Synthetic method of cefathiamidine

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis method of cefathiamidine. The preparation method comprises the following steps: enabling N,N-diisopropylthiourea to react with ethyl chloroacetate, performing an acylation reaction by using thionyl chloride, and further performing a reaction with silanized 7-ACA to generate cefathiamidine. According to the synthetic method of cefathiamidine provided by the invention, two silanization reagents are used, and the second silanization reagent plays a role in catalysis of silanization, so silanization efficiency is improved; and N,N-diisopropylthiourea and ethyl chloroacetate generate acyl chloride which then react with 7-ACA to synthesize thiamidine, s chloroacetyl 7-ACA impurities generated by reaction of acyl chloride and 7-ACA are avoided.

Description

technical field

[0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of cefathiamidine. Background technique

[0002] Cefathiamidine, whose chemical name is (6R,7R)-3[(acetoxy)methyl]-7-[α-(N,N-diisopropylthiamidino)-acetamido]8-oxo -5-Thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate betaine.

[0003] Cefathiamidine is a β-lactam antibiotic belonging to the first-generation cephalosporins. Its antibacterial spectrum is similar to that of cephalothin. It has a good effect on Gram-positive bacteria and is an exclusive cephalosporin against G+ enterococci. Bacterin is mainly used for respiratory tract infection, biliary tract, urinary tract, gynecological disease, septicemia, pneumonia, meningitis and other infections caused by sensitive bacteria. It is a sterile crystalline powder for clinical use.

[0004] At present, the production of cefathiamidine is commonly used to react 7-ACA with bromoacetyl bromide under the...

Examples

Embodiment 1

[0030] Add 60mL of dichloromethane into a 250mL reaction bottle, add 10.88g of 7-ACA while stirring, add 7.10g of hexamethyldisilazane, 1.74g of trimethylchlorosilane, stir at room temperature for 1h, and monitor the reaction by HPLC to form Reaction solution A is reserved.

[0031] Add 60mL of dichloromethane to a 500mL reaction bottle, add 6.40g of N,N-diisopropylthiourea, add 5.09g of sodium carbonate, 0.64g of sodium iodide, control the temperature at 15-25°C, add 1.80g of ethyl chloroacetate, Stir for 15 minutes, add 1.80 g of ethyl chloroacetate, stir for 15 minutes, add 1.80 g of ethyl chloroacetate, stir at a temperature of 20 to 25°C for 2 hours, HPLC detects that the reaction is complete, add concentrated hydrochloric acid to adjust the pH to 1.5, stir for 30 minutes, and cool down to - 5-5°C, add 5.23g of thionyl chloride, slowly dropwise add 2.92g of N,N-dimethylformamide, stir at -5-5°C for 1h, HPLC detects that the reaction is over, add reaction solution A, add N...

Embodiment 2

[0033] Add 60mL of dichloromethane into a 250mL reaction bottle, add 10.88g of 7-ACA while stirring, add 7.75g of hexamethyldisilazane, 2.17g of trimethylchlorosilane, stir at room temperature for 1h, and monitor the reaction by HPLC to form Reaction solution A is reserved.

[0034] Add 60mL of dichloromethane to a 500mL reaction bottle, add 6.40g of N,N-diisopropylthiourea, add 7.19g of potassium carbonate, 0.64g of potassium iodide, control the temperature at 15-25°C, add 1.80g of ethyl chloroacetate, and stir for 15min , add 1.80 g of ethyl chloroacetate, stir for 15 min, add 1.80 g of ethyl chloroacetate, stir at 20-25°C for 2 h, HPLC detects that the reaction is over, add hydrochloric acid to adjust the pH to 2.0, stir for 30 min, and cool down to -5-5 ℃, add 5.23g of thionyl chloride, slowly add 2.92g of N,N-dimethylformamide dropwise, control the temperature at -5~5℃ and stir for 1h, HPLC detects that the reaction is over, add reaction solution A, add N,N- 5.23g of dim...

Embodiment 3

[0036] Add 60mL of dichloromethane into a 250mL reaction bottle, add 10.88g of 7-ACA while stirring, add 8.39g of hexamethyldisilazane, 2.61g of trimethylchlorosilane, stir at room temperature for 1h, monitor the reaction by HPLC, and form Reaction solution A is reserved.

[0037] Add 60mL of dichloromethane to a 500mL reaction bottle, add 6.40g of N,N-diisopropylthiourea, add 4.70g of sodium bicarbonate, 0.64g of sodium iodide, control the temperature at 15-25°C, and add 1.80g of ethyl chloroacetate , stirred for 15 minutes, added 1.80 g of ethyl chloroacetate, stirred for 15 minutes, added 1.80 g of ethyl chloroacetate, stirred at a temperature of 20-25°C for 2 hours, HPLC detected that the reaction was completed, added hydrochloric acid to adjust the pH to 2.5, stirred for 30 minutes, and cooled to - 5-5°C, add 5.23g of thionyl chloride, slowly dropwise add 2.92g of N,N-dimethylformamide, stir at -5-5°C for 1h, HPLC detects that the reaction is over, add reaction solution A...

technical field

[0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of cefathiamidine. Background technique

[0002] Cefathiamidine, whose chemical name is (6R,7R)-3[(acetoxy)methyl]-7-[α-(N,N-diisopropylthiamidino)-acetamido]8-oxo -5-Thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate betaine.

[0003] Cefathiamidine is a β-lactam antibiotic belonging to the first-generation cephalosporins. Its antibacterial spectrum is similar to that of cephalothin. It has a good effect on Gram-positive bacteria and is an exclusive cephalosporin against G+ enterococci. Bacterin is mainly used for respiratory tract infection, biliary tract, urinary tract, gynecological disease, septicemia, pneumonia, meningitis and other infections caused by sensitive bacteria. It is a sterile crystalline powder for clinical use.

[0004] At present, the production of cefathiamidine is commonly used to react 7-ACA with bromoacetyl bromide under the...

Examples

Embodiment 1

[0030] Add 60mL of dichloromethane into a 250mL reaction bottle, add 10.88g of 7-ACA while stirring, add 7.10g of hexamethyldisilazane, 1.74g of trimethylchlorosilane, stir at room temperature for 1h, and monitor the reaction by HPLC to form Reaction solution A is reserved.

[0031] Add 60mL of dichloromethane to a 500mL reaction bottle, add 6.40g of N,N-diisopropylthiourea, add 5.09g of sodium carbonate, 0.64g of sodium iodide, control the temperature at 15-25°C, add 1.80g of ethyl chloroacetate, Stir for 15 minutes, add 1.80 g of ethyl chloroacetate, stir for 15 minutes, add 1.80 g of ethyl chloroacetate, stir at a temperature of 20 to 25°C for 2 hours, HPLC detects that the reaction is complete, add concentrated hydrochloric acid to adjust the pH to 1.5, stir for 30 minutes, and cool down to - 5-5°C, add 5.23g of thionyl chloride, slowly dropwise add 2.92g of N,N-dimethylformamide, stir at -5-5°C for 1h, HPLC detects that the reaction is over, add reaction solution A, add N...

Embodiment 2

[0033] Add 60mL of dichloromethane into a 250mL reaction bottle, add 10.88g of 7-ACA while stirring, add 7.75g of hexamethyldisilazane, 2.17g of trimethylchlorosilane, stir at room temperature for 1h, and monitor the reaction by HPLC to form Reaction solution A is reserved.

[0034] Add 60mL of dichloromethane to a 500mL reaction bottle, add 6.40g of N,N-diisopropylthiourea, add 7.19g of potassium carbonate, 0.64g of potassium iodide, control the temperature at 15-25°C, add 1.80g of ethyl chloroacetate, and stir for 15min , add 1.80 g of ethyl chloroacetate, stir for 15 min, add 1.80 g of ethyl chloroacetate, stir at 20-25°C for 2 h, HPLC detects that the reaction is over, add hydrochloric acid to adjust the pH to 2.0, stir for 30 min, and cool down to -5-5 ℃, add 5.23g of thionyl chloride, slowly add 2.92g of N,N-dimethylformamide dropwise, control the temperature at -5~5℃ and stir for 1h, HPLC detects that the reaction is over, add reaction solution A, add N,N- 5.23g of dim...

Embodiment 3

[0036] Add 60mL of dichloromethane into a 250mL reaction bottle, add 10.88g of 7-ACA while stirring, add 8.39g of hexamethyldisilazane, 2.61g of trimethylchlorosilane, stir at room temperature for 1h, monitor the reaction by HPLC, and form Reaction solution A is reserved.

[0037] Add 60mL of dichloromethane to a 500mL reaction bottle, add 6.40g of N,N-diisopropylthiourea, add 4.70g of sodium bicarbonate, 0.64g of sodium iodide, control the temperature at 15-25°C, and add 1.80g of ethyl chloroacetate , stirred for 15 minutes, added 1.80 g of ethyl chloroacetate, stirred for 15 minutes, added 1.80 g of ethyl chloroacetate, stirred at a temperature of 20-25°C for 2 hours, HPLC detected that the reaction was completed, added hydrochloric acid to adjust the pH to 2.5, stirred for 30 minutes, and cooled to - 5-5°C, add 5.23g of thionyl chloride, slowly dropwise add 2.92g of N,N-dimethylformamide, stir at -5-5°C for 1h, HPLC detects that the reaction is over, add reaction solution A...

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