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Synthetic method of cefathiamidine

A technology of cefathiamidine and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of high reaction activity of bromoacetyl bromide, complicated operation, easy hydrolysis of bromoacetyl bromide, etc., and achieves the effect of improving silanization efficiency

Active Publication Date: 2020-04-17
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] CN101921284A discloses a new method of cefathiamidine. First, 7-ACA is silanized with BSA, then reacted with bromoacetyl bromide, and then reacted with N,N-diisopropylthiourea in an alkaline reagent to generate cefathiazone Amidine, this method uses BSA silanization to solve the operation inconvenience caused by the dissolution of sodium bicarbonate in production, and avoids the instability of 7-ACA in alkaline solvents for a long time, but the purity after purification is 98.48%, which is not ideal
[0010] (1) In the process of synthesizing the cefathiamidine intermediate, the reaction solvent has water, and bromoacetyl bromide is easily hydrolyzed, which is unfavorable for carrying out the reaction
[0011] (2) bromoacetyl bromide has high reactivity, but is expensive, and is prone to produce bromoacetyl 7-ACA impurity; chloroacetyl chloride has lower price, but lower reactivity
[0012] (3) The reaction process requires acid-base double-dropping, which is complicated to operate and difficult to control

Method used

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Examples

Experimental program
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Effect test

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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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/28C07D501/08
CPCC07D501/28C07D501/08
Inventor 宋丽丽李俊广孙运贝王晓
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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