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Synthesis process of cefathiamidine

A technique for cefathiamidine and synthesis process, which is applied in the field of cefathiamidine synthesis process, can solve problems such as unsatisfactory operation, complicated operation, and high price, and achieve the effects of promoting smooth progress, high yield and purity, and improved yield

Active Publication Date: 2020-05-05
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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  • Synthesis process of cefathiamidine
  • Synthesis process of cefathiamidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Add 60ml of dichloromethane to a 250mL reaction flask, add 10.17g of 1,3-diisopropylamidino-2-thioacetic acid hydrochloride, add 8.90g of 4-pyrrolidinylpyridine, and add Sodium 1.76g, lower the temperature to 0-10°C, slowly add the dichloromethane solution of p-nitrobenzenesulfonyl chloride (9.72g dissolved in 30ml methylene chloride) dropwise, the dropwise addition is completed in about 15 minutes, control the temperature at 0-10°C and stir for 1h , HPLC detected that the reaction was substantially complete, and filtered to obtain filtrate A.

[0031] (2) Add 2.92g of N,N-dimethylformamide to filtrate A, slowly add 10.88g of 7-ACA, dropwise add 30% sodium hydroxide solution to adjust the pH to 4.5, stir for 15min, add dropwise 30% hydroxide Adjust the pH to 4.5 with sodium solution, stir for 15 minutes, add dropwise 30% sodium hydroxide solution to adjust the pH to 4.5, stir at room temperature for 2 hours, monitor the end of the reaction by HPLC, distill under red...

Embodiment 2

[0033] (1) Add 60ml of dichloromethane to a 250mL reaction flask, add 10.17g of 1,3-diisopropylamidino-2-thioacetic acid hydrochloride, add 9.77g of 4-dimethylaminopyridine, and add Potassium 2.69g, lower the temperature to 0-10°C, slowly add the dichloromethane solution of p-nitrobenzenesulfonyl chloride (9.72g dissolved in 30ml methylene chloride) dropwise, the dropwise addition is completed in about 15 minutes, control the temperature at 0-10°C and stir for 1h , HPLC detected that the reaction was substantially complete, and filtered to obtain filtrate A.

[0034] (2) Add 3.48g of N,N-dimethylacetamide to filtrate A, slowly add 10.88g of 7-ACA, add dropwise 30% sodium hydroxide solution to adjust the pH to 5.0, stir for 15min, add dropwise 30% hydroxide Adjust the pH to 5.0 with sodium solution, stir for 15 minutes, add dropwise 30% sodium hydroxide solution to adjust the pH to 5.0, stir at room temperature for 2 hours, monitor the end of the reaction by HPLC, distill under...

Embodiment 3

[0036] (1) Add 60ml of dichloromethane to a 250mL reaction flask, add 10.17g of 1,3-diisopropylamidino-2-thioacetic acid hydrochloride, add 7.72g of 2,6-lutidine, add Sodium carbonate 6.36g, lower the temperature to 0-10°C, slowly add p-nitrobenzenesulfonyl chloride dichloromethane solution (9.72g dissolved in 30ml methylene chloride) dropwise, the dropwise addition is completed in about 15 minutes, control the temperature at 0-10°C and stir After 1 h, the reaction was detected by HPLC to be almost complete, and filtered to obtain filtrate A.

[0037] (2) Add 5.17g of N,N-diisopropylethylamine to filtrate A, slowly add 10.88g of 7-ACA, add dropwise 30% sodium hydroxide solution to adjust the pH to 5.5, stir for 15min, and dropwise add 30% hydrogen Adjust the pH to 5.5 with sodium oxide solution, stir for 15 minutes, add 30% sodium hydroxide solution dropwise to adjust the pH to 5.5, stir at room temperature for 2 hours, monitor the end of the reaction by HPLC, distill under re...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis process of cefathiamidine. Firstly, 1, 3-diisopropylamidino-2-thioacetic acid hydrochloride is enabledto react with p-nitrobenzenesulfonyl chloride, and then amidation reaction with 7-ACA is performed to generate cefathiamidine. The synthesis process of cefathiamidine provided by the invention is completed in one pot, the operation is simple, and the yield is obviously improved.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis process 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 ac...

Claims

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Application Information

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IPC IPC(8): C07D501/28C07D501/08C07C335/32
CPCC07D501/28C07D501/08C07C335/32
Inventor 陈维彩张元乐岳淑娟
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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