CN112458142B - Method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by biocatalysis - Google Patents
Method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by biocatalysis Download PDFInfo
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Abstract
The invention discloses a method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by biocatalysis, which takes 2-carbonyl cyclopentanitrile as a substrate in a liquid phase reaction system and prepares (1R, 2R) -2-hydroxycyclovaleronitrile by ketoreductase catalytic carbonyl reduction in the presence of a hydrogen source and coenzyme. The conversion rate of the (1R, 2R) -2-hydroxycyclovaleronitrile prepared by the method is not lower than 85 percent, and the diastereomer excess value is not lower than 85 percent.
Description
Technical Field
The invention belongs to the technical field of biopharmaceuticals and biochemical engineering, and particularly relates to a method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by taking ketoreductase as a catalyst through reduction.
Background
The structural formula of the (1R, 2R) -2-hydroxycyclovaleronitrile is shown as a formula II, has chiral hydroxyl and chiral cyano, and is an important chiral intermediate.
The (1R, 2R) -2-hydroxycyclovaleronitrile can be prepared by asymmetrically reducing 2-carbonyl cyclopentanitrile by using ketoreductase. The related literature (org. Lett.2016,18, 3366-3369) reports that the asymmetric reduction of 2-carbonyl-cyclopentanitrile by using Codex KRED yields (1 r,2 r) -2-hydroxycyclovaleronitrile with a final substrate conversion of more than 99%, but with a diastereomeric excess of the product, yields a product (1 r,2 r) -2-hydroxycyclovaleronitrile of only 80%.
At present, no relevant literature report exists on a biological preparation method of (1R, 2R) -2-hydroxycyclovaleronitrile with high conversion rate and optical purity.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by biocatalysis, which aims to solve the technical problem that the (1R, 2R) -2-hydroxycyclovaleronitrile cannot be prepared with high conversion rate and high optical purity by biocatalysis in the prior art.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by biocatalysis comprises the steps of taking 2-carbonyl cyclopentanitrile (formula I) as a substrate in a liquid phase reaction system, and preparing the (1R, 2R) -2-hydroxycyclovaleronitrile (formula II) by catalyzing carbonyl reduction by ketoreductase in the presence of a hydrogen source and coenzyme.
The reaction formula is as follows:
in particular we have found that the use of the above ketoreductase has very good chiral selectivity for this reduction.
Preferably, the ketoreductase is selected from the group consisting of:
1) A ketoreductase from Lactobacillus kefiri, the amino acid sequence of which is shown in SEQ ID NO. 1;
2) Ketoreductase from Rhodococcus sp.WB1, the amino acid sequence of which is shown in SEQ ID NO. 2;
3) And carrying out substitution, deletion, change, insertion or addition of one or more amino acids to any one of the amino acid sequences shown in SEQ ID NO. 1-2 within the range of maintaining the enzymatic activity.
In a preferred embodiment, the ketoreductase is added in an amount of 0.1 to 10g of ketoreductase per g of substrate. Preferably, the ketoreductase is added in an amount of 1 to 5g of ketoreductase per g of substrate. Preferably, the ketoreductase is added in an amount of 2 to 3g of ketoreductase per g of substrate. Preferably, the ketoreductase is added in an amount of 2.5g of ketoreductase per g of substrate.
In a preferred embodiment, the hydrogen source is selected from at least one of isopropanol, glucose. Preferably, the hydrogen source is glucose; preferably, when the hydrogen source is glucose, glucose Dehydrogenase (GDH) is additionally added for use in combination.
In a preferred embodiment, the hydrogen source is added in an amount of 0.5 to 50g of hydrogen source per g of substrate; or 0.01 to 1g of Glucose Dehydrogenase (GDH) is additionally added.
In a preferred embodiment, the coenzyme is any one or more selected from NAD, NADH, NADP or NADPH.
In a preferred embodiment, the coenzyme is NADP or NAD.
In a preferred embodiment, the amount of coenzyme added is 0.01 to 1.0g of coenzyme per g of substrate.
In a preferred embodiment, the ketoreductase catalyzed reaction is carried out at a pH in the range of 7 to 9. When the pH is less than 7, the catalytic activity of the enzyme may be significantly reduced. When the pH is more than 9, the enzyme activity may be reduced.
Preferably, the pH of the ketoreductase catalyzed reaction is between 6.2 and 7.5. The pH control is carried out by adding a buffer to the reaction solvent.
In a preferred embodiment, the reaction is pH controlled by adding a buffer to the reaction solvent.
In a preferred embodiment, the buffer includes, but is not limited to KH 2 PO 4 -K 2 HPO 4 Buffer or NaH 2 PO 4 -Na 2 HPO 4 And (3) a buffer solution.
In a preferred embodiment, the ketoreductase catalyzed reaction is carried out at a temperature of 15 to 60 ℃. When the temperature is lower than 15 ℃, the reaction speed is slow. However, at temperatures above 60℃the enzyme is irreversibly inactivated.
Preferably, the reaction temperature is 20-40 ℃, and the stable and efficient reaction can be ensured. More preferably, the reaction temperature is 25-35 ℃,
in a preferred embodiment, the reaction solvent of the reaction system is water or a buffered saline solution. The pH of the reaction system was controlled by a buffer. Commonly used buffers include, but are not limited to KH 2 PO 4 -K 2 HPO 4 Or NaH 2 PO 4 -Na 2 HPO 4 And (3) a buffer solution. Wherein the concentration of phosphate in the phosphate buffer solution is 0.1-2 mmol/L, preferably 0.2mol/L; the pH of the phosphate buffer solution ranges from 7 to 9, preferably ph=6.2 to 7.5.
In a preferred embodiment, the reaction system further comprises a cosolvent. The cosolvent is an organic solvent.
In a preferred embodiment, the co-solvent is selected from the group consisting of: n, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetone, or a combination thereof. Preferably, the cosolvent is selected from N, N-dimethylformamide or dimethyl sulfoxide. The co-solvent is used to further increase the solubility of the substrate.
In a preferred embodiment, the preparation process of the present invention further comprises the step of isolating (1R, 2R) -2-hydroxycyclovaleronitrile.
The conversion rate of the (1R, 2R) -2-hydroxycyclovaleronitrile prepared by the method is not lower than 85 percent, and the diastereomer excess value is not lower than 85 percent; preferably, the conversion is not less than 90% and the diastereomeric excess is not less than 90%; more preferably, the conversion is not less than 95% and the diastereomeric excess is not less than 95%.
The invention realizes the selective reduction of 2-carbonyl cyclopentanitrile by a novel enzyme catalysis process technology, thereby realizing the purpose of preparing pure (1R, 2R) -2-hydroxy cyclopentanitrile on a large scale.
The method has the beneficial effects that the conversion rate of the (1R, 2R) -2-hydroxycyclovaleronitrile prepared by the method is not lower than 85 percent, and the diastereomer excess value is not lower than 85 percent. The high-efficiency production of enantiomerically pure (1R, 2R) -2-hydroxycyclovaleronitrile by a novel enzyme catalysis technology is of great importance. The method has the advantages of simple and easy operation, high yield and good selectivity.
Drawings
FIG. 1 is a high performance gas chromatography chart of (1R, 2R) -2-hydroxycyclovaleronitrile in example 1.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The inventors of the present application have conducted intensive studies and have unexpectedly found a method for biocatalytically preparing (1R, 2R) -2-hydroxycyclovaleronitrile for the first time. Specifically, the method of the present invention generally comprises the steps of:
(1) Catalytic reduction of 2-carbonyl cyclopentanitrile using ketoreductase. The amount of ketoreductase added is 0.1 to 10g of ketoreductase per g of substrate (preferred range is 2.5g of ketoreductase per g of substrate). 0.5 to 50g of glucose/g of substrate is selected as a hydrogen source, and 0.01 to 1g of Glucose Dehydrogenase (GDH)/g of substrate is further added as a hydrogen source, 0.01 to 1.0g of Nicotinamide Adenine Dinucleotide Phosphate (NADP)/g of substrate and 0.01 to 1.0g of Nicotinamide Adenine Dinucleotide (NAD)/g of substrate are used as coenzymes. The reaction temperature is 15 to 60℃and preferably 25 to 35 ℃. The reaction medium used is pure water or KH with phosphate concentration of 0.02-2 mol/L (preferably 0.2 mol/L) and pH range of 5-9 (preferably pH=6.2-7.5) 2 PO 4 -K 2 HPO 4 Or NaH 2 PO 4 -Na 2 HPO 4 The buffer solution can also be pure water or a two-phase system consisting of the buffer solution and a water-immiscible organic solvent (such as N, N-dimethylformamide or dimethyl sulfoxide and the like).
(2) After the reaction is finished, extracting with methyl tertiary butyl ether, collecting an organic phase, and evaporating the solvent to obtain the product.
The reagents and materials used in the present invention are commercially available. The ketoreductase used in the invention is derived from a synthetic enzyme library.
Example 1
First, 120mg of 2-carbonyl cyclopentanonitrile was dissolved in 0.3mL of dimethyl sulfoxide to prepare a raw material liquid. In a 15mL glass reaction flask, 6mL of phosphate buffer (6 mL of water, 0.064g KH was added) 2 PO 4 And 0.167g K 2 HPO 4 Stirring until the solid is dissolved; adding potassium hydroxide to adjust the pH value to 6.2-7.5; 360mg of glucose, 12mg of NADP, 12mg of GDH and 5mg Lactobacillus kefiri ketone reductase are added into the reaction liquid, and after shaking and mixing, 0.3mL of raw material liquid is added; the reaction solution was adjusted and controlled to 30℃and pH 7.0, and stirred continuously for 18 hours.
The reaction mixture was extracted with 2mL of methyl tert-butyl ether, and the organic phase was collected and analyzed by high performance gas chromatography with a conversion of 95% and a cis-enantiomer excess of 99.1%. Analysis conditions: the island body gas chromatograph, alpha DEX120 (30X 0.25mm,0.25 μm) chiral chromatographic column, the temperature is kept at 150 ℃ for 5min, then the temperature is raised to 180 ℃ per minute for 1 min, and the carrier gas is nitrogen (carrier gas flow rate 30 mL/min); hydrogen (carrier gas flow rate 40 mL/min). The gas chromatography spectrum of the product is shown in figure 1
Example 2
First, 120mg of 2-carbonyl cyclopentanonitrile was dissolved in 0.3mL of dimethyl sulfoxide to prepare a raw material liquid. In a 15mL glass reaction flask, 6mL of phosphate buffer (6 mL of water, 0.064g KH was added) 2 PO 4 And 0.167g K 2 HPO 4 Stirring until the solid is dissolved; adding potassium hydroxide to adjust the pH value to 6.2-7.5; 360mg of glucose, 12mg of NADP, 12mg of GDH and 5mg of sp.WB1 ketoreductase from Rhodococcus are added into the reaction solution, and after shaking and mixing, 0.3mL of raw material solution is added; the reaction solution was adjusted and controlled to 30℃and pH 7.0, and stirred continuously for 18 hours.
The reaction mixture was extracted with 2mL of methyl tert-butyl ether, and the organic phase was collected and analyzed by high performance gas chromatography, with a conversion of 99% and a cis-enantiomer excess of 95.1%. Analysis conditions: the island body gas chromatograph, alpha DEX120 (30X 0.25mm,0.25 μm) chiral chromatographic column, the temperature is kept at 150 ℃ for 5min, then the temperature is raised to 180 ℃ per minute for 1 min, and the carrier gas is nitrogen (carrier gas flow rate 30 mL/min); hydrogen (carrier gas flow rate 40 mL/min); air (carrier gas flow rate 400 mL/min), the diluent is methanol.
In summary, the above embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, but any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the scope of the present invention.
Sequence listing
<110> Shanghai full pharmaceutical research and development Co., ltd
<120> method for biocatalytically preparing (1R, 2R) -2-hydroxycyclovaleronitrile
<130> CPC-NP-20-101843
<160> 2
<170> SIPOSequenceListing 1.0
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<212> PRT
<213> Ketone reductase (Lactobacillus kefir)
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Ile Cys Val Tyr Leu Ala Ser Asp Glu Ser Lys Phe Ala Thr Gly Ala
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Glu Phe Val Val Asp Gly
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Claims (20)
1. A method for preparing (1R, 2R) -2-hydroxycyclovaleronitrile by biocatalysis is characterized in that in a liquid phase reaction system, 2-carbonyl cyclopentanitrile is used as a substrate, and (1R, 2R) -2-hydroxycyclovaleronitrile is prepared by ketoreductase catalytic carbonyl reduction in the presence of a hydrogen source and coenzyme;
the ketoreductase is selected from the group consisting of:
1) A ketoreductase from Lactobacillus kefiri, the amino acid sequence of which is shown in SEQ ID NO. 1;
2) Ketoreductase from Rhodococcus sp.WB1, the amino acid sequence of which is shown in SEQ ID NO. 2;
the pH of the ketoreductase catalyzed reaction is 6.2-7.5.
2. The method of claim 1, wherein the ketoreductase is added in an amount of 0.1 to 10g of ketoreductase per g of substrate.
3. The method of claim 2, wherein the ketoreductase is added in an amount of 1 to 5g of ketoreductase per g of substrate.
4. A method according to claim 3, wherein the ketoreductase is added in an amount of 2 to 3g of ketoreductase per g of substrate.
5. A method according to claim 3, wherein the ketoreductase is added in an amount of 2.5g of ketoreductase per g of substrate.
6. The method of claim 1, wherein the hydrogen source is selected from at least one of isopropanol and glucose.
7. The method of claim 6, wherein the hydrogen source is glucose and the additional glucose dehydrogenase is used in combination.
8. The method of claim 1, wherein the hydrogen source is added in an amount of 0.5 to 50g of hydrogen source per g of substrate; or 0.01 to 1g of glucose dehydrogenase is additionally added.
9. The method of claim 1, wherein the coenzyme is any one or more selected from NAD, NADH, NADP or NADPH.
10. The method of claim 9, wherein the coenzyme is NADP or NAD.
11. The method according to claim 1, wherein the coenzyme is added in an amount of 0.01 to 1.0g of coenzyme per g of substrate.
12. The method of claim 1, wherein the ketoreductase catalyzed reaction has a reaction temperature of 15 to 60 ℃.
13. The method of claim 12, wherein the ketoreductase catalyzed reaction has a reaction temperature of 20 to 40 ℃.
14. The method of claim 13, wherein the ketoreductase catalyzed reaction has a reaction temperature of 25 to 35 ℃.
15. The method of claim 1, wherein the reaction solvent of the reaction system is water or a buffered saline solution.
16. The method of claim 15, wherein the buffered saline solution is KH 2 PO 4 -K 2 HPO 4 Buffer or NaH 2 PO 4 -Na 2 HPO 4 And (3) a buffer solution.
17. The method of claim 1, wherein the reaction system further comprises a co-solvent.
18. The method of claim 17, wherein the co-solvent is an organic solvent selected from the group consisting of: n, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetone, or a combination thereof.
19. The method of claim 18, wherein the co-solvent is selected from the group consisting of N, N-dimethylformamide and dimethylsulfoxide.
20. The method of claim 1, further comprising the step of isolating (1 r,2 r) -2-hydroxycyclovaleronitrile.
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