Racemization recovery and purification method of chiral intermediate resolution byproduct (2R)-2, 4-dimethyl-4-nitro-valeric acid

Abstract

The invention relates to a racemization recovery and purification method of a chiral intermediate resolution byproduct (2R)-2, 4-dimethyl-4-nitro-pentanoic acid, which comprises the following specific steps: 1) carrying out esterification reaction on (2R)-2, 4-dimethyl-4-nitro-pentanoic acid (I) to obtain (2R)-2, 4-dimethyl-4-nitro-pentanoic acid methyl ester (II); (2) racemizing the (2R)-2, 4-dimethyl-4-nitro-pentanoic acid methyl ester (II) to obtain racemic 2, 4-dimethyl-4-nitro-pentanoic acid methyl ester (III), and then carrying out enzyme hydrolysis to obtain a useful intermediate and (2R)-2, 4-dimethyl-4-nitro-pentanoic acid; and (3) repeating the steps (1) and (2) on (2R)-2, 4-dimethyl-4-nitro-valeric acid for utilization. According to the method provided by the invention, certain economic value can be created, waste of raw materials is avoided, and environmental pollution is reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a method for racemization recovery and purification of (2R)-2,4-dimethyl-4-nitro-pentanoic acid, a by-product of chiral intermediate resolution. Background Art

[0002] (S)-2,2,4-trimethylpyrrolidine free base and its salt forms, (R)-2,2,4-trimethylpyrrolidine free base and its salt forms, (S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one and 5,5-dimethyl-3-methylenepyrrolidine-2-one can all be used to synthesize pharmaceutically active molecules such as CFTR activity regulators and are used clinically.

[0003] WO2020242935A reports a method for obtaining (S)-2,2,4-trimethylpyrrolidine using 2-nitropropane and methyl methacrylate as raw materials through Michael addition reaction, chiral resolution, reduction condensation, and amide reduction steps. The method uses enzymes for chiral resolution to obtain a useful intermediate (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester and a chiral byproduct (2R)-2,4-dimethyl-4-nitro-pentanoic acid, with an ee value of approximately 90%.

[0004] The utilization method of (2R)-2,4-dimethyl-4-nitro-pentanoic acid has not been reported so far. It is generally treated as waste, resulting in a waste of resources and causing environmental pollution. Therefore, it is very necessary to explore a simple, safe, efficient and low-cost method for its recycling. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a racemization recovery and purification method for (2R)-2,4-dimethyl-4-nitro-pentanoic acid, a by-product of chiral intermediate splitting, in view of the deficiencies in the prior art. The method can effectively recover and utilize (2R)-2,4-dimethyl-4-nitro-pentanoic acid, increase industrial output and reduce pollutant emissions.

[0006] The present invention provides a method for racemization recovery and purification of (2R)-2,4-dimethyl-4-nitro-pentanoic acid, a by-product of chiral intermediate resolution, and the specific steps are as follows:

[0007] 1) subjecting (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to an esterification reaction with methanol and thionyl chloride (as a catalyst) to obtain (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II);

[0008] 2) racemizing the (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) obtained in step 1) under the action of a base to obtain a rac-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III), and then hydrolyzing the rac-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) using an enzyme to obtain a useful intermediate (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (IV) and (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee value is about 90%);

[0009] 3) Repeat the above steps 1) and 2) for the (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in step 2) and utilize it.

[0010] Preferably, the optical purity of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) in step 1) is improved by the following method: reacting the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) with a chiral amine to form a salt (V), and then adjusting the acid to precipitate the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (VI) with high optical purity.

[0011] According to the above scheme, the chiral amine is one of ephedrine, strychnine, cinchonidine, cinchonine, quinidine, S-1-naphthylethylamine, S-1-phenylethylamine, and spartine, preferably S-1-naphthylethylamine.

[0012] Taking S-1-naphthylethylamine as an example, the reaction formula is as follows:

[0013]

[0014] According to the above scheme, the specific steps are as follows: under heating conditions, (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is dissolved in a solvent, a chiral amine is added to react to generate a salt, recrystallized, filtered, and a salt (V) with high optical purity is obtained, the salt (V) is dissolved in water, an acid is added, and the salt is extracted and concentrated to obtain (2R)-2,4-dimethyl-4-nitro-pentanoic acid (VI) with high optical purity.

[0015] According to the above scheme, the solvent is selected from one of acetonitrile, methanol, ethanol, n-propanol, isopropanol, butyl acetate, isopropyl acetate, ethyl acetate, 1,4-dioxane, tetrahydrofuran, acetone and toluene, preferably acetonitrile or acetone.

[0016] According to the above scheme, the mass volume ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to the solvent is 0.08-0.12 g / mL.

[0017] According to the above scheme, the molar ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to the chiral amine is 1:0.7-1.2.

[0018] According to the above scheme, the heating temperature is 80-100°C and the reaction time is 2-4 hours.

[0019] According to the above scheme, step 1) (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is subjected to an esterification reaction with methanol and thionyl chloride. The specific steps are as follows: (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is dissolved in methanol, and then thionyl chloride is added under ice-water bath conditions, and the temperature is raised to room temperature (15-35°C) for esterification reaction, and post-treatment is performed to obtain (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II).

[0020] According to the above scheme, the mass volume ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to methanol is 0.2-0.5 g / mL; the molar ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to thionyl chloride is 1:1.8-2.1.

[0021] According to the above scheme, the esterification reaction time is 2-4 hours.

[0022] According to the above scheme, the post-treatment includes: quenching with ice water, extraction, and concentration steps.

[0023] According to the above scheme, the specific method of step 2) is as follows: (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) is dissolved in a solvent, a base is added to carry out a racemization reaction, and 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) is purified to obtain a racemic 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III), and then the obtained racemic 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) is added to a buffer solution, and lipase is added to carry out a selective hydrolysis reaction to obtain a useful intermediate (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (IV) and (2R)-2,4-dimethyl-4-nitro-pentanoic acid.

[0024] According to the above scheme, the solvent is selected from one of acetonitrile, methanol, ethanol, n-propanol, butyl acetate, isopropyl acetate, ethyl acetate, 1,4-dioxane, tetrahydrofuran, acetone, and toluene, preferably methanol or ethanol, and the mass volume ratio of (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) to the solvent is 0.2-0.5 g / mL.

[0025] According to the above scheme, the base is an inorganic base or an organic base, wherein the inorganic base is potassium carbonate or cesium carbonate, and the organic base is one of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), DABCO (triethylenediamine), sodium methoxide, sodium ethoxide, triethylamine, DIPEA (N,N-diisopropylethylamine), sodium hydride, and potassium tert-butoxide, and the molar ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) to the base is 1:0.7-3.

[0026] According to the above scheme, the racemization reaction conditions are: 80-100°C for 8-12 hours.

[0027] According to the above scheme, the buffer solution is selected from one of PBS buffer solution, potassium dihydrogen phosphate solution, sodium dihydrogen phosphate solution or Tris-HCl buffer solution, with a pH value of 7-8, and the mass volume ratio of mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) to the buffer solution is 0.08-0.12 g / mL.

[0028] According to the above scheme, the mass ratio of the mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) to the lipase is 1:0.2-1.

[0029] According to the above scheme, the hydrolysis reaction conditions are: reaction at 30-40°C for 24-48 hours.

[0030] The beneficial effects of the present invention are as follows: the racemization recovery and purification method of the chiral intermediate splitting by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid provided by the present invention has a simple process and low cost, and can recycle useless by-products produced in large quantities in industry, create certain economic value, avoid waste of raw materials, and reduce environmental pollution. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in step 3) of Example 1;

[0032] Figure 2 This is the liquid chromatogram of the chromatographic 2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 2) of Example 1;

[0033] Figure 3 This is the liquid chromatogram of (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 3) of Example 1;

[0034] Figure 4 This is the liquid chromatogram of (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in Example 3. DETAILED DESCRIPTION

[0035] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below using embodiments in conjunction with the accompanying drawings.

[0036] The raw material (2R)-2,4-dimethyl-4-nitro-pentanoic acid used in the examples of the present invention is a by-product of the industrial production of (S)-2,2,4-trimethylpyrrolidine, and the ee value is 90%.

[0037] Example 1

[0038] A method for recovering the racemization of (2R)-2,4-dimethyl-4-nitro-pentanoic acid, a by-product of the resolution of a chiral intermediate,

[0039] Here are the steps:

[0040] 1) Take a 50mL single-necked flask, add 5.0g (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 90%) and 12mL methanol, add 4.15mL thionyl chloride dropwise under ice-water bath conditions, then warm to room temperature (25°C) and react for 2h. After the reaction, add 10mL ice water to quench the reaction, then add 10mL dichloromethane to extract 3 times, combine the organic phases, and wash with 20mL saturated NaHCO 3 The solution was washed three times, an appropriate amount of anhydrous sodium sulfate was added, filtered, and the solvent was dried at 40° C. to obtain 5.07 g of yellow oily liquid (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (yield 94.0%, ee value 90%), and this step was repeated several times to collect (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester;

[0041] 2) Take a 50mL single-mouth bottle, add 5.23g of (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 1), 22.3mL of ethanol and 4.75g of sodium ethoxide, heat to 80°C and reflux overnight. After the reaction is completed, cool to room temperature, spin-dry ethanol at 50°C, add 10mL of ethyl acetate and extract twice, add 10mL of 2mol / L hydrochloric acid solution to wash and remove alkali during each extraction process, then wash the organic phase with 10mL of saturated brine, add an appropriate amount of anhydrous sodium sulfate and then spin-dry the solvent at 45°C to obtain 4.65g of yellow oily liquid, i.e., mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (yield 89.0%), repeat this step several times to collect mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester;

[0042] 3) Take a 100mL single-mouth bottle, add 5.04g of the mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 2), then add 50mL PBS buffer solution (pH=7) and 2.92g lipase, heat the reaction system to 35°C and stir the reaction, maintain the pH value of the reaction solution at 7.0±0.2 by adding 0.25g / mL potassium carbonate solution, and stop heating when the racemic starting material is converted into the S enantiomer with an ee value of 100% by LC monitoring (reaction 36h), then filter the reaction solution to remove the enzyme, extract the filtrate with methyl tert-butyl ether 3 times, combine the organic phases, and wash twice with 20mL saturated brine, add an appropriate amount of anhydrous sodium sulfate to the organic phase, spin dry at 40°C, and obtain 2.01 g yellow oily liquid, namely (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (yield 40.0%, ee value 100%), and then the pH value of the aqueous phase obtained after extraction with methyl tert-butyl ether was adjusted to 3-4 with 6 mol / L hydrochloric acid solution, and then extracted with ethyl acetate 3 times, the organic phases were combined, washed with 15 mL saturated brine twice, an appropriate amount of anhydrous sodium sulfate was added, filtered, and then the solvent was spin-dried at 40° C. to obtain 2.57 g yellow oily liquid, namely (2R)-2,4-dimethyl-4-nitro-pentanoic acid (yield 55.2%, ee value 90%);

[0043] 4) Repeat the above steps 1) to 3) for the (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in step 3) and utilize it.

[0044] like Figure 1 The figure shows the hydrogen nuclear magnetic resonance spectrum of (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in step 3) of this embodiment. 1 H NMR (500MHz, Chloroform-d): δ10.64(s,1H),2.66–2.21(m,2H),2.19–1.93(m,1H),1.56(dt,J=11.9,2.0Hz,6H),1.27–1.14(m,3H).

[0045] Figure 2 This is the liquid chromatogram of the rac-2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 2) of this embodiment. It can be seen from the figure that (S)-configuration: (R)-configuration = 48%:52%, and the effect of racemization can be achieved.

[0046] Figure 3 This is the liquid chromatogram of (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 3) of this embodiment. The ee value of (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester was measured to be 100%.

[0047] Example 2

[0048] A method for recovering the racemization of (2R)-2,4-dimethyl-4-nitro-pentanoic acid, a byproduct of the resolution of a chiral intermediate, comprises the following specific steps:

[0049] 1) Take a 100 mL single-necked flask, add 20.0 g (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 90%) and 46 mL methanol, then add 16.58 mL thionyl chloride dropwise under ice-water bath conditions, then warm to room temperature for 2 h, add 40 mL ice water after the reaction is completed to quench the reaction, then add 40 mL dichloromethane for extraction 3 times, combine the organic phases, and wash with 80 mL saturated NaHCO 3 The solution was washed three times, an appropriate amount of anhydrous sodium sulfate was added, filtered, and the solvent was dried at 40°C to obtain 20.32 g of yellow oily liquid (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (yield 94.1%, ee 90%), and this step was repeated several times to collect (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester;

[0050] 2) Take a 100mL single-mouth bottle, add 20.32g of (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 1), 43mL of ethanol and 18.48g of sodium ethoxide, heat to 80°C and reflux overnight. After the reaction is completed, cool to room temperature, spin-dry ethanol at 50°C, add 30mL of ethyl acetate and extract twice, add 30mL of 2mol / L hydrochloric acid solution to wash and remove alkali during each extraction process, then wash the organic phase with 30mL of saturated brine, add an appropriate amount of anhydrous sodium sulfate and then spin-dry the solvent at 45°C to obtain 18.5g of yellow oily liquid, i.e., mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (yield 90.0%), repeat this step several times to collect mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester;

[0051] 3) Take a 1000mL single-mouth bottle, add 85.82g of the mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester obtained in step 2), then add 800mL PBS buffer solution (pH=7) and 49.30g lipase, heat the reaction system to 35°C and stir the reaction, maintain the pH value of the reaction solution at 7.0±0.2 by adding 0.25g / mL potassium carbonate solution, stop heating when the racemic starting material is converted into the S enantiomer with an ee value of 100% by LC monitoring (reaction 36h), then filter the reaction solution to remove the enzyme, extract the filtrate with methyl tert-butyl ether 3 times, combine the organic phases, and wash twice with 100mL saturated brine, add an appropriate amount of anhydrous sodium sulfate to the organic phase, filter, and spin dry at 40°C to obtain 35.0 g of yellow oily liquid was obtained, namely (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (yield 40.78%, ee value 100%), and the pH value of the aqueous phase obtained after extraction was adjusted to 3-4 with 6 mol / L hydrochloric acid solution, and then extracted with ethyl acetate for 3 times, the organic phases were combined, washed with 100 mL of saturated brine for 2 times, an appropriate amount of anhydrous sodium sulfate was added, and the solvent was dried at 40°C to obtain 45.29 g of yellow oily liquid, namely (2R)-2,4-dimethyl-4-nitro-pentanoic acid (yield 56.99%, ee value 90%).

[0052] 4) Repeat the above steps 1) to 3) for the (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in step 3) and utilize it.

[0053] Example 3

[0054] The optical purity of (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 90%) can be improved by the following method. The specific steps are as follows:

[0055] Take a 25mL single-necked flask, add 2.0g (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 90%) and 20mL acetone, add 1.75g ​​S-1-naphthylethylamine under ice-water bath conditions, a white solid precipitates, heat to 80°C and reflux for 2h to dissolve all the solids, cool at room temperature for crystallization, filter to obtain a white powdery solid, add 10mL water to dissolve the white powdery solid, adjust the pH to 4-5 with phosphoric acid, add 15mL ethyl acetate to extract three times, take the organic phase and evaporate under reduced pressure at 50°C to obtain 1.4g yellow oily liquid, that is, (2R)-2,4-dimethyl-4-nitro-pentanoic acid, with a yield of 70%.

[0056] Figure 4 This is the liquid chromatogram of (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in this example. It can be seen that the ee value of (2R)-2,4-dimethyl-4-nitro-pentanoic acid is 99.4%.

[0057] Example 4

[0058] The optical purity of (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 90%) can be improved by the following method. The specific steps are as follows:

[0059] Take a 25mL single-necked flask, add 2.0g (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 90%) and 20mL 1,4-dioxane, add 1.75g ​​S-1-naphthylethylamine under ice-water bath conditions, and a white solid precipitates. Heat to 100°C and reflux for 2h to dissolve all the solids. Cool at room temperature to crystallize, filter to obtain a white powdery solid, add 10mL water to dissolve the white powdery solid, adjust the pH to 4-5 with phosphoric acid, and then add 15mL ethyl acetate to extract three times. Take the organic phase and evaporate it under reduced pressure at 50°C to obtain 1.6g of yellow oily liquid, which is (2R)-2,4-dimethyl-4-nitro-pentanoic acid (ee 99%), with a yield of 80%.

[0060] The upper and lower limit values ​​and interval values ​​of each raw material of the present invention can realize the present invention, and each raw material listed can realize the present invention, and the embodiments are not listed one by one here.

[0061] It should be noted that all documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference separately. In addition, it should be understood that the above description is a specific embodiment of the present invention and the technical principles used. After reading the above content of the present invention, those skilled in the art can make various improvements and modifications to the present invention without departing from the spirit and scope of the present invention, and these equivalent forms also fall within the scope of the present invention.

Claims

1. A method for recovering and purifying the racemization of (2R)-2,4-dimethyl-4-nitro-pentanoic acid, a by-product of the resolution of a chiral intermediate. It is characterized in that The specific steps are as follows: 1) subjecting (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to an esterification reaction with methanol and thionyl chloride to obtain (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II); 2) racemizing the (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) obtained in step 1) under the action of a base to obtain a rac-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III), and then hydrolyzing the rac-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) using an enzyme to obtain a useful intermediate (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (IV) and (2R)-2,4-dimethyl-4-nitro-pentanoic acid; 3) Repeat the above steps 1) and 2) for the (2R)-2,4-dimethyl-4-nitro-pentanoic acid obtained in step 2) and utilize it.

2. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 1, It is characterized in that In step 1), the optical purity of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is improved by the following method: (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is reacted with a chiral amine to form a salt (V), and then the acid is adjusted to precipitate the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (VI) with high optical purity.

3. The method for racemization recovery and purification of the chiral intermediate split by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 2, It is characterized in that The chiral amine is one of ephedrine, strychnine, cinchonidine, cinchonine, quinidine, S-1-naphthylethylamine, S-1-phenylethylamine and spartine.

4. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 1, It is characterized in that Step 1: (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is subjected to an esterification reaction with methanol and thionyl chloride. The specific steps are as follows: (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) is dissolved in methanol, and thionyl chloride is added under ice-water bath conditions. The temperature is raised to room temperature for esterification reaction, and post-treatment is performed to obtain (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II).

5. The method for racemization recovery and purification of the chiral intermediate split by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 4, It is characterized in that The mass volume ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to methanol is 0.2-0.5 g / mL; the molar ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid (I) to thionyl chloride is 1:1.8-2.

1.

6. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 4, It is characterized in that The esterification reaction time is 2-4 hours.

7. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 1, It is characterized in that Step 2) The specific method is as follows: (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) is dissolved in a solvent, a base is added to carry out a racemization reaction, and 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) is purified to obtain a racemic 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III), and then the obtained racemic 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) is added to a buffer solution, and lipase is added to carry out a selective hydrolysis reaction to obtain a useful intermediate (2S)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (IV) and (2R)-2,4-dimethyl-4-nitro-pentanoic acid.

8. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 7, It is characterized in that The solvent is selected from one of acetonitrile, methanol, ethanol, n-propanol, butyl acetate, isopropyl acetate, ethyl acetate, 1,4-dioxane, tetrahydrofuran, acetone and toluene, and the mass volume ratio of (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) to the solvent is 0.2-0.5 g / mL.

9. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 7, It is characterized in that The base is an inorganic base or an organic base, wherein the inorganic base is potassium carbonate or cesium carbonate, and the organic base is one of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylenediamine, sodium methoxide, sodium ethoxide, triethylamine, N,N-diisopropylethylamine, sodium hydride, and potassium tert-butoxide. The molar ratio of the (2R)-2,4-dimethyl-4-nitro-pentanoic acid methyl ester (II) to the base is 1:0.7-3. The racemization reaction conditions are: reacting at 80-100°C for 8-12 hours.

10. The method for racemization recovery and purification of the chiral intermediate resolution by-product (2R)-2,4-dimethyl-4-nitro-pentanoic acid according to claim 7, It is characterized in that The buffer solution is selected from one of PBS buffer solution, potassium dihydrogen phosphate solution, sodium dihydrogen phosphate solution or Tris-HCl buffer solution, with a pH value of 7-8, and the mass volume ratio of mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) to the buffer solution is 0.08-0.12 g / mL; the mass ratio of mixed 2,4-dimethyl-4-nitro-pentanoic acid methyl ester (III) to lipase is 1:0.2-1; and the hydrolysis reaction conditions are: reaction at 30-40°C for 24-48 hours.

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