Preparation method of R-3-hydroxypentyl-4-tenoic acid tert-butyl ester

Abstract

The invention belongs to the technical field of compounds, and provides a preparation method of R-3-hydroxypentyl-4-tenoic acid tert-butyl ester. The preparation method comprises the following steps: firstly, mixing tert-butyl 5-chloro-3-oxo-4-valerate, a first alkaline substance, a specific catalyst and a solvent, carrying out asymmetric hydrogenation reaction, and then sequentially carrying out substitution reaction, elimination reaction and deprotection reaction to prepare R-3-hydroxypent-4-olefine acid tert-butyl ester, so that the chiral purity of the product is high. The catalyst is easy to separate and recycle and can be reused, materials are saved, and production cost is reduced. Moreover, the preparation method provided by the invention improves the yield of R-3-hydroxypentyl-4-tenoic acid tert-butyl ester, has the advantages of low requirements on equipment, easily available raw materials, easy product separation, simple and easy reaction operation, environmental friendliness, green and safe synthesis process, stability and low production cost, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of compounds, and more specifically, to a method for preparing tert-butyl R-3-hydroxypent-4-enoate. Background Art

[0002] Vaborbactam, chemical name is (3R,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborane-6-acetic acid, and its structure is shown in the following formula (5). Vaborbactam (RPX7009) is a β-lactamase inhibitor that can be used as a new type of antibacterial drug. The drug is a fixed-dose combination drug composed of the carbapenem antibiotic meropenem trihydrate and the β-lactamase inhibitor vaborbactam. Its trade name is Vabomere. The drug is suitable for the treatment of complicated urinary tract infections in patients aged 18 years and above, including pyelonephritis caused by specific bacteria such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and other susceptible microorganisms.

[0003]

[0004] As shown in the structural formula (5), faborbactam has two chiral centers, one of which is generally constructed through the important intermediate R-3-hydroxypent-4-enoic acid tert-butyl ester. The structure of R-3-hydroxypent-4-enoic acid tert-butyl ester is shown in formula (4):

[0005]

[0006] The traditional preparation method of R-3-hydroxypent-4-enoic acid tert-butyl ester is to use its corresponding racemate as a raw material, selectively esterify it with a resolving agent such as lipase, and then separate it, but this method has a low yield and wastes a lot of raw materials. At the same time, there are also prior art reports that 5-hydroxypent-3-enoate is used to prepare R-3-hydroxypent-4-enoic acid tert-butyl ester through a series of reactions such as epoxidation, esterification, reduction and elimination; but as a drug, the chiral purity of faborbactam is closely related to its efficacy, and the chiral purity of R-3-hydroxypent-4-enoic acid tert-butyl ester prepared by this method (ee value is 94-95%) is low, which is not conducive to improving the efficacy of faborbactam.

[0007] Therefore, there is an urgent need to develop a method for preparing R-3-hydroxypent-4-enoic acid tert-butyl ester with high chiral purity and high yield, and the prepared R-3-hydroxypent-4-enoic acid tert-butyl ester can be well used in the preparation of faborbactam. Summary of the invention

[0008] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a method for preparing R-3-hydroxypent-4-enoic acid tert-butyl ester. The product purity of R-3-hydroxypent-4-enoic acid tert-butyl ester prepared by the present invention is high (can reach 98.5-98.8%), high chiral purity (ee value can reach 99.8-99.9%), and the preparation method of the present invention also improves the yield and molar total yield of R-3-hydroxypent-4-enoic acid tert-butyl ester (can reach 82-85%), and the catalyst used can be recycled to avoid heavy metal pollution, save raw materials, reduce costs, and facilitate large-scale production and application. The prepared R-3-hydroxypent-4-enoic acid tert-butyl ester can be further used to prepare faborbactam, which helps to improve the efficacy of faborbactam.

[0009] A first aspect of the present invention provides a method for preparing tert-butyl R-3-hydroxypent-4-enoate.

[0010] Specifically, a method for preparing tert-butyl R-3-hydroxypent-4-enoate comprises the following steps:

[0011] (1) mixing 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester (Formula 1), a first alkaline substance, a catalyst, and a solvent, introducing hydrogen gas, and performing an asymmetric hydrogenation reaction to obtain R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester (Formula 2);

[0012] The structure of the catalyst is shown below:

[0013]

[0014] in, represents a bisphosphine ligand; X is selected from one of -Cl, -Br, -I or -H; Y is selected from one of -Cl, -Br or -I; R is selected from -H or C1-C12 alkyl; the degree of polymerization of PEG (polyethylene glycol) is 400-2000;

[0015] (2) subjecting the R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester (Formula 2) to a substitution reaction with tert-butyldimethylchlorosilane under alkaline conditions to obtain R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester (Formula 3);

[0016] (3) The R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester (Formula 3) is subjected to an elimination reaction under alkaline conditions, and then subjected to a deprotection reaction under acidic conditions to obtain the R-3-hydroxypent-4-enoic acid tert-butyl ester (Formula 4).

[0017] The preparation route of R-3-hydroxypent-4-enoic acid tert-butyl ester in the above steps (1) to (4) is as follows:

[0018]

[0019] The invention uses 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester as a starting material, and an asymmetric hydrogenation reaction occurs under the action of a specific catalyst. The conjugation of the ester group and the special chiral center structure of the catalyst are conducive to the asymmetric hydrogenation reaction and improve the selectivity of the chiral center during the asymmetric hydrogenation reaction, thereby improving the chiral purity of the product. Then, a substitution reaction and an elimination reaction are sequentially performed, and finally the protecting group is removed to obtain R-3-hydroxypent-4-enoic acid tert-butyl ester.

[0020] Preferably, in step (1), the first alkaline substance is at least one of potassium carbonate, potassium bicarbonate, cesium carbonate and sodium carbonate.

[0021] Preferably, in step (1), the solvent is at least one of ethanol, methanol, isopropanol, tetrahydrofuran and toluene.

[0022] Preferably, in step (1), the hydrogen is introduced to a pressure of 0.1-10 atm.

[0023] Further preferably, in step (1), hydrogen is introduced to a pressure of 3-8 atm.

[0024] Preferably, in step (1), tert-butyl 5-chloro-3-oxo-4-pentanoate (Formula 1), a first alkaline substance, a catalyst, and a solvent are mixed in a protective gas atmosphere, and then hydrogen is introduced to replace the protective gas.

[0025] Preferably, the protective gas is nitrogen.

[0026] Preferably, in step (1), the temperature of the asymmetric hydrogenation reaction is 20-50°C.

[0027] Further preferably, in step (1), the temperature of the asymmetric hydrogenation reaction is 35-40°C.

[0028] Preferably, in step (1), the asymmetric hydrogenation reaction is carried out until the system pressure no longer changes, and the reaction is terminated.

[0029] Preferably, in step (1), the mass ratio of 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester (Formula 1) to the catalyst is 100:(0.05-0.1).

[0030] Preferably, in step (2), the alkaline condition is to add a second alkaline substance, and the second alkaline substance is at least one of imidazole, pyridine, and N,N-diisopropylethylamine.

[0031] Preferably, in step (2), the temperature of the substitution reaction is 0-10° C., and / or the time of the substitution reaction is 1-3 h.

[0032] Further preferably, in step (2), the temperature of the substitution reaction is 3-8°C, and / or the time of the substitution reaction is 1-2h.

[0033] Preferably, in step (3), the temperature of the elimination reaction is 55-65° C., and / or the time of the elimination reaction is 8-15 h.

[0034] Further preferably, in step (3), the temperature of the elimination reaction is 60-65° C., and / or the time of the elimination reaction is 10-15 h.

[0035] Preferably, in step (3), the temperature of the deprotection reaction is 10-20° C., and / or the time of the deprotection reaction is 1-5 h.

[0036] Further preferably, in step (3), the temperature of the deprotection reaction is 10-15° C., and / or the time of the deprotection reaction is 2-5 h.

[0037] Preferably, in step (3), the alkaline condition is to add a third alkaline substance, and the third alkaline substance is potassium tert-butoxide and / or sodium tert-butoxide.

[0038] Preferably, in step (3), the acid condition is adding an acidic solution, and the acidic solution is at least one of trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, and hydrofluoric acid.

[0039] The second aspect of the present invention provides an application of the method for preparing tert-butyl R-3-hydroxypent-4-enoate.

[0040] A method for preparing tert-butyl R-3-hydroxypent-4-enoate and its application in the preparation of faborbactam.

[0041] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0042] The present invention first mixes 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester, a first alkaline substance, a specific catalyst and a solvent, uses a suitable catalyst to catalyze the asymmetric hydrogenation reaction of 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester, and then sequentially performs a substitution reaction, an elimination reaction and a deprotection reaction to obtain R-3-hydroxypent-4-enoic acid tert-butyl ester, and the product has high purity (can reach 98.5-98.8%) and high chiral purity (ee value can reach 99.8-99.9%). In addition, after the asymmetric hydrogenation reaction is completed, the catalyst can be separated and removed from the reaction product by simple filtration, which well solves the risk of metal residues, has a high recovery rate, and the catalyst can be reused, saving materials and reducing the production cost of the final product drug (such as faborbactam). Moreover, the preparation method of the present invention improves the yield and total molar yield of R-3-hydroxypent-4-enoic acid tert-butyl ester (which can reach 82-85%), has low requirements for equipment, is easy to obtain raw materials, is easy to separate products, is simple and easy to operate, is environmentally friendly, has a green and safe synthesis process, is stable, has low production costs, and is suitable for large-scale industrial production. The R-3-hydroxypent-4-enoic acid tert-butyl ester prepared by the present invention is an important intermediate for synthesizing borbactam, can effectively improve the chiral purity of borbactam, and is undoubtedly of great significance for improving its efficacy and reducing its side effects, and the mild reaction conditions that are convenient for industrial application are conducive to reducing its cost and large-scale promotion. DETAILED DESCRIPTION

[0043] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0044] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0045] The catalysts used in the following examples are all RuCl 2 [(R,R)-diop][(R)-Me-P-BIMAH] is a P-BIAMH catalyst system with the following structural formula:

[0046]

[0047] Example 1

[0048] A method for preparing tert-butyl R-3-hydroxypent-4-enoate comprises the following steps:

[0049] (1) Nitrogen was introduced into a 1L autoclave to replace the air and form a nitrogen atmosphere. 100g of raw material 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester was added from the feed port of the autoclave, and 500mL of toluene was added to fully dissolve the raw material. Nitrogen was continued to be introduced for bubbling and degassing. Bubbling was continued for 1h to complete the degassing. Under the nitrogen atmosphere, 0.05g of catalyst (wherein, the degree of polymerization of PEG n = 1000) was added from the feed port of the autoclave, and finally 50g of potassium carbonate was added. After the addition was completed, the feed port was quickly closed. The nitrogen in the autoclave was replaced with hydrogen, and then hydrogen was slowly introduced until the pressure in the autoclave was 3atm, and the charging valve was closed; the reaction was stirred rapidly at a temperature of 35-40°C. During the reaction, if the pressure dropped during the reaction, hydrogen was introduced in time to replenish the pressure to 3atm until the pressure stopped dropping and remained basically unchanged, and the reaction was considered to have stopped. At the same time, samples were taken for gas phase analysis to confirm that the remaining raw material was less than 0.5%. After the reaction, the system was filtered to recover the catalyst (recovery rate was 80%); the filtrate was washed with 200 mL of water, 100 mL of 1N hydrochloric acid aqueous solution, and 100 mL of saturated brine in sequence, and then the organic layer was concentrated to obtain an oily product, namely R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester, with a purity of 99% and an ee value of 99.8%. The oily product can be directly used in the next step reaction.

[0050] (2) In a 1L reaction bottle, add the above-prepared R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester, 500mL of dichloromethane, 50g of imidazole, and 90g of tert-butyldimethylsilyl chloride. Maintain the reaction temperature at 3-8°C. Continue to keep the temperature for 1h after adding. Take a sample and send it for gas phase analysis to confirm that the remaining raw material is less than 0.5%, and the reaction is over. Add 100mL of water to quench the reaction, separate the organic layer, and wash it with 100mL of 1N hydrochloric acid aqueous solution, 100mL of saturated sodium bicarbonate aqueous solution, and 100mL of saturated brine in sequence. Then concentrate the organic layer to obtain an oily product, namely R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester, with a purity of 99% and an ee value of 99.8%. The oily product can be directly used for the next step reaction.

[0051] (3) In a 1L reaction bottle, add the R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester prepared above, 500mL of tetrahydrofuran, 81g of potassium tert-butoxide, raise the temperature to 60-65°C, keep the temperature for 10h, take a sample and send it for gas phase analysis to confirm that the remaining raw material is less than 0.5%, the reaction is over, cool to 10-15°C, add 83g of trifluoroacetic acid, and then keep the temperature at 10-15°C for 2h; add 500mL of water to quench the reaction, add 300mL of methyl tert-butyl ether for extraction, separate the organic layer, wash with 100mL of 1N hydrochloric acid aqueous solution and 100mL of saturated brine in sequence, and then concentrate the organic layer to obtain 70.8g of oily substance with a molar total yield of 85%, i.e. R-3-hydroxypent-4-enoic acid tert-butyl ester with a purity of 98.5% and an ee value of 99.8%.

[0052] The above preparation route is as follows:

[0053]

[0054] Example 2

[0055] A method for preparing tert-butyl R-3-hydroxypent-4-enoate comprises the following steps:

[0056] (1) Nitrogen was introduced into a 1L autoclave to replace the air and form a nitrogen atmosphere. 100g of raw material 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester was added from the feed port of the autoclave, and then 500mL of ethanol was added to fully dissolve the raw material. Nitrogen was continued to be introduced for bubbling and degassing. The bubbling was continued for 1h to complete the degassing. Under the nitrogen atmosphere, 0.05g of catalyst (wherein, the degree of polymerization of PEG n = 1000) was added from the feed port of the autoclave, and finally 75g of potassium bicarbonate was added. After the addition was completed, the feed port was quickly closed. The nitrogen in the autoclave was replaced with hydrogen, and then hydrogen was slowly introduced until the pressure in the autoclave was 3atm, and the charging valve was closed; the reaction was stirred rapidly at a temperature of 35-40°C. During the reaction, if the pressure dropped during the reaction, hydrogen was introduced in time to replenish the pressure to 3atm until the pressure stopped dropping and remained basically unchanged, and the reaction was considered to have stopped. At the same time, samples were taken for gas phase analysis to confirm that the remaining raw material was less than 0.5%. After the reaction, the system was filtered to recover the catalyst (recovery rate was 80%); 500 mL of water and ethyl acetate were added to the filtrate, the organic layer was separated, and it was washed with 100 mL of 1N hydrochloric acid aqueous solution and 100 mL of saturated brine in sequence, and then the organic layer was concentrated to obtain an oily product, namely R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester, with a purity of 99% and an ee value of 99.8%. The oily product can be directly used in the next step reaction.

[0057] (2) Add the above-prepared R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester, 500 mL of dichloromethane, 60 g of pyridine, and 90 g of tert-butyldimethylsilyl chloride to a 1L reaction bottle, maintain the reaction temperature at 3-8°C, continue to keep warm for 1 hour, take a sample and send it for gas phase analysis to confirm that the remaining raw material is less than 0.5%, and the reaction is over. Add 100 mL of water to quench the reaction, separate the organic layer, wash it with 100 mL of 1N hydrochloric acid aqueous solution, 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of saturated brine in sequence, and then concentrate the organic layer to obtain an oily product, namely R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester, with a purity of 99% and an ee value of 99.8%. The oily product can be directly used for the next step reaction.

[0058] (3) Add the R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester obtained in the above step, 500 mL of tetrahydrofuran, and 81 g of sodium tert-butoxide to a 1 L reaction bottle, raise the temperature to a reaction temperature of 60-65° C., and keep the temperature for reaction for 10 h. Take a sample and send it for gas phase analysis to confirm that the remaining raw material is less than 0.5%, and the reaction is completed. Cool the temperature to 10-15° C., add 50 g of acetic acid, and keep the temperature at 10-15° C. for 2 h. Add 500 mL of water to quench the reaction, add 300 mL of methyl tert-butyl ether for extraction, separate the organic layer, wash it with 100 mL of 1N hydrochloric acid aqueous solution and 100 mL of saturated brine in sequence, and then concentrate the organic layer to obtain 68.3 g of an oily substance with a molar total yield of 82%, i.e., R-3-hydroxypent-4-enoic acid tert-butyl ester with a purity of 98.7% and an ee value of 99.9%.

[0059] Example 3

[0060] A method for preparing tert-butyl R-3-hydroxypent-4-enoate comprises the following steps:

[0061] (1) Nitrogen was introduced into a 1L autoclave to replace the air and form a nitrogen atmosphere. 100g of raw material 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester was added from the feed port of the autoclave, and then 500mL of isopropanol was added to fully dissolve the raw material. Nitrogen was continued to be introduced for bubbling and degassing. The bubbling was continued for 1h until the degassing was completed. Under a nitrogen atmosphere, 0.05g of catalyst (wherein, the degree of polymerization of PEG n = 1000) was added from the feed port of the autoclave, and finally 80g of cesium carbonate was added. After the addition was completed, the feed port was quickly closed. The nitrogen in the autoclave was replaced with hydrogen, and then hydrogen was slowly introduced until the pressure in the autoclave was 3atm, and the charging valve was closed; the reaction was stirred rapidly at a temperature of 35-40°C. During the reaction, if the pressure dropped during the reaction, hydrogen was introduced in time to replenish the pressure to 3atm until the pressure stopped dropping and remained basically unchanged, which was considered to be the end of the reaction. At the same time, sampling was sent for gas phase analysis to confirm that the remaining raw material was less than 0.5%. After the reaction, the system was filtered to recover the catalyst (recovery rate was 80%); 500 mL of water and ethyl acetate were added to the filtrate, the organic layer was separated, and it was washed with 100 mL of 1N hydrochloric acid aqueous solution and 100 mL of saturated brine in sequence, and then the organic layer was concentrated to obtain an oily product, namely R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester, with a purity of 99% and an ee value of 99.8%. The oily product can be directly used in the next step reaction.

[0062] (2) Add the above-mentioned R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester, 500 mL of dichloromethane, 94 g of N, N-diisopropylethylamine, and 90 g of tert-butyldimethylchlorosilane to a 1L reaction bottle, maintain the reaction temperature at 3-8°C, continue to keep warm for 1 hour, take samples and send them for gas phase analysis to confirm that the remaining raw material is less than 0.5%, and the reaction is over. Add 100 mL of water to quench the reaction, separate the organic layer, wash it with 100 mL of 1N hydrochloric acid aqueous solution, 100 mL of saturated sodium bicarbonate aqueous solution, and 100 mL of saturated brine in sequence, and then concentrate the organic layer to obtain an oily product, namely R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester, with a purity of 99% and an ee value of 99.8%. The oily product can be directly used for the next step reaction.

[0063] (3) Add the R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester obtained in the above step, 500 mL of tetrahydrofuran, and 81 g of sodium tert-butoxide to a 1 L reaction bottle, raise the temperature to a reaction temperature of 60-65° C., and keep the temperature for reaction for 10 h. Take a sample and send it for gas phase analysis to confirm that the remaining raw material is less than 0.5%, and the reaction is completed. Cool the bottle to 10-15° C., add 126 g of p-toluenesulfonic acid, and keep the temperature for reaction at 10-15° C. for 2 h. Add 500 mL of water to quench the reaction, add 300 mL of methyl tert-butyl ether for extraction, separate the organic layer, wash it with 100 mL of 1N hydrochloric acid aqueous solution and 100 mL of saturated brine in sequence, and then concentrate the organic layer to obtain 69.5 g of an oily substance with a total molar yield of 83.4%, i.e., R-3-hydroxypent-4-enoic acid tert-butyl ester with a purity of 98.8% and an ee value of 99.86%.

[0064] In the actual synthesis of faborbactam, the oily substance obtained is R-3-hydroxypent-4-enoic acid tert-butyl ester, which can also be directly used in the next reaction.

Claims

1. A method for preparing tert-butyl R-3-hydroxypent-4-enoate, characterized in that: The steps include: (1) mixing tert-butyl 5-chloro-3-oxo-4-pentanoate, a first alkaline substance, a catalyst, and a solvent, introducing hydrogen gas, and performing an asymmetric hydrogenation reaction to obtain R-5-chloro-3-hydroxy-4-pentanoate; The structural formula of the catalyst is shown below: in, represents a bisphosphine ligand; X is selected from one of -Cl, -Br, -I or -H; Y is selected from one of -Cl, -Br or -I; R is selected from -H or C1-C12 alkyl; the degree of polymerization of PEG is 400-2000; (2) subjecting the R-5-chloro-3-hydroxy-4-pentanoic acid tert-butyl ester to a substitution reaction with tert-butyldimethylchlorosilane under alkaline conditions to obtain R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester; (3) subjecting the R-5-chloro-3-tert-butyldimethylsilyloxy-4-pentanoic acid tert-butyl ester to an elimination reaction under alkaline conditions, and then subjecting it to a deprotection reaction under acidic conditions to obtain the R-3-hydroxypent-4-enoic acid tert-butyl ester.

2. The preparation method according to claim 1, characterized in that: In step (1), the first alkaline substance is at least one of potassium carbonate, potassium bicarbonate, cesium carbonate and sodium carbonate.

3. The preparation method according to claim 1, characterized in that: In step (1), hydrogen is introduced to a pressure of 0.1-10 atm.

4. The preparation method according to claim 1, characterized in that: In step (1), the temperature of the asymmetric hydrogenation reaction is 20-50°C.

5. The preparation method according to claim 1, characterized in that: In step (1), the mass ratio of 5-chloro-3-oxo-4-pentanoic acid tert-butyl ester to the catalyst is 100:(0.05-0.1).

6. The preparation method according to claim 1, characterized in that: In step (2), the alkaline condition is to add a second alkaline substance, and the second alkaline substance is at least one of imidazole, pyridine, and N,N-diisopropylethylamine.

7. The preparation method according to claim 1, characterized in that: In step (2), the temperature of the substitution reaction is 0-10° C., and / or the time of the substitution reaction is 1-3 h.

8. The preparation method according to claim 1, characterized in that: In step (3), the temperature of the elimination reaction is 55-65° C., and / or the time of the elimination reaction is 8-15 h.

9. The preparation method according to claim 1, characterized in that: In step (3), the temperature of the deprotection reaction is 10-20° C., and / or the time of the deprotection reaction is 1-5 h.

10. Use of the preparation method of tert-butyl R-3-hydroxypent-4-enoate according to any one of claims 1 to 9 in the preparation of faborbactam.

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