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Synthesis method of new cephalosporin side-chain intermediate compound

A synthetic method and intermediate technology, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of increased difficulty in solvent recovery, serious environmental pollution, high cost, etc., and achieve high raw material utilization and conversion rate, high raw material conversion rate and yield , the effect of reducing pollution emissions

Active Publication Date: 2013-08-07
APELOA PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0041] The applicant found that the shortcoming of the above method is that the yield of the last step of the esterification reaction is relatively low, about 60%; the catalyst pyridine used has a special odor, and is not easy to fully recycle, causing serious environmental pollution. It affects the application of tert-butyl α-bromoisobutyrate
There are also people who used triethylamine instead of pyridine as a catalyst to make the yield of esterification reach 88.1%, but the yield is still unsatisfactory, which is not conducive to large-scale industrial production
[0042] The alkylation reaction of histidine side-chain acid reacts with α-bromoisobutyrate tert-butyl ester and desmethylaminothioxamic acid ethyl ester, by compound 6 and compound 2, solvent adopts DMF or DMSO, condensation reaction obtains compound 3, because These solvents are highly polar and have a high boiling point. Although the production process is beneficial to the ionization of the inorganic salt potassium carbonate and the promotion of the reaction, it is necessary to dilute the reactants after the reaction with water so that the product can be precipitated from the solvent, resulting in solvent recovery. Difficult to carry out, the difficulty of solvent recovery is increased, and the cost is high

Method used

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  • Synthesis method of new cephalosporin side-chain intermediate compound
  • Synthesis method of new cephalosporin side-chain intermediate compound
  • Synthesis method of new cephalosporin side-chain intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] 1) Preparation of α-bromoisobutyric acid

[0069] Add 88.1g (1.0mol) of isobutyric acid into a clean 500ml four-necked reaction flask, raise the temperature to 110°C, keep stirring for 10 minutes, add 40g (0.25mol) of bromine slowly for the first time, and control the dropping time for 3 hours After the dropwise addition, the reaction was kept for 10 minutes; then 18g (0.25mol) of chlorine gas was slowly introduced, and the time of introduction was controlled for 3 hours; the second time, 20g (0.125mol) of bromine was slowly added dropwise and continued for 3 hours, and the reaction was kept for 30 minutes. Minutes; then continue to introduce 8.5g (0.120mol) of chlorine gas and control the time for 1 hour; continue to drop bromine 20g (0.125mol) for the third time, control the dropping time for 3 hours, and keep the temperature at 115°C for 2-3 hours after the dropping , and then 8.8 g (0.125 mol) of chlorine gas was slowly introduced into the mixture for a controlled t...

Embodiment 2

[0077] 1) Preparation of α-bromoisobutyric acid

[0078] Add 88.1g (1.0mol) of isobutyric acid into a clean 500ml four-necked reaction flask, raise the temperature to 125°C, keep stirring for 10 minutes, add 40g (0.25mol) of bromine slowly for the first time, and control the dropping time for 3 hours , the dropwise addition is completed and the heat preservation reaction is 30 minutes; then slowly feed 0.3 mol of chlorine gas, and the time of feeding is controlled for 3 hours; the second time, 0.2 mol of bromine is slowly added dropwise, and the time of the dropwise addition is controlled for 2 hours, and the dropwise addition is completed for 10 minutes of heat preservation reaction ; Then slowly feed 0.22mol of chlorine gas, and control the feed time for 2 hours. Distill under reduced pressure (vacuum degree ≥ -0.095Mpa), collect a colorless transparent liquid after the temperature is constant, and become a white solid α-bromoisobutyric acid after cooling in the receiving bo...

Embodiment 3

[0086] 1) Preparation of α-bromoisobutyric acid

[0087] Add 88.1g (1.0mol) of isobutyric acid into a clean 500ml four-necked reaction flask, raise the temperature to 120°C, keep warm and stir for 5 minutes, add 48g (0.3mol) of bromine slowly for the first time, and control the dropping time for 3 hours , the dropwise addition is completed and the insulation reaction is 20 minutes; then the chlorine gas 21.3 (0.3mol) is slowly introduced, and the feeding time is controlled for 3 hours; the second time, bromine 20g (0.125mol) is slowly added dropwise and continued to drop for 2 hours, and the insulation reaction is 20 minutes. Minutes; then continue to introduce 8.8g (0.125mol) of chlorine gas for 1 hour; continue to add bromine 20g (0.125mol) dropwise for the third time, control the dropping time for 2 hours, and keep warm at 125°C for 2 hours after the dropping Slowly feed 8.8g (0.125mol) of chlorine gas for a controlled time of 1 hour. Distill under reduced pressure (vacuum...

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Abstract

The invention discloses a synthesis method of a new cephalosporin side-chain intermediate compound, which comprises the following steps: by taking isobutyric acid and element bromine as raw materials, dropwisely adding the element bromine more than once, reacting to obtain alpha-bromoisobutyric acid, wherein after the element bromine is dropwisely added each time, chlorine gas is introduced to further react, so that the HBr byproduct is converted into element bromine which can be used for reaction with the isobutyric acid; reacting the obtained alpha-bromoisobutyric acid and isobutylene under the action of a protonic acid strong catalyst, and performing direct distillation to obtain tert-butyl alpha-bromoisobutyrate; performing alkylation reaction on the tert-butyl alpha-bromoisobutyrate and ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate under the catalytic action of a phase-transfer catalyst by taking acetone as solvent; and hydrolyzing to obtain (Z)-2-amino-alpha-[[2-(tert-butoxy)-1,1-demethyl-2-oxoethoxy]imino]-4-thiazol acetic acid. The production process disclosed by the invention has the advantages of simple process, high raw material conversion rate and yield, environment friendliness and low cost.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to the key intermediate (Z)-2-amino-α-[[2-(tert-butoxy)-1,1- Dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid synthesis technology. Background technique [0002] The current synthesis technology of (Z)-2-amino-α-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid There have been reports in domestic and foreign literature, generally demethylaminothiaxamic acid (Z)-2-(2-amino-4thiazole)-hydroxyimine ethyl acetate (compound 2) and tert-butyl α-bromoisobutyrate (Compound 6) is used as a raw material through alkanization, hydrolysis and acidification to obtain (Z)-2-amino-α-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy base]imino]-4-thiazoleacetic acid (compound 1). [0003] synthetic route: [0004] 1) [0005] [0006] 2) [0007] [0008] Among them, α-tert-butyl bromoisobutyrate is one of the important intermediates fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/40C07C69/63C07C67/293
Inventor 厉昆江海波陈亮任红阳陈治周国营
Owner APELOA PHARM CO LTD
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