Method for catalytic synthesis of cefazolin sodium intermediate TDA

Abstract

The invention provides a method for catalytic synthesis of a cefazolin sodium intermediate TDA, and belongs to the technical field of synthesis of drug intermediates. The method provided by the invention comprises the following steps: mixing methanesulfonic acid, methyl mercaptothiadiazole, 7-aminocephalosporanic acid and an organic solvent, and sequentially carrying out substitution reaction and crystallization to obtain the cefazolin sodium intermediate TDA and crystallization mother liquor. According to the method, the methanesulfonic acid is used as the catalyst to catalyze 7-ACA to synthesize TDA, harsh anhydrous conditions are not needed, the methanesulfonic acid is small in toxicity and corrosivity, can be effectively recycled and is environmentally friendly, and meanwhile it can be guaranteed that TDA has the excellent recovery rate and purity.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of pharmaceutical intermediates, and particularly relates to a method for catalytically synthesizing the cefazolin sodium intermediate TDA. Background Art

[0002] Cefazolin sodium is a cephalosporin antibiotic, which is mainly used clinically for the treatment of inflammatory infections such as respiratory tract and urinary tract caused by sensitized bacteria.

[0003] All along, cefazolin sodium has basically been synthesized by chemical methods. In the prior art, the synthesis route of cefazolin sodium is to transform the 3-position of 7-aminocephalosporanic acid (7-ACA) to obtain TDA, and then use acylating bioenzyme as a catalyst to synthesize CEZ, and form salt to obtain cefazolin sodium. At present, the production methods of synthesizing TDA from 7-ACA mainly include acid catalysis, base catalysis and organosilicon method. Among them, although the base-catalyzed reaction system has mild reaction conditions and low toxicity, the yield is not high and the color of TDA is relatively deep; while the organosilicon method has a high yield, but it requires an anhydrous environment and the price of organosilicon is relatively high. Therefore, most manufacturers use the acid-catalysis method. When using an acid catalyst to synthesize TDA in the prior art, BF3 complex is generally used as a catalyst, but BF3 requires a harsh anhydrous environment, and has high toxicity and strong corrosiveness, thus limiting its production. Therefore, there is an urgent need for a method for catalytically synthesizing the cefazolin sodium intermediate TDA with low reaction condition requirements, low toxicity and low corrosiveness. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for catalytically synthesizing the cefazolin sodium intermediate TDA. The present invention uses methanesulfonic acid as a catalyst, which does not require a harsh anhydrous environment, and has low toxicity and low corrosiveness.

[0005] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0006] The present invention provides a method for catalytically synthesizing the cefazolin sodium intermediate TDA, comprising:

[0007] Mix methanesulfonic acid, methyl mercaptothiadiazole, 7-aminocephalosporanic acid and an organic solvent, and successively carry out a substitution reaction and crystallization to obtain the cefazolin sodium intermediate TDA and a crystallization mother liquor.

[0008] Preferably, the volume ratio of the methanesulfonic acid to the mass of methyl mercaptothiadiazole is (15-30) mL:(3-8) g.

[0009] Preferably, the volume ratio of the methanesulfonic acid to the mass of 7-aminocephalosporanic acid is (15-30) mL:(5-15) g.

[0010] Preferably, the organic solvent includes dimethyl carbonate, acetonitrile or dichloromethane.

[0011] Preferably, the volume ratio of the methanesulfonic acid to the organic solvent is (15 - 30):(5 - 20).

[0012] Preferably, the method for mixing the methanesulfonic acid, methyl mercaptothiadiazole, 7 - aminocephalosporanic acid and the organic solvent is as follows: mix the methanesulfonic acid, methyl mercaptothiadiazole and 7 - aminocephalosporanic acid to obtain a mixed solution; taking the time when the mixed solution is obtained as 0 s, add the organic solvent to the mixed solution in portions at 30 - 50 s, 1.4 - 1.6 min, 2.5 - 3.5 min, 9 - 11 min and 17 - 19 min in sequence.

[0013] Preferably, the temperature of the substitution reaction is 28 - 35 °C, and the time of the substitution reaction is 20 - 40 min.

[0014] Preferably, it further includes mixing the crystallization mother liquor with a first base and then performing a first filtration to obtain a filtrate; mixing the filtrate with a second base and heating to obtain a concentrated suspension; mixing the concentrated suspension with water and activated carbon, and performing a second filtration, a first concentration, drying, dissolution in concentrated sulfuric acid and a second concentration in sequence to obtain methanesulfonic acid.

[0015] Preferably, the temperature of the heating is 70 - 80 °C.

[0016] Preferably, the temperature of the second concentration is 70 - 80 °C.

[0017] The present invention provides a method for catalytically synthesizing cefazolin sodium intermediate TDA, including: mixing methanesulfonic acid, methyl mercaptothiadiazole, 7 - aminocephalosporanic acid and an organic solvent, and performing a substitution reaction and crystallization in sequence to obtain cefazolin sodium intermediate TDA and a crystallization mother liquor. The present invention uses methanesulfonic acid as a catalyst to catalyze the synthesis of TDA from 7 - ACA, without requiring harsh anhydrous conditions. Methanesulfonic acid has low toxicity and corrosiveness, can be effectively recovered, is green and environmentally friendly, and can ensure that TDA has excellent recovery rate and purity. The results of the examples show that the molar yield of TDA obtained by the method of the present invention is 90%, and the purity is 97%. Description of the Drawings

[0018] Figure 1 It is a schematic flow chart of the recovery of methanesulfonic acid in steps (4) and (5) of Example 1;

[0019] Figure 2 It is a chromatogram of the reaction solution obtained in step (1) of Example 1;

[0020] Figure 3 It is an infrared spectrum of cefazolin sodium intermediate TDA prepared in step (3) of Example 1. Detailed implementation mode

[0021] The present invention provides a method for catalytically synthesizing the cefazolin sodium intermediate TDA, including:

[0022] Mix methanesulfonic acid, methyl mercaptothiadiazole, 7-aminocephalosporanic acid and an organic solvent, and successively carry out a substitution reaction and crystallization to obtain the cefazolin sodium intermediate TDA and a crystallization mother liquor.

[0023] Unless otherwise specified, the present invention has no special limitation on the sources of each raw material, and commercially available products well-known to those skilled in the art can be used.

[0024] In the present invention, the volume ratio of the methanesulfonic acid to the mass of methyl mercaptothiadiazole (MMTD) is preferably (15-30) mL:(3-8) g. As an implementation mode, the volume ratio of the methanesulfonic acid to the mass of methyl mercaptothiadiazole can specifically be 15 mL:3 g, 15 mL:5 g, 15 mL:8 g or 25 mL:5 g. By controlling the volume ratio of the methanesulfonic acid to the mass of methyl mercaptothiadiazole within the above range, the present invention can enable the raw materials to react fully, improving the yield and purity of TDA.

[0025] In the present invention, the volume ratio of the methanesulfonic acid to the mass of 7-aminocephalosporanic acid (7-ACA) is preferably (15-30) mL:(5-15) g. As an implementation mode, the volume ratio of the methanesulfonic acid to the mass of 7-aminocephalosporanic acid can specifically be 15 mL:5 g, 15 mL:10 g, 15 mL:15 g or 25 mL:10 g. By controlling the volume ratio of the methanesulfonic acid to the mass of 7-aminocephalosporanic acid within the above range, the present invention can enable the raw materials to react fully, improving the yield and purity of TDA.

[0026] In the present invention, the organic solvent preferably includes dimethyl carbonate (DMC), acetonitrile (ACN) or methylene chloride (MDC), and more preferably DMC.

[0027] In the present invention, the volume ratio of the methanesulfonic acid to the organic solvent is preferably (15-30):(5-20). As an implementation mode, the volume ratio of the methanesulfonic acid to the organic solvent can be (15-25):(10-15), and can also be 25:10. By controlling the volume ratio of the methanesulfonic acid to the organic solvent within the above range, the present invention can enable the raw materials to be fully dissolved.

[0028] In the present invention, the method for mixing methanesulfonic acid, methyl mercaptothiadiazole, 7-aminocephalosporanic acid and an organic solvent is preferably as follows: Mix methanesulfonic acid, methyl mercaptothiadiazole and 7-aminocephalosporanic acid to obtain a mixed solution; starting from the time when the mixed solution is obtained as 0 s, add the organic solvent to the mixed solution in portions at 30 - 50 s, 1.4 - 1.6 min, 2.5 - 3.5 min, 9 - 11 min and 17 - 19 min in sequence; more preferably: Under the stirring rate of 20 - 25 °C and 300 - 400 rpm, add methyl mercaptothiadiazole and 7-aminocephalosporanic acid to methanesulfonic acid in sequence and mix to obtain a mixed solution; starting from the time when the mixed solution is obtained as 0 s, heat the mixed solution to 28 - 35 °C, and at the stirring rate of 420 - 500 rpm, add the organic solvent to the mixed solution in portions at 40 s, 1.5 min, 3 min, 10 min and 18 min in sequence. In the present invention, adding the organic solvent in portions and intermittently can effectively reduce the generation of impurities and improve the purity of TDA. In the present invention, when adding the organic solvent in portions, the amount of the organic solvent added each time is preferably the same.

[0029] In the present invention, the temperature of the substitution reaction is preferably 28 - 35 °C. As an implementation manner, the temperature of the substitution reaction can specifically be 28 °C, 29 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C or 35 °C.

[0030] In the present invention, the time of the substitution reaction is preferably 20 - 40 min. As an implementation manner, the time of the substitution reaction can specifically be 20 min, 25 min, 30 min, 35 min or 40 min. In the present invention, the time of the substitution reaction is calculated starting from the time when methanesulfonic acid, methyl mercaptothiadiazole and 7-aminocephalosporanic acid are mixed to obtain a mixed solution. By controlling the temperature and time of the substitution reaction within the above ranges in the present invention, the raw materials can fully react, further improving the yield and purity of TDA.

[0031] After the substitution reaction is completed, in the present invention, it is preferred to cool down the product of the substitution reaction and then perform crystallization.

[0032] In the present invention, it is preferably cooled down to 0 - 15 °C.

[0033] In the present invention, the cooling is preferably carried out under stirring conditions; the stirring rate is preferably 300 - 400 rpm. In the present invention, there is no special limitation on the cooling time, and it is sufficient to cool down to the above temperature range. Cooling down and controlling the temperature in the present invention are more conducive to the subsequent crystallization process.

[0034] The present invention preferably adds a mixed solution to the cooled product for first crystallization, then adds an alkali, and successively performs second crystallization, filtration, washing, and drying to obtain the cefazolin sodium intermediate TDA and the crystallization mother liquor.

[0035] In the present invention, the mixed solution preferably comprises water, a pH regulator, a chelating agent, and an antioxidant.

[0036] In the present invention, the water is preferably purified water.

[0037] In the present invention, the pH regulator preferably comprises ammonia water, barium hydroxide, calcium hydroxide, sodium hydroxide, or potassium hydroxide; the mass concentration of the ammonia water is preferably 15-25%, more preferably 20%.

[0038] In the present invention, the chelating agent preferably comprises EDTA-2Na, citric acid, triethylamine tricarboxylate, or pentetic acid.

[0039] In the present invention, the antioxidant preferably comprises sodium metabisulfite, sodium sulfite, ascorbic acid, sodium thiosulfate, or sodium gluconate.

[0040] In the present invention, when the pH regulator is ammonia water with a mass concentration of 20%, the volume ratio of the water, the volume of the pH regulator, the mass of the chelating agent, and the mass of the antioxidant is preferably (50-80) mL: (10-20) mL: (0.3-0.5) g: (0.5-1.0) g.

[0041] In the present invention, the preparation method of the mixed solution is preferably: mixing water, a pH regulator, a chelating agent, and an antioxidant at 0-15°C to obtain the mixed solution.

[0042] In the present invention, the preparation of the mixed solution is preferably carried out in a flask.

[0043] In the present invention, the volume ratio of methanesulfonic acid to the water in the mixed solution is preferably (15-30): (50-80), more preferably 25:70. By controlling the volume ratio of methanesulfonic acid to the water in the mixed solution within the above range in the present invention, the crystallization can be fully carried out, and the yield and purity of TDA can be further improved.

[0044] The present invention preferably slowly adds the mixed solution to the cooled product. By slowly adding the mixed solution in the present invention, the temperature rise caused by the exothermic reaction can be avoided.

[0045] After adding the mixed solution, the present invention preferably uses 10-20 mL of purified water to wash the flask, and then adds the washed purified water to the cooled product.

[0046] In the present invention, the temperature of the first crystallization is preferably 0 to 10 °C; the time of the first crystallization is preferably 25 to 35 min; the first crystallization is preferably carried out under stirring conditions; the stirring rate is preferably 10 to 50 rpm.

[0047] In the present invention, the base preferably includes ammonia water, barium hydroxide, calcium hydroxide, sodium hydroxide or potassium hydroxide, and more preferably ammonia water.

[0048] In the present invention, the mass concentration of the ammonia water is preferably 15 to 25%, and more preferably 20%.

[0049] In the present invention, the pH value after adding the base is preferably 3.5 to 4.5, and more preferably 4. There is no special limitation on the dosage of the base in the present invention, as long as the pH value after adding the base is within the above range.

[0050] In the present invention, the temperature of the second crystallization is preferably 0 to 10 °C; the time of the second crystallization is preferably 50 to 75 min; the second crystallization is preferably carried out under stirring conditions; the stirring rate is preferably 50 to 100 rpm.

[0051] In the present invention, the filtration is preferably vacuum filtration. There is no special limitation on the operation of the vacuum filtration in the present invention, and the technical solution of vacuum filtration well-known to those skilled in the art can be adopted.

[0052] In the present invention, the washing is preferably carried out by washing twice with purified water first, and then washing once by pulping with acetone. There is no special limitation on other operations of the washing in the present invention, and the technical solutions well-known to those skilled in the art can be adopted.

[0053] In the present invention, the drying is preferably natural air drying in a fume hood.

[0054] By adopting the above crystallization process, the present invention can further improve the yield and purity of TDA.

[0055] After obtaining the crystallization mother liquor, the present invention preferably mixes the crystallization mother liquor with a first base and then performs a first filtration to obtain a filtrate; mixes the filtrate with a second base and then heats it to obtain a concentrated suspension; mixes the concentrated suspension with water and activated carbon, and sequentially performs a second filtration, a first concentration, drying, dissolution in concentrated sulfuric acid, and a second concentration to obtain methanesulfonic acid.

[0056] In the present invention, the first base preferably includes barium hydroxide, calcium hydroxide, sodium hydroxide or potassium hydroxide.

[0057] In the present invention, the pH value after mixing the crystallization mother liquor and the first alkali is preferably 6.5 to 7.5, more preferably 7. The present invention has no special limitation on the dosage of the first alkali, as long as the pH value after mixing the crystallization mother liquor and the first alkali is within the above range.

[0058] The present invention has no special limitation on the operation of the first filtration, and a technical solution well-known to those skilled in the art can be adopted.

[0059] In the present invention, the second alkali preferably includes barium hydroxide, calcium hydroxide, sodium hydroxide or potassium hydroxide.

[0060] In the present invention, the pH value after mixing the filtrate and the second alkali is preferably 13 to 14, more preferably 14. In the present invention, when synthesizing the intermediate TDA of cefazolin sodium, the volume ratio of methanesulfonic acid to the mass of the second alkali is preferably (15 - 30) mL: 55.08 g, more preferably 25 mL: 55.08 g.

[0061] In the present invention, the heating temperature is preferably 70 to 80 °C, more preferably 75 °C.

[0062] In the present invention, the heating is preferably carried out under stirring and reduced pressure conditions. The present invention has no special limitation on the operations of the stirring and reduced pressure, and a technical solution well-known to those skilled in the art can be adopted.

[0063] In the present invention, during the heating process, ammonia gas generated and water in the system are drawn out under stirring and reduced pressure conditions. The present invention has no special limitation on the heating time, until no more ammonia gas can be drawn out. In the present invention, during the heating process, if there is still a large amount of ammonia gas when it is about to be dried up, purified water is preferably added. The present invention has no special limitation on the dosage of the added purified water, as long as the ammonia gas can be completely drawn out.

[0064] In the present invention, the water is preferably purified water.

[0065] The present invention has no special limitation on the dosage of the purified water, as long as it can dilute and dissolve the concentrated suspension.

[0066] In the present invention, the mixing of the concentrated suspension with water and activated carbon is preferably as follows: the concentrated suspension and water are mixed, filtered to obtain a filtrate, and then the filtrate is mixed with activated carbon.

[0067] The present invention has no special limitation on the operation of the filtration, and a technical solution well-known to those skilled in the art can be adopted.

[0068] In the present invention, when synthesizing the intermediate TDA of cefazolin sodium, the volume ratio of methanesulfonic acid to the mass of activated carbon is preferably (15 - 30) mL: (2 - 5) g, more preferably 25 mL: 3 g.

[0069] In the present invention, the mixing of the filtrate and the activated carbon is preferably carried out under stirring conditions; the mixing time is preferably 15 to 30 min. The present invention has no special limitation on the operation of the stirring, and the technical solutions well-known to those skilled in the art can be adopted.

[0070] In the present invention, the second filtration is preferably carried out by using an F-type polyvinylidene fluoride microporous membrane with a pore size of 0.4 to 0.5 μm.

[0071] In the present invention, the temperature of the first concentration is preferably 70 to 80 °C; the vacuum degree of the first concentration is preferably -0.08 to -0.10 MPa. The present invention has no special limitation on the time of the first concentration, and the technical solutions well-known to those skilled in the art can be adopted.

[0072] The present invention has no special limitation on the operation of the drying, and the technical solutions well-known to those skilled in the art can be adopted.

[0073] In the present invention, the mass concentration of the concentrated sulfuric acid is preferably 98%. In the present invention, the volume ratio of methanesulfonic acid to concentrated sulfuric acid when synthesizing the cefazolin sodium intermediate TDA is preferably (15 to 30):15, more preferably 25:15.

[0074] In the present invention, the temperature of the second concentration is preferably 70 to 80 °C; the vacuum degree of the second concentration is preferably -0.08 to -0.10 MPa. The present invention has no special limitation on the time of the second concentration, and the technical solutions well-known to those skilled in the art can be adopted.

[0075] The present invention can recycle and reuse methanesulfonic acid by the above method, and the recovered methanesulfonic acid has a high purity.

[0076] The present invention uses methanesulfonic acid as a catalyst, and the reaction condition temperature does not require harsh anhydrous conditions. Methanesulfonic acid has low toxicity, no oxidizing property, low corrosivity, is easily biodegradable and can be effectively recovered. At the same time, the amount of organic solvent used is small (one-third of the solvent amount when BF3 is used as a catalyst), and there is no need to deal with the high cost of fluorine-containing waste liquid. The main three wastes generated by the present invention are waste residues (sulfates), which are easier to handle than waste liquids and can be treated by landfill or converted into by-products, etc. Without reducing the yield and purity of TDA, the production cost is reduced, the three wastes are reduced, and the fluorine-free synthesis of TDA is realized, which is green and environmentally friendly and is beneficial to practical production applications.

[0077] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0078] Example 1

[0079] A method for catalytically synthesizing the intermediate TDA of cefazolin sodium: (1) Cool 25 mL of methanesulfonic acid to 22 ± 2 °C in an ice bath, and sequentially add 5 g of MMTD and 10 g of 7-ACA at a stirring rate of 350 rpm to obtain a mixed solution. Start timing, heat up to 30 ± 1 °C, and sequentially add DMC to the mixed solution at 450 rpm at 40 s, 1.5 min, 3 min, 10 min, and 18 min. Add 2 mL each time, for a total of 10 mL. React for 30 min until the reaction solution is clear and there is no visible solid. Cool to 5 °C in an ice bath to obtain a reaction solution;

[0080] (2) Mix 70 mL of purified water, 15 mL of ammonia water with a mass concentration of 20%, 0.4 g of EDTA-2Na, and 0.8 g of sodium metabisulfite in a flask to obtain a mixed solution. Control the temperature at 0 - 10 °C during the mixing process;

[0081] (3) Slowly add the mixed solution in step (2) to the reaction solution in step (1). Wash the flask with 15 mL of purified water, and then add the purified water after washing the flask to the reaction solution. Crystallize at 5 °C for 30 min at a stirring rate of 30 rpm, increase the rotation speed to 80 rpm, add ammonia water with a mass concentration of 20% until the pH value of the system is 4, and crystallize at 5 °C for 60 min to obtain a crystallization solution. Vacuum filter the crystallization solution to obtain a filter cake and a crystallization mother liquor. Wash the filter cake twice with purified water and once with acetone slurry, and then place it in a fume hood to dry naturally to obtain the intermediate TDA of cefazolin sodium;

[0082] (4) Add barium hydroxide to the crystallization mother liquor (pH value is 4) obtained in step (3) until the pH value is 7, filter to obtain a filtrate. Continue to add 55.08 g of barium hydroxide to the filtrate, heat to 75 °C, and under stirring, decompress and extract the ammonia gas and water generated by the reaction until no ammonia gas can be extracted to obtain a concentrated suspension;

[0083] (5) Add purified water to the concentrated suspension obtained in step (4) to dilute and dissolve it, filter, add 3 g of activated carbon to the filtrate, stir for 20 min, filter using an F-type polyvinylidene fluoride microporous membrane with a pore size of 0.45 μm, subject the obtained filtrate to vacuum distillation at 75 °C and -0.09 MPa to evaporate the water, further dry the solid in a vacuum drying oven, then dissolve it with 15 mL of concentrated sulfuric acid with a mass concentration of 98%, and then conduct vacuum distillation at 75 °C and -0.09 MPa to evaporate the water to obtain methanesulfonic acid.

[0084] Comparative Example 1

[0085] Add 50 g of DMC and 69 g of BF3-DMC (the mass ratio of BF3 to 7-ACA is 1.2) to the condensation tank, start stirring, put 13 g of thiodiazole and 25 g of 7-ACA into the tank, simultaneously raise the temperature, the reaction temperature is 40 °C, and react until the residue of 7-ACA is less than 1.0%. After the reaction is completed, cool down to below 10 °C, transfer the reaction solution to a three-necked flask containing 300 mL of deionized water, add sodium carbonate solution dropwise until the pH is 4, cool down to 10 °C, and stir for crystal cultivation for 1 h. Filter, wash with acetone and then dry to obtain the cefazolin sodium intermediate TDA.

[0086] The schematic diagram of the recovery process of methanesulfonic acid in steps (4) and (5) of Example 1 is as Figure 1 shown. Adjust the pH value of the crystallization mother liquor with a pH value of 4 to 7 with barium hydroxide, then filter, add barium hydroxide again, heat, conduct vacuum distillation to distill out ammonia and water, dilute and dissolve the remaining part with water, filter, filter with activated carbon added, subject the filtrate to vacuum distillation and then dissolve it with concentrated sulfuric acid, and then conduct vacuum distillation to obtain methanesulfonic acid (K acid).

[0087] The chromatogram of the reaction solution obtained in step (1) of Example 1 is as Figure 2 shown. The structural formula of impurity A is The structural formula of impurity B is The structural formula of impurity C is

[0088] From Figure 2 it can be seen that there are fewer impurities and the area percentage of the main peak is relatively large. At the end of the reaction, the mass percentage content of TDA in the reaction solution reached 91.99%.

[0089] The infrared spectrum of the cefazolin sodium intermediate TDA prepared in step (3) of Example 1 is as Figure 3 shown. From Figure 3 it can be seen that at 1803.98 cm -1The peak at [wavenumber] is the stretching vibration peak of C=O in the β-lactam ring of TDA. The infrared absorption wavelength of this characteristic group is reduced due to the strong strain of the four-membered ring, that is, a blue shift occurs. The C-N stretching vibration peak in the β-lactam ring of TDA is [wavenumber]. -1 The peak at [wavenumber] is the stretching vibration peak of C=O in the β-lactam ring of TDA. The infrared absorption wavelength of this characteristic group is reduced due to the strong strain of the four-membered ring, that is, a blue shift occurs. The C-N stretching vibration peak in the β-lactam ring of TDA is [wavenumber]. -1 The peak at [wavenumber] is the stretching vibration peak of C=C in -C=C-. The peak at [wavenumber] is the stretching vibration peak of C=N in -C=N-. The stretching vibration peak of the C=O bond in the 2-carboxyl group of TDA is [wavenumber]. -1 The peak at [wavenumber] is the stretching vibration peak of C=C in -C=C-. The peak at [wavenumber] is the stretching vibration peak of C=N in -C=N-. The stretching vibration peak of the C=O bond in the 2-carboxyl group of TDA is [wavenumber]. -1 The infrared absorption spectrum shows that the sample contains a β-lactam ring and there are characteristic functional groups such as carboxyl, C=C, and C=N, which are basically consistent with the structure of TDA.

[0090] The molar yields, purities, catalyst dosages, catalyst evaluations, and reaction times of TDA in Example 1 and Comparative Example 1 are shown in Table 1.

[0091] Table 1 Molar yields, purities, catalyst dosages, catalyst evaluations, and reaction times of TDA in Example 1 and Comparative Example 1

[0092]

[0093] As can be seen from Table 1, the purity and yield of TDA obtained by the method of the present invention are basically the same as those of the original process, but the production cost is lower and the time is shorter.

[0094] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for catalytically synthesizing TDA, an intermediate of cefazolin sodium, comprising: Methanesulfonic acid, methylthiothiadiazole, 7-aminocephalosporanic acid and an organic solvent are mixed, and substitution reaction and crystallization are carried out in sequence to obtain a cefazolin sodium intermediate TDA and a crystallization mother liquor.

2. The method according to claim 1, characterized in that The volume ratio of the methanesulfonic acid to the mass ratio of methylmercaptothiadiazole is (15-30) mL: (3-8) g.

3. The method according to claim 1, characterized in that The volume ratio of the methanesulfonic acid to the mass ratio of 7-aminocephalosporanic acid is (15-30) mL: (5-15) g.

4. The method according to claim 1, characterized in that The organic solvent includes dimethyl carbonate, acetonitrile or dichloromethane.

5. The method according to claim 1 or 4, characterized in that: The volume ratio of the methanesulfonic acid to the organic solvent is (15-30):(5-20).

6. The method according to claim 1, characterized in that The method for mixing the methanesulfonic acid, methylthiothiadiazole, 7-aminocephalosporanic acid and the organic solvent is as follows: methanesulfonic acid, methylthiothiadiazole and 7-aminocephalosporanic acid are mixed to obtain a mixed solution; taking the time for obtaining the mixed solution as 0 s, adding the organic solvent to the mixed solution in batches at 30 to 50 s, 1.4 to 1.6 min, 2.5 to 3.5 min, 9 to 11 min and 17 to 19 min.

7. The method according to claim 1, characterized in that The temperature of the substitution reaction is 28-35° C., and the time of the substitution reaction is 20-40 minutes.

8. The method according to claim 1, characterized in that The method also includes mixing the crystallization mother liquor with a first alkali and then performing a first filtration to obtain a filtrate; mixing the filtrate with a second alkali and then heating to obtain a concentrated suspension; mixing the concentrated suspension with water and activated carbon, and sequentially performing a second filtration, a first concentration, drying, dissolving in concentrated sulfuric acid, and a second concentration to obtain methanesulfonic acid.

9. The method according to claim 8, characterized in that The heating temperature is 70-80°C.

10. The method according to claim 8, characterized in that The temperature of the second concentration is 70-80°C.

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