Process for the production of high purity (1r,2s,5r)-ws-3

Abstract

This invention discloses a method for producing high-purity (1R,2S,5R)-WS-3, comprising the following steps: using a mixture of menthol containing eight stereoisomers or naturally extracted menthol as raw material, and reacting it with diethylamine and phosgene under solvent-free conditions at 55-65°C; using a non-chiral adsorbent to separate six diastereomers of (1R,2S,5R)-WS-3 from the obtained WS-3 mixture, and then using a chiral adsorbent to separate the remaining two enantiomers, thus obtaining high-purity (1R,2S,5R)-WS-3. This invention achieves the production of high optical purity (1R,2S,5R)-WS-3 menthol amide cooling agent under mild operating conditions, and has significant industrial application value for the efficient production and quality upgrading of cooling agents.

Description

Technical Field

[0001] This invention relates to the field of chemical separation, and in particular to a method for producing high-purity (1R,2S,5R)-WS-3. Background Technology

[0002] N-Ethyl-2-isopropyl-5-methylcyclohexaneformamide (WS-3) is the most widely used menthol amide cooling agent, and it is widely used in oral care, food and beverage, cosmetics, and biomedicine (Johnson S, Tian M, Sheldon G, et al. Trigeminal Receptor Study of High-Intensity Cooling Agents[J]. Journal of Agricultural and Food Chemistry, 2018, 66(10): 2319-2323). WS-3 has eight stereoisomers, which have significant differences in activity and cooling quality. The eight isomers can be divided into four groups of enantiomers in terms of chiral configuration. The enantiomers have very similar properties, making separation and purification very difficult and affecting the quality of the cooling agent.

[0003] The most active WS-3 configuration is (1R,2S,5R)-WS-3. Currently, commercially available WS-3 is mainly obtained through the direct acylation of menthol. The purity of (1R,2S,5R)-WS-3 depends on the purity of L-menthol in the menthol feedstock. Crude peppermint oil contains other isomers, and direct acylation yields a WS-3 configuration with lower biological activity. The artificial synthesis of high optical purity menthol requires expensive asymmetric catalytic processes, energy-intensive isomer resolution, and enantiomer resolution of multi-chiral centers of menthol, which is difficult to achieve with current technology. In conventional production processes, the total energy consumption from crude peppermint oil to the final product is approximately 680–920 MJ / kg, with the main energy-consuming step being distillation purification. This results in a 47% higher price for high-purity L-menthol compared to crude peppermint oil, leading to persistently high overall raw material costs. Furthermore, current production methods inevitably introduce trace amounts of isomer impurities during the amidation process. Therefore, there is an urgent need to develop efficient synthesis and enantiomeric purification processes for high-quality (1R,2S,5R)-WS-3 to support the quality upgrade and cost control of high-end cooling agents. Such technologies have significant industrial value. Summary of the Invention

[0004] To address the bottlenecks in the enantiomeric production of optically pure (1R,2S,5R)-WS-3 in existing technologies, this invention aims to provide a method for producing high-purity (1R,2S,5R)-WS-3. This method addresses the issues of reliance on raw material purity and high energy consumption in purification processes. The invention proposes a chemical total synthesis coupled with isomer separation technology. Using a mixture of menthol with eight configurations or natural extracts as raw materials, the mixture is acylated to WS-3. A highly selective chiral adsorbent is then used to enrich and separate (1R,2S,5R)-WS-3, achieving low-energy, green production of optically pure (1R,2S,5R)-WS-3.

[0005] The objective of this invention is achieved through the following technical solution:

[0006] This invention provides a method for producing high-purity (1R, 2S, 5R)-WS-3, comprising the following steps:

[0007] WS-3 mixture was obtained by reacting racemic menthol mixture or naturally extracted menthol with diethylamine and phosgene at 55-65°C under solvent-free conditions.

[0008] The obtained WS-3 mixture was separated into six diastereomers of (1R,2S,5R)-WS-3 by adsorption with a non-chiral adsorbent. Then, the remaining two enantiomers were separated by adsorption with a chiral adsorbent to obtain high-purity (1R,2S,5R)-WS-3. The separated isomers can be returned to the reactor for further isomerization.

[0009] In some embodiments, the non-chiral adsorbent is filled in a first adsorption unit, and the chiral adsorbent is filled in a second adsorption unit;

[0010] or,

[0011] The non-chiral adsorbent and the chiral adsorbent are packed into the same adsorption unit to form a combined bed.

[0012] In actual production, two adsorption units can be combined into a combined bed, or multiple functional adsorption materials can be mixed and added in the same unit operation to achieve a more efficient separation process.

[0013] In some embodiments, the desorption reaction of the first adsorption unit and the second adsorption unit can be carried out at room temperature, such as 20~40°C; in other embodiments, considering material regeneration, the desorption reaction of the first adsorption unit and the second adsorption unit can be carried out at 160~200°C.

[0014] In some embodiments, the racemic menthol mixture contains 2 to 4 enantiomers, and one of the enantiomers is (1R,2S,5R)-WS-3 and (1S,2R,5S)-WS-3.

[0015] In some embodiments of the present invention, the non-chiral adsorbent is a 13X type molecular sieve.

[0016] In some embodiments of the present invention, the non-chiral adsorbent is prepared by the following method:

[0017] Water glass, sodium aluminate, sodium hydroxide, and water are mixed in a ratio of 1:3.66:4.81:181 to form a gel. The gel is then heated to about 102°C and crystallized for 13-17 hours. It is then kneaded with an adhesive, shaped, and activated by calcination to obtain the finished 13X molecular sieve.

[0018] In some embodiments of the present invention, the chiral adsorbent is a metal-organic framework highly selective adsorbent.

[0019] In some embodiments of the present invention, the highly selective metal-organic framework adsorbent is a chiral small molecule @Zr-BTC material; the chiral small molecule @Zr-BTC material is synthesized from achiral Zr-BTC and a chiral small molecule with a carboxyl group, wherein the chiral small molecule with a carboxyl group is at least one of L-tartaric acid and L-mandelic acid.

[0020] In some embodiments of the present invention, the highly selective metal-organic framework adsorbent is prepared by the following method:

[0021] (1) Add a methanol solution of 4-pyridinecarboxaldehyde dropwise to an aqueous solution containing sodium carbonate and L-leucine, stir at room temperature for 1 to 4 hours, add sodium borohydride aqueous solution dropwise under ice-water bath conditions, continue stirring for 0.5 to 2 hours, filter, and adjust the pH of the filtrate to 4 to 7; rotary evaporate to obtain a white solid, dissolve in methanol at 55 to 65°C, filter, and rotary evaporate to obtain a chiral ligand;

[0022] (2) Dissolve the chiral ligand obtained in step (1) in water, adjust the pH to 6-8, then mix it with an organic solvent containing zinc salt and sonicate for 2-60 min, centrifuge to collect the white solid and wash it.

[0023] In some embodiments of the present invention, the menthol mixture is prepared as follows:

[0024] Thymol was obtained by alkylating m-cresol and propylene under AlCl3 catalysis. Thymol was then hydrogenated with Ni as a catalyst at 280-320℃ and 5-10 MPa to obtain a mixture of menthol containing eight stereoisomers.

[0025] In some embodiments of the present invention, the non-chiral adsorbent is a 13X molecular sieve; the chiral adsorbent is an L-Leu-Pyridine@Zn-MOFs adsorbent.

[0026] In some embodiments of the present invention, the non-chiral adsorbent is a 13X molecular sieve; the chiral adsorbent is an L-Tar@Zr-BTC adsorbent.

[0027] In some embodiments of the present invention, the obtained (1R,2S,5R)-WS-3 is optically pure and has a recovery rate of more than 94%.

[0028] Preferably, the non-chiral adsorbent exhibits a selectivity coefficient K > 3.0 for one group of enantiomers (1R,2S,5R)-WS-3 and (1S,2R,5S)-WS-3 among the eight isomers at room temperature, a saturated adsorption capacity of not less than 120 mg / g, and maintains ≥90% of its initial adsorption capacity after five consecutive regeneration cycles. It also possesses good mechanical stability, chemical stability, and regenerability.

[0029] Preferably, the chiral adsorbent has a selectivity coefficient K > 3.0 for (1R,2S,5R)-WS-3 at room temperature, a saturated adsorption capacity of not less than 120 mg / g, and maintains ≥90% of its initial adsorption capacity after 5 consecutive regeneration cycles. It also has good mechanical stability, chemical stability, and regenerability.

[0030] Preferably, the adsorbent is desorbed using a gradient heating method, with a heating rate of 5℃ / min, from 40℃ to 180℃ to complete the desorption. Inert gas or low-pressure gas flow is used for purging, so that the adsorbent can be reused for subsequent separation operations after cooling to room temperature.

[0031] Preferably, the first adsorption unit is filled with a non-chiral adsorbent, and the second adsorption unit is filled with a highly selective chiral adsorbent. In practical applications, the designed amount of adsorbent can be affected by various factors, including but not limited to the raw material composition, the selectivity and adsorption capacity of the adsorbent, operating conditions (such as temperature, pressure, and flow rate), the design and scale of the adsorption bed, the regeneration cycle of the adsorbent, the gas flow rate, and the required purity. In conventional separation processes, the amount of adsorbent used in the two units is approximately 5% to 7% of the amount of WS-3 processed per cycle.

[0032] This invention focuses on the purity requirements of WS-3 and proposes a production process for optically pure (1R,2S,5R)-WS-3 based on chiral adsorbents. This process achieves efficient chemical separation of highly active components from various configurations of WS-3 under mild operating conditions, simplifying the production process while reducing energy consumption. This addresses a significant technological need in the field and provides an efficient, economical, and green production process for the separation of multi-chiral center isomers. In this invention, the first adsorption unit primarily captures (1R,2S,5R)-WS-3 and its enantiomer (1S,2R,5S)-WS-3, while the second adsorption unit performs deep selective removal of (1S,2R,5S)-WS-3. The selective windows of the adsorbents in the two adsorption units are complementary, jointly achieving a final product optical purity ≥99.9% and a yield higher than 94%.

[0033] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0034] (1) The production method of high purity (1R,2S,5R)-WS-3 of the present invention has a simple synthesis process, low raw material requirements, and is easy to scale up synthesis.

[0035] (2) The production method of high purity (1R,2S,5R)-WS-3 of the present invention achieves the production of high optical purity (1R,2S,5R)-WS-3 menthol amide cooling agent under mild working conditions by constructing a "racemic synthesis-stereoisomer identification and separation" technical route. The purity of (1R,2S,5R)-WS-3 can reach an optical purity of more than 99% ee value, reducing energy consumption by about 20% and cost by about 25%. Attached Figure Description

[0036] Figure 1 This is a schematic diagram of the process for producing optically pure (1R,2S,5R)-WS-3 according to an embodiment of the present invention.

[0037] Figure 2 The results of WS-3 enantiomer detection under the conditions of Example 2 of the present invention are shown. Detailed Implementation

[0038] The present invention is further described below through specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0039] Unless otherwise specified in the embodiments of this invention, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. All raw materials and reagents used, unless otherwise specified, are commercially available conventional products.

[0040] Embodiments of the present invention provide a method for producing high-purity (1R,2S,5R)-WS-3, such as... Figure 1 As shown, it includes the following steps:

[0041] Thymol was obtained by alkylating m-cresol and propylene under AlCl3 catalysis. Thymol was then hydrogenated with Ni as a catalyst at 280-320℃ and 5-10MPa to obtain a mixture of menthol containing eight stereoisomers.

[0042] A mixture of menthol containing eight stereoisomers was reacted with diethylamine and phosgene (COCl2) at 55–65 °C under solvent-free conditions to obtain a mixture of WS-3.

[0043] The obtained WS-3 mixture is passed into the first adsorption unit filled with a non-chiral adsorbent, and the desorbed liquid enters the second adsorption unit filled with a chiral adsorbent. The desorption product of the second adsorption unit is high-purity (1R,2S,5R)-WS-3.

[0044] In the following examples and comparative examples, the preparation method of 13X type molecular sieve is as follows:

[0045] Water glass, sodium aluminate, sodium hydroxide, and water were mixed in a ratio of 1:3.66:4.81:181 to form a gel. The gel was then heated to approximately 102°C to crystallize for 13-17 hours, followed by kneading with a binder, molding, and calcination activation to obtain the finished 13X molecular sieve.

[0046] Example 1

[0047] The material to be separated in this embodiment is a mixture of WS-3, and the synthesis route is as follows: alkylation of m-cresol and propylene under AlCl3 catalysis yields thymol, which is then hydrogenated at 280-320℃ and 5-10MPa using Ni as a catalyst to obtain a mixture of menthol. The menthol mixture is then reacted with diethylamine and phosgene (COCl2) at 55-65℃ under solvent-free conditions to obtain a mixture of WS-3.

[0048] Adsorption unit I and adsorption unit II are two independent fixed-bed columns with an inner diameter of 2 cm and a length of 30 cm. Adsorption unit I is filled with approximately 50 g of 13X type molecular sieve, and adsorption unit II is filled with approximately 50 g of L-Leu-Pyridine@Zn-MOFs adsorbent disclosed in Example 1 of Chinese Patent CN118480184A. The materials to be separated were transported using a hexane:ethanol = 90:10 volume ratio solvent system. A WS-3 mixture solution (concentration: 0.4 mM) was continuously introduced into adsorption unit I at a flow rate of 2 mL / min, with the temperature maintained at room temperature (25°C) and the pressure kept constant at 1 MPa. Detection revealed that one group of enantiomers (1R,2S,5R) and (1S,2R,5S) were enriched within the column, while the contents of the other three enantiomers of WS-3 in the effluent increased significantly. Subsequently, the desorbate was introduced into the second-stage adsorption unit II, with a flow rate controlled at 2 mL / min, temperature maintained at room temperature (25°C), and pressure kept constant at 1 MPa for secondary enhanced separation. Enantiomers (1R, 2S, 5R) were enriched within the column, further removing impurities. After two tandem separations, the overall separation efficiency increased to over 96%, with impurity residue below 2‰ and a yield of 96%. Gradient desorption was performed in adsorption units I and II using 50 mL methanol as eluent and a temperature ramp rate of 5°C / min, increasing from 40°C to 180°C. The desorbate was collected, concentrated by rotary evaporation, and the excess value (ee) of enantiomers (1R, 2S, 5R) was determined by high-performance chiral HPLC to be 99.8%.

[0049] Example 2

[0050] The material to be separated in this embodiment is a mixture of WS-3, and the synthesis route is the same as in Example 1.

[0051] Adsorption unit I and adsorption unit II are two independent fixed-bed columns with an inner diameter of 2 cm and a length of 30 cm. Adsorption unit I is filled with approximately 50 g of 13X type molecular sieve, and adsorption unit II is filled with approximately 50 g of the L-Tar@Zr-BTC adsorbent disclosed in Example 6 of Chinese Patent CN115678026B. The materials to be separated were transported using a hexane:ethanol = 90:10 volume ratio solvent system. A WS-3 mixture solution (concentration: 0.4 mM) was continuously introduced into adsorption unit I at a flow rate of 2 mL / min, with the temperature maintained at room temperature (25°C) and the pressure kept constant at 1 MPa. Analysis revealed that the (1R,2S,5R) and (1S,2R,5S) enantiomers were enriched within the column, while the contents of the other three enantiomers of WS-3 in the effluent increased significantly. Subsequently, the desorption solution was introduced into adsorption unit II, with a flow rate controlled at 2 mL / min, temperature maintained at room temperature (25°C), and pressure kept constant at 1 MPa for secondary enhanced separation. Enantiomers (1R, 2S, 5R) were enriched within the column, further removing impurities. After two tandem separations, the overall separation efficiency increased to over 99%, with impurity residue below 2‰ and a yield of 98%. Gradient desorption was performed in adsorption units I and II using 50 mL methanol as eluent and a temperature ramp rate of 5°C / min, increasing from 40°C to 180°C. The desorption solution was collected, concentrated by rotary evaporation, and the excess value (ee) of enantiomers (1R, 2S, 5R) was determined by high-performance chiral HPLC to be 99.9%. The results are shown below. Figure 2 As shown, the ee value is obtained by the difference in peak area.

[0052] Comparative Example 1

[0053] The material to be separated in this comparative example is a mixture of WS-3, and the synthesis route is the same as in Example 1.

[0054] A single fixed bed column (2 cm inner diameter × 30 cm length) was used, filled with approximately 50 g of 13X molecular sieve. The materials to be separated were transported using a solvent system of n-hexane:ethanol = 90:10 (v / v). The flow rate was controlled at 2 mL / min, the temperature was maintained at room temperature (25°C), and the pressure was constant. A WS-3 mixture solution (0.4 mM concentration) was continuously introduced; the adsorption unit was subjected to gradient desorption at a heating rate of 5°C / min, from 40°C to 180°C, with subsequent processing as in Example 1. The recovery rate of (1R,2S,5R)-WS-3 was only 62.8%; the separation efficiency was only 6.43%, with impurity residue exceeding 40.5%; severe tailing of the main peak occurred, and the enantiomeric excess (ee) of (1R,2S,5R) was 0.06%, failing to achieve chiral separation.

[0055] Comparative Example 2

[0056] The material to be separated in this comparative example is a mixture of WS-3, and the synthesis route is the same as in Example 1.

[0057] Using only a single fixed bed column (2 cm inner diameter × 30 cm length), the L-Leu-Pyridine@Zn-MOFs adsorbent disclosed in Example 1 of Chinese Patent CN118480184A was employed. The materials to be separated were transported using a hexane:ethanol = 90:10 volume ratio solvent system. The flow rate was controlled at 2 mL / min, the temperature was maintained at room temperature (25°C), and the pressure was constant. A WS-3 mixture solution (0.4 mM concentration) was continuously introduced; gradient desorption was performed on the adsorption unit at a heating rate of 5°C / min, increasing from 40°C to 180°C. Subsequent processing was the same as in Example 1. The results showed that the enantiomeric excess (ee) of (1R, 2S, 5R) was only 88.6%, failing to meet the high purity requirements.

[0058] Comparative Example 3

[0059] The material to be separated in this comparative example is a mixture of WS-3, and the synthesis route is the same as in Example 1.

[0060] A single fixed bed column (2 cm inner diameter × 30 cm length) was used, filled with approximately 50 g of the L-Tar@Zr-BTC adsorbent disclosed in Example 1 of Chinese Patent CN115678026B. The materials to be separated were transported using a solvent system of n-hexane:ethanol = 90:10 (v / v). The flow rate was controlled at 2 mL / min, the temperature was maintained at room temperature (25°C), and the pressure was constant. A WS-3 mixture solution (0.4 mM concentration) was continuously introduced; gradient desorption was performed on the adsorption unit at a heating rate of 5°C / min, increasing from 40°C to 180°C, with subsequent processing as in Example 1. The results showed that the enantiomeric (1R, 2S, 5R) excess value (ee) was only 78.6%, failing to meet the high purity requirements.

[0061] Comparative Example 4

[0062] The material to be separated in this embodiment is a mixture of WS-3, and the synthesis route is the same as in Example 1.

[0063] Adsorption unit I and adsorption unit II are two independent fixed-bed columns with an inner diameter of 2 cm and a length of 30 cm. Adsorption unit I is filled with approximately 50 g of the L-Leu-Pyridine@Zn-MOFs adsorbent disclosed in Example 1 of Chinese Patent CN118480184A, and adsorption unit II is filled with approximately 50 g of 13X type molecular sieve. The materials to be separated are transported using a hexane:ethanol = 90:10 volume ratio solvent system, with a flow rate controlled at 2 mL / min, temperature maintained at room temperature (25°C), and pressure kept constant. A WS-3 mixture solution (concentration: 0.4 mM) is continuously passed into adsorption unit I. Subsequently, the effluent is introduced into the second-stage adsorption unit II, and the same conditions are repeated for a second enhanced separation to further remove unidentified components. After two tandem separations, the overall separation efficiency is as low as 49.7%, and the impurity content is as high as 5.1‰. Adsorption units I and II were desorbed using 50 mL methanol as eluent and a gradient desorption process was performed at a heating rate of 5 °C / min, increasing from 40 °C to 180 °C. The desorbates were collected, concentrated by rotary evaporation, and the enantiomeric excess (ee) of 1R, 2S, and 5R was determined by high-performance chiral HPLC. The result was only 90.2%, indicating that the order of packing different columns significantly affects the purity of WS-3.

[0064] In the above embodiments, the material to be separated can also be naturally extracted menthol. The naturally extracted menthol is mixed with diethylamine and phosgene (COCl2) at 55~65°C under solvent-free conditions to obtain WS-3 mixture.

[0065] The obtained WS-3 mixture is passed into the first adsorption unit filled with a non-chiral adsorbent, and the desorbed liquid enters the second adsorption unit filled with a chiral adsorbent. The desorption product of the second adsorption unit is high-purity (1R,2S,5R)-WS-3.

[0066] Those skilled in the art will readily understand that the above description is merely an embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements 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 producing high-purity (1R, 2S, 5R)-WS-3, characterized in that, Includes the following steps: WS-3 mixture was obtained by reacting racemic menthol mixture or naturally extracted menthol with diethylamine and phosgene at 55-65°C under solvent-free conditions. The obtained WS-3 mixture was separated by adsorption and separation of diastereomers using a non-chiral adsorbent and enantiomers using a chiral adsorbent to obtain high-purity (1R,2S,5R)-WS-3.

2. The production method of high-purity (1R,2S,5R)-WS-3 according to claim 1, characterized in that, The non-chiral adsorbent is filled in the first adsorption unit, and the chiral adsorbent is filled in the second adsorption unit; or, The non-chiral adsorbent and the chiral adsorbent are packed into the same adsorption unit to form a combined bed.

3. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 1, characterized in that, The racemic menthol mixture contains 2 to 4 enantiomers, and one of the enantiomers is (1R,2S,5R)-WS-3 and (1S,2R,5S)-WS-3.

4. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 3, characterized in that, The non-chiral adsorbent exhibits a selectivity coefficient K > 3.0 for the enantiomers (1R,2S,5R)-WS-3 and (1S,2R,5S)-WS-3 at room temperature, and a saturated adsorption capacity of not less than 120 mg / g; the chiral adsorbent exhibits a selectivity coefficient K > 3.0 for (1R,2S,5R)-WS-3 at room temperature, and a saturated adsorption capacity of not less than 120 mg / g.

5. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 4, characterized in that, The non-chiral adsorbent is a 13X type molecular sieve.

6. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 5, characterized in that, The chiral adsorbent is a highly selective metal-organic framework adsorbent.

7. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 6, characterized in that, The highly selective adsorbent of the metal-organic framework is a chiral small molecule @Zr-BTC material; the chiral small molecule @Zr-BTC material is synthesized from achiral Zr-BTC and a chiral small molecule with a carboxyl group, wherein the chiral small molecule with a carboxyl group is at least one of L-tartaric acid and L-mandelic acid.

8. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 6, characterized in that, The highly selective metal-organic framework adsorbent is prepared by the following method: (1) Add a methanol solution of 4-pyridinecarboxaldehyde dropwise to an aqueous solution containing sodium carbonate and L-leucine, stir at room temperature for 1 to 4 hours, add sodium borohydride aqueous solution dropwise under ice-water bath conditions, continue stirring for 0.5 to 2 hours, filter, and adjust the pH of the filtrate to 4 to 7; rotary evaporate to obtain a white solid, dissolve in methanol at 55 to 65°C, filter, and rotary evaporate to obtain a chiral ligand; (2) Dissolve the chiral ligand obtained in step (1) in water, adjust the pH to 6-8, then mix it with an organic solvent containing zinc salt and sonicate for 2-60 min, centrifuge to collect the white solid and wash it.

9. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 1, characterized in that, The racemic menthol mixture is prepared as follows: Thymol was obtained by alkylating m-cresol and propylene under AlCl3 catalysis. Thymol was then hydrogenated with Ni as a catalyst at 280-320℃ and 5-10 MPa to obtain a mixture of menthol containing 8 stereoisomers.

10. The method for producing high-purity (1R,2S,5R)-WS-3 according to claim 7 or 8, characterized in that, The obtained (1R,2S,5R)-WS-3 was optically pure, with a recovery rate greater than 94%.

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