Preparation method of high-purity pimemecillin hydrochloride crystal form

Abstract

The invention discloses a preparation method of a high-purity pimezlocillin hydrochloride crystal form, and relates to the field of preparation of pimezlocillin hydrochloride. The method comprises the following steps: dissolving 6-APA serving as an initial raw material in an organic solvent under an alkaline condition, carrying out nucleophilic substitution reaction on the 6-APA and chloromethyl pivalate, and generating 6-aminopenicillanic acid methyl pivalate salt from the 6-aminopenicillanic acid methyl pivalate salt and organic acid; then dissolving in an organic solvent under an alkaline condition, and carrying out an addition elimination reaction with N-dimethoxy methyl azacycloheptane to obtain pimemecillin; and salifying and crystallizing the obtained pimecillin to obtain the stable crystal form pimecillin hydrochloride. The pimemecillin hydrochloride crystal form reaches the medicinal purity, the effective component is greater than 99.0%, the impurity content is less than 0.1%, and the pimemecillin hydrochloride crystal form is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing a high-purity pivmecillinam hydrochloride crystal. Background Art

[0002] Pivimecillin hydrochloride is a prodrug of mecillin. After oral absorption, it is rapidly hydrolyzed into mecillin in the body, binds to penicillin-binding protein-2 (PBP-2), interferes with bacterial cell wall biosynthesis, causes bacterial morphology changes and cell lysis, and thus exerts an antibacterial effect. Pivimecillin is more active against Gram-negative bacteria than Gram-positive bacteria, and has strong activity against Escherichia coli that produces extended-spectrum β-lactamases (ESBLs). The drug has been on the market overseas for decades. It is safe and effective, has a low resistance rate, and has pharmacoeconomic advantages.

[0003]

[0004] Based on the literature and laboratory data, no polymorphism of pivmecillin hydrochloride has been found.

[0005] At present, there are several main ways to synthesize pivmecillin hydrochloride in domestic and foreign literature patents:

[0006] (1) Patents US3957764 and CN114573603A report that 6-APA is used as the starting material, which first undergoes a nucleophilic substitution reaction with chloromethyl pivalate to produce 6-aminopenicillanic acid methyl pivalate, and then undergoes an addition-elimination reaction with N-formylcycloheximide dimethyl sulfate to produce pivmecillin.

[0007]

[0008] Route 1 has the following problems: 1) Since the amino group of the starting material 6-APA is not protected, while the carboxyl group undergoes a nucleophilic substitution reaction with chloromethyl pivalate, the amino group will also react with chloromethyl pivalate to produce a by-product; 2) The intermediate 6-aminopenicillanic acid methyl pivalate base is an oily substance, which must react with p-toluenesulfonic acid to form a sulfonate solid, and the sulfonate solid must be converted back to a base before reacting with N-formylcycloheximide dimethyl sulfate to produce pivmecillin, which increases the operation steps; 3) The starting material N-formylcycloheximide dimethyl sulfate is not easy to purchase on the market, and the detection method for it is still imperfect, and the highly toxic dimethyl sulfate and expensive N-formylcycloheximide are used in its preparation process. Therefore, it is not suitable for industrial production.

[0009] (2) Patents JPH0236186A and CN101024648A reported that 6-APA was used as the starting material, which first reacted with N-dimethoxymethylazepane to undergo an addition-elimination reaction to produce mecillinam, and then reacted with chloromethyl pivalate to produce pivmecillinam through a nucleophilic substitution reaction.

[0010]

[0011] Route 2 has the following problems: the starting material N-dimethoxymethylazepane has a higher market price than chloromethyl pivalate, and the preparation of pivmecillin according to the synthesis sequence in the literature reduces the utilization rate of raw materials, which is not conducive to cost control. Moreover, using chloromethyl pivalate as the last step of the synthesis easily produces pivmecillin dimer impurities, which are difficult to control, resulting in impurities exceeding the standard in the finished product of pivmecillin hydrochloride. Summary of the invention

[0012] Based on the technical problems existing in the background technology, the present invention proposes a new preparation method of a high-purity, stable pivmecillin hydrochloride crystal form. The present invention avoids the use of toxic and harmful reagents and raw materials, has low synthesis cost, short process steps, low equipment requirements, simple operation and less environmental pollution, effectively improves the purity of the finished product, and reduces the content of dimers and other impurities.

[0013] A method for preparing a high-purity pivmecillin hydrochloride crystal form, the method comprising the following steps:

[0014]

[0015] In some specific technical solutions, the method includes the following steps:

[0016] 1) Under alkaline conditions, 6-APA reacts with chloromethyl pivalate to produce 6-aminopenicillanic acid pivalate methyl ester;

[0017] 2) 6-aminopenicillanic acid pivalate methyl ester undergoes addition elimination reaction with N-dimethoxymethylazepane under alkaline conditions to obtain pivmecillin;

[0018] 3) crystallizing pivmecillin through acid adjustment to obtain a crude product of pivmecillin hydrochloride;

[0019] 4) The crude product of pivmecillin hydrochloride is dissolved in an organic solvent, decolorized, filtered, and crystallized to obtain a stable crystalline form of pivmecillin hydrochloride.

[0020] In the above method, the reaction temperature of step 1) is 0-25°C, preferably, the feeding temperature is 0-5°C, and the reaction temperature is 20-25°C;

[0021] Step 1) the reaction solvent is acetone, N-methylpyrrolidone, N,N-dimethylacetamide or N,N-dimethylformamide, preferably, acetone is used as the reaction solvent, and the mass ratio of acetone to 6-APA is 5 to 6;

[0022] The base used in step 1) is triethylamine, N,N-diisopropylethylamine or potassium carbonate, preferably triethylamine is used as the base.

[0023] In the above method, the molar ratio of the base used in step 1) to 6-APA is 1-1.2:1, the molar ratio of chloromethyl pivalate to 6-APA is 1-1.2:1, and the molar ratio of the organic acid to 6-APA is 1.5-2.0:1. Preferably, the molar ratio of triethylamine to 6-APA is 1.1:1, the molar ratio of chloromethyl pivalate to 6-APA is 1.1:1, the organic acid is p-toluenesulfonic acid, and the molar ratio of the organic acid to 6-APA is 1.5:1.

[0024] In the above method, the reaction temperature of step 2) is 0-25°C, preferably, the feeding temperature and the reaction temperature are both 0-5°C;

[0025] The solvent used in the reaction in step 2) is acetone, anhydrous methanol, anhydrous ethanol or dichloromethane. Preferably, the solvent used is acetone, and the mass ratio of acetone to 6-aminopenicillanic acid pivalate methyl ester is 5 to 6;

[0026] The base used in the reaction in step 2) is triethylamine or N,N-diisopropylethylamine, preferably, triethylamine is used as the base.

[0027] In the above method, the molar ratio of the base to 6-aminopenicillanic acid methyl pivalate in step 2) is 1 to 1.2:1, and the molar ratio of N-dimethoxymethylazacycloheptane to 6-aminopenicillanic acid methyl pivalate is 1 to 1.2:1. Preferably, the molar ratio of triethylamine to 6-aminopenicillanic acid methyl pivalate is 1.1:1, and the molar ratio of N-dimethoxymethylazacycloheptane to 6-aminopenicillanic acid methyl pivalate is 1.2:1.

[0028] In the above method, the reagent used for acid adjustment in step 3) is 5%-30% hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, hydrogen chloride ethyl acetate solution, hydrogen chloride acetone solution and hydrochloric acid aqueous solution, and the pH is adjusted to 3-4. Preferably, the acid adjustment reagent is 5% hydrogen chloride isopropanol solution, and the corresponding solvent is isopropanol, which is 10 times the mass of pivmecillinam.

[0029] In the above method, in step 3), the crystallization temperature is -5 to 25°C, preferably, the acid adjustment temperature is -5 to 0°C, and the crystallization temperature is -5 to 0°C.

[0030] In the above method, the organic solvent in step 4) is methanol, ethanol, isopropanol, ethyl acetate or isopropyl ether. Preferably, the organic solvent is a mixed solvent of methanol and isopropyl ether, the mass ratio of methanol to isopropyl ether is 1:2, and the mass ratio of methanol to crude pivmecillinam hydrochloride is 1:1.

[0031] In the above method, in step 4), the dissolution temperature is 30-50°C, and the crystallization temperature is -5-10°C. Preferably, the dissolution temperature is 30-35°C, and the crystallization temperature is -5-0°C.

[0032] Among some more specific technical solutions, the specific solutions are as follows:

[0033] A method for preparing a high-purity, stable crystalline form of pivmecillinam hydrochloride comprises the following steps:

[0034] The preparation method of 1.6-aminopenicillanic acid pivalic acid methyl ester salt is as follows: 6-APA is dispersed in an organic solvent, an organic base is added dropwise at 0-5°C, and the mixture is stirred to dissolve, pivalic acid chloromethyl ester is added dropwise at below 5°C, and the mixture is stirred at 20-25°C for 5 hours, and the mixture is filtered, and an acetone solution of an organic acid is added dropwise at below 5°C until a white solid precipitates, and after the addition, the mixture is stirred for half an hour, and the mixture is filtered. After washing with acetone, the mixture is vacuum dried at 40-50°C for 6 hours to obtain a white crystalline powder.

[0035] 2. The preparation method of pivmecillin is as follows: 6-aminopenicillanic acid pivalate methyl ester is dispersed in an organic solvent, an organic base is added at 0-5°C, and after stirring to dissolve, N-dimethoxymethylazacycloheptane is added dropwise at below 5°C, and the reaction is stirred at 0-5°C for 2 hours. After the reaction is completed, the reaction solution is slowly added into ice water to quench, and the temperature is raised to reflux with stirring to dissolve, and the temperature is lowered to 20-25°C for crystallization, and filtered, washed with an organic solvent / water mixed solvent, and then vacuum dried at 40-50°C for 10 hours to obtain an off-white crystalline powder.

[0036] 3. The preparation method of crude pivmecillin hydrochloride is as follows: disperse pivmecillin in an organic solvent, add hydrogen chloride organic solvent solution at -5 to 0°C to adjust the pH to 3 to 4, dissolve, crystallize at -5 to 0°C, filter, wash with cold organic solvent, and then vacuum dry at 40 to 50°C for 8 hours to obtain an off-white crystalline powder.

[0037] 4. The preparation method of pivmecillin hydrochloride is as follows: mix the crude product of pivmecillin hydrochloride with an organic solvent, dissolve it at 30-35°C, decolorize it, keep it warm and stir it for 15 minutes, cool it to -5-0°C to crystallize it, filter it, wash it with an organic solvent, and then vacuum dry it at 40-50°C for 5 hours to obtain a white crystalline powder.

[0038] The invention has the advantages that: the process can effectively prepare a stable crystal form of pivmecillin hydrochloride, with a yield of more than 60%, a content of more than 99.0%, and a maximum single impurity of less than 0.1%. The process uses N-dimethoxymethylazacycloheptane to synthesize pivmecillin in step 2 for the first time, and uses experimental data to illustrate the feasibility of the method. Compared with route 1 in the background technology, the method avoids the use of toxic and harmful reagents (dimethyl sulfate) and expensive raw materials (N-formylcycloheximide). Compared with route 2 in the background technology, the method changes the order of feeding, improves the utilization rate of raw materials, effectively reduces the synthesis cost, and simultaneously improves the purity of the finished product and reduces the content of dimers and other impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the HPLC analysis spectrum of pivmecillinam hydrochloride.

[0040] Figure 2 This is the infrared spectrum of pivmecillin hydrochloride.

[0041] Figure 3 This is the XRD diffraction pattern of pivmecillin hydrochloride.

[0042] Figure 4 This is the DSC differential thermal analysis spectrum of pivmecillinam hydrochloride.

[0043] Figure 5 This is the TG thermogravimetric analysis spectrum of pivmecillinam hydrochloride. DETAILED DESCRIPTION

[0044] The technical solution of the present invention is described in detail below through specific embodiments. The following description of the embodiments of the present invention by those skilled in the art based on the present disclosure is only exemplary and is not intended to limit the solution of the present invention.

[0045] Example 1

[0046] Synthesis of 6-aminopenicillanic acid pivalate methyl ester

[0047] In a 50-liter glass reactor, add 2.000 kg of 6-APA and 10.000 kg of acetone, add 1.030 kg of triethylamine at 0-5°C, stir until dissolved, then add 1.532 kg of chloromethyl pivalate dropwise at 0-5°C, and control the addition temperature below 10°C. After the addition is complete, move to room temperature (20-25°C) and stir to react for 5 hours, filter, and add 20% p-toluenesulfonic acid in acetone solution (2.390 kg of p-toluenesulfonic acid, 9.550 kg of acetone) dropwise at 0-5°C to precipitate solid, crystallize at 0-5°C for 3 hours, filter, wash with acetone, and vacuum dry at 45°C for 6 hours to obtain 3.788 kg of white crystalline powder with a yield of 81.5%.

[0048] Example 2

[0049] Synthesis of Pivmecillinam

[0050] In a 50-liter glass reactor, 3.000 kg of 6-aminopenicillanic acid pivalic acid methyl ester salt was dispersed in 15.000 kg of acetone, and 0.670 kg of triethylamine was added at 0-5 ° C. The dropping temperature was controlled below 10 ° C. After stirring and dissolving, 1.230 kg of N-dimethoxymethylazepane was added dropwise at 0-5 ° C. The dropping temperature was controlled below 10 ° C. After the addition was completed, the reaction was stirred at 0-5 ° C for 2 hours, and the reaction solution was slowly added to 16.000 kg of ice water for quenching. The quenching temperature was controlled below 20 ° C. After the quenching was completed, the mixture was stirred and heated to reflux (55-65 ° C) to dissolve, decolorized, and crystallized at room temperature (20-25 ° C) for 3 hours. Filter, wash with acetone / water (w / w=1), and then vacuum dry at 50 ° C for 10 hours to obtain 2.360 kg of off-white crystalline powder with a yield of 90.0%.

[0051] Example 3

[0052] Synthesis of Crude Pivmecillin Hydrochloride

[0053] Add 2.000 kg of pivmecillin and 20.000 kg of isopropanol into a 50 L glass reactor, stir and disperse, cool the system to -5-0°C, maintain the temperature, add 5% HCl / isopropanol solution dropwise into the system, adjust the pH to 3-4, dissolve clearly, crystallize at -5-0°C for 2 hours, filter, wash with cold isopropanol, and dry in vacuo at 45°C for 8 hours to obtain 1.848 kg of off-white crystalline powder with a yield of 85.3%.

[0054] Example 4

[0055] Pivimecillin hydrochloride purification

[0056] Add 1.800 kg of crude pivmecillin hydrochloride and 1.800 kg of methanol into a 20 L glass reactor, stir at 30-35 °C to dissolve, decolorize with activated carbon, filter, add 3.600 kg of isopropyl ether, clarify, cool to -5-0 °C to crystallize for 2 hours, filter, wash with isopropyl ether, and dry in vacuo at 45 °C for 5 hours to obtain 1.440 kg of white crystalline powder with a yield of 80.0%.

[0057] Example 5: Detection method of pivmecillinam hydrochloride

[0058] Test solution Take an appropriate amount of the product, weigh it accurately, dissolve it in solvent and quantitatively dilute it to make a solution containing about 1 mg of pivmecillinam hydrochloride per 1 ml.

[0059] Control solution: Accurately measure 1 mL of the test solution, place it in a 100 mL volumetric flask, dilute to the mark with solvent, and shake well.

[0060] System suitability solution: Take appropriate amounts of impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance and pivmecillin hydrochloride reference substance, weigh them accurately, dissolve them in a solvent and quantitatively dilute them to make a mixed solution containing approximately 15 μg of impurity A, 15 μg of impurity B, 15 μg of impurity C, 15 μg of impurity D, 15 μg of dimer and 1 mg of pivmecillin hydrochloride per 1 mL.

[0061] Chromatographic conditions: use octadecylsilane bonded silica gel as filler (4.0mm×250mm, 5μm or chromatographic column with equivalent performance); flow rate is 1.0mL per minute; detection wavelength is 220nm; injection volume is 20μl; take 0.55g tetraethylammonium hydrogen sulfate and 1.0g tetramethylammonium hydrogen sulfate, dissolve and dilute to 1000mL with solvent as mobile phase.

[0062] System suitability requirements In the system suitability solution chromatogram, the order of peaks is impurity A peak, dimer peak, impurity B peak, pivmecillin hydrochloride peak, impurity C peak and impurity D peak.

[0063] Determination method: Accurately measure the test solution, control solution and system suitability solution, inject them into the liquid chromatograph respectively, and record the chromatogram to 3 times the retention time of the main component peak. The chromatographic results are shown in Table 1.

[0064] Table 1 Relative retention time and limit of pivmecillin hydrochloride and its impurities

[0065]

[0066]

[0067] Figure 1 This is the HPLC analysis spectrum of pivmecillinam hydrochloride, with an HPLC purity of 99.415% and a maximum single impurity of 0.090%.

[0068] Figure 2 This is the infrared spectrum of pivmecillin hydrochloride.

[0069] Figure 3 This is the XRD diffraction pattern of pivmecillin hydrochloride.

[0070] Figure 4 This is the DSC differential thermal analysis spectrum of pivmecillinam hydrochloride.

[0071] Figure 5 This is the TG thermogravimetric analysis spectrum of pivmecillinam hydrochloride.

[0072] Example 6: Crystalline stability of pivmecillin hydrochloride

[0073] The stability of the pivmecillin hydrochloride crystal was investigated by placing it at a temperature of 30°C ± 2°C and a humidity of 65% ± 5% for 15 days, 1 month, 3 months, and 6 months. The solubility, melting point, dimer impurity (%), and purity (%) of the samples were tested. The results are shown in Table 2

[0074] Table 2 Stability test results

[0075]

[0076] The crystal form of pivmecillinam hydrochloride synthesized by the above process has stable structure and physical and chemical properties during the six-month sample retention period.

[0077] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a high-purity pivmecillinam hydrochloride crystal form, characterized in that: The steps include:

2. The method according to claim 1, characterized in that The method comprises the following steps: 1) Under alkaline conditions, 6-APA reacts with chloromethyl pivalate to undergo nucleophilic substitution reaction, and reacts with organic acid to generate 6-aminopenicillanic acid pivalate methyl ester; 2) 6-aminopenicillanic acid pivalate methyl ester undergoes addition elimination reaction with N-dimethoxymethylazepane under alkaline conditions to obtain pivmecillin; 3) crystallizing pivmecillin through acid adjustment to obtain a crude product of pivmecillin hydrochloride; 4) The crude product of pivmecillin hydrochloride is dissolved in an organic solvent, decolorized, filtered, and crystallized to obtain a stable crystalline form of pivmecillin hydrochloride.

3. The method according to claim 2, characterized in that: The reaction temperature of step 1) is 0-25°C; the reaction solvent is acetone, N-methylpyrrolidone, N,N-dimethylacetamide or N,N-dimethylformamide, the base is triethylamine, N,N-diisopropylethylamine or potassium carbonate, and the organic acid is p-toluenesulfonic acid.

4. The method according to claim 2 or 3, characterized in that: The molar ratio of the base used in step 1) to 6-APA is 1-1.2:1, the molar ratio of chloromethyl pivalate to 6-APA is 1-1.2:1, and the molar ratio of the organic acid to 6-APA is 1.5-2.0:

1.

5. The method according to claim 2, characterized in that: In step 2), the solvent used for the reaction is acetone, anhydrous methanol, anhydrous ethanol or dichloromethane, the base is triethylamine or N,N-diisopropylethylamine, and the reaction temperature is 0 to 25°C.

6. The method according to claim 2, characterized in that: In step 2), the molar ratio of the base to 6-aminopenicillanic acid methyl pivalate is 1-1.2:1, and the molar ratio of N-dimethoxymethylazepane to 6-aminopenicillanic acid methyl pivalate is 1-1.2:

1.

7. The method according to claim 2, characterized in that: The reagents used for acid adjustment in step 3) are 5%-30% hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, hydrogen chloride ethyl acetate solution, hydrogen chloride acetone solution and hydrochloric acid aqueous solution, and the pH is adjusted to 3-4.

8. The method according to claim 2, characterized in that: In step 3), the crystallization temperature is -5 to 25°C.

9. The method according to claim 2, characterized in that: In step 4), the organic solvent is methanol, ethanol, isopropanol, ethyl acetate or isopropyl ether.

10. The method according to claim 2, characterized in that: Step 4) The dissolution temperature is 30 to 50°C, and the crystallization temperature is -5 to 10°C.

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