A method for preparing 5-hydroxyvaleric acid benzyl ester

Abstract

The application discloses a synthesis method of 5-hydroxypentanoic acid benzyl ester, which comprises the following steps: taking benzyl alcohol and 1,5-pentanolactone as raw materials, and preparing 5-hydroxypentanoic acid benzyl ester in the presence of p-methylbenzenesulfonic acid and Dowex 50WX8-100 cation exchange resin. The synthesis route is as follows: The preparation method has the advantages of fast reaction, few by-products and high yield, and meanwhile, process conditions are mild, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for synthesizing the compound benzyl 5-hydroxyvalerate. Background Technology

[0002] Benzyl 5-hydroxyvalerate is a valuable chemical intermediate and a fundamental raw material for the synthesis of homopolymer poly(5-hydroxyvalerate). Homopolymer poly(5-hydroxyvalerate) possesses excellent biocompatibility, biodegradability, and thermal processing properties, making it a research hotspot in biomedical materials and biodegradable packaging materials. In drug development, benzyl 5-hydroxyvalerate is also an important linker raw material, highly valuable and expensive in areas such as nucleic acid drug target development. Its synthesis method has attracted widespread attention due to its high commercial value. As early as 1999, Massimo Curini, Francesco Epifano, et al. reported its synthesis method in their article "Oxone®: A Convenient Reagent for the Oxidation of Acetals," but the expensive starting material 2-benzyloxytetrahydropyran hindered industrial production.

[0003] The route reported in patent CA2950960A1 involves a two-step reaction. In the reaction of benzyl bromide with sodium 5-hydroxyvalerate, byproducts are easily generated, as shown below, affecting the product yield.

[0004] .

[0005] Table 1. Major side reaction impurities in the CA2950960A1 patent route.

[0006] Impurity number Impurity structure 1 2 3

[0007] Patent WO2019 / 053661A2 reports a route that uses glutaric anhydride as a starting material to synthesize the target product through a two-step reaction. The yields of the two steps are 47% and 62%, respectively, with an overall yield of less than 30%. Moreover, the route and operation time are relatively long, and industrial-scale production suffers from problems such as low conversion rate and complex operation. The synthetic route is as follows:

[0008] .

[0009] Patent CA2970801A1 reports a synthetic method that uses inexpensive delta-valerolactone (1,5-valerolactone) and benzyl alcohol as raw materials to synthesize the target product in one step, and the reaction process is relatively simple. A cation exchange resin (Dowex 50WX8-100) is added during the reaction to suppress byproducts and improve product conversion. However, the reaction process requires heating to 75°C and a reaction time exceeding 12 hours, with a relatively low overall yield of 56%. The synthetic route is as follows:

[0010] . Summary of the Invention

[0011] In view of the various defects in the existing synthesis methods of benzyl 5-hydroxyvalerate, such as long reaction time, many operation steps, high raw material cost, low product conversion rate, difficulty in removing by-products, and low yield of target product, this invention provides a method for preparing benzyl 5-hydroxyvalerate with high yield and mild process conditions.

[0012] This invention provides a method for synthesizing benzyl 5-hydroxyvalerate, comprising the following steps: benzyl 5-hydroxyvalerate is prepared by reacting benzyl alcohol and 1,5-valerate in the presence of p-toluenesulfonic acid and Dowex 50WX8-100 cation exchange resin. The synthetic route is as follows:

[0013] .

[0014] Beneficial effects

[0015] 1. The reaction rate is increased, shortening the reaction time from more than 12 hours overnight to just 2 hours to complete the reaction.

[0016] 2. The reaction raw materials have a high conversion rate, with no raw materials remaining and a high product yield, with the yield of 5-hydroxyvalerate benzyl ester reaching over 90%.

[0017] 3. The reaction is carried out under mild conditions at room temperature, eliminating the need for heating and high / low temperature control, which greatly reduces energy consumption.

[0018] 4. Compared with the existing two-step synthesis process, it is shortened to one step, which is simpler to operate and suitable for industrial production.

[0019] 5. High product purity (HPLC analysis purity above 98.5%), few byproducts, avoiding the problem of excessively high levels of key impurities 1, 2, and 3 in the CA2950960A1 route. Detailed Implementation

[0020] The specific embodiments of the present invention will be further described in detail below with reference to examples. The experimental methods in the embodiments of the present invention will be clearly and completely described below. The described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps. Furthermore, to better illustrate the present invention, numerous specific details are given in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, raw materials, methods, means, etc., well-known to those skilled in the art, are not described in detail in order to highlight the spirit of the present invention.

[0021] This invention first provides a method for synthesizing benzyl 5-hydroxyvalerate, comprising the following steps: benzyl 5-hydroxyvalerate is prepared by reacting benzyl alcohol and 1,5-valerate in the presence of p-toluenesulfonic acid and Dowex 50WX8-100 cation exchange resin. The synthetic route is as follows:

[0022] .

[0023] In the above preparation method, the molar ratio of p-toluenesulfonic acid to 1,5-pentanolide is 0.05-0.2:1; preferably 0.1-0.15:1.

[0024] In the above preparation method, the weight ratio of Dowex 50WX8-100 cation exchange resin to 1,5-pentanolide is 0.01-1:1; preferably 0.01-0.02:1.

[0025] Preferably, in the above preparation method, the reaction temperature is 20±5℃.

[0026] Impurities 1, 2, and 3, as described in the CA2950960A1 route, did not appear in the product prepared by the method of this invention.

[0027] The preparation method of the present invention, with its preferred conditions, yields products with higher purity.

[0028] The present invention will be described in detail below through examples.

[0029] In the following examples, unless otherwise specified, all raw materials used are commercially available and are of chemical purity.

[0030] Example 1: Preparation of benzyl 5-hydroxyvalerate

[0031]

[0032] Add benzyl alcohol (51.84 g, 0.4793 mol, 3.0 Eq) to a three-necked flask, followed by delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (0.320 mg), with a weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone of 0.02:1. Then add p-toluenesulfonic acid (2.752 g, 0.01598 mol, 0.1 Eq), with an equivalent ratio of p-toluenesulfonic acid to delta-valerolactone of 0.1:1. React at 20±5℃ for 1-2 hours. After monitoring and TLC to ensure no delta-valerolactone remains, filter the reaction system, wash the filter cake with DCM (dichloromethane), collect the filtrate, and add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 31.95g of pure product, with a yield of 96% and an HPLC purity of 98.85%. No impurities were detected.

[0033] Example 2 Preparation of benzyl 5-hydroxyvalerate

[0034] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, then add delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (320 mg), where the weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone is 0.02:1. Then add p-toluenesulfonic acid (1.375 g, 0.00799 mol, 0.05 Eq), where the molar ratio of p-toluenesulfonic acid to delta-valerolactone is 0.05:1. React at 20±5℃ for 1-2 hours. After monitoring and TLC detection to ensure no delta-valerolactone remains, filter, wash the filter cake with DCM, collect the filtrate, and add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 29.96g of pure product, with a yield of 90% and an HPLC purity of 98.81%. No impurities were detected.

[0035] Example 3 Preparation of benzyl 5-hydroxyvalerate

[0036] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, then add delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (320 mg), with a weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone of 0.02:1. Then add p-toluenesulfonic acid (5.5 g, 0.03196 mol, 0.2 Eq), with a molar ratio of p-toluenesulfonic acid to delta-valerolactone of 0.2:1. React at 20±5℃ for 1-2 hours. After monitoring for delta-valerolactone residue by TLC, filter the filtrate and add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 31.61g of pure product, with a yield of 95% and an HPLC purity of 98.79%. No impurities were detected.

[0037] Example 4: Preparation of benzyl 5-hydroxyvalerate

[0038] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, then add delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (320 mg), where the weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone is 0.02:1. Then add p-toluenesulfonic acid (1.92 g, 0.01118 mol, 0.07 Eq), where the molar ratio of p-toluenesulfonic acid to delta-valerolactone is 0.07:1. React at 20±5℃ for 1-2 hours. Monitor by TLC to ensure no delta-valerolactone remains. Filter the reaction system, collect the filtrate, and add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 30.28g of pure product, with a yield of 91% and an HPLC purity of 98.76%. No impurities were detected.

[0039] Example 5 Preparation of benzyl 5-hydroxyvalerate

[0040] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, then add delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir. Maintain the temperature at 20±5℃, then add Dowex 50WX8-100 cation exchange resin (320 mg), where the weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone is 0.02:1. Next, add p-toluenesulfonic acid (4.127 g, 0.02397 mol, 0.15 Eq), where the molar ratio of p-toluenesulfonic acid to delta-valerolactone is 0.15:1. React at 20±5℃ for 1-2 hours. After TLC monitoring shows no residual delta-valerolactone, filter, wash the filter cake with DCM, collect the filtrate, and add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 31.94g of pure product, with a yield of 96% and an HPLC purity of 98.85%. No impurities were detected.

[0041] Example 6 Preparation of benzyl 5-hydroxyvalerate

[0042] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, then add delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (160 mg), where the weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone is 0.01:1. Then add p-toluenesulfonic acid (2.752 g, 0.01598 mol, 0.10 Eq), where the equivalent ratio of p-toluenesulfonic acid to delta-valerolactone is 0.1:1. React at 20±5℃ for 1-2 hours. After monitoring by TLC and confirming that no delta-valerolactone remains, add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 31.62g of pure product, with a yield of 95% and an HPLC purity of 98.88%. No impurities were detected.

[0043] Example 7 Preparation of benzyl 5-hydroxyvalerate

[0044] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, followed by delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq). Stir the reaction at 20±5℃. Add Dowex 50WX8-100 cation exchange resin (320 mg), with a weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone of 0.02:1. Then add p-toluenesulfonic acid (2.752 g, 0.01598 mol, 0.1 Eq), with an equivalent ratio of p-toluenesulfonic acid to delta-valerolactone of 0.1:1. React at 20±5℃ for 1-2 hours. Monitor by TLC. After no delta-valerolactone remains, filter and collect the filtrate, then add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 32.25g of pure product, with a yield of 97% and an HPLC purity of 98.91%. No impurities were detected.

[0045] Example 8 Preparation of benzyl 5-hydroxyvalerate

[0046] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) to a three-necked flask, then add delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (960 mg), where the weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone is 0.06:1. Then add p-toluenesulfonic acid (2.752 g, 0.01598 mol, 0.1 Eq), where the equivalent ratio of p-toluenesulfonic acid to delta-valerolactone is 0.1:1. React at 20±5℃ for 1-2 hours. Monitor by TLC to ensure no delta-valerolactone remains. Filter and collect the filtrate, then add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 31.62g of pure product, with a yield of 95% and an HPLC purity of 98.92%. No impurities were detected.

[0047] Example 9 Preparation of benzyl 5-hydroxyvalerate

[0048] Add benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq), followed by delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stir until dissolved. The reaction temperature is 20±5℃. Add Dowex 50WX8-100 cation exchange resin (16 g), where the weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone is 1:1. Then add p-toluenesulfonic acid (2.752 g, 0.01598 mol, 0.1 Eq), where the equivalent ratio of p-toluenesulfonic acid to delta-valerolactone is 0.1:1. React at 20±5℃ for 1-2 hours. Monitor by TLC to ensure no delta-valerolactone remains. After filtration and washing the filter cake with DCM, collect the filtrate and add 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After the organic phase was concentrated under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, in which the eluent system was a mixture of ethyl acetate and n-hexane, with n-hexane content ranging from 0% to 20%. The product filtrate was collected and concentrated under reduced pressure at 40℃ to obtain 29.61g of pure product, with a yield of 89% and an HPLC purity of 98.88%. No impurities were detected.

[0049] Comparative Example 1: Preparation of Benzyl 5-Hydroxyvalerate

[0050] Benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) was added to a three-necked flask, followed by delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq), and stirred until dissolved. The reaction temperature was 20±5℃, and the reaction was carried out at 20±5℃ for 1-2 hours. TLC monitoring showed a large amount of delta-valerolactone remaining and very little product. The reaction time was extended to 12 hours. A significant amount of raw material remained, and 5% sodium bicarbonate aqueous solution (2.0 V) was added. An appropriate amount of DCM (10.0 V) was added, and the mixture was stirred and separated at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0 V). After concentration under reduced pressure below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, with the eluent system being a mixture of ethyl acetate and n-hexane—where the n-hexane content ranged from 0% to 20%. The product filtrate was collected, and the purity of the product in the eluent was detected by TLC. After concentration under reduced pressure at 40℃, 1.6g of pure product was obtained with an HPLC purity of 98.12% and a yield of 5%. HPLC monitoring showed that impurities 1-3 were generated during the reaction, and the polymer impurity content was about 13%.

[0051] Comparative Example 2: Preparation of Benzyl 5-Hydroxypentanoate

[0052] Benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) was added to a three-necked flask, followed by delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq), and stirred until dissolved. The reaction temperature was 20 ± 5 °C. Dowex 50WX8-100 cation exchange resin (320 mg) was added, with a weight ratio of Dowex 50WX8-100 cation exchange resin to delta-valerolactone of 0.02:1. The reaction was carried out at 20 ± 5 °C for 1-2 hours. TLC monitoring showed that only a small amount of delta-valerolactone remained. The reaction time was extended to 12 hours. After filtration and washing the filter cake with DCM, the filtrate was collected and 5%... Sodium bicarbonate aqueous solution (2.0V) was mixed with an appropriate amount of DCM (10.0V) and stirred at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After concentration of the organic phase under reduced pressure below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, with the eluent system being a mixture of ethyl acetate and n-hexane, where the n-hexane content ranged from 0% to 20%. The product filtrate was collected, and the purity of the product in the eluent was detected by TLC. After concentration under reduced pressure at 40℃, 7.3g of pure product was obtained, with an HPLC purity of 98.32% and a yield of 22%.

[0053] Comparative Example 3: Preparation of Benzyl 5-Hydroxyvalerate

[0054] Benzyl alcohol (51.84 g, 0.4794 mol, 3.0 Eq) was added to a three-necked flask, followed by delta-valerolactone (16 g, 0.1598 mol, 1.0 Eq) and stirred until dissolved. The reaction temperature was 20 ± 5 °C. Then, p-toluenesulfonic acid (5.5 g, 0.03196 mol, 0.2 Eq) was added, with an equivalent ratio of p-toluenesulfonic acid to delta-valerolactone of 0.2:1. The reaction was carried out at 20 ± 5 °C for 1-2 hours. TLC monitoring showed that a large amount of delta-valerolactone remained, while very few product spots were observed. After extending the reaction time to 12 hours, 5% sodium bicarbonate aqueous solution (2.0V) was added, followed by the addition of an appropriate amount of DCM (10.0V). The mixture was stirred and separated at room temperature. The organic phase was washed 2-3 times with sodium bicarbonate aqueous solution (2.0V). After concentration of the organic phase under reduced pressure at below 40℃, column chromatography was performed using a silica gel column. An eluent gradient was set, with the eluent system consisting of a mixture of ethyl acetate and n-hexane, where the n-hexane content ranged from 0% to 20%. The product filtrate was collected, and the purity of the product in the eluent was detected by TLC. After concentration under reduced pressure at 40℃, 2.33g of pure product was obtained, with an HPLC purity of 98.02% and a yield of 7%. Impurities 1-3 were observed to be generated during the reaction, and the polymer impurity content was approximately 9%.

[0055] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing benzyl 5-hydroxyvalerate, characterized in that, Benzyl 5-hydroxyvalerate was prepared from benzyl alcohol and 1,5-valerate in the presence of p-toluenesulfonic acid and Dowex 50WX8-100 cation exchange resin. The synthetic route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of p-toluenesulfonic acid to 1,5-valerolactone is 0.05-0.2:1; preferably 0.1-0.15:

1.

3. The preparation method according to claim 1, characterized in that, The weight ratio of Dowex 50WX8-100 cation exchange resin to 1,5-pentanolide is 0.01-1:1; preferably 0.01-0.02:1.

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