METHOD FOR RESOLVING OPTICAL ISOMER BY MEANS OF ELECTRODIALYSIS TECHNIQUE

Abstract

Disclosed is a method for resolving an optical isomer from a racemate by means of electrodialysis. Specifically, an electrodialysis technique is used in an enzymatic resolution process, mainly in the separation of products after enzymatic resolution. Taking a preparation process for D-pantolactone as an example, the key point is that D-pantoic acid and L-pantolactone are separated from an enzymatic resolution solution by means of an electrodialysis method, which replaces the existing organic solvent extraction method. The process method is simple and easy to operate, has a high yield of D-pantoic acid of a good purity, greatly reduces the usage amount of an organic solvent, reduces production costs and is environmentally friendly, such that the working environment of workers can be improved to a great extent, and the operation safety index is improved.

Claims

1. A method for resolving an optical isomer from a racemate by using electrodialysis, comprising: a) reacting the racemate in the presence of a catalyst to form a mixture comprising an ionizable form of a first optical isomer and a non-ionized form of a second optical isomer; b) electrodialyzing the mixture to allow the ionizable form of the first optical isomer and the non-ionized form of the second optical isomer to be separated; and c) collecting the separated ionizable form of the first optical isomer, and/or collecting the separated non-ionized 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 ionizable 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 ionizable 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. The method according to claim 8, wherein the enzyme composition comprises a purified enzyme, an enzyme-expressing cell, or an enzyme-expressing cell lysate.

11. (canceled)

12. The method according to claim 1, wherein after step a) and before step b), the method further comprising removing a residue of the catalyst in the mixture.

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

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

15. The method according to claim 1, wherein the electrodialyzing is carried out in an electrodialysis cell, wherein the electrodialysis cell comprises a dilute compartment and a concentrate compartment separated by an ion-exchange membrane.

16. The method according to claim 15, wherein the electrodialyzing comprises placing the mixture in the dilute compartment, placing a solvent in the concentrate compartment, and energizing the electrodialysis cell to allow the ionizable form of the first optical isomer in the dilute compartment to migrate into the solvent in the concentrate compartment.

17-19. (canceled)

20. The method according to claim 1, wherein the racemate is DL-pantolactone, the ionizable form of the first optical isomer is D-pantoic acid, and the non-ionized form of the second optical isomer is L-pantolactone.

21. The method according to claim 1, wherein the racemate is methyl 3-cyclohexene-1-carboxylate, the ionizable form of the first optical isomer is (R)-3-cyclohexene-1-carboxylic acid, and the non-ionized form of the second optical isomer is (S)-methyl 3-cyclohexene-1-carboxylate.

22. The method according to claim 1, wherein the racemate is α-hydroxy-γ-butyrolactone, the ionizable form of the first optical isomer is (R)-α-hydroxy-γ-butyric acid, and the non-ionized form of the second optical isomer is (S)-α-hydroxy-γ-butyrolactone.

23. The method according to claim 1, wherein the racemate is β-hydroxy-γ-butyrolactone, the ionizable form of the first optical isomer is (R)-β-hydroxy-γ-butyric acid, and the non-ionized form of the second optical isomer is (S)-β-hydroxy-γ-butyrolactone.

24. The method according to claim 1, wherein the racemate is α-acetyl-γ-butyrolactone, the ionizable form of the first optical isomer is (R)-α-acetyl-γ-butyric acid, and the non-ionized form of the second optical isomer is (S)-α-acetyl-γ-butyrolactone.

25. (canceled)

Description

DETAILED DESCRIPTION

[0050] 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

[0051] ##STR00001##

[0052] 1. Preparation of an enzymatic conversion solution: 600 g of racemic pantolactone and 300 g of immobilized cells containing D-pantolactone hydrolase were added into a 2 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.

[0053] 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.

[0054] 3. Electrodialysis separation: A homogeneous membrane stack B (size: 10*30 cm; number of membrane pairs: 5 pairs) was used, a supernatant of the ultrafiltrate was pumped into an electrodialysis dilute compartment, 2 L of pure water was added into a concentrate compartment, the flow rate was adjusted to equalize the pressures of three compartments, and the electrodialysis was performed at a constant voltage of 10 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0055] A supernatant of the concentrate compartment was pumped into a dilute compartment of a second-stage electrodialysis device, 2 L of pure water was added into a concentrate compartment, the flow rate was adjusted to equalize the pressures of three compartments, and the electrodialysis was performed at a constant voltage of 10 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0056] 4. Concentration and acidification: A supernatant of the electrodialysis concentrate compartment was injected into a concentration equipment to be concentrated to about 400 mL under reduced pressure, and sulfuric acid was added into the concentrated supernatant to about pH1 to lactonize it.

[0057] 5. Crystallization: After the concentration, an upper layer of the acidified solution was removed to obtain 259.2 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%.

EXAMPLE 2

[0058] ##STR00002##

[0059] 1. Preparation of an enzymatic conversion solution: 900 g of racemic pantolactone and 90 g of 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 5 h.

[0060] 2. Pretreatment of the enzymatic conversion solution: the enzymatic conversion solution was first centrifuged with a butterfly centrifuge, then filtered with a 0.4 μm microfiltration membrane, and then filtered with a 20 kD ultrafiltration membrane.

[0061] 3. Electrodialysis separation: A heterogeneous membrane stack Z (size: 10*20 cm; number of membrane pairs: 10 pairs) was used, a supernatant of the ultrafiltrate was pumped into an electrodialysis dilute compartment, 3 L of pure water was added into a concentrate compartment, the flow rate was adjusted to make the pressure of the concentrate compartment 3 times that of the dilute compartment, and the electrodialysis was performed at a constant voltage of 25 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0062] A supernatant of the concentrate compartment was pumped into a dilute compartment of a second-stage electrodialysis device, 3 L of pure water was added into a concentrate compartment, the flow rate was adjusted to make the pressure of the concentrate compartment 3 times that of the dilute compartment, and the electrodialysis was performed at a constant voltage of 25 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0063] A supernatant of the concentrate compartment was pumped into a dilute compartment of a third-stage electrodialysis device, 3 L of pure water was added into a concentrate compartment, the flow rate was adjusted to make the pressure of the concentrate compartment 3 times that of the dilute compartment, and the electrodialysis was performed at a constant voltage of 25 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0064] A supernatant of the concentrate compartment was pumped into a dilute compartment of a fourth-stage electrodialysis device, 3 L of pure water was added into a concentrate compartment, the flow rate was adjusted to make the pressure of the concentrate compartment 3 times that of the dilute compartment, and the electrodialysis was performed at a constant voltage of 25 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0065] 4. Concentration and acidification: a supernatant of the electrodialysis concentrate compartment 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.

[0066] 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 97.6%.

EXAMPLE 3

[0067] ##STR00003##

[0068] 1. Preparation of an enzymatic conversion solution: 20 mL of methyl 3-cyclohexene-1-carboxylate and 10 g of Novozyme 435 lipase were added into a 1 L system at 35° C. with a pH of 7.5, the mixture was mechanically stirred at 200 rpm, and was titrated with 1N NaOH to keep the pH value at 7.5, to react for 5 h.

[0069] 2. Pretreatment of the enzymatic conversion solution: the enzymatic conversion solution was first filtered with a filter paper, and then filtered with a 0.4 μm microfiltration membrane.

[0070] 3. Electrodialysis separation: a homogeneous membrane stack S (size: 10*20 cm; number of membrane pairs: 10 pairs) was used, a supernatant of the ultrafiltrate was pumped into an electrodialysis dilute compartment, 1 L of pure water was added into a concentrate compartment, the flow rate was adjusted to equalize the pressures of three compartments, and the electrodialysis was performed at a constant voltage of 14 V until the electrical conductivity of the dilute compartment dropped to <100 μs/cm.

[0071] A supernatant of the concentrate compartment was pumped into a dilute compartment of a second-stage electrodialysis device, 1 L of pure water was added into a concentrate compartment, the flow rate was adjusted to equalize the pressures of three compartments, and the electrodialysis was performed at a constant voltage of 14 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0072] A supernatant of the concentrate compartment was pumped into a dilute compartment of a third-stage electrodialysis device, 1 L of pure water was added into a concentrate compartment, the flow rate was adjusted to equalize the pressures of three compartments, and the electrodialysis was performed at a constant voltage of 14 V until the electrical conductivity of the dilute compartment was <100 μs/cm.

[0073] 4. Treatment of a supernatant of the concentrate compartment: a supernatant of the electrodialysis concentrate compartment was injected into a concentration equipment to be concentrated to about 350 mL under reduced pressure, sulfuric acid was added into the concentrated supernatant to about pH5, an equal volume of ethyl acetate was added to extract and collect an organic phase, and distillation was performed under reduced pressure, to obtain (R)-3-cyclohexene-1-carboxylic acid with an ee value >99% and a yield of about 25.2%.

[0074] 5. Treatment of a supernatant of the dilute compartment: supernatants of the three stages of dilute compartments were mixed and injected into a concentration equipment to be concentrated to about 400 mL under reduced pressure, an equal volume of ethyl acetate was added to extract and collect an organic phase, and distillation was performed under reduced pressure, to obtain (S)-methyl 3-cyclohexene-1-carboxylate with an ee of 74.1% and a yield of about 41.2%.