Novel synthesis process of (R)-(-)-4-cyano-3-ethyl hydroxybutyrate

Abstract

The invention relates to a novel process for synthesizing ethyl (R)-(-)-4-cyano-3-hydroxybutyrate, which adopts 3-oxygen-glutaric acid monoethyl ester as a raw material and comprises the following steps of: 1, reacting the 3-oxygen-glutaric acid monoethyl ester as a raw material with a chlorination reagent to generate 4-formyl chloride ethyl acetoacetate; 2, enabling the 4-formyl chloride ethyl acetoacetate to react with an amination reagent to generate 4-formyl amino ethyl acetoacetate; 3, the 4-formamido ethyl acetoacetate and a dehydrating agent are subjected to a reaction, and 4-cyano ethyl acetoacetate is generated; and 4, reacting the 4-cyanoacetoacetic acid ethyl ester with hydrogen under the action of a hydrogenation catalyst to generate (R)-(-)-4-cyano-3-hydroxybutyric acid ethyl ester. According to the method, ethyl 3-oxoglutarate is innovatively adopted as a raw material, and the (R)-4-cyano-3-hydroxybutyrate meeting the quality standard is finally obtained through chlorination, amination, dehydration and chiral hydrogenation reaction. Sodium cyanide is not used as a cyaniding reagent, the amount of three wastes is small, reaction conditions are mild, and the method is suitable for industrial production.

Description

Technical fields: This invention relates to a novel process for the synthesis of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester. Background technology: (R)-4-cyano-3-hydroxybutyrate ethyl ester is an important chiral intermediate in the side chain of the cholesterol-lowering drug atorvastatin (Lipitor). It is an inhibitor of human HMG-COA, effectively inhibiting cholesterol synthesis and thus lowering cholesterol levels. Clinically, it is commonly used to treat coronary heart disease, ischemic cardiomyopathy, transient ischemic attack, and hypercholesterolemia. Most drugs are composed of chiral molecules, and two enantiomers may have significant differences in pharmacological, toxicological, pharmacokinetic, and metabolic activities.

[0001] Currently, there are three main synthetic routes for (R)-4-cyano-3-hydroxybutyrate ethyl ester: (1) In the article "Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester" published in the Chinese Journal of Pharmaceutical Industry, (S)-epoxychloropropane was used as the starting compound to form (S)-4-chloro-3-hydroxybutyronitrile by ring-opening with cyanide, followed by hydrolysis and esterification in the presence of ethanol and hydrochloric acid to (S)-4-chloro-3-hydroxybutyrate ethyl ester. (S)-4-chloro-3-hydroxybutyrate ethyl ester was protected with hexamethyldisilazane and further cyanided with sodium cyanide. After deprotection with hydrochloric acid, (R)-4-cyano-3-hydroxybutyrate ethyl ester was obtained. The reaction route is long, uses highly toxic sodium cyanide as the cyaniding reagent, requires additional cyanide removal equipment for industrial production, uses trimethylsilane protection, and requires deprotection, making the route long, complex, and costly. .

[0002] (2) Based on this, Chinese Patent Publication No. CN102627580A discloses the use of epichlorohydrin reacting with hydrogen cyanide to obtain 4-chloro-3-hydroxybutyronitrile, reacting the generated 4-chloro-3-hydroxybutyronitrile with ethanol and adding a strong acid to obtain ethyl 4-chloro-3-hydroxybutyrate. Solid sodium cyanide is then added to the mixture to finally obtain ethyl 4-cyano-3-hydroxybutyrate, which requires further separation to obtain (R)-4-cyano-3-hydroxybutyrate. This generates a large amount of cyanide-containing wastewater, resulting in high wastewater treatment costs. .

[0003] (3) An alternative process for the production of ethyl (R)-4-cyano-3-hydroxybutyrate based on L-malic acid. L-malic acid is converted to diethyl (S)-malate via esterification, and then asymmetrically reduced with borane to form ethyl (3S)-3,4-dihydroxybutyrate. Subsequently, ethyl (3S)-3,4-dihydroxybutyrate is brominated with hydrogen bromide and cyaninated with sodium cyanide in ethanol / water to obtain ethyl (R)-4-cyano-3-hydroxybutyrate. The total yield of this process is approximately 56.7%. The malic acid process has two significant drawbacks that limit its industrial application: one is the low overall yield; the other is that borane, as a reducing agent in this process, is quite expensive and extremely dangerous, and the reduction reaction needs to be carried out under nitrogen protection, which increases production costs. . Summary of the Invention: The present invention addresses the problems existing in the prior art, namely, the technical problem to be solved by the present invention is to provide a new process for synthesizing (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester.

[0004] To achieve the above objectives, the technical solution adopted by this invention is: a novel synthesis process for (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester, using 3-oxoglutaric acid monoethyl ester as a raw material, comprising the following steps: First step: Use 3-oxoglutaric acid monoethyl ester as a raw material to react with a chlorinating reagent to generate ethyl 4-formyl chloride acetoacetate; Second step: React the ethyl 4-formyl chloride acetoacetate produced in the first step with an amination reagent to generate ethyl 4-formamidoacetoacetate; Third step: React the ethyl 4-formamidoacetoacetate produced in the second step with a dehydrating agent to generate ethyl 4-cyanoacetoacetate; Step 4: Ethyl 4-cyanoacetoacetate produced in step 3 is reacted with hydrogen in the presence of a hydrogenation catalyst to generate ethyl (R)-(-)-4-cyano-3-hydroxybutyrate.

[0005] Further, the first step is as follows: the chlorination reagent is added dropwise to the mixture of 3-oxoglutaric acid monoethyl ester and organic solvent, the reaction temperature is controlled at 20-30℃, after the addition is complete, the reaction is kept at 20-30℃ for 2 hours, and then distilled to obtain ethyl 4-formyl chloride acetoacetate.

[0006] Furthermore, the chlorination reagent is 1.1–1.5 eq; the organic solvents include: dichloromethane and dichloroethane.

[0007] Further, the second step is as follows: Ethyl 4-formyl chloride acetoacetate is added dropwise to the amination reagent, the reaction temperature is controlled at 0-10℃, after the addition is complete, the reaction is kept at 0-10℃ for 1 hour, ethyl acetate is added for extraction, the mixture is separated, and the solvent is removed to obtain ethyl 4-formamidoacetoacetate.

[0008] Furthermore, the amination reagent is 2.5–5 eq.

[0009] Further, the third step is as follows: add a dehydrating agent to ethyl 4-formamidoacetoacetate, heat to 70-80℃, keep the reaction at this temperature for 3 hours, slowly cool to room temperature, add water to quench, add ethyl acetate to extract and separate the solvent to obtain ethyl 4-cyanoacetoacetate.

[0010] Furthermore, the dehydrating agent is 1-1.3 eq.

[0011] Further, the fourth step is as follows: Ethyl 4-cyanoacetoacetate, hydrogenation catalyst, and organic solvent are added to a high-pressure reactor. Hydrogen gas is introduced, and the temperature is slowly raised to 120-130℃, maintaining a hydrogenation pressure of 1-2 MPa. After the reaction is complete, the mixture is filtered and distilled to obtain ethyl (R)-(-)-4-cyano-3-hydroxybutyrate.

[0012] Furthermore, the catalyst addition amount is 0.1%-0.5% m / m, the organic solvent addition amount is 0-1 m / m, and the hydrogenation pressure is 1-2 MPa.

[0013] Furthermore, the chlorination reagent is thionyl chloride, oxalyl chloride, or phosphorus oxychloride; the amination reagent is ammonia; the dehydrating agent is thionyl chloride, phosphorus oxychloride, or trifluoromethanesulfonic anhydride; and the catalyst is a ruthenium-based chiral catalyst.

[0014] Compared with the prior art, the present invention has the following advantages: The present invention innovatively uses 3-oxoglutaric acid monoethyl ester as raw material, and obtains (R)-4-cyano-3-hydroxybutyrate ethyl ester that meets the quality standards through chlorination, amination, dehydration and chiral hydrogenation reactions. It avoids the use of sodium cyanide as a cyaniding reagent, produces less waste, and has mild reaction conditions, making it suitable for industrial production. Attached image description: Figure 1 This is a diagram of the chemical reaction process of the present invention; Figure 2 This is a diagram of Embodiment 17 of the present invention; Figure 3 This is a diagram of Embodiment 19 of the present invention. Detailed implementation method: The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited by the embodiments.

[0015] Unless otherwise specified, the materials, reagents, methods, and instruments used in the following embodiments are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0016] like Figure 1 As shown, the present invention discloses a novel process for synthesizing ethyl (R)-(-)-4-cyano-3-hydroxybutyrate, using ethyl 3-oxoglutaric acid as a raw material, comprising the following steps: First step: Use 3-oxoglutaric acid monoethyl ester as a raw material to react with a chlorinating reagent to generate ethyl 4-formyl chloride acetoacetate; Second step: React the ethyl 4-formyl chloride acetoacetate produced in the first step with an amination reagent to generate ethyl 4-formamidoacetoacetate; Third step: React the ethyl 4-formamidoacetoacetate produced in the second step with a dehydrating agent to generate ethyl 4-cyanoacetoacetate; Step 4: Ethyl 4-cyanoacetoacetate produced in step 3 is reacted with hydrogen in the presence of a hydrogenation catalyst to generate ethyl (R)-(-)-4-cyano-3-hydroxybutyrate.

[0017] The chlorination reagent is thionyl chloride (SOCl2), oxalyl chloride (CO2Cl2), or phosphorus oxychloride; the amination reagent is ammonia; the dehydrating agent is thionyl chloride (SOCl2), phosphorus oxychloride (POCl3), or trifluoromethanesulfonic anhydride; and the catalyst is a ruthenium-based chiral catalyst.

[0018] Specifically, the first step is as follows: Chlorination reagent is added dropwise to a mixture of 3-oxoglutaric acid monoethyl ester and an organic solvent, and the reaction temperature is controlled at 20-30℃. After the addition is complete, the mixture is kept at 20-30℃ for 2 hours, and then distilled to obtain ethyl 4-formyl chloride acetoacetate. The chlorination reagent is 1.1-1.5 eq (calculated as 3-oxoglutaric acid monoethyl ester).

[0019] The first step is carried out in the presence of an organic solvent, including dichloromethane, dichloroethane, etc.

[0020] Specifically, the second step is as follows: Ethyl 4-formyl chloride acetoacetate is added dropwise to the amination reagent, and the reaction temperature is controlled at 0-10℃. After the addition is complete, the reaction is maintained at 0-10℃ for 1 hour. Ethyl acetate is added for extraction, and the mixture is separated and dissolved to obtain ethyl 4-formamidoacetoacetate. The amination reagent is 2.5-5 eq (calculated as ethyl 4-formyl chloride acetoacetate).

[0021] Specifically, the third step is as follows: add a dehydrating agent to ethyl 4-formamidoacetoacetate, heat to 70-80℃, maintain the temperature for 3 hours, slowly cool to room temperature, quench with water, add ethyl acetate for extraction and separation to obtain ethyl 4-cyanoacetoacetate. The dehydrating agent is 1-1.3 eq (calculated as ethyl 4-formamidoacetoacetate).

[0022] Specifically, the fourth step is as follows: Ethyl 4-cyanoacetoacetate, a hydrogenation catalyst, and an organic solvent are added to a high-pressure reactor. Hydrogen gas is introduced, and the temperature is slowly raised to 120-130℃, maintaining a hydrogenation pressure of 1-2 MPa. After the reaction is complete, the mixture is filtered and distilled to obtain ethyl (R)-(-)-4-cyano-3-hydroxybutyrate. The catalyst addition amount is 0.1%-0.5% m / m, the organic solvent addition amount is 0-1 m / m (based on ethyl 4-formamidoacetoacetate), and the hydrogenation pressure is 1-2 MPa.

[0023] Hydrogenation is carried out in the presence of an organic solvent or in the absence of an organic solvent, wherein the organic solvent is ethanol.

[0024] Example 1: Preparation of ethyl 4-formyl chloride acetoacetate Thionyl chloride (130.8 g, 1.1 mol) was added dropwise to a mixture of ethyl 3-oxoglutarate (174.1 g, 1 mol) and dichloromethane (348.2 g). The reaction temperature was controlled at 20-30 °C. After the addition was complete, the mixture was kept at 20-30 °C for 2 h. After solvent removal, ethyl 4-formyl chloride acetoacetate was obtained by distillation, yielding 173.3 g (yield 90%, purity 99.3%).

[0025] Example 2: Preparation of ethyl 4-formyl chloride acetoacetate Oxaloyl chloride (139.6 g, 1.1 mol) was added dropwise to a mixture of ethyl 3-oxoglutarate (174.1 g, 1 mol) and dichloromethane (348.2 g). The reaction temperature was controlled at 20-30 °C. After the addition was complete, the mixture was kept at 20-30 °C for 2 h. After solvent removal, ethyl 4-formyl chloride acetoacetate was obtained by distillation (yield 93%, purity 99.1%).

[0026] Example 3: Preparation of ethyl 4-formyl chloride acetoacetate Phosphorus oxychloride (168.7 g, 1.1 mol) was added dropwise to a mixture of ethyl 3-oxoglutarate (174.1 g, 1 mol) and dichloroethane (348.2 g). The reaction temperature was controlled at 20-30 °C. After the addition was complete, the mixture was kept at 20-30 °C for 2 h. After solvent removal, ethyl 4-formyl chloride acetoacetate was obtained by distillation, yielding 171.4 g (yield 89%, purity 99.4%).

[0027] Example 4: Preparation of ethyl 4-formyl chloride acetoacetate Thionyl chloride (178.4 g, 1.5 mol) was added dropwise to a mixture of ethyl 3-oxoglutarate (174.1 g, 1 mol) and dichloromethane (348.2 g). The reaction temperature was controlled at 20-30 °C. After the addition was complete, the mixture was kept at 20-30 °C for 2 h. After solvent removal, ethyl 4-formyl chloride acetoacetate was obtained by distillation, yielding 167.5 g (yield 87%, purity 99.3%).

[0028] Example 5: Preparation of ethyl 4-formyl chloride acetoacetate Oxaloyl chloride (165.0 g, 1.3 mol) was added dropwise to a mixture of ethyl 3-oxoglutarate (174.1 g, 1 mol) and dichloroethane (348.2 g). The reaction temperature was controlled at 20-30 °C. After the addition was complete, the mixture was kept at 20-30 °C for 2 h. After solvent removal, ethyl 4-formyl chloride acetoacetate was obtained by distillation (yield 92%, purity 99.5%).

[0029] Example 6: Preparation of Ethyl 4-formamidoacetoacetate Ethyl 4-formyl chloride acetoacetate (192.6 g, 1 mol) was added dropwise to ammonia water (170 g, 25%, 2.5 mol) while controlling the reaction temperature at 0-10 °C. After the addition was complete, the reaction was maintained at 0-10 °C for 1 h. Ethyl acetate (192.6 g) was added for extraction, and the mixture was separated and dissolved to obtain 147.2 g of ethyl 4-formamide acetoacetate (yield 85%, purity 99.0%).

[0030] Example 7: Preparation of Ethyl 4-formamidoacetoacetate Ethyl 4-formyl chloride acetoacetate (192.6 g, 1 mol) was added dropwise to ammonia water (141.7 g, 30%, 2.5 mol) while controlling the reaction temperature at 0-10℃. After the addition was complete, the reaction was kept at 0-10℃ for 1 h. Ethyl acetate (192.6 g) was added for extraction, and the mixture was separated and dissolved to obtain 152.4 g of ethyl 4-formamide acetoacetate (yield 88%, purity 98.9%).

[0031] Example 8: Preparation of Ethyl 4-formamidoacetoacetate Ethyl 4-formyl chloride acetoacetate (192.6 g, 1 mol) was added dropwise to ammonia water (340 g, 25%, 5 mol) and the reaction temperature was controlled at 0-10℃. After the addition was complete, the reaction was kept at 0-10℃ for 1 h. Ethyl acetate (192.6 g) was added for extraction, and the mixture was separated and dissolved to obtain 157.6 g of ethyl 4-formamide acetoacetate (yield 91%, purity 98.7%).

[0032] Example 9: Preparation of Ethyl 4-formamidoacetoacetate Ethyl 4-formyl chloride acetoacetate (192.6 g, 1 mol) was added dropwise to ammonia water (226.7 g, 30%, 4 mol) while controlling the reaction temperature at 0-10℃. After the addition was complete, the reaction was maintained at 0-10℃ for 1 h. Ethyl acetate (192.6 g) was added for extraction, and the mixture was separated and dissolved to obtain 157.6 g of ethyl 4-formamide acetoacetate (yield 148.9%, purity 98.6%).

[0033] Example 10: Preparation of Ethyl 4-cyanoacetoacetate Thionyl chloride (119.0 g, 1 mol) was added to ethyl 4-formamidoacetoacetate (173.2 g, 1 mol), heated to 70-80 °C, and reacted for 3 h. The mixture was then slowly cooled to room temperature, quenched with water (119.0 g), and then extracted with ethyl acetate (173.2 g). The solution was separated to obtain 141.2 g of ethyl 4-cyanoacetoacetate (yield: 91%, purity: 99.7%).

[0034] Example 11: Preparation of Ethyl 4-cyanoacetoacetate Phosphorus oxychloride (153.3 g, 1 mol) was added to ethyl 4-formamidoacetoacetate (173.2 g, 1 mol), heated to 70-80 °C, and reacted for 3 h. The mixture was then slowly cooled to room temperature, quenched with water (153.3 g), and extracted with ethyl acetate (173.2 g). The mixture was separated to obtain 138.1 g of ethyl 4-cyanoacetoacetate (yield: 89%, purity: 99.5%).

[0035] Example 12: Preparation of Ethyl 4-cyanoacetoacetate Add trifluoromethanesulfonic anhydride (282.1 g, 1 mol) to ethyl 4-formamidoacetoacetate (173.2 g, 1 mol), heat to 70-80 °C, maintain the temperature for 3 h, then slowly cool to room temperature, add water (282.1 g) to quench, add ethyl acetate (173.2 g) to extract, and separate the solution to obtain 133.4 g of ethyl 4-cyanoacetoacetate (yield: 86%, purity 98.7%).

[0036] Example 13: Preparation of Ethyl 4-cyanoacetoacetate Thionyl chloride (178.5 g, 1.5 mol) was added to ethyl 4-formamidoacetoacetate (173.2 g, 1 mol), heated to 70-80 °C, and reacted for 3 h. The mixture was then slowly cooled to room temperature, quenched with water (178.5 g), and then extracted with ethyl acetate (173.2 g). The solution was separated to obtain 139.6 g of ethyl 4-cyanoacetoacetate (yield: 90%, purity: 99.2%).

[0037] Example 14: Preparation of Ethyl 4-cyanoacetoacetate Phosphorus oxychloride (230 g, 1.5 mol) was added to ethyl 4-formamidoacetoacetate (173.2 g, 1 mol), heated to 70-80 °C, and reacted for 3 h. The mixture was then slowly cooled to room temperature, quenched with water (230 g), and then extracted with ethyl acetate (173.2 g). The mixture was separated to obtain 136.5 g of ethyl 4-cyanoacetoacetate (yield: 88%, purity: 99.0%).

[0038] Example 15: Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester Ethyl 4-cyanoacetoacetate (155.2 g, 1 mol) and hydrogenation catalyst (0.16 g, 0.1% m / m) were added to a high-pressure reactor. Hydrogen gas was introduced, and the temperature was slowly raised to 120-130 °C while maintaining the hydrogenation pressure at 1 MPa. After the reaction was completed, the catalyst was removed by filtration, and 133.6 g of ethyl (R)-(-)-4-cyano-3-hydroxybutyrate was obtained by distillation (yield: 85%, purity: 99.7%, optical rotation: -29.4°).

[0039] Example 16: Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester Ethyl 4-cyanoacetoacetate (155.2 g, 1 mol) and hydrogenation catalyst (0.47 g, 0.3% m / m) were added to a high-pressure reactor. Hydrogen gas was introduced, and the temperature was slowly raised to 120-130 °C while maintaining the hydrogenation pressure at 1 MPa. After the reaction was completed, the catalyst was removed by filtration, and 138.3 g of ethyl (R)-(-)-4-cyano-3-hydroxybutyrate was obtained by distillation (yield: 88%, purity: 99.5%, optical rotation: -30.1°).

[0040] Example 17: Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester Ethyl 4-cyanoacetoacetate (155.2 g, 1 mol) and hydrogenation catalyst (0.78 g, 0.5% m / m) were added to a high-pressure reactor. Hydrogen gas was introduced, and the temperature was slowly raised to 120-130 °C while maintaining the hydrogenation pressure at 1 MPa. After the reaction was completed, the catalyst was removed by filtration, and 139.9 g of ethyl (R)-(-)-4-cyano-3-hydroxybutyrate was obtained by distillation (yield: 89%, purity: 99.2%, optical rotation: -29.0°).

[0041] Example 18: Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester Ethyl 4-cyanoacetoacetate (155.2 g, 1 mol) and hydrogenation catalyst (0.47 g, 0.3% m / m) were added to a high-pressure reactor. Hydrogen gas was introduced, and the temperature was slowly raised to 120-130 °C while maintaining the hydrogenation pressure at 1.5 MPa. After the reaction was completed, the catalyst was removed by filtration, and 143.04 g of ethyl (R)-(-)-4-cyano-3-hydroxybutyrate was obtained by distillation (yield: 91%, purity: 99.6%, optical rotation: -30.5°).

[0042] Example 19: Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester Ethyl 4-cyanoacetoacetate (155.2 g, 1 mol) and hydrogenation catalyst (0.16 g, 0.1% m / m) were added to a high-pressure reactor. Hydrogen gas was introduced, and the temperature was slowly raised to 120-130 °C while maintaining the hydrogenation pressure at 2 MPa. After the reaction was completed, the catalyst was removed by filtration, and 136.8 g of ethyl (R)-(-)-4-cyano-3-hydroxybutyrate was obtained by distillation (yield: 87%, purity: 99.1%, optical rotation: -29.7°).

[0043] Example 20: Preparation of (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester Ethyl 4-cyanoacetoacetate (155.2 g, 1 mol) and hydrogenation catalyst (0.78 g, 0.5% m / m) were added to a high-pressure reactor. Hydrogen gas was introduced, and the temperature was slowly raised to 120-130 °C while maintaining the hydrogenation pressure at 2 MPa. After the reaction was completed, the catalyst was removed by filtration, and the product was distilled to obtain ethyl (R)-(-)-4-cyano-3-hydroxybutyrate 132.1 (yield: 0.84%, purity: 99.5%, optical rotation: -30.9°).

[0044] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A novel process for the synthesis of (R)-(-)-ethyl 4-cyano-3-hydroxybutyrate, characterized by the fact that: The method comprises the following steps: The first step is to react 3-oxo-glutaric acid monoethyl ester with a chlorinating agent to produce 4-formylchloroacetoacetic acid ethyl ester; The second step is to react 4-formylchloroacetoacetic acid ethyl ester with an aminating agent to produce 4-formylaminoacetoacetic acid ethyl ester; The third step is to react 4-formylaminoacetoacetic acid ethyl ester with a dehydrating agent to produce 4-cyanoacetoacetic acid ethyl ester; The fourth step is to react 4-cyanoacetoacetic acid ethyl ester with hydrogen in the presence of a hydrogenation catalyst to produce (R)-(-)-4-cyano-3-hydroxybutyric acid ethyl ester.

2. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 1, wherein: The first step is to drop the chlorinating agent into a mixture of 3-oxo-glutaric acid monoethyl ester and an organic solvent, control the reaction temperature to be 20-30 DEG C, keep the temperature for 2 hours after dropping, and distill to obtain 4-formylchloroacetoacetic acid ethyl ester.

3. The novel synthesis process for (R)-(-)-4-cyano-3-hydroxybutyrate ethyl ester according to claim 2, characterized in that: The chlorinating agent is 1.1-1.5 eq; the organic solvent includes dichloromethane and dichloroethane.

4. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 1, wherein: The second step is to drop 4-formylchloroacetoacetic acid ethyl ester into an aminating agent, control the reaction temperature to be 0-10 DEG C, keep the temperature for 1 hour after dropping, extract with ethyl acetate, separate, and remove the solvent to obtain 4-formylaminoacetoacetic acid ethyl ester.

5. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 4, wherein: The aminating agent is 2.5-5 eq.

6. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 1, wherein: The third step is to add a dehydrating agent to 4-formylaminoacetoacetic acid ethyl ester, heat to 70-80 DEG C, slowly reduce the temperature to room temperature after keeping the temperature for 3 hours, quench with water, extract with ethyl acetate, separate, and remove the solvent to obtain 4-cyanoacetoacetic acid ethyl ester.

7. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 6, wherein: The dehydrating agent is 1-1.3 eq.

8. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 1, wherein: The fourth step is to add 4-cyanoacetoacetic acid ethyl ester, a hydrogenation catalyst, and an organic solvent into a high-pressure reaction kettle, introduce hydrogen, slowly heat to 120-130 DEG C, maintain the hydrogenation pressure to be 1-2 MPa, filter after the reaction is completed, and distill to obtain (R)-(-)-4-cyano-3-hydroxybutyric acid ethyl ester.

9. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 8, wherein: The catalyst is added in an amount of 0.1%-0.5% m / m, the organic solvent is added in an amount of 0-1 m / m, and the hydrogenation pressure is 1-2 MPa.

10. A novel process for synthesis of (R)-(-)-ethyl-4-cyano-3-hydroxybutyrate as claimed in claim 1, wherein: The chlorinating agent is thionyl chloride, oxalyl chloride, or phosphorus oxychloride; the aminating agent is ammonia; the dehydrating agent is thionyl chloride, phosphorus trichloride, or triflic anhydride; and the catalyst is a ruthenium-based chiral catalyst.

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