METHOD FOR RESOLVING OPTICAL ISOMER BY USING SUPERCRITICAL FLUID EXTRACTION TECHNOLOGY

Abstract

Provided is a method for resolving an optical isomer from a racemate by using supercritical fluid extraction technology. The method is mainly applied to the separation of a product obtained after enzymatic resolution. Taking a preparation process of D-pantolactone as an example, the key point is to separate D-pantolactone and L-pantolactone from an enzymatic resolution liquid by means of supercritical fluid extraction.

Claims

1. A method for resolving an optical isomer from a racemate by using a supercritical fluid extraction technique, comprising: a) reacting the racemate in the presence of a catalyst to form a mixture comprising a first form of a first optical isomer and a second form of a second optical isomer; b) performing an extraction with supercritical fluid on the mixture to allow the first form of the first optical isomer and the second form of the second optical isomer to be separated; and c) collecting the separated first form of the first optical isomer, and/or collecting the separated second form of the second optical isomer.

2. The method according to claim 1, wherein the racemate has a hydrolyzable functional group.

3. The method according to claim 2, wherein the functional group is hydrolyzed to form an ionizable group.

4. The method according to claim 2, wherein the catalyst specifically hydrolyzes the hydrolyzable functional group of the first optical isomer to form the first form of the first optical isomer.

5. The method according to claim 1, wherein the racemate has a ring structure, and the hydrolyzable functional group is within the ring structure.

6. The method according to claim 5, wherein the ring structure is selected from the group consisting of a lactone and a lactam.

7. The method according to claim 5, wherein the ring structure is ring-opened in the first form of the first optical isomer.

8. The method according to claim 1, wherein the catalyst comprises an enzyme composition.

9. The method according to claim 8, wherein the enzyme composition comprises an ester hydrolase and/or a lactamase.

10-12. (canceled)

13. The method according to claim 1, further comprising purifying and/or concentrating the separated first form of the first optical isomer, and/or purifying and/or concentrating the separated second form of the second optical isomer.

14. The method according to claim 1, further comprising converting the second form of the second optical isomer into the racemate.

15. The method according to claim 1, wherein the extraction with supercritical fluid is carried out in a supercritical fluid extraction system, wherein the supercritical fluid extraction system comprises a vessel containing a fluid, a cooling system, a compression system, an extraction kettle, and a separation kettle.

16. The method according to claim 1, wherein the solubilities of the first form of the first optical isomer and the second form of the second optical isomer in a supercritical fluid are different under an extraction temperature and an extraction pressure.

17. The method according to claim 16, wherein the solubility of the first form of the first optical isomer in the supercritical fluid is significantly less than the solubility of the second form of the second optical isomer in the supercritical fluid.

18. The method according to claim 15, wherein the extraction with supercritical fluid comprises placing the mixture in the extraction kettle, allowing the fluid from the vessel to enter the cooling system and the compression system to form the supercritical fluid, allowing the supercritical fluid to enter the extraction kettle to be in contact with the mixture to undergo extraction under the extraction temperature and the extraction pressure, allowing an extracted component with the supercritical fluid to enter the separation kettle to be separated, and collecting the extracted component.

19. The method according to claim 15, wherein the supercritical fluid is CO.sub.2, N.sub.2O, SF.sub.6, ethane, heptane, NH.sub.3, or a combination thereof.

20. The method according to claim 19, wherein the supercritical fluid is CO.sub.2.

21-23. (canceled)

24. The method according to claim 15, wherein the separation kettle comprises separation kettles in series.

25. The method according to claim 15, wherein the separation kettle comprises three-stage separation kettles in series, wherein for a first-stage separation kettle, the separation temperature is 35-40° C. and the separation pressure is 7-9 MPa; for a second-stage separation kettle, the separation temperature is 25-28° C. and the separation pressure is 3-5 MPa; and for a third-stage separation kettle, the separation temperature is 45-48° C. and the separation pressure is 3-5 MPa.

26. The method according to claim 1, wherein (a) the racemate is DL-pantolactone, the first form of the first optical isomer is D-pantoic acid, and the second form of the second optical isomer is L-pantolactone; (b) the racemate is methyl 3-cyclohexene-1-carboxylate, the first form of the first optical isomer is (R)-3-cyclohexene-1-carboxylic acid, and the second form of the second optical isomer is (S)-methyl 3-cyclohexene-1-carboxylate; (c) the racemate is α-hydroxy-γ-butyrolactone, the first form of the first optical isomer is (R)-α-hydroxy-γ-butyric acid, and the second form of the second optical isomer is S)-α-hydroxy-γ-butyrolactone; (d) the racemate is β-hydroxy-γ-butyrolactone, the first form of the first optical isomer is (R)-β-hydroxy-γ-butyric acid, and the second form of the second optical isomer is (S)-β-hydroxy-γ-butyrolactone; or (e) the racemate is α-acetyl-γ-butyrolactone, the first form of the first optical isomer is (R)-α-acetyl-γ-butyric acid, and the second form of the second optical isomer is (S)-α-acetyl-γ-butyrolactone.

27-31. (canceled)

Description

EXAMPLES

[0056] The present disclosure is further described below with reference to specific examples, but the protection scope of the present disclosure is not limited thereto.

Example 1

[0057] ##STR00001##

[0058] 1. Preparation of an enzymatic conversion solution: 300 g of racemic DL-pantolactone and 150 g of immobilized cells containing D-pantolactone hydrolase were added into a 1 L system at 30° C. with a pH of 7.0, the mixture was mechanically stirred at 200 rpm, and was titrated with 15N NH.sub.3—H.sub.2O to keep the pH value at 7.0, to react for 3 h.

[0059] 2. Pretreatment of the enzymatic conversion solution: the enzymatic conversion solution was first filtered with a filter cloth, then filtered with a 0.2 μm microfiltration membrane, and then filtered with a 50 kD ultrafiltration membrane.

[0060] 3. Supercritical fluid extraction: the filtered reaction liquid was poured into an extraction kettle of a supercritical fluid extraction system, the temperature of the extraction kettle was increased to 40° C., a supercritical fluid CO.sub.2 was introduced and the flow rate was adjusted to 20 kg/h, and the pressure was increased to 35 MPa, to perform the extraction for 2 h; and the extracted L-pantolactone with CO.sub.2 entered three-stage separation kettles in series (wherein for a first-stage separation kettle, the separation temperature was 40° C., and the separation pressure was 9 MPa; for a second-stage separation kettle, the separation temperature was 28° C., and the separation pressure was 5 MPa; and for a third-stage separation kettle, the separation temperature was 48° C., and the separation pressure was 5 MPa) for separation.

[0061] 4. Concentration and acidification: a supernatant removed from the extraction kettle was injected into a concentration equipment to be concentrated to about 200 mL under reduced pressure, and sulfuric acid was added into the concentrated supernatant to about pH 1 to lactonize it.

[0062] 5. Crystallization: after the concentration, an upper layer of the acidified solution was removed to obtain 123.9 g of D-pantolactone with a yield of 41.3% (based on DL-pantolactone), and the ee value of the D-pantolactone measured by HPLC was 98.6%.

Example 2

[0063] ##STR00002##

[0064] 1. Preparation of an enzymatic conversion solution: 900 g of racemic DL-pantolactone and 450 g of immobilized cells containing D-pantolactone hydrolase were added into a 3 L system at 30° C. with a pH of 7.0, the mixture was mechanically stirred at 200 rpm, and was titrated with 15N NH.sub.3—H.sub.2O to keep the pH value at 7.0, to react for 4 h.

[0065] 2. Pretreatment of the enzymatic conversion solution: 3 L of the enzymatic conversion solution was filtered with a 0.4 μm microfiltration membrane, and then filtered with a 20 kD ultrafiltration membrane; and then the filtered supernatant was concentrated under reduced pressure to 500 mL.

[0066] 3. Supercritical fluid extraction: the concentrate was poured into an extraction kettle of a supercritical fluid extraction system, the temperature of the extraction kettle was increased to 35° C., a supercritical fluid CO.sub.2 was introduced and the flow rate was adjusted to 30 kg/h, and the pressure was increased to 35 MPa, to perform the extraction for 4 h; and the extracted L-pantolactone with CO.sub.2 entered three-stage separation kettles in series (wherein for a first-stage separation kettle, the separation temperature was 40° C., and the separation pressure was 9 MPa; for a second-stage separation kettle, the separation temperature was 28° C., and the separation pressure was 5 MPa; and for a third-stage separation kettle, the separation temperature was 48° C., and the separation pressure was 5 MPa) for separation.

[0067] 4. Concentration and acidification: sulfuric acid was added into a supernatant removed from the extraction kettle to about pH 1 to lactonize it.

[0068] 5. Crystallization: after the concentration, an upper layer of the acidified solution was removed to obtain 364.5 g of D-pantolactone with a yield of 40.5% (based on DL-pantolactone), and the ee value of the D-pantolactone measured by HPLC was 96.6%.

Example 3

[0069] ##STR00003##

[0070] 1. Preparation of an enzymatic conversion solution: 900 g of racemic DL-pantolactone and 450 g of immobilized cells containing D-pantolactone hydrolase were added into a 3 L system at 30° C. with a pH of 7.0, the mixture was mechanically stirred at 200 rpm, and was titrated with 15N NH.sub.3—H.sub.2O to keep the pH value at 7.0, to react for 4 h.

[0071] 2. Pretreatment of the enzymatic conversion solution: 3 L of the enzymatic conversion solution was filtered with a 0.4 μm microfiltration membrane, and then filtered with a 20 kD ultrafiltration membrane.

[0072] 3. Supercritical fluid extraction: the filtered reaction liquid was poured into an extraction kettle of a supercritical fluid extraction system, the temperature of the extraction kettle was increased to 40° C., a supercritical fluid CO.sub.2 was introduced and the flow rate was adjusted to 20 kg/h, and the pressure was increased to 35 MPa, to perform the extraction for 6 h; and the extracted L-pantolactone with CO.sub.2 entered three-stage separation kettles in series (wherein for a first-stage separation kettle, the separation temperature was 40° C., and the separation pressure was 9 MPa; for a second-stage separation kettle, the separation temperature was 28° C., and the separation pressure was 5 MPa; and for a third-stage separation kettle, the separation temperature was 48° C., and the separation pressure was 5 MPa) for separation.

[0073] 4. Concentration and acidification: a supernatant removed from the extraction kettle was injected into a concentration equipment to be concentrated to about 500 mL under reduced pressure, and sulfuric acid was added into the concentrated supernatant to about pH1 to lactonize it.

[0074] 5. Crystallization: after the concentration, an upper layer of the acidified solution was removed to obtain 388.8 g of D-pantolactone with a yield of 43.2% (based on DL-pantolactone), and the ee value of the D-pantolactone measured by HPLC was 98.9%.

[0075] The specific examples of the present disclosure are described above. It should be understood that the present disclosure is not limited to the foregoing specific embodiments, and a person skilled in the art may make various changes or modifications within the scope of the claims, which does not affect the essence of the present disclosure. The examples and the features in the examples of the present disclosure may be combined with each other randomly with no conflict.