Preparation method of ceflozan key intermediate

Abstract

The invention discloses a preparation method of a ceftolozane intermediate, TATD and BCLE are used as initial raw materials, carboxyl activation and amidation reaction are performed to obtain the ceftolozane intermediate TATD-CLE, carboxyl activation and amide condensation two-step reaction are skillfully completed by a one-pot method, strict anhydrous and anaerobic conditions are not needed, the experiment is shortened, the operation is simple and convenient, the cost is low, and the method is suitable for industrial production. The reaction conditions are mild, the yield is high, the intermediate does not need to be separated and purified, and the next-step reaction is directly carried out. In addition, according to the route, ice water is added for crystallization, amplification is easy, and batch repeatability is good. In conclusion, the invention develops a synthetic process of the ceflozan intermediate benzhydryl 7 beta-[(Z)-2-(5-amino-1, 2, 4-thiadiazole-3-yl)-2-(1-tert-butyloxycarbonyl-1-methyl ethyoxyl imino) acetamido]-3-chloromethyl-3-cephem-4-carboxylic ester, which is green and environment-friendly, mild in condition, high in yield and simple, convenient and safe to operate. Good industrial application prospects are realized.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis, specifically relating to a method for preparing a ceftolozane intermediate, diphenylmethyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephalosporin-4-carboxylic acid ester. Background Technology

[0002] Ceftolozane is a novel intravenously administered "fifth-generation" cephalosporin antibiotic with good tolerability and a broad antibacterial spectrum. It exhibits strong activity against both Gram-positive and Gram-negative bacteria and has shown potent antibacterial activity against Pseudomonas aeruginosa and multidrug-resistant Pseudomonas aeruginosa in in vitro and in vivo studies. Its development code is CXA-101 or FR264205. The FDA has approved its sulfate form, cefoloza sulfate, chemically named 5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-2-{[(6R,7R)-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(l-carboxy-l-methylethoxy)imino]acetyl}amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-methyl-1H-pyrazolium monosulfate, with the following chemical structure:

[0003]

[0004] TATD-CLE, an important intermediate for cefoloza, has high economic value. Its chemical name is diphenylmethyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephalosporin-4-carboxylic acid ester, and its chemical structural formula is as follows:

[0005]

[0006] The literature (Bioorganic & Medicinal Chemistry (2008), 16(5), 2261-2275) reports a method for synthesizing the cefoloza intermediate TATD-CLE, using (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-tert-butoxy)-2-methyl-1-oxopropane-2-yl)oxy)imino)acetic acid (TATD) as the starting material. After activating the carboxyl group with phosphorus pentachloride, the acyl chloride is separated, and then the mixture is subjected to low temperature and... Under alkaline conditions, a condensation reaction was carried out with 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride (BCLE). The addition of diisopropyl ether to the reaction solution precipitated diphenylmethyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephalosporin-4-carboxylic acid ester (TATD-CLE). The synthetic route is as follows:

[0007]

[0008] This route uses phosphorus pentachloride, which is highly corrosive and reacts violently with water to produce HCl and POCl3. Strict anhydrous conditions are required, increasing the complexity of the process. Post-treatment generates large amounts of phosphoric acid-containing wastewater, placing significant pressure on environmental protection and resulting in high costs. Therefore, developing an environmentally friendly, mild, high-yield, and simple method for synthesizing the cefoloza intermediate TATD-CLE would have significant social and economic benefits. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides a method for preparing the ceftolozane intermediate diphenylmethyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephalosporin-4-carboxylic acid ester (TATD-CLE). This method uses TATD and BCLE as starting materials, and obtains the target product TATD-CLE through carboxyl activation and amidation reactions.

[0010] The specific technical solution of the present invention is as follows:

[0011] This invention provides a method for preparing a cefoloza intermediate as shown in formula TATD-CLE.

[0012]

[0013] The preparation method is carried out according to the following steps:

[0014] (1) Dissolve TATD in organic solvent A, slowly add carboxyl activating reagent at -20 to 20℃ (preferably -5℃), keep the reaction at this temperature for 30 to 60 min, then add alkaline substance A, keep the reaction at this temperature for 2 to 6 h, and obtain a solution containing TATD-A (no purification required, can be directly added to the next step of the reaction).

[0015] (2) Dissolve 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in formula BCLE in organic solvent B, add it slowly to the solution containing TATD-A described in step (1) at -20 to 20°C (preferably -5°C), keep the reaction at this temperature for 30 to 60 min, then add alkaline substance B, keep the reaction at this temperature for 1 to 4 h to obtain a reaction solution, slowly drop the reaction solution into ice water, keep the mixture at this temperature and stir for 5 to 12 h, filter off the liquid, wash the filter cake with ice water, and vacuum dry at 25°C for 12 to 48 h to obtain the cefoloza intermediate as shown in formula TATD-CLE.

[0016] The molar ratio of 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride, TATD, carboxyl activating agent, basic substance A, and basic substance B, as shown in formula BCLE, is 1.0:1.0-1.2:1.0-1.4:1.0-2.0:1.0-3.0 (preferably 1.0:1.0:1.2:1.5:2.0).

[0017] Furthermore, the organic solvent A is one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or acetonitrile (preferably N,N-dimethylformamide).

[0018] Furthermore, the volume of the organic solvent A, based on the mass of the TATD, is 2-10 mL / g (preferably 5 mL / g).

[0019] Furthermore, the carboxyl activating agent is added in the form of an organic solvent C, wherein the organic solvent C is one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or acetonitrile (preferably N,N-dimethylformamide).

[0020] Furthermore, the carboxyl activating agent is one or more of benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, methanesulfonyl chloride, ethylsulfonyl chloride, p-toluenesulfonylimidazole, methanesulfonylimidazole, ethyl chloroformate, isobutyl chloroformate, or trifluoromethanesulfonic anhydride (preferably p-toluenesulfonyl chloride or methanesulfonyl chloride).

[0021] Furthermore, the alkaline substance A is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, or N-methylmorpholine (preferably triethylamine).

[0022] Furthermore, the alkaline substance B is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, or N-methylmorpholine (preferably triethylamine).

[0023] Furthermore, the organic solvent B is one or more of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, or N,N-dimethylacetamide (preferably methanol).

[0024] Furthermore, the volume of the organic solvent B is 5-15 mL / g (preferably 10 mL / g) based on the mass of the 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in Formula BCLE.

[0025] Furthermore, the volume of the ice water is 20 to 100 mL / g (preferably 40 mL / g) based on the mass of the 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in Formula BCLE.

[0026] Compared with known synthetic routes, the present invention is characterized by the use of inexpensive and readily available carboxyl activating reagents instead of highly corrosive phosphorus pentachloride, which not only reduces the reaction hazard but also reduces environmental pollution and alleviates the pressure on environmental protection. The reaction is greener, more environmentally friendly, and lower in cost. At the same time, the route of the present invention ingeniously completes the two-step reaction of carboxyl activation and amidation in a "one-pot" process, which simplifies the reaction operation and has the advantages of high yield and simple post-processing.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention uses TATD and BCLE as raw materials, ingeniously completing the two-step reaction of carboxyl activation and amide condensation in a "one-pot" process. It eliminates the need for strictly anhydrous and oxygen-free conditions, shortening the experimental steps and simplifying the reaction operation. Furthermore, the reaction conditions are mild, the yield is high, and post-processing is simple; the intermediate does not require separation and purification and can be directly used in the next reaction. In addition, this route facilitates scale-up and exhibits good batch-to-batch reproducibility through the addition of ice water for crystallization. In summary, this invention develops a green, environmentally friendly, mild, high-yield, simple, and safe synthetic process for the ceftolozane intermediate diphenylmethyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephalosporin-4-carboxylic acid ester (TATD-CLE), which has promising prospects for industrial application. Detailed Implementation

[0029] The present invention is further described below through specific embodiments, but the scope of protection of the present invention is not limited thereto. Example 1: Preparation of compound TATD-CLE (i.e., cefoloza intermediate, diphenylmethyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephalosporin-4-carboxylic acid ester).

[0030] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.11 g, 11.08 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 5 h, and obtain a solution containing TATD-A. Add BCLE (i.e., 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride, 5 g, 11.08 mmol) to a 500 mL three-necked round-bottom flask, add methanol (50 mL), stir to dissolve, cool to -5 °C, add a solution containing TATD-A dropwise, keep the reaction at this temperature for 30 min, then add triethylamine (4.22 g, 22.15 mmol), keep the reaction at this temperature for 4 h, and after the reaction is completed by TLC monitoring, slowly add the above reaction system dropwise to ice water (200 mL), complete the addition in 2 h, crystallize for 10 h, filter, wash the filter cake with ice water, and dry under vacuum below 25 °C to obtain a white solid, which is compound TATD-CLE (6.19 g), with a reaction yield of 77%.

[0031] White solid, melting point: 110-112℃, R f=0.62 (DCM / MeOH = 40:1, V / V). 1 H NMR(400MHz,Chloroform-d)δ7.76(s,1H),7.48–7.46(m,2H),7.40–7.33(m,8H),7.32(s,2H),6.99(s,1H),6.1 2(dd,J=8.0,4.0Hz,1H),5.12(d,J=4.0Hz,1H),4.40–4.47(m,2H),3.69–3.50(m,2H),1.62(s,6H),1.45(s,9H). 13 C NMR(100MHz,Chloroform-d)δ173.69,164.27,160.49,139.09,138.93,128.66,128.59,128.35,128. 22,127.64,127.25,127.02,125.72,84.42,82.80,80.03,58.85,57.82,43.13,28.06,27.41,23.79.

[0032] Example 2: Preparation of compound TATD-CLE

[0033] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.32 g, 12.18 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 4h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise over 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (6.75g), white solid with a melting point of 110-112℃ and a reaction yield of 84%.

[0034] Example 3: Preparation of compound TATD-CLE

[0035] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.53 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise. The addition is completed in 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 90%.

[0036] Example 4: Preparation of compound TATD-CLE

[0037] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.745 g, 14.4 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise. The addition is completed in 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 91%.

[0038] Example 5: Preparation of compound TATD-CLE

[0039] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.957 g, 15.51 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise. The addition is completed in 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 87%.

[0040] Example 6: Preparation of compound TATD-CLE

[0041] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add methanesulfonyl chloride (1.52 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise. The addition is completed in 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 94%.

[0042] Example 7: Preparation of compound TATD-CLE

[0043] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add 4-nitrobenzenesulfonyl chloride (2.95 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise. The addition is completed in 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 55%.

[0044] Example 8: Preparation of compound TATD-CLE

[0045] Add TATD (4.02 g, 12.18 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.53 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise. The addition is completed in 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 88%.

[0046] Example 9: Preparation of compound TATD-CLE

[0047] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.53 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add methanol (50mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (3.17g, 16.6mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise over 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid with a melting point of 110-112℃ and a reaction yield of 81%.

[0048] Example 10: Preparation of compound TATD-CLE

[0049] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.53 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, then add ethyl acetate (25mL) and water (25mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise over 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), a white solid with a melting point of 110-112℃ and a reaction yield of 43%.

[0050] Example 11: Preparation of compound TATD-CLE

[0051] Add TATD (3.66 g, 11.08 mmol) to a dry 250 mL three-necked round-bottom flask, add N,N-dimethylformamide (18 mL), stir to dissolve, cool to -5 °C, add p-toluenesulfonyl chloride (2.53 g, 13.29 mmol) dissolved in N,N-dimethylformamide (18 mL), keep the reaction at this temperature for 30 min, then add triethylamine (3.17 g, 16.6 mmol), keep the reaction at this temperature for 4 h, and obtain a solution containing TATD-A. Add BCLE (5g, 11.08mmol) to a 500mL three-necked round-bottom flask, add N,N-dimethylformamide (25mL) and stir to dissolve. Cool to -5℃, add a solution containing TATD-A dropwise, and keep the reaction at this temperature for 30min. Then add triethylamine (4.22g, 22.15mmol) dropwise and keep the reaction at this temperature for 2h. After the reaction is complete as monitored by TLC, slowly add the above reaction system to ice water (200mL) dropwise over 2h. Crystallize for 10h, filter, wash the filter cake with ice water, and dry under vacuum below 25℃ to obtain a white solid, which is compound TATD-CLE (7.24g), white solid, melting point: 110-112℃, reaction yield 56%.

[0052] It should be noted that the above embodiments are merely illustrative of the concept and features of the present invention, intended to enable those skilled in the art to understand the experiment and implement it accordingly, and do not limit the scope of protection of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing a cefoloza intermediate as shown in formula TATD-CLE, Its features are, The preparation method is carried out according to the following steps: (1) Dissolve TATD in organic solvent A, add carboxyl activating reagent dropwise at -20 to 20℃, keep the reaction at the temperature for 30 to 60 min, then add alkaline substance A, keep the reaction at the temperature for 2 to 6 h, and obtain a solution containing TATD-A; (2) Dissolve 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in formula BCLE in organic solvent B, add the solution containing TATD-A described in step (1) at -20 to 20°C, keep the reaction at this temperature for 30 to 60 min, then add alkaline substance B, keep the reaction at this temperature for 1 to 4 h to obtain a reaction solution, drop the reaction solution into ice water, keep the reaction solution at this temperature and stir for 5 to 12 h, filter off the liquid, wash the filter cake with ice water, and vacuum dry at 25°C for 12 to 48 h to obtain the cefoloza intermediate as shown in formula TATD-CLE; the molar ratio of 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in formula BCLE, TATD, carboxyl activating reagent, alkaline substance A, and alkaline substance B is 1.0:1.0 to 1.2:1.0 to 1.4:1.0 to 2.0:1.0 to 3.

0.

2. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The organic solvent A is one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or acetonitrile.

3. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The volume of the organic solvent A, based on the mass of the TATD, is 2-10 mL / g.

4. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The carboxyl activating agent is added in the form of an organic solvent C, wherein the organic solvent C is one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or acetonitrile.

5. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The carboxyl activating agent is one or more of benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, methanesulfonyl chloride, ethylsulfonyl chloride, p-toluenesulfonylimidazole, methanesulfonylimidazole, ethyl chloroformate, isobutyl chloroformate, or trifluoromethanesulfonic anhydride.

6. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The alkaline substance A is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, or N-methylmorpholine.

7. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The alkaline substance B is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, or N-methylmorpholine.

8. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The organic solvent B is one or more of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, or N,N-dimethylacetamide.

9. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The volume of the organic solvent B is 5-15 mL / g based on the mass of the 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in Formula BCLE.

10. The method for preparing the cefoloza intermediate as shown in formula TATD-CLE according to claim 1, characterized in that, The volume of the ice water is 20 to 100 mL / g, calculated by the mass of the 7β-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid diphenylmethyl ester hydrochloride as shown in Formula BCLE.

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