Preparation method of ticarcillin sodium side chain 3-ATMA

Abstract

The invention belongs to the technical field of medical chemistry, and relates to a preparation method of ticarcillin sodium side chain 3-ATMA. The method comprises the following steps: adding thiophenemalonic acid and acetone into a reactor at 20-60 DEG C, and dissolving; then, cooling to 0-10 DEG C, adding zinc chloride and anhydride, heating to 15-40 DEG C, and carrying out heat preservation reaction for 10-20 hours; the preparation method comprises the following steps: adding 2, 2-dimethyl-5-(3-thienyl)-1, 3-dioxane-4, 6-diketone into a reaction kettle, adding purified water for hydrolysis after the reaction is completed, continuously stirring for reaction, and then filtering, washing and drying to obtain the ticarcillin sodium side chain 2, 2-dimethyl-5-(3-thienyl)-1, 3-dioxane-4, 6-diketone. The preparation method disclosed by the invention is simple and convenient to operate, the used materials are safer, the technological process is green and environment-friendly, and the 3-ATMA is high in yield and good in quality.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and relates to a preparation method of a ticarcillin sodium side chain, namely 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (3-ATMA). Background Art

[0002] Ticarcillin is a broad-spectrum penicillin antibiotic. The mechanism of action of ticarcillin is to inhibit the biosynthesis of bacterial cell walls to achieve bactericidal effects. Clavulanic acid itself has only weak antibacterial activity, but has a strong broad-spectrum β-lactamase inhibitory effect. Therefore, the combination of the two can protect ticarcillin from β-lactamase hydrolysis. Ticarcillin has broad-spectrum bactericidal activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. Potassium clavulanate can inhibit the destruction of ticarcillin by β-lactamase produced by pathogens such as Staphylococcus aureus, Haemophilus influenzae, Catarrhalis, Escherichia coli, Klebsiella, Proteus mirabilis, Proteus vulgaris, Neisseria gonorrhoeae, Legionella, and Bacteroides fragilis. Therefore, it is effective against enzyme-producing or non-enzyme-producing strains of the above pathogens. After ticarcillin sodium and potassium clavulanate are combined to make ticarcillin sodium-potassium clavulanate for injection, it becomes an antibiotic with a broad-spectrum antibacterial range, suitable for the treatment of a wide range of bacterial infections.

[0003] Ticarcillin is generally used in the form of ticarcillin sodium salt. The current synthesis route of ticarcillin sodium can be summarized as follows: the raw material 6-APA (6-aminopenicillanic acid) or the thienyl intermediate is protected by carboxyl or amino groups, and then a condensation reaction is carried out. The reaction product is then hydrolyzed and salified to obtain the final product. Usually, the amino and carboxyl groups in 6-aminopenicillanic acid are protected with trimethylchlorosilane, and then condensed with 3-thienyl-malonyl chloride to obtain the intermediate N-trimethylsilane-6-[α-chlorocarbonyl-2-(3-thienyl)-acetamide]-penicillanic acid trimethylsilyl ester. After hydrolysis, it is salified with sodium 2-ethylhexanoate and refined with ethyl acetate to obtain the final product. This method requires group protection first, and then the reaction product is hydrolyzed. The steps are cumbersome, and the hydrolysis reaction is difficult to carry out and difficult to control.

[0004] Wang Mijuan et al. provided a process improvement method for ticarcillin in the June 2006 issue of Volume 16, Issue 3 of the Chinese Journal of Medicinal Chemistry, mentioning that the synthesis of 2,2-dimethyl-5-(3-thienyl)-4,6-dione-1,3-dioxane mainly includes the following process:

[0005] Thiophenemalonic acid is added to acetic anhydride, and then a boron trifluoride-ether solution is added and then an acetone solution is added, and water is added after the reaction under a low temperature environment to obtain the product. The above process uses a boron trifluoride-ether solution, and the boron trifluoride-ether solution is immediately hydrolyzed when it encounters moisture in the air, decomposes to generate highly toxic fluoride smoke, burns when it encounters an open flame, and decomposes to generate toxic gases when it encounters high temperature, which can react with oxidants and can generate toxic and corrosive smoke with water and water vapor. In the process, there is a step of adding water, which inevitably contacts with the boron trifluoride-ether solution, generates side reactions, and is not conducive to industrial production. In addition, the yield of the embodiment is only 65%, which limits industrial production.

[0006] Therefore, it is necessary to study and improve the synthesis process of the intermediate of ticarcillin sodium, that is, the side chain 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (3-ATMA), in order to seek a new preparation process with simple operation, safer materials and green and environmentally friendly process. Summary of the invention

[0007] Therefore, the object of the present invention is to provide a method for preparing a side chain of ticarcillin sodium, namely 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (3-ATMA), which is simple to operate, uses safer materials, is green and environmentally friendly during the process, and has a high yield of 3-ATMA and good quality.

[0008] According to the present invention, the preparation method of ticarcillin sodium side chain 3-ATMA provided by the present invention comprises: adding thiophenemalonic acid and acetone into a reactor at 20°C to 60°C for dissolution; then, cooling to 0°C to 10°C, adding zinc chloride and acid anhydride, and then heating to 15°C to 40°C, and keeping the temperature for reaction for 10 to 20 hours; after the reaction is completed, adding purified water for hydrolysis, continuing to stir the reaction, and then filtering, washing, and drying to obtain ticarcillin sodium side chain 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione.

[0009] The following is a more detailed description of the preparation method of the ticarcillin sodium side chain 3-ATMA of the present invention.

[0010] In the preparation method of the ticarcillin sodium side chain 3-ATMA of the present invention, due to the strong water absorption of acid anhydrides such as acetic anhydride, thiophene malonic acid is self-dehydrated to generate thiophene malonic anhydride, but thiophene malonic anhydride is an unstable four-membered ring, and the keto carbonyl attacks the four-membered ring, and thiophene malonic anhydride opens the ring, and further reacts to generate ticarcillin side chain 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione.

[0011] According to one embodiment of the present invention, thiophene malonic acid and acetone are added to a reactor at 20°C to 60°C for dissolution, preferably at 40°C to 60°C, for 0.5 to 5h, preferably 0.5 to 1h; wherein the amounts of thiophene malonic acid and acetone are by weight, thiophene malonic acid: acetone = 1: 1 to 2, preferably thiophene malonic acid: acetone = 1: 1 to 1.5, more preferably thiophene malonic acid: acetone = 1: 1 to 1.25.

[0012] After thiophenemalonic acid is dissolved in acetone, the temperature is lowered to 0°C to 10°C, preferably 3°C to 8°C, more preferably 5°C to 6°C, and zinc chloride and acid anhydride are added.

[0013] The usage ratio of thiophenemalonic acid to zinc chloride is thiophenemalonic acid: zinc chloride = 1: 0.1-0.5, preferably thiophenemalonic acid: zinc chloride = 1: 0.2-0.25, by weight.

[0014] The acid anhydride is acetic anhydride or propionic anhydride, preferably acetic anhydride. The ratio of thiophene malonic acid to acid anhydride is, for example, thiophene malonic acid: acetic anhydride = 1: 1 to 3, preferably thiophene malonic acid: acetic anhydride = 1: 2 to 3, more preferably thiophene malonic acid: acetic anhydride = 1: 2 to 2.55, by weight.

[0015] Then, the temperature is raised to 15°C to 40°C, preferably to 15°C to 30°C, more preferably to 15°C to 20°C, and the reaction time is kept warm for 10 to 20 hours, preferably for 14 to 20 hours, more preferably for 14 to 16 hours.

[0016] After the reaction is completed, purified water is added for hydrolysis, and the usage ratio of thiophenemalonic acid to purified water is thiophenemalonic acid: purified water = 1:5-15, preferably thiophenemalonic acid: purified water = 1:8-10, more preferably thiophenemalonic acid: purified water = 1:9.5-10, by weight.

[0017] The hydrolysis reaction time is 0.5 to 3 h, preferably 1 to 2 h, more preferably 1 to 1.5 h.

[0018] Then, filtering, washing, and drying are performed to obtain 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione as the side chain of ticarcillin sodium. Specifically, after the reaction is completed, filtering and drying are performed, the filter cake is washed with purified water, then washed with ethanol, and then dried in a vacuum to obtain 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione as the side chain of ticarcillin sodium.

[0019] Beneficial Effects

[0020] The invention discloses a method for preparing the side chain of ticarcillin sodium, namely 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (3-ATMA). The method is simple to operate, uses safer materials, is green and environmentally friendly during the process, and has a high yield of 3-ATMA and good quality. DETAILED DESCRIPTION

[0021] The preparation method of ticarcillin sodium side chain 3-ATMA of the present invention is further described in detail below through examples, and the protection scope of the present invention is not limited to the following examples, which are listed only for illustrative purposes and do not limit the present invention in any way.

[0022] Example 1

[0023] Add 100 kg of thiophenemalonic acid and 120 kg of acetone to the reaction tank in sequence, start stirring, heat the reaction solution to 40 ° C, and keep stirring for 0.5 h. Then, cool to 5 ° C, add 22 kg of zinc chloride and 220 kg of acetic anhydride, and heat the reaction solution to 15 ° C for 15 h. After the insulation reaction is completed, add 1000 kg of purified water and continue stirring for 1 h. Filter, wash with water and ethanol, and dry to obtain 100 kg of 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione, a side chain of ticarcillin. The yield is 82.30%, the purity is 99.89% detected by HPLC, and the melting point is 129.5 ° C.

[0024] Example 2

[0025] Add 102kg of thiophenemalonic acid and 120kg of acetone to the reaction tank in sequence, start stirring, heat the reaction solution to 45°C, and keep stirring for 1h. Then, cool to 7°C, add 22kg of zinc chloride and 220kg of acetic anhydride, and heat the reaction solution to 20°C for 20h. After the insulation reaction, add 1000kg of purified water and continue stirring for 1.5h. Filter, wash with water and ethanol, and dry to obtain 100kg of 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione, a side chain of ticarcillin. The yield is 80.65%, the purity is 99.92% as determined by HPLC, and the melting point is 130.3°C.

[0026] Example 3

[0027] Add 105kg of thiophenemalonic acid and 125kg of acetone to the reaction tank in sequence, start stirring, heat the reaction solution to 30°C, and keep stirring for 1h. Then, cool to 5°C, add 22kg of zinc chloride and 220kg of acetic anhydride, and heat the reaction solution to 25°C for 15h. After the insulation reaction, add 1000kg of purified water and continue stirring for 1.5h. Filter by suction, wash with water and ethanol, and dry to obtain 103kg of 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione, a side chain of ticarcillin. The yield is 80.73%, the purity is 99.83% as determined by HPLC, and the melting point is 130.1°C.

Claims

1. A method for preparing 3-ATMA, a side chain of ticarcillin sodium, comprising: At 20°C to 60°C, thiophenemalonic acid and acetone are added into a reactor to dissolve; then, the temperature is lowered to 0°C to 10°C, zinc chloride and acid anhydride are added, and the temperature is raised to 15°C to 40°C, and the reaction is kept warm for 10 to 20 hours; after the reaction is completed, purified water is added for hydrolysis, and the reaction is continued by stirring, and then, the reaction is filtered, washed, and dried to obtain ticarcillin sodium side chain 3-ATMA, i.e. 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione.

2. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: At 20°C to 60°C, thiophenemalonic acid and acetone are added into a reactor and dissolved for 0.5 to 5 hours; wherein the amounts of thiophenemalonic acid and acetone are based on weight, thiophenemalonic acid: acetone = 1:1 to 2.

3. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: At 40°C to 60°C, thiophenemalonic acid and acetone are added into a reactor for dissolution for 0.5 to 1 hour; wherein the amounts of thiophenemalonic acid and acetone are calculated by weight, thiophenemalonic acid: acetone = 1:1 to 1.

5.

4. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: After thiophenemalonic acid is dissolved in acetone, the temperature is lowered to 3°C to 8°C, and zinc chloride and acid anhydride are added.

5. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: The acid anhydride is acetic anhydride or propionic anhydride.

6. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: The usage ratio of thiophenemalonic acid to zinc chloride is thiophenemalonic acid: zinc chloride = 1: 0.1-0.5, preferably thiophenemalonic acid: zinc chloride = 1: 0.2-0.25, by weight.

7. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 5, characterized in that: The usage ratio of thiophene malonic acid and acetic anhydride is thiophene malonic acid: acetic anhydride = 1: 1-3, preferably thiophene malonic acid: acetic anhydride = 1: 2-3, more preferably thiophene malonic acid: acetic anhydride = 1: 2-2.55, by weight.

8. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: After adding zinc chloride and acid anhydride, raise the temperature to 15°C to 30°C and keep the reaction for 14 to 20 hours.

9. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: After the reaction is completed, purified water is added for hydrolysis, the usage ratio of thiophenemalonic acid and purified water is thiophenemalonic acid: purified water = 1:5-15, and the hydrolysis reaction time is 0.5-3h.

10. The method for preparing 3-ATMA side chain of ticarcillin sodium according to claim 1, characterized in that: At 20°C to 60°C, thiophenemalonic acid and acetone are added into a reactor to dissolve for 0.5 to 5 hours; wherein the amounts of thiophenemalonic acid and acetone are calculated by weight, thiophenemalonic acid: acetone = 1:1 to 2; After the thiophenemalonic acid is dissolved in acetone, the temperature is lowered to 3°C to 8°C, and zinc chloride and acetic anhydride are added, wherein the ratio of thiophenemalonic acid to zinc chloride is thiophenemalonic acid: zinc chloride = 1:0.1-0.5, and the ratio of thiophenemalonic acid to acetic anhydride is thiophenemalonic acid: acetic anhydride = 1:1-3, preferably thiophenemalonic acid: acetic anhydride = 1:2-3; After adding zinc chloride and acetic anhydride, the temperature is raised to 15°C to 30°C and the reaction time is kept at this temperature for 14 to 20 hours; After the reaction is completed, purified water is added for hydrolysis, the ratio of thiophenemalonic acid to purified water is thiophenemalonic acid: purified water = 1:5-15, and the hydrolysis reaction time is 0.5-3h; then, the mixture is filtered and dried, the filter cake is washed with purified water, and then with ethanol, dried and vacuum dried to obtain ticarcillin sodium side chain 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione.