A preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride

Abstract

The present invention discloses a method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride, and belongs to the field of pharmaceutical chemicals. The method comprises the following steps: adding D-p-hydroxyphenylglycine to methanol, mixing uniformly, adding an acylating agent, reacting, and obtaining D-p-hydroxyphenylglycine methyl ester hydrochloride through post-processing after the reaction. The method of the present invention has low production cost, high yield, short reaction time, simple post-processing operation, environmental friendliness, high product purity, easy transportation and storage, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride, an antibiotic drug intermediate, and belongs to the field of pharmaceutical chemical industry. Background Art

[0002] D-(p-Hydroxyphenylglycine) methyl ester hydrochloride is an intermediate used in the biosynthesis of drugs such as amoxicillin, cefoperazone, and cefuroxime. As domestic manufacturers gradually adopt biosynthesis of amoxicillin, demand for D-(p-Hydroxyphenylglycine) methyl ester hydrochloride is rapidly increasing. In the biosynthesis of amoxicillin, D-(p-Hydroxyphenylglycine) methyl ester is used instead of the original D-(p-Hydroxyphenylglycine) Dunn's salt. This ester is directly condensed with the parent nucleus in water under the catalysis of acylase, resulting in a simple synthesis process, minimal environmental pollution, and low production costs.

[0003] At present, some methods for preparing D-p-hydroxyphenylglycine methyl ester or its hydrochloride have been reported. Patent application CN103113250A discloses a method for esterifying p-hydroxyphenylglycine and anhydrous methanol in the presence of hydrogen chloride gas to obtain p-hydroxyphenylglycine methyl ester. However, the hydrogen chloride used in this method is highly volatile and highly corrosive to equipment, and simultaneously brings certain negative impacts to the environment. Patent application CN103641729A discloses a method for reacting D-p-hydroxyphenylglycine with a methanol solution of methanol or hydrogen chloride in the presence of trimethylchlorosilane to obtain D-p-hydroxyphenylglycine methyl ester or its hydrochloride through post-treatment. However, the trimethylchlorosilane used in this method is irritating and has high raw material costs. Patent application CN111153821A discloses a method for producing p-hydroxyphenylglycine methyl ester from a methanol solution of p-hydroxyphenylglycine under the action of concentrated sulfuric acid. However, the concentrated sulfuric acid used in this method has strong oxidizing and corrosive properties, is highly corrosive to equipment, and is troublesome for waste liquid treatment. The prior art (https: / / wenku.baidu.com / view / 613c8f140a12a21614791711cc7931b765ce7bd2.html) also provides a method for preparing D-(p-hydroxyphenylglycine) methyl ester hydrochloride using D-(p-hydroxyphenylglycine) as a raw material through an esterification reaction in the presence of methanol and thionyl chloride. The specific steps are as follows: 750 kg of D-(p-hydroxyphenylglycine) is placed in an esterification tank, 2800 L of methanol is added, stirring is initiated, and 400 L of thionyl chloride is added over 25-35 minutes. The steam automatic control valve is opened to control the temperature of the esterification tank to 55-65°C. The reaction is stirred at this temperature for 2-4 hours. The reaction is considered complete when the purity of D-(p-hydroxyphenylglycine) methyl ester hydrochloride in the reaction solution is ≥97%. The reaction was stopped, and the mixture was concentrated to dryness under reduced pressure with a vacuum degree of ≤-0.06 MPa, so that D-p-hydroxyphenylglycine methyl ester hydrochloride precipitated as a solid in the esterification tank. This method overcomes the drawbacks of the previous method, such as the high corrosion of raw materials to equipment, high raw material costs, and high environmental pressure. However, the inventors of the present invention repeated the method using 2.00 g of D-p-hydroxyphenylglycine according to the material ratio provided in the prior art and conducted a small-scale test. They found that the purity of D-p-hydroxyphenylglycine methyl ester hydrochloride obtained by this method was 97.44%, and the yield was 90.63%. The purity and yield need to be further improved. Summary of the Invention

[0004] In response to the problems existing in the prior art, the present invention provides a method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride, which has low production cost, high yield, simple post-processing operation, is environmentally friendly, and is suitable for industrial production. The product obtained by the method of the present invention has high purity and is easy to transport and store.

[0005] The invention provides a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride. The method comprises the following steps: adding D-p-hydroxyphenylglycine to methanol, mixing uniformly, adding an acylating agent, reacting, and performing post-treatment after the reaction to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride; wherein the volume mass ratio of the acylating agent to the D-p-hydroxyphenylglycine is 0.70-1.20 mL / g, and the volume mass ratio of the methanol to the D-p-hydroxyphenylglycine is 3.50-5.20 mL / g.

[0006] Furthermore, the volume mass ratio of the acylating agent to D-p-hydroxyphenylglycine is 0.72-1.15 mL / g, and the volume mass ratio of methanol to D-p-hydroxyphenylglycine is 3.65-5.03 mL / g.

[0007] Furthermore, the acylating agent is oxalyl chloride, acetyl chloride, acetic anhydride or thionyl chloride, preferably thionyl chloride.

[0008] Furthermore, the acylating agent is added dropwise.

[0009] Furthermore, the temperature of the dropping is 0-30° C., preferably 15-25° C.; and / or the speed of the dropping is 0.05-0.5 mL / min, preferably 0.1 mL / min.

[0010] Furthermore, the reaction temperature is 30-80° C., and the reaction time is 1-7 h.

[0011] Furthermore, the reaction temperature is 55-60° C., and the reaction time is 2-3 hours.

[0012] Furthermore, the post-treatment operation includes: cold concentrating the reaction liquid to obtain a solid, dispersing the solid in an organic solvent, filtering, and washing to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride.

[0013] Furthermore, the organic solvent is one or a mixture of two or more of diethyl ether, isopropyl ether, ethyl acetate, and petroleum ether.

[0014] Furthermore, the organic solvent is diethyl ether.

[0015] The beneficial effects achieved by the preparation method of the present invention are:

[0016] The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride provided by the present invention changes the synthesis, crystallization and recovery processes in the prior art. The method of the present invention has low production cost, high yield, short reaction time, simple post-processing operation, is environmentally friendly, and the product has high purity, is easy to transport and store, and is suitable for industrial production.

[0017] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0018] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 : The HPLC chromatogram of D-p-hydroxyphenylglycine methyl ester hydrochloride obtained in Example 5.

[0020] Figure 2 : Mass spectrum of D-p-hydroxyphenylglycine methyl ester hydrochloride obtained in Example 5. DETAILED DESCRIPTION

[0021] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0022] The reaction formulas of the following examples are as follows:

[0023]

[0024] Example 1. Preparation of D-p-hydroxyphenylglycine methyl ester hydrochloride

[0025] Weigh 2.00g of D-p-hydroxyphenylglycine and place it in a reactor. Add 7.3mL of anhydrous methanol and stir to mix thoroughly. Slowly add 2.3mL of thionyl chloride dropwise to the reactor at 0-5°C at a rate of 0.1mL / min. After the addition is complete, raise the temperature to 60°C and maintain the reactor temperature between 55-60°C under reflux. Track the reaction progress by TLC. The reaction is complete after 2.5h. After the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain a white solid. Add 20mL of ether, stir, filter, and dry to obtain 1.74g of a white solid with a yield of 67.18% and a purity of 91.41%.

[0026] Example 2, Preparation of D-p-hydroxyphenylglycine methyl ester hydrochloride

[0027] Weigh 2.00g of D-p-hydroxyphenylglycine and place it in a reactor. Then add 10mL of anhydrous methanol and stir to mix evenly. At 25°C, slowly add 2.3mL of thionyl chloride dropwise to the reactor at a rate of 0.1mL / min. After the addition is complete, raise the temperature to 60°C and maintain the temperature in the reactor between 55-60°C for reflux. Track the reaction progress based on TLC detection. The reaction is complete after 3h. After the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain a white solid. Add 10mL of isopropyl ether, stir, filter, wash with 5mL of isopropyl ether, filter, and dry to obtain 2.30g of a white solid with a yield of 88.38% and a purity of 97.30%.

[0028] Example 3: Preparation of D-p-hydroxyphenylglycine methyl ester hydrochloride

[0029] Weigh 2.00g of D-p-hydroxyphenylglycine and place it in a reactor. Then add 7.3mL of anhydrous methanol and stir to mix evenly. At 25°C, slowly add 2.3mL of thionyl chloride dropwise to the reactor at a rate of 0.1mL / min. After the addition is complete, raise the temperature to 60°C and maintain the temperature in the reactor between 55-60°C for reflux. Track the reaction progress based on TLC detection. The reaction is complete after 2h. After the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain a white solid. Add 10mL of ether, stir, filter, wash twice with 5mL of ether, filter, and dry to obtain 2.31g of a white solid with a yield of 90.98% and a purity of 98.90%.

[0030] Example 4. Preparation of D-p-hydroxyphenylglycine methyl ester hydrochloride

[0031] Weigh 2.00g of D-p-hydroxyphenylglycine and place it in a reactor. Then add 7.3mL of anhydrous methanol and stir to mix evenly. At 25°C, slowly add 1.4mL of thionyl chloride dropwise to the reactor at a rate of 0.1mL / min. After the addition is complete, raise the temperature to 60°C and maintain the temperature in the reactor between 55-60°C for reflux. Track the reaction progress based on TLC detection. The reaction is complete after 2h. After the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain a white solid. Add 10mL of ether, stir, filter, wash twice with 5mL of ether, filter, and dry to obtain 2.21g of a white solid with a yield of 87.04% and a purity of 98.89%.

[0032] Example 5. Preparation of D-p-hydroxyphenylglycine methyl ester hydrochloride

[0033] Weigh 1.95g of D-p-hydroxyphenylglycine and place it in a reactor. Add 9.8mL of anhydrous methanol and stir until evenly mixed. At 25°C, slowly add 1.4mL of thionyl chloride dropwise to the reactor at a rate of 0.1mL / min. After the addition is complete, raise the temperature to 60°C and maintain the reactor temperature between 55-60°C under reflux. Track the reaction progress by TLC. The reaction is complete after 2.5h. After the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain a white solid. Add 10mL of ether, stir, filter, wash with 5mL of ether, filter, and dry to obtain 2.41g of a white solid with a yield of 94.92% and a purity of 99.52%.

[0034] Structural characterization data of the final product obtained in Example 5 Figure 1-Figure 2 shown.

[0035] In summary, the present invention provides a method for preparing D-(4-hydroxyphenylglycine) methyl ester hydrochloride. The method has low production cost, high yield, short reaction time, simple post-processing operation, environmental friendliness, high product purity, easy transportation and storage, and is suitable for industrial production.

Claims

1. A method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride, characterized in that: The method comprises the following steps: adding D-p-hydroxyphenylglycine to methanol, mixing uniformly, adding an acylating agent, reacting, and performing post-treatment after the reaction to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride; wherein the volume mass ratio of the acylating agent to D-p-hydroxyphenylglycine is 0.72 mL / g, and the volume mass ratio of methanol to D-p-hydroxyphenylglycine is 5.03 mL / g; the acylating agent is thionyl chloride, the acylating agent is added dropwise, the dropping temperature is 25° C., and the dropping speed is 0.1 mL / min; the reaction temperature is 55-60° C., and the reaction time is 2-3 hours; The post-treatment operation includes: cooling and concentrating the reaction liquid to obtain a solid, dispersing the solid in diethyl ether, filtering, and washing to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride.

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