CN105969815B - Biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester - Google Patents
Biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester Download PDFInfo
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- CN105969815B CN105969815B CN201610398199.7A CN201610398199A CN105969815B CN 105969815 B CN105969815 B CN 105969815B CN 201610398199 A CN201610398199 A CN 201610398199A CN 105969815 B CN105969815 B CN 105969815B
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
- C12P7/6436—Fatty acid esters
Abstract
The invention discloses a biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, which takes 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester as a substrate, the substrate is subjected to reduction reaction in the presence of a biocatalyst, a cofactor and a cofactor regeneration system to generate (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, the biocatalyst is monooxygenase, the cofactor regeneration system comprises glucose and glucose dehydrogenase, the reduction reaction is carried out in an aqueous phase buffer solution with the temperature of 20-30 ℃ and the pH value of 7.0-8.0. Compared with the prior art, the method has the advantages that no dangerous goods and organic hydroxylation reagent are used in the whole reaction process, the economical efficiency of the production process is greatly improved, the method is environment-friendly, and the substrate conversion rate is high.
Description
Technical Field
The invention relates to the technical field of biochemical engineering, and in particular relates to a biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester.
Background
According to the statistics of the world grain and crop organization, the loss of crops caused by the invasion of diseases, pests and weeds is equivalent to one third of the annual crop yield of the world. At present, agricultural chemicals in China are mainly high-toxicity agricultural chemicals such as organic phosphorus, carbamate and the like, and the development of efficient, low-toxicity and environment-friendly insecticides is urgent.
The oxadiazine pesticide is a novel pesticide which is discovered after pyrethrin, imidacloprid and other pesticides and has epoch-making significance. Indoxacarb (indoxacarb) is a novel oxadiazine (oxadiazine) insecticide developed by DuPont in the United states, has the trade name Ammate/Avatar, is a sodium channel inhibition broad-spectrum insecticide, has killing capacity on almost all lepidoptera pests, has the advantages of high insecticidal activity, good environmental compatibility, low toxicity on mammals and safety on birds, fishes and beneficial insects, and is an ideal variety for replacing high-toxicity organophosphorus insecticides.
Indoxacarb (indoxacarb)
The key of the preparation method of the indoxacarb is to obtain a chiral intermediate (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester (1). From a green chemistry perspective, one-step hydroxylation of its precursor 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester (2) is the most efficient method:
the currently disclosed routes for producing the compound 1 are patents disclosed by the U.S. DUPONT company (DUPONT), such as WO 1992011249, US 5462938, US 5510505 and WO 199529171, and the routes use hydrogen as a raw material, require a pressurized kettle for reaction, and have potential safety hazards such as explosion; and some improved routes are made on the basis of the above patents, such as CN 105152958, CN 104193696, CN 104193620 and the like. The chemical routes, which are usually carried out in organic solvents, require the addition of organic hydroxylating reagents (such as organic hydrazine and cinchona alkaloid), which are limited in practical sources and expensive, so that the economical efficiency and environmental friendliness of the chemical routes need to be improved.
Disclosure of Invention
The invention aims to provide a biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, which overcomes the defects of the prior art, has good economy and is environment-friendly.
In order to achieve the purpose, the invention adopts the technical scheme that: a biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester uses 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester as a substrate, the substrate is subjected to a reduction reaction in the presence of a biocatalyst, a cofactor and a cofactor regeneration system to generate (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, the biocatalyst is monooxygenase, the cofactor regeneration system comprises glucose and glucose dehydrogenase, the reduction reaction is carried out at a temperature of 20-30 ℃, The pH value is 7.0-8.0, the concentration of the substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester in an initial reaction system is 15-25mg/mL, and the mass ratio of the monooxygenase to the substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 1: 1-20. Preferably, the concentration of the substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 20mg/mL, and the mass ratio of the monooxygenase to the substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 1: 10.
Preferably, the monooxygenase enzyme is one or a combination of monooxygenases available from seoul hanse biotechnology limited under the designation EW1531, EW1535, EW1536, or EW 1538.
Further preferably, the monooxygenase enzyme is a monooxygenase enzyme available from Suzhou Han enzymes Biotechnology Limited under the designation EW 1535.
Preferably, in the initial reaction system, the ratio of glucose: glucose dehydrogenase: the mass ratio of the 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 1.6-15:1: 1-20; more preferably, the ratio of glucose: glucose dehydrogenase: the feeding mass ratio of the 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 15:1: 10.
Preferably, the cofactor is NADP in a mass ratio to methyl 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylate of 1:1 to 100, more preferably, NADP in a mass ratio to methyl 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylate of 1: 100.
Preferably, the reaction is carried out under co-solvent conditions.
Further preferably, the cosolvent is one or a combination of cyclohexane, polyethylene glycol 400, polyethylene glycol 200, glycerol, toluene, ethylene glycol and tween-60.
Preferably, the aqueous phase buffer solution is a phosphate buffer solution.
Preferably, the specific implementation process is as follows: sequentially adding the aqueous phase buffer solution and a substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester into a reaction container, uniformly stirring, then adding the monooxygenase, the cofactor, glucose and glucose dehydrogenase, carrying out oscillation reaction at the temperature of 20-30 ℃, detecting the reaction process by HPLC (high performance liquid chromatography), filtering to remove the enzyme when the conversion rate reaches 90-99%, then adding equal volume of ethyl acetate for multiple extraction, combining organic phases, and removing the solvent to obtain the (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester product.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: according to the invention, 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is reduced by adopting biological enzyme to generate (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, the whole preparation process is carried out in a water phase, and compared with the prior art, hydrogen is not needed, and explosion hidden danger is avoided; meanwhile, an organic hydroxylation reagent is not required to be added, the economy is good, the environment is friendly, the conversion rate of the substrate is high, and the ee value of the product is high.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples. The implementation conditions adopted in the examples can be further adjusted according to different requirements of specific use, and the implementation conditions not indicated are those in routine experiments.
Example 1
975. mu.L of 100mM phosphate buffer solution with pH 8.0, 2mg of substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester and 25. mu.L of methanol were sequentially added to a 2mL centrifuge tube, and after stirring uniformly, 2mg of different monooxygenases (from Han Su enzyme Biotechnology, Ltd.) and 2mg of NADP, 3.2mg of glucose and 2mg of glucose dehydrogenase were added, followed by shaking reaction at 30 ℃ and 24-hour HPLC analysis of the reaction results shown in Table 1.
TABLE 1
| EW1531 | EW1535 | EW1536 | EW1538 | |
| Conversion rate | 33％ | 48.3％ | 47.3％ | 43.9％ |
| Product ee | 96.1％ | 96.7％ | 92.5％ | 100％ |
As can be seen from Table 1, the highest substrate conversion was obtained with the monooxygenase enzyme having the designation EW1535, whereas the highest product e e value was obtained with the monooxygenase enzyme having the designation EW1538, under otherwise identical reaction conditions.
Example 2
Into a 5mL centrifuge tube, 1950. mu.L of 100mM phosphate buffer solution with pH 8.0, 4mg of substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester and 50. mu.L of methanol were added in this order, and after stirring well, 1mg of monooxygenase EW1538 (from Han enzyme Biotechnology, Suzhou Co., Ltd.), 0.5mg of NADP, 6mg of glucose and 1mg of glucose dehydrogenase were added, and shaking reaction was carried out at different temperatures, and the results of HPLC detection are shown in Table 2.
TABLE 2
| Temperature/. degree.C | 20 | 30 | 40 |
| 1h | 27.9％ | 24.5％ | 7.0％ |
| 3h | 57.5％ | 67.6％ | 7.5％ |
| 24h | 67.6％ | 71.4％ | 7.6％ |
As can be seen from Table 2, the conversion of the substrate was the highest when the reaction was carried out at a temperature of 30 ℃ under otherwise identical reaction conditions.
Example 3
1950. mu.L of 100mM buffer solutions with different pH values were sequentially added to a 5mL centrifuge tube, 4mg of substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester and 50. mu.L of methanol were added, and after stirring uniformly, 1mg of monooxygenase EW1538 (from Han Su dynasty enzyme Biotechnology Co., Ltd., Suzhou), 0.5mg of NADP, 6mg of glucose and 1mg of glucose dehydrogenase were added, and shaking reaction was carried out at 30 ℃ and the reaction results were measured by HPLC as shown in Table 3.
TABLE 3
| pH | 5.5 | 6.0 | 7.0 | 8.0 |
| 1h | 14.9％ | 20.7％ | 27.0％ | 24.5％ |
| 3h | 23.9％ | 39.8％ | 72.8％ | 67.6％ |
| 24h | 19.4％ | 33.6％ | 80.1％ | 71.4％ |
As can be seen from Table 3, the highest substrate conversion was obtained when the above reaction was carried out in an aqueous buffer solution at pH 7.0 under otherwise identical reaction conditions.
Example 4
Into a 5mL centrifuge tube, 1900. mu.L of 100mM pH 7.0 buffer solution, 4mg of substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester and 100. mu.L of different cosolvents were sequentially added, and after stirring well, 1mg of monooxygenase EW1538 (from Han enzyme Biotechnology, Suzhou Co., Ltd.), 0.5mg of NADP, 6mg of glucose, 1mg of glucose dehydrogenase were added, shaking reaction was performed at 30 ℃ and reaction results were measured by HPLC for 24 hours as shown in Table 4.
TABLE 4
| Cosolvent | Control group | Cyclohexane | PEG400 | PEG200 | Glycerol | Toluene | Ethylene glycol |
| 2h | 10.4％ | 17.58％ | 17.21％ | 14.63％ | 14.10％ | 10.50％ | 10.7％ |
| 4h | 15.3％ | 25.55％ | 22.06％ | 20.21％ | 20.57％ | 19.07％ | 16.5％ |
| Cosolvent | Tween 60 | Triton | DMSO | Methanol | N-hexanol | MTBE | |
| 2h | 7.6％ | 10.5％ | 9.9％ | 8.3％ | 7.5％ | 6.9％ | |
| 4h | 16.9％ | 15.8％ | 14.1％ | 14.1％ | 12.6％ | 12.1％ |
As can be seen from Table 4, the highest substrate conversion was obtained with cyclohexane as the co-solvent under otherwise identical reaction conditions.
Example 5
In a 100mL reaction vessel, 47.5mL of 100mM phosphate buffer solution with pH 7.0 is sequentially added, 1g of substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester and 2.5mL of cyclohexane are added, after uniform stirring, 0.1g of monooxygenase EW1538 (from Suzhou Han enzyme biotechnology limited), 0.01g of NADP, 1.5g of glucose and 0.1g of glucose dehydrogenase are added, shaking reaction is carried out at 30 ℃, the reaction conversion rate is 99% by 24-hour HPLC (high performance liquid chromatography), equal volume ethyl acetate is extracted for 3 times after enzyme is filtered out, organic phases are combined, and the solvent is removed to obtain 1.05g of a product with purity of 95% and an ee value of 99%.
The above-mentioned embodiments are merely illustrative of the technical idea and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered in the scope of the present invention.
Claims (7)
1. A biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, which takes 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester as a substrate, the substrate is subjected to reduction reaction in the presence of a biocatalyst, a cofactor and a cofactor regeneration system to generate (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, characterized in that the biocatalyst is monooxygenase, the cofactor regeneration system comprises glucose and glucose dehydrogenase, the reduction reaction is carried out in an aqueous buffer solution with the temperature of 20-30 ℃ and the pH value of 7.0-8.0, in an initial reaction system, the concentration of the substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 15-25mg/mL, the mass ratio of the monooxygenase to the substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 1:10-20, the monooxygenase is one or more of monooxygenases which are produced by Suzhou Han enzyme biotechnology limited and have the brand numbers of EW1531, EW1535, EW1536 or EW1538, and the reaction is carried out under the condition of a cosolvent.
2. The process for the biological preparation of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester according to claim 1 wherein the monooxygenase enzyme is a monooxygenase enzyme available from sehamia tsugami biotechnology limited under the designation EW 1535.
3. The process for the biological production of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester according to claim 1, wherein in the initial reaction system, the ratio of glucose: glucose dehydrogenase: the mass ratio of the 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 15:1: 10.
4. The biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester according to claim 1, characterized in that the cofactor is NADP, and the mass ratio of the cofactor to 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester is 1: 1-100.
5. The process for the biological preparation of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester according to claim 1, wherein the cosolvent is one or more of cyclohexane, polyethylene glycol 400, polyethylene glycol 200, glycerol, toluene, ethylene glycol, tween-60.
6. The process for the biological preparation of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester according to claim 1, characterized in that the aqueous buffer solution is a phosphate buffer solution.
7. The biological preparation method of (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester according to claim 1, characterized in that the specific implementation process is as follows: sequentially adding the aqueous phase buffer solution and a substrate 5-chloro-2, 3-dihydro-1-oxo-1H-indene-2-carboxylic acid methyl ester into a reaction container, uniformly stirring, then adding the monooxygenase, the cofactor, glucose and glucose dehydrogenase, carrying out oscillation reaction at the temperature of 20-30 ℃, detecting the reaction process by HPLC (high performance liquid chromatography), filtering to remove the enzyme when the conversion rate reaches 90-99%, then adding equal volume of ethyl acetate for multiple extraction, combining organic phases, and removing the solvent to obtain the (S) -5-chloro-2, 3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester product.
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