereoisomer mixture of 4-(trifluoromethyl)cyclohexane-1-ol and the acyl donor in an organic solvent; S2. Add Candida antarctica lipase B to the system of step S1. After the reaction, trans-4-(trifluoromethyl)cyclohexane-1-ol and cis-I compound are obtained: , In Formula 1, R is selected from C1-C6 straight-chain or branched alkanes.

[0006] In this invention, cis-4-(trifluoromethyl)cyclohexane-1-ol reacts with an acyl donor under the catalysis of *Candida antarcticus* lipase B to generate a lipid compound of formula I. This compound is a cis-ester compound, while trans-4-(trifluoromethyl)cyclohexane-1-ol hardly reacts. This achieves the resolution of the stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol, yielding trans-4-(trifluoromethyl)cyclohexane-1-ol, and simultaneously obtaining the cis-form I compound. *Candida antarcticus* lipase B in this invention is a biological enzyme that enables the kinetic resolution of 4-(trifluoromethyl)cyclohexane-1-ol, making it more environmentally friendly, with high product yield and mild reaction conditions. When *Candida antarcticus* lipase B is used in a supported form, it is easy to recover and reuse, which helps reduce production costs and has high production utilization value. It should be noted that, as needed, the compound of formula I can also be converted into trans-4-(trifluoromethyl)cyclohexane-1-ol, which can be achieved using existing technologies and will not be elaborated further.

[0007] In one specific embodiment, in S1, the acyl donor includes vinyl acetate, vinyl butyrate, and di-tert-butyl dicarbonate. Understandably, the acyl donor in this invention refers to a compound that can react with cis-4-(trifluoromethyl)cyclohexane-1-ol to generate an acyl group. For example, when the acyl donor is vinyl acetate, the R group in the compound of Formula I is methyl; when the acyl donor is vinyl butyrate, the R group is n-butyl; when the acyl donor is di-tert-butyl dicarbonate, the R group is tert-butyl, and so on. Therefore, in Formula I, R is selected from C1-C6 straight-chain or branched alkanes.

[0008] In one specific embodiment, in S1, the organic solvent includes acetonitrile, benzene solvents, ester solvents, ketone solvents, and ether solvents. Understandably, benzene solvents include, for example, toluene; ester solvents include, for example, ethyl acetate; ketone solvents include, for example, acetone and tetrahydrofuran; and ether solvents include, for example, diethyl ether.

[0009] In one specific embodiment, in step S1, the concentration of the stereoisomer mixture of 4-(trifluoromethyl)cyclohexane-1-ol is 1-50 mg / mL. Preferably, the molar ratio of the acyl donor to the stereoisomer mixture of 4-(trifluoromethyl)cyclohexane-1-ol is 0.5-10:1. The mass ratio of *Candida antarcticis* lipase B to the stereoisomer mixture of 4-(trifluoromethyl)cyclohexane-1-ol is 0.1-10:1. In step S2, the reaction temperature is 20℃-70℃, and the reaction time is not less than 10 h.

[0010] In one specific embodiment, S2 also includes filtering the system after the reaction is complete, concentrating the filtrate to separate the organic phase, and obtaining trans-4-(trifluoromethyl)cyclohexane-1-ol and cis-I compound.

[0011] This invention utilizes *Candida antarcticis* lipase B to convert cis-4-(trifluoromethyl)cyclohexanol in the stereoisomer of 4-(trifluoromethyl)cyclohexanol into a cis-esterified product, thereby achieving the resolution of trans-4-(trifluoromethyl)cyclohexanol in a mixture of 4-(trifluoromethyl)cyclohexanol stereoisomers, and further obtaining the cis-esterified product. The *Candida antarcticis* lipase B in this invention is a more environmentally friendly biological enzyme with high product yield and mild reaction conditions. When used in immobilized form, *Candida antarcticis* lipase B is easy to recover and reuse, which helps reduce production costs and has high production utilization value. Attached Figure Description

[0012] To more clearly illustrate the technical solution of the present invention, the accompanying drawings used in the present invention will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0013] Figure 1 This is the GC spectrum of the reaction system after 110 h of reaction in Example 1; Figure 2 This is the GC spectrum of trans-4-(trifluoromethyl)cyclohexanol, the product in Example 2; Figure 3 This is the GC spectrum of cis-4-(trifluoromethyl)cyclohexyl acetate, the product of Example 2. Detailed Implementation

[0014] The technical solutions of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention. Example 1

[0015] 20 mg of a mixture of 4-(trifluoromethyl)cyclohexanol isomers and 30 mg of vinyl acetate were dissolved in 1 mL of acetone. 5 mg of immobilized *Candida antarcticis* lipase B was added to the mixture. The reaction was carried out at 35 °C for 110 h. The reaction system was then filtered, and the filtrate was concentrated to obtain 4-(trifluoromethyl)cyclohexanol with a trans / cis ratio of 87% / 13%. The resulting cis-esterified product (4-(trifluoromethyl)cyclohexyl acetate) had a trans / cis ratio of 3% / 97%. The gas chromatogram (GC spectrum) of the system after the 110-h reaction is shown below. Figure 1 As shown. Example 2

[0016] A mixture of 1.96 g of 4-(trifluoromethyl)cyclohexanol isomers and 3.01 g of vinyl acetate were dissolved in 50 mL of acetone. 0.50 g of immobilized Candida antarctica lipase B was added to the mixture. The reaction was carried out at 35 °C for 18 h. The filtrate was concentrated, and the starting material and product were separated by medium-pressure liquid chromatography to obtain 1.11 g of 4-(trifluoromethyl)cyclohexanol with a trans-to-cis ratio of 99% / 1% and a yield of 80% (i.e., (1.11*0.99) / (1.96*0.7)). The GC chromatogram of trans-4-(trifluoromethyl)cyclohexanol is shown below. Figure 2 As shown; the obtained esterified product (4-(trifluoromethyl)cyclohexyl acetate) has a trans / cis ratio of 2% / 98%, and the GC spectrum of cis-4-(trifluoromethyl)cyclohexyl acetate is shown below. Figure 3 As shown.

[0017] In both embodiments of the present invention, the GC test conditions were as follows: flow rate of 1.5 mL / min, initial temperature of 40 °C, held at 40 °C for 1 min, then increased to 100 °C at a rate of 30 °C / min, and then increased to 270 °C at a rate of 10 °C / min. The total gas chromatography run time was 21 min. The column type was: Agilent J&W HP-5MS UI 30M*0.25mmID*0.25µm.

[0018] The mixture of 4-(trifluoromethyl)cyclohexanol stereoisomers, vinyl acetate, acetone, and immobilized Candida antarcticis lipase B are all commercially available. The ratio of trans to cis in the mixture of 4-(trifluoromethyl)cyclohexanol stereoisomers is 7:3.

[0019] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for resolving the stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol, characterized in that, Includes the following steps: S1. Dissolve the stereoisomer mixture of 4-(trifluoromethyl)cyclohexane-1-ol and the acyl donor in an organic solvent; S2. Add Candida antarctica lipase B to the system of step S1. After the reaction, trans-4-(trifluoromethyl)cyclohexane-1-ol and cis-I compound are obtained: ， In Formula 1, R is selected from C1-C6 straight-chain or branched alkanes.

2. The splitting method as described in claim 1, characterized in that, In S1, the acyl donors include vinyl acetate, vinyl butyrate, and di-tert-butyl dicarbonate.

3. The splitting method as described in claim 1, characterized in that, In S1, organic solvents include acetonitrile, benzene solvents, ester solvents, ketone solvents, and ether solvents.

4. The splitting method as described in claim 1, characterized in that, In S1, the concentration of the mixture of stereoisomers of 4-(trifluoromethyl)cyclohexane-1-ol is 1-50 mg / mL.

5. The splitting method as described in claim 1, characterized in that, In S1, the molar ratio of the acyl donor to the stereoisomer of 4-(trifluoromethyl)cyclohexane-1-ol is 0.5-10:

1.

6. The splitting method as described in claim 1, characterized in that, In S2, the mass ratio of Candida antarcticis lipase B to the stereoisomer mixture of 4-(trifluoromethyl)cyclohexane-1-ol is 0.1-10:

1.

7. The splitting method as described in claim 1, characterized in that, In S2, the reaction temperature is 20℃-70℃, and the reaction time is not less than 10h.

8. The splitting method as described in claim 1, characterized in that, In S2, Candida antarcticis lipase B is used as an immobilized enzyme.

9. The splitting method as described in claim 1, characterized in that, S2 also includes filtering the system after the reaction is complete, concentrating the filtrate to separate the organic phase, and obtaining trans-4-(trifluoromethyl)cyclohexane-1-ol and cis-I compound.

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