Synthesis method of ticarcillin sodium

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and relates to a synthesis method of ticarcillin sodium. The synthesis method comprises the following steps: a condensation reaction step: in a nitrogen atmosphere, in an organic solvent and in the presence of N, N-bis (trimethylsilyl) urea, carrying out a reaction on 6-aminopenicillanic acid and 2, 2-dimethyl-5-(3-thienyl)-1, 3-dioxane-4, 6-diketone to generate ticarcillin, and filtering to obtain a solution containing ticarcillin; and a salt forming reaction step: carrying out a one-step salt forming reaction on the obtained solution containing ticarcillin and a sodium isooctanoate solution to obtain ticarcillin sodium. In the synthesis process, no acid or alkali is used for adjusting the pH value, so that open-loop degradation of a lactam ring in a ticarcillin structure is avoided; no water is added in the synthesis process, an organic solvent is used in the whole process, and other impurities generated by hydrolysis reaction are avoided; meanwhile, tedious steps such as extraction or reduced pressure distillation are not needed, the preparation process is easy and convenient to operate, the yield is high, the purity is high, and large-scale production is easy.

Description

Technical Field

[0001] The present invention relates to the technical field of organic compound synthesis, and in particular to a method for synthesizing ticarcillin sodium. Background Art

[0002] Ticarcillin sodium, also known as carboxyticillin sodium, has a chemical name: (2S, 5R, 6R)-3,3-dimethyl-6-[2-carboxylic acid-2-(3-thienyl)acetylamino]-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid disodium salt, and its structural formula is as follows:

[0003]

[0004] Ticarcillin sodium was created by the British company Beecham and was first marketed in 1977. Ticarcillin sodium is a semi-synthetic anti-pseudomonal penicillin with similar antibacterial spectrum and pharmacological properties to ticarcillin, and has a stronger effect, with broad-spectrum bactericidal activity against Gram-positive, Gram-negative aerobic and anaerobic bacteria. The combined dosage form of ticarcillin sodium and clavulanate potassium for injection, ticarcillin sodium and clavulanate potassium, has stronger antibacterial activity and a wider antibacterial spectrum.

[0005] At present, the common synthesis methods of Ticarcillin Sodium include freeze-drying and solvent crystallization. In the freeze-drying process, Ticarcillin Sodium is prepared by mixing monosodium Ticarcillin with sodium hydroxide to form an aqueous solution, and then decolorizing, filtering and freeze-drying to obtain Ticarcillin Sodium. However, the freeze-drying process has obvious disadvantages. There is no impurity removal process in its preparation process. The prepared product has high moisture content, is easy to degrade, has low content, high impurities, and poor stability. In the solvent crystallization process of synthesizing Ticarcillin Sodium, since Ticarcillin has two carboxyl groups in its structure, the pH and temperature requirements for the synthesis are relatively high. However, strong acids or strong bases are often used to adjust the pH in the synthesis process, and the solvent is evaporated under reduced pressure, which can easily cause the lactam ring in the structure to open and degrade. In addition, most synthesis processes have a hydrolysis process, and the hydrolysis reaction will produce other impurities. This preparation process has problems such as complex operation, low yield, and high impurities. Summary of the invention

[0006] Technical issues

[0007] Therefore, the present invention is made in view of the above problems. The purpose of the present invention is to provide a method for synthesizing ticarcillin sodium, which has simple process operation, high product yield, high purity, and is suitable for industrial production.

[0008] Technical Solution

[0009] According to the present invention, the synthesis method of ticarcillin sodium provided by the present invention comprises the following steps:

[0010] Condensation reaction steps

[0011] Under a nitrogen atmosphere, in an organic solvent, in the presence of N,N-bistrimethylsilylurea (BSU), 6-aminopenicillanic acid (6-APA) reacts with 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (i.e., a side chain compound, referred to as 3-ATMA) to generate ticarcillin; after the reaction, filtering is performed to obtain a solution containing ticarcillin;

[0012] Salt formation reaction step

[0013] Under stirring, the solution containing ticarcillin obtained above is subjected to a one-step salt-forming reaction with a sodium isooctanoate solution to obtain ticarcillin sodium.

[0014] Beneficial Effects

[0015] Due to the special structure of ticarcillin, the present invention does not require an acid or base to perform a pH adjustment step during the synthesis process, thereby avoiding the ring-opening degradation of the lactam ring in the ticarcillin structure; no water is added during the synthesis process, and organic solvents are used throughout the process to avoid other impurities generated by hydrolysis reactions; at the same time, there are no cumbersome steps such as extraction or reduced pressure distillation, and the preparation process is simple to operate, has a high yield, high purity, and is easy to mass produce. DETAILED DESCRIPTION

[0016] Hereinafter, the synthesis method of ticarcillin sodium of the present invention will be described in detail to facilitate the understanding of the present invention. However, the embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments to be described below. The embodiments of the present invention are provided to make the present disclosure clear and complete, so as to fully illustrate the present invention to those of ordinary skill in the art.

[0017] According to the present invention, in the condensation reaction step, under a nitrogen atmosphere, in an organic solvent, in the presence of N,N-bistrimethylsilylurea (BSU), 6-aminopenicillanic acid (6-APA) reacts with 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (i.e., a side chain compound, abbreviated as 3-ATMA) to generate ticarcillin; after the reaction, the solution containing ticarcillin is obtained by filtration.

[0018] Among them, BSU is a silanization agent, which is used to silylate the active hydrogen atoms in 6-APA. Specifically, in the condensation reaction step, the reaction formula is as follows:

[0019]

[0020] In the condensation reaction, the molar ratio of 3-ATMA, 6-APA and BSU is 1:1.0-2.0:1.0-3.0, and preferably 1:1.0-1.2:1.5-2.5. The amount of organic solvent used per gram of 3-ATMA is 5-20 ml, preferably 10-13 ml, relative to the side chain 3-ATMA.

[0021] In the condensation reaction, the reaction temperature is 15°C to 40°C, preferably 25°C to 35°C; the reaction time is 15 to 30 hours, preferably 20 to 30 hours, more preferably 24 to 26 hours.

[0022] After the condensation reaction, the reaction system is cooled to 0°C to 5°C, stirred for 1 to 1.5 hours, filtered, the filter cake is rinsed with ethyl acetate, the mother liquor and the washing liquid are combined, and an appropriate amount of organic solvent is added for dilution, and the amount of organic solvent used for dilution is 0.5 to 2.0 times the amount of organic solvent used for the condensation reaction, preferably 0.5 to 1.0 times.

[0023] In the condensation reaction, the organic solvent used for the condensation reaction can be a halogenated hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride, etc.; the organic solvent used for dilution can be an ester solvent, such as methyl acetate, ethyl acetate, butyl acetate or a mixture thereof.

[0024] According to the present invention, in the salt-forming reaction step, the solution containing ticarcillin obtained above and the sodium isooctanoate solution are subjected to a one-step salt-forming reaction under stirring to obtain ticarcillin sodium, and the reaction formula is as follows:

[0025]

[0026] Specifically, at 5°C to 30°C, preferably 10°C to 15°C, under stirring (e.g., stirring speed of 60 rpm), a sodium isooctanoate solution is added dropwise to the solution containing ticarcillin to carry out a salt-forming reaction, wherein the molar ratio of sodium isooctanoate to 3-ATMA is 2.0 to 4.0:1, preferably 2.05 to 2.6:1; the sodium isooctanoate solution is an ethyl acetate solution of sodium isooctanoate, and the concentration is 300 to 550 g / L, preferably 450 to 550 g / L; the sodium isooctanoate solution is added dropwise at a speed of 100 to 140 L / h. Then, after the sodium isooctanoate solution is added dropwise, the system temperature is adjusted to 5°C to 0°C, and stirring and crystallizing is continued for 4 to 5 hours, and then the stirring speed is reduced (e.g., stirring speed of 20 rpm), a crystallization solvent is added thereto, stirring and crystallizing is carried out, and then the filter cake is washed with ethyl acetate and dried to obtain the finished product of ticarcillin sodium. The crystallization solvent may be an alcohol, such as methanol, ethanol, isopropanol or a mixture thereof, and the amount of the crystallization solvent used is 0.1 to 1.0 times, preferably 0.2 to 0.5 times, the amount of the organic solvent used for the condensation reaction.

[0027] The synthesis method of ticarcillin sodium 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.

[0028] Example 1

[0029] Condensation reaction steps

[0030] In a reactor, add 86.4kg 6-APA (399.5mol), 90.0kg side chain 3-ATMA (397.8mol) and 1000L dichloromethane, start stirring and keep the suspension state; add 163kg N,N-bistrimethylsilyl urea (BSU) (797.5mol) to the above suspension; replace the air in the reactor with vacuum-nitrogen, and keep the reaction at 25°C for 24h; after the reaction, cool the reaction system to 5°C, stir for 1.5h, filter, rinse the filter cake with 300L ethyl acetate, combine the mother liquor and the washing liquid, add 700L ethyl acetate, stir for 30min, filter, and collect the filtrate.

[0031] Salt formation reaction step

[0032] 143kg of sodium isooctanoate (860.5mol) was added to 300L of ethyl acetate, stirred and dissolved to obtain a sodium isooctanoate solution; at 10°C, under stirring (stirring speed 60rpm), the sodium isooctanoate solution was added dropwise to the filtrate obtained above, and the dropping time was 180min; then the temperature was adjusted to 5°C, and stirring and crystallization was continued for 4h; the stirring speed was changed to 20rpm, 200L of anhydrous ethanol was added, and stirring and crystallization was continued for 30min; then, it was filtered, the filter cake was rinsed with 300L of ethyl acetate, and dried to obtain 163.37kg of ticarcillin sodium finished product (molar yield was 95.87%). Ticarcillin sodium was detected by HPLC, with a content of 99.02% and a total impurity content of 1.22%; the pH of ticarcillin sodium was detected to be 7.0, wherein the pH detection method was: 0.2g of sample was dissolved in 20ml of purified water, and the pH of the solution was detected (the pH of ticarcillin sodium specified in the pharmacopoeia is 6.0-8.0).

[0033] Example 2

[0034] Condensation reaction steps

[0035] In a reactor, add 89.6kg 6-APA (414.3mol), 90.0kg side chain 3-ATMA (397.8mol) and 1000L chloroform, start stirring and keep the suspension state; add 170kg N,N-bistrimethylsilyl urea (BSU) (831.7mol) to the above suspension; replace the air in the reactor with vacuum-nitrogen, and keep the reaction at 30°C for 24h; after the reaction, cool the reaction system to 5°C, stir for 1.5h, filter, rinse the filter cake with 300L ethyl acetate, combine the mother liquor and the washing liquid, add 800L ethyl acetate, stir for 30min, filter, and collect the filtrate.

[0036] Salt formation reaction step

[0037] 150 kg of sodium isooctanoate (902.6 mol) was added to 300 L of ethyl acetate, and stirred to dissolve to obtain a sodium isooctanoate solution; at 15 ° C, under stirring (stirring speed 60 rpm), the sodium isooctanoate solution was added dropwise to the filtrate obtained above, and the dropping time was 160 min; then the temperature was adjusted to 5 ° C, and stirring and crystallization were continued for 4 h; the stirring speed was changed to 20 rpm, 250 L of anhydrous ethanol was added, and stirring and crystallization were continued for 30 min; then, filtered, the filter cake was rinsed with 300 L of ethyl acetate, and dried to obtain 162.78 kg of ticarcillin sodium finished product (molar yield was 95.52%). The ticarcillin sodium content was 99.13% and the total impurity content was 1.06% by HPLC; the pH of ticarcillin sodium was detected to be 6.9.

[0038] Example 3

[0039] Condensation reaction steps

[0040] In a reactor, add 90.8kg 6-APA (419.9mol), 90.0kg side chain 3-ATMA (397.8mol) and 1100L dichloromethane, start stirring and keep the suspension state; add 169kg N,N-bistrimethylsilyl urea (BSU) (826.8mol) to the above suspension; replace the air in the reactor with vacuum-nitrogen, and keep the reaction at 25°C for 26h; after the reaction, cool the reaction system to 5°C, stir for 1.5h, filter, rinse the filter cake with 300L ethyl acetate, combine the mother liquor and the washing liquid, add 1000L ethyl acetate, stir for 30min, filter, and collect the filtrate.

[0041] Salt formation reaction step

[0042] 155kg of sodium isooctanoate (932.7mol) was added to 300L of ethyl acetate, and stirred to dissolve to obtain a sodium isooctanoate solution; at 10°C, under stirring (stirring speed 60rpm), the sodium isooctanoate solution was added dropwise to the filtrate obtained above, and the dropping time was 150min; then the temperature was adjusted to 5°C, and stirring and crystallization was continued for 4h; the stirring speed was changed to 20rpm, 450L of anhydrous ethanol was added, and stirring and crystallization was continued for 30min; then, the mixture was filtered, the filter cake was rinsed with 300L of ethyl acetate, and dried to obtain 162.93kg of ticarcillin sodium finished product (molar yield was 95.61%). The ticarcillin sodium content was 99.18% and the total impurity content was 1.02% by HPLC; the pH of ticarcillin sodium was detected to be 7.1.

[0043] Those skilled in the art should understand that various changes and modifications can be made to the synthesis method of ticarcillin sodium provided by the present invention without departing from the spirit and scope of the present invention. It should be understood that these changes and modifications are within the scope of the attached claims, and the scope of protection of the present invention should be determined by the content of the attached claims.

Claims

1. A method for synthesizing ticarcillin sodium, comprising the following steps: Condensation reaction steps Under a nitrogen atmosphere, in an organic solvent, in the presence of N,N-bistrimethylsilylurea (BSU), 6-aminopenicillanic acid (6-APA) reacts with 2,2-dimethyl-5-(3-thienyl)-1,3-dioxane-4,6-dione (3-ATMA) to generate ticarcillin; after the reaction, filtering is performed to obtain a solution containing ticarcillin; Salt formation reaction step Under stirring, the solution containing ticarcillin obtained above is subjected to a one-step salt-forming reaction with a sodium isooctanoate solution to obtain ticarcillin sodium.

2. The method for synthesizing ticarcillin sodium according to claim 1, characterized in that In the condensation reaction, the molar ratio of 3-ATMA, 6-APA and BSU is 1:1.0-2.0:1.0-3.0, and preferably 1:1.0-1.2:1.5-2.

5.

3. The method for synthesizing ticarcillin sodium according to claim 1, characterized in that In the condensation reaction, the organic solvent is a halogenated hydrocarbon; relative to the side chain 3-ATMA, the amount of the organic solvent used per gram of 3-ATMA is 5 to 20 ml, preferably 10 to 13 ml.

4. The method for synthesizing ticarcillin sodium according to claim 1, characterized in that: In the condensation reaction, the reaction temperature is 15°C to 40°C, and the reaction time is 15 to 30 hours.

5. The method for synthesizing ticarcillin sodium according to claim 4, characterized in that: After the condensation reaction, the reaction system is cooled to 0°C to 5°C, stirred for 1 to 1.5 hours, filtered, the filter cake is rinsed with ethyl acetate, the mother liquor and the washing liquid are combined, and an appropriate amount of organic solvent is added for dilution, and the amount of organic solvent used for dilution is 0.5 to 2.0 times the amount of organic solvent used for the condensation reaction, and the organic solvent used for dilution is an ester solvent.

6. The method for synthesizing ticarcillin sodium according to claim 5, characterized in that: The organic solvent used for the condensation reaction is dichloromethane, chloroform or carbon tetrachloride; the organic solvent used for dilution is methyl acetate, ethyl acetate, butyl acetate or a mixture thereof.

7. The method for synthesizing ticarcillin sodium according to claim 1, characterized in that In the salt-forming reaction step, a sodium isooctanoate solution is added dropwise to the solution containing ticarcillin at 5°C to 30°C under stirring to carry out a salt-forming reaction, wherein the molar ratio of sodium isooctanoate to 3-ATMA is 2.0 to 4.0:1; the sodium isooctanoate solution is an ethyl acetate solution of sodium isooctanoate with a concentration of 300 to 550 g / L, and the sodium isooctanoate solution is added dropwise at a speed of 100 to 140 L / h.

8. The method for synthesizing ticarcillin sodium according to claim 1, characterized in that In the salt-forming reaction step, after the sodium isooctanoate solution is added dropwise, the system temperature is adjusted to 5°C to 0°C, and stirring and crystallization are continued for 4 to 5 hours. After that, the stirring speed is reduced, and a crystallization solvent is added thereto, stirring and crystallization is carried out, and then the mixture is filtered, the filter cake is washed with ethyl acetate, and dried to obtain a finished product of ticarcillin sodium, wherein the crystallization solvent is alcohol.

9. The method for synthesizing ticarcillin sodium according to claim 8, characterized in that: The crystallization solvent is methanol, ethanol, isopropanol or a mixture thereof, and the amount of the crystallization solvent is 0.1 to 1.0 times the amount of the organic solvent used for the condensation reaction.

10. The method for synthesizing ticarcillin sodium according to claim 1, characterized in that: In the condensation reaction, the molar ratio of 3-ATMA, 6-APA and BSU is 1:1.0-2.0:1.0-3.0; the organic solvent used for the condensation reaction is dichloromethane, chloroform or carbon tetrachloride; the condensation reaction temperature is 15°C-40°C, and the reaction time is 15-30h; after the condensation reaction, the reaction system is cooled to 0°C-5°C, stirred for 1-1.5h, filtered, the filter cake is rinsed with ethyl acetate, the mother liquor and the washing liquid are combined, and an appropriate amount of organic solvent is added for dilution, and the amount of organic solvent used for dilution is 0.5-2.0 times the amount of organic solvent used for the condensation reaction, and the organic solvent used for dilution is methyl acetate, ethyl acetate, butyl acetate or a mixture thereof; In the salt-forming reaction step, under stirring at 5°C to 30°C, a sodium isooctanoate solution is added dropwise to the solution containing ticarcillin for salt-forming reaction, wherein the molar ratio of sodium isooctanoate to 3-ATMA is 2.0 to 4.0:1; the sodium isooctanoate solution is an ethyl acetate solution of sodium isooctanoate, with a concentration of 300 to 550 g / L, and the sodium isooctanoate solution is added at a rate of 100 to 140 L / h; after the sodium isooctanoate solution is added dropwise, the system temperature is adjusted to 5°C to 0°C, stirring and crystallizing is continued for 4 to 5 hours, then the stirring speed is reduced, a crystallization solvent is added thereto, stirring and crystallizing is carried out, and then the product of ticarcillin sodium is obtained by filtering, eluting the filter cake with ethyl acetate, and drying, wherein the crystallization solvent is methanol, ethanol, isopropanol or a mixture thereof.

Images