A method for synthesizing p-methylaminobenzoxy glutamic acid diethyl ester

Abstract

This invention discloses a method for synthesizing p-methylaminobenzoylglutamate diethyl ester. Using p-methylaminobenzoic acid and diethyl glutamate hydrochloride as raw materials, and carbonyl diimidazole as an ester activator, the specific synthesis method involves dissolving carbonyl diimidazole in a solvent under inert gas protection, stirring, adding p-methylaminobenzoic acid to generate the active ester, then adding diethyl glutamate hydrochloride and reacting. The mixture is then concentrated, cooled, water is added dropwise, filtered, and dried to obtain p-methylaminobenzoylglutamate diethyl ester. This method is simple, convenient, low-cost, and has a high yield, showing great promise for industrialization.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for synthesizing p-methylaminobenzoyl-L-glutamic acid diethyl ester, a methotrexate intermediate. Background Technology

[0002] Methotrexate, as an antifolate drug, has good efficacy in diseases such as tumors and rheumatoid arthritis.

[0003]

[0004] The p-methylaminobenzoyl-L-glutamic acid diethyl ester involved in this invention is an important intermediate required for the synthesis of methotrexate. The existing synthesis methods mainly include those reported in Journal of Heterocyclic Chemistry, 1967, 4:475-481, which use p-aminobenzoic acid ethyl ester as a raw material, protect the amino group of p-toluenesulfonic acid acyl group, and then condense it with diethyl glutamic acid ester. This method has many steps and requires highly hazardous materials such as sodium hydride and hydrogen bromide.

[0005]

[0006] CN115504897A reports a method that uses p-chlorobenzoyl chloride as a raw material to add methylamine and then condenses it with diethyl glutamic acid. This method involves many steps and also requires palladium carbon hydrogenation. The condensing agent HBTU used is relatively expensive.

[0007]

[0008] And Pharmaceutical and Clinical Research. 2023, 31(2), 136-139. The method for direct condensation of p-methylaminobenzoic acid and diethyl glutamic acid used in this method is volatile and inconvenient to store.

[0009] Summary of the Invention

[0010] To address the aforementioned problems, this invention discloses a method for synthesizing diethyl p-methylaminobenzoyl glutamate. This invention uses p-methylaminobenzoic acid and diethyl glutamate hydrochloride as raw materials, which are condensed under the action of carbonyl diimidazole.

[0011] To achieve the above objectives, the technical solution of the present invention is as follows:

[0012] This invention discloses a method for synthesizing diethyl p-methylaminobenzoylglutamate, the process route of which is shown below:

[0013]

[0014] Specifically, the steps include: dissolving carbonyl diimidazole in a solvent, under inert gas protection, stirring, adding p-methylaminobenzoic acid, generating an active ester, then adding diethyl glutamate hydrochloride, reacting, concentrating, cooling, adding water dropwise, filtering, and drying to obtain diethyl p-methylaminobenzoyl glutamate.

[0015] Furthermore, the solvent is one or more of acetonitrile, ethanol, and tetrahydrofuran.

[0016] Furthermore, after adding p-methylaminobenzoic acid, the reaction is carried out at 20℃~30℃ for 30~50 min to generate an active ester.

[0017] Furthermore, the reaction temperature is 20–80°C.

[0018] Furthermore, the reaction time is 6 to 25 hours.

[0019] Furthermore, the cooling range is 0–10°C.

[0020] Furthermore, the diethyl glutamate hydrochloride includes L-diethyl glutamate hydrochloride and its enantiomers.

[0021] Furthermore, the p-methylaminobenzoyl glutamate diethyl ester includes p-methylaminobenzoyl-L-glutamate diethyl ester and its enantiomers.

[0022] The beneficial effects of this invention are as follows:

[0023] This invention provides a method for synthesizing diethyl p-methylaminobenzoyl glutamate, which is simple, convenient, low-cost, and has a high yield, showing great promise for industrialization. The condensing agent used in this invention, carbonyl diimidazole, is inexpensive, has a small molecular weight, and allows for direct product precipitation after post-treatment, simplifying the operation. This invention utilizes the imidazole byproduct generated during the formation of the active ester as a weakly basic catalyst to promote the esterification reaction. At this stage, the diethyl glutamate should be in its hydrochloride form, eliminating the need for alkali addition, which would disrupt the catalytic process. Attached Figure Description

[0024] Figure 1 The photometric NMR spectrum of p-methylaminobenzoyl-L-glutamic acid diethyl ester, a product of this invention, is shown below. Detailed Implementation

[0025] The present invention will be further illustrated below with reference to the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0026] In the following examples, the room temperature is 20℃~30℃.

[0027] Example 1:

[0028] Carbonyl diimidazole (64.4 g, 0.4 mol) was dissolved in acetonitrile (500 mL) under nitrogen protection and stirred at room temperature. p-Methylaminobenzoic acid (50 g, 0.33 mol) was added, and the reaction was continued for 50 min. Then, L-glutamic acid diethyl ester hydrochloride (79.3 g, 0.33 mol) was added, and the reaction was continued for 24 h. The solution was concentrated to 1 / 3 volume under reduced pressure, cooled to 0–10 °C, and 800 mL of water was added dropwise. A solid precipitated, was filtered, and dried to obtain 99 g of a white solid, p-methylaminobenzoyl-L-glutamic acid diethyl ester, with a yield of 89% and a purity of 98.8%. Product characterization data are as follows: LC-MS: 337.2 [M+1]; 1 H NMR (400MHz, Chloroform-d) δ7.67(d,J=8.7Hz,2H),6.76(d,J=7.6Hz,1H),6.57(d,J=8.8Hz,2H),4.78(m,1H),4.22(m,2H),4.10(m,3H),2.87( s,3H),2.55-2.36(m,2H),2.29(dtd,J=14.5,7.2,4.9Hz,1H),2.11(dtd ,J=14.5,7.9,6.7Hz,1H),1.29(t,J=7.1Hz,3H),1.21(t,J=7.1Hz,3H).

[0029] Example 2:

[0030] Carbonyl diimidazole (64.4 g, 0.4 mol) was dissolved in ethanol (500 mL) under nitrogen protection and stirred at room temperature. p-Methylaminobenzoic acid (50 g, 0.33 mol) was added, and the reaction was allowed to proceed for 30 min. Then, L-glutamic acid diethyl ester hydrochloride (79.3 g, 0.33 mol) was added, and the mixture was heated to 75–80 °C and reacted for 5 h. The mixture was concentrated under reduced pressure to 1 / 3 of its volume, cooled to 0–10 °C, and 800 mL of water was added dropwise. A solid precipitated, was filtered, and dried to obtain 103 g of a white solid, p-methylaminobenzoyl-L-glutamic acid diethyl ester, with a yield of 92.8% and a purity of 97.5%.

[0031] Comparative example:

[0032] Carbonyl diimidazole (6.44 g, 0.04 mol) was dissolved in acetonitrile (50 mL) under nitrogen protection and stirred at room temperature. Then, p-methylaminobenzoic acid (5 g, 0.033 mol) was added and reacted for 30 min. Then, L-glutamic acid diethyl ester hydrochloride (79.3 g, 0.033 mol) and triethylamine (3.34 g, 0.033 mol) were added. The mixture was heated to 75–80 °C and reacted for 5 h. TLC analysis showed only a small amount of product.

[0033] It should be noted that the above content merely illustrates the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. For those skilled in the art, various improvements and modifications can be made without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing diethyl p-methylaminobenzoylglutamate, characterized in that, The process includes the following steps: dissolving carbonyl diimidazole in a solvent, under inert gas protection, stirring, adding p-methylaminobenzoic acid to generate an active ester, then adding diethyl glutamate hydrochloride to react, concentrating, cooling, adding water dropwise, filtering, and drying to obtain p-methylaminobenzoyl glutamate diethyl ester. The diethyl glutamate hydrochloride includes L - Diethyl glutamate hydrochloride and its enantiomers.

2. The method for synthesizing diethyl p-methylaminobenzoylglutamate according to claim 1, characterized in that, The solvent is one or more of acetonitrile, ethanol, and tetrahydrofuran.

3. The method for synthesizing diethyl p-methylaminobenzoylglutamate according to claim 1, characterized in that: After adding p-methylaminobenzoic acid, the reaction is carried out at 20℃~30℃ for 30~50 min to generate an active ester.

4. The method for synthesizing diethyl p-methylaminobenzoylglutamate according to claim 1, characterized in that: The reaction temperature for adding diethyl glutamate hydrochloride is 20~80℃.

5. The method for synthesizing diethyl p-methylaminobenzoylglutamate according to claim 1, characterized in that: The reaction time for adding diethyl glutamate hydrochloride is 6 to 25 hours.

6. The method for synthesizing diethyl p-methylaminobenzoylglutamate according to claim 1, characterized in that: The temperature is reduced to 0~10℃.

7. The method for synthesizing diethyl p-methylaminobenzoylglutamate according to claim 1, characterized in that: The p-methylaminobenzoyl glutamate diethyl ester includes p-methylaminobenzoyl- L - Diethyl glutamate and its enantiomers.

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