CN111848535B - Process for synthesizing 1H-tetrazole acetic acid - Google Patents
Process for synthesizing 1H-tetrazole acetic acid Download PDFInfo
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- CN111848535B CN111848535B CN202010720905.1A CN202010720905A CN111848535B CN 111848535 B CN111848535 B CN 111848535B CN 202010720905 A CN202010720905 A CN 202010720905A CN 111848535 B CN111848535 B CN 111848535B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Abstract
The invention discloses a novel process for synthesizing 1H-tetrazole acetic acid. Adopts glycine ester hydrochloride, triethyl orthoformate, sodium azide and the like as raw materials to synthesize the 1H-tetrazole acetic acid in an ethanol solution by a one-pot method. And (3) dropwise adding alkali into ethanol solution of glycine ester hydrochloride, triethyl orthoformate and sodium azide, reacting the generated glycine ester with the triethyl orthoformate and the sodium azide in the system, dropwise adding concentrated sulfuric acid and purified water into the reaction solution after the reaction is finished, closing the ring, and hydrolyzing to prepare 1H-tetrazole acetic acid. The solvent ethanol used in the invention can be recycled, can inhibit the hydrolysis of the triethyl orthoformate, improves the reaction progress and effectively reduces the cost. The synthetic process has the advantages of simple route, wide application range and low production cost, improves the safety of the production process, has no pollution, and completely meets the production requirements of modern green chemical industry. The synthesis route is simple, the yield is high, the product purity is high, the operability and the repeatability are high, and the industrial production is facilitated.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and in particular relates to a novel synthesis process of 1H-tetrazole acetic acid.
Background
Tetrazole acetic acid compounds are very important organic intermediates, and have the functions of resisting bacteria, diminishing inflammation, regulating plant growth and the like. And 1H-tetrazole acetic acid is an important intermediate for producing penicillin and cephalosporin, and downstream products thereof are cefazolin, ceftezole and the like. With the rapid increase of the demand of penicillin and cephalosporin antibiotics, the development and demand of 1H-tetrazole acetic acid are promoted.
At present, four main methods for synthesizing 1H-tetrazoleacetic acid are as follows: (1) The tetrazole is obtained by condensation hydrolysis of tetrazole and ethyl bromoacetate under the catalysis of triethylamine, and the raw material tetrazole is difficult to obtain in the method; (2) The method is prepared by cyclization and hydrolysis of sodium azide and ethyl isocyanoacetate, and the raw material ethyl isocyanoacetate is difficult to obtain, expensive and unstable; (3) The method is obtained by cyclization and hydrolysis of ethyl cyanoformate, ethyl chloroacetate and sodium azide, and has the advantages of long reaction time, complex process, high cost, easy generation of highly toxic cyanide and great environmental protection pressure due to three wastes; (4) The method is directly obtained by a one-pot method of glycine, sodium azide and triethyl orthoformate, and the solvent glacial acetic acid is difficult to recover, so that the product crystallization rate is low, and the safety coefficient is low. Due to the sudden rise of medical and health events, the demand of cephalosporin antibiotics is rapidly increased, so that 1H-tetrazole acetic acid on the market is difficult to solve. Meanwhile, under the pressure of technical bottlenecks and environmental protection, manufacturers are in a production stopping or semi-production stopping state.
Therefore, the novel synthetic process route of the 1H-tetrazole acetic acid, which has the advantages of high safety coefficient, small environmental pollution, low production cost and simple operation, accords with the modern green chemical industry, and has very important practical significance.
Disclosure of Invention
The invention aims to overcome the defects and technical problems of the existing process route, and provides a novel process route for synthesizing 1H-tetrazole acetic acid.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a process for synthesizing tetrazole acetic acid, which is prepared from glycine ester hydrochloride, triethyl orthoformate and sodium azide as raw materials, comprises the following steps:
the process for synthesizing tetrazole acetic acid comprises the following specific steps:
(3) Adding glycine ester hydrochloride, triethyl orthoformate and sodium azide into a solvent, heating, adding alkali into a system, and carrying out heat preservation reaction for 3-5 h;
(4) Heating the reaction liquid in the step (1) to reflux, dropwise adding 98% concentrated sulfuric acid and purified water into the system, continuing to react for 2-4 hours after the dropwise adding is finished, ending the reaction, rotationally steaming the reaction liquid to recover ethanol, extracting with ethyl acetate, rotationally steaming to recover ethyl acetate, precipitating crystals, and drying to obtain the 1H-tetrazole acetic acid.
Preferably, the glycine ester hydrochloride in step (1) is selected from ethyl glycine hydrochloride or methyl glycine hydrochloride;
preferably, the solvent in the step (1) is ethanol, and the molar ratio of glycinate hydrochloride to ethanol is 1:8-10;
preferably, the alkali in the step (1) is dimethylamine, triethylamine, sodium hydroxide and sodium bicarbonate, and the molar ratio of glycine ester hydrochloride to alkali is 1:1-1.05;
preferably, the molar ratio of the glycine ester hydrochloride to the triethyl orthoformate in the step (1) is 1:0.8-1.0;
preferably, the molar ratio of glycine ester hydrochloride to sodium azide in the step (1) is 1:0.8-1.0;
preferably, the temperature in the step (1) is 35-55 ℃;
preferably, the molar ratio of the glycine ester hydrochloride to the 98% concentrated sulfuric acid in the step (2) is 1:0.3-0.5.
Preferably, the molar ratio of glycine ester hydrochloride to purified water in the step (2) is 1:1-1.2
The beneficial results of the invention are:
according to the invention, glycine ethyl ester hydrochloride is used as a raw material, alkali is slowly added dropwise under an ethanol system, and along with the addition of the alkali, glycine ethyl ester is generated by the glycine ethyl ester hydrochloride, and simultaneously, amino of glycine ethyl ester, triethyl orthoformate and sodium azide react to generate tetrazole ethyl acetate. The reaction avoids side reaction, realizes in-situ reaction of glycine ethyl ester and improves atom utilization rate.
The invention adopts a novel process for synthesizing tetrazole acetic acid by taking ethanol as a solvent and glycine ester hydrochloride, triethyl orthoformate, sodium azide and concentrated sulfuric acid as raw materials. Firstly, dropwise adding alkali into ethanol solution of glycinate hydrochloride, triethyl orthoformate and sodium azide to generate an azido intermediate; and then adding concentrated sulfuric acid into the system dropwise, heating to reflux, closing the ring of the reaction solution, and hydrolyzing to obtain 1H-tetrazole acetic acid.
The new process route of the synthesis of the invention uses ethanol as solvent, can effectively inhibit the hydrolysis of triethyl orthoformate, and the solvent ethanol can be recycled, and simultaneously, the safety coefficient of the reaction process is improved, the yield of the product is increased, and the production cost is reduced; the hydrochloride of glycine ester and alkali are used as raw materials, and the progress of the reaction can be effectively controlled in the process of adding alkali. Slowly dropwise adding alkali into the reaction system, and after the added alkali reacts with hydrochloric acid of glycine ethyl ester hydrochloride, freeing glycine ethyl ester, so as to promote the reaction of glycine ethyl ester, sodium azide and triethyl orthoformate. The adding speed is controlled in the alkaline adding process to keep proper pH value of the system, the adding speed is too high, the system is too strong in alkalinity and unfavorable for reaction, and the dripping time is preferably 3-6 h.
The process synthesizes a new route, no three wastes are generated in the whole process, the production requirement of modern green chemical industry is met, the co-production of sodium sulfate can be further processed and sold, and the production cost is reduced again. The process has the advantages of simple synthetic route, wide application range, easy control of reaction conditions, strong operability and repeatability, high purity and yield of the obtained product, and convenient industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance chart of tetrazole acetic acid
Detailed Description
The present invention will be further illustrated by the following examples, which are given by way of illustration only and are not intended to be limiting.
Example 1:
69.79g (0.5 mol) of glycine ethyl ester hydrochloride, 74.10g (0.5 mol) of triethyl orthoformate, 32.51g (0.5 mol) of sodium azide and 230.0g (5 mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is raised to 45 ℃, 50.60g (0.5 mol) of triethylamine is added dropwise into the reaction system, and the reaction is continued for 4 hours after the dropwise addition. Then the reaction system is heated to reflux, 25.0g (0.25 mol) of 98% concentrated sulfuric acid and 9.0g (0.5 mol) of purified water are added into the reaction liquid in a dropwise manner, the reaction is continued for 3 hours after the addition, and the reaction is finished. Recovering ethanol from the reaction liquid by rotary evaporation, extracting reaction solid by using ethyl acetate, recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain 51.87g of 1H-tetrazole acetic acid, wherein the yield is as follows: 80.75%, content 99.8% (HPLC), melting point: 128-129 deg.c.
Example 2:
62.79g (0.5 mol) of glycine methyl ester hydrochloride, 74.10g (0.5 mol) of triethyl orthoformate, 32.51g (0.5 mol) of sodium azide and 207.05g (4.5 mol) of absolute ethyl alcohol are weighed into a reaction flask, the temperature is raised to 55 ℃, 22.99g (0.51 mol) of ethanol solution containing dimethylamine is dropwise added into the reaction system, and the reaction is continued for 3 hours after the dropwise addition. Then the reaction system is heated to reflux, 25.0g (0.25 mol) of 98% concentrated sulfuric acid and 10.8g (0.6 mol) of purified water are added into the reaction liquid in a dropwise manner, the reaction is continued for 4 hours after the addition, and the reaction is finished. Recovering ethanol from the reaction liquid by rotary evaporation, extracting reaction solid by using ethyl acetate, recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain 52.06g of 1H-tetrazole acetic acid, wherein the yield is as follows: 81.05%, content 99.6% (HPLC), melting point: 126-129 deg.c.
Example 3:
62.79g (0.5 mol) of glycine ethyl ester hydrochloride, 74.10g (0.5 mol) of triethyl orthoformate, 32.51g (0.5 mol) of sodium azide and 184.04g (4.0 mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is raised to 55 ℃, an ethanol solution containing 20.8g (0.52 mol) of sodium hydroxide is dropwise added into the reaction system, and the reaction is continued for 5 hours after the dropwise addition. Then the reaction system is heated to reflux, meanwhile, 20.0g (0.20 mol) of 98 percent concentrated sulfuric acid and 10.8g (0.6 mol) of purified water are added into the reaction liquid in a dropwise manner, the reaction is continued for 2 hours after the addition, and the reaction is finished. Recovering ethanol from the rotary evaporation reaction liquid, extracting reaction solid by using ethyl acetate, then recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain 53.46g of 1H-tetrazole acetic acid, wherein the yield is as follows: 83.26%, content 99.7% (HPLC), melting point: 128-129 deg.c.
Example 4
62.79g (0.5 mol) of glycine ethyl ester hydrochloride, 59.28g (0.4 mol) of triethyl orthoformate, 26.0g (0.4 mol) of sodium azide and 230.05g (5.0 mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is raised to 35 ℃, 50.5g (0.5 mol) of ethanol solution of triethylamine is dropwise added into the reaction system, and the reaction is continued for 5 hours after the dropwise addition. Then the reaction system is heated to reflux, 15.0g (0.15 mol) of 98% concentrated sulfuric acid and 10.8g (0.6 mol) of purified water are added into the reaction liquid in a dropwise manner, the reaction is continued for 3 hours after the dropwise addition is finished, and the reaction is finished. Ethanol is recovered from the rotary evaporation reaction liquid, the reaction solid is extracted by ethyl acetate, then the ethyl acetate is recovered by rotary evaporation, crystals are separated out, and the crystals are dried to obtain 41.77g of 1H-tetrazole acetic acid, and the yield is: 81.27%, content 99.6% (HPLC), melting point: 126-128 deg.c.
Example 5:
69.79g (0.5 mol) of glycine ethyl ester hydrochloride, 74.10g (0.5 mol) of triethyl orthoformate, 32.51g (0.5 mol) of sodium azide and 230.0g (5 mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is raised to 45 ℃, 52.61g (0.525 mol) of triethylamine is added dropwise into the reaction system, and the reaction is continued for 4 hours after the dropwise addition. Then the reaction system is heated to reflux, 25.0g (0.25 mol) of 98% concentrated sulfuric acid and 10.80g (0.6 mol) of purified water are added into the reaction liquid in a dropwise manner, the reaction is continued for 3 hours after the addition, and the reaction is finished. Recovering ethanol from the reaction liquid by rotary evaporation, extracting reaction solid by using ethyl acetate, recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain 54.17g of 1H-tetrazole acetic acid, wherein the yield is as follows: 84.35%, content 99.6% (HPLC), melting point: 127-129 ℃.
Claims (7)
1. The process for synthesizing tetrazole acetic acid is characterized by being prepared from glycine ester hydrochloride, triethyl orthoformate and sodium azide as raw materials, and comprises the following steps of:
；
the process for synthesizing tetrazole acetic acid comprises the following specific steps:
(1) Adding glycine ester hydrochloride, triethyl orthoformate and sodium azide into a solvent, heating, adding alkali into a system, and carrying out heat preservation reaction for 3-5 h;
(2) Heating the reaction liquid in the step (1) to reflux, dropwise adding 98% concentrated sulfuric acid and purified water into the system, continuing to react for 2-4 hours after the dropwise adding is finished, ending the reaction, rotationally steaming the reaction liquid to recover ethanol, extracting with ethyl acetate, rotationally steaming to recover ethyl acetate, precipitating crystals, and drying to obtain 1H-tetrazole acetic acid;
the glycine ester hydrochloride in the step (1) is selected from glycine ethyl ester hydrochloride or glycine methyl ester hydrochloride;
the alkali in the step (1) is dimethylamine, triethylamine, sodium hydroxide and sodium bicarbonate, and the molar ratio of glycine ester hydrochloride to alkali is 1:1-1.05.
2. The process for synthesizing tetrazole acetic acid according to claim 1, wherein the solvent in the step (1) is ethanol, and the molar ratio of glycinate hydrochloride to ethanol is 1:8-10.
3. The process for synthesizing tetrazole acetic acid according to claim 1, wherein the molar ratio of glycine ester hydrochloride to triethyl orthoformate in step (1) is 1:0.8-1.0.
4. The process for synthesizing tetrazole acetic acid of claim 1, wherein the molar ratio of glycine ester hydrochloride to sodium azide in step (1) is from 1:0.8 to 1.0.
5. The process for synthesizing tetrazole acetic acid according to claim 1, wherein the temperature in step (1) is from 35 ℃ to 55 ℃.
6. The process for synthesizing tetrazole acetic acid according to claim 1, wherein the molar ratio of glycine ester hydrochloride to 98% concentrated sulfuric acid in step (2) is 1:0.3-0.5.
7. The process for synthesizing tetrazole acetic acid according to claim 1, wherein the molar ratio of glycine ester hydrochloride to purified water in the step (2) is 1:1-1.2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831628A (en) * | 2017-03-07 | 2017-06-13 | 山东省化工研究院 | A kind of new technique for synthesizing of tetrazoleacetic acid |
| CN110305070A (en) * | 2019-08-16 | 2019-10-08 | 山东省化工研究院 | A kind of method of hydrazine hydrate method synthesis tetrazoleacetic acid |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831628A (en) * | 2017-03-07 | 2017-06-13 | 山东省化工研究院 | A kind of new technique for synthesizing of tetrazoleacetic acid |
| CN110305070A (en) * | 2019-08-16 | 2019-10-08 | 山东省化工研究院 | A kind of method of hydrazine hydrate method synthesis tetrazoleacetic acid |
Non-Patent Citations (3)
| Title |
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| Johannes Heppekausen等.Synthesis of Functionalized Tetrazenes as Energetic Compounds.J. Org. Chem..2009,第74卷2460-2466. * |
| Mohamed, Yasser Mahmoud A等.The influence of ultrasonic irradiation on catalytic performance of ZnO nanoparticles toward the synthesis of chiral 1-substituted-1H-tetrazole derivatives from α-amino acid ethyl esters.Applied Organometallic Chemistry.2020,第34卷(第9期),e5758. * |
| 胡波等.甘氨酸法合成四氮唑乙酸的研究.山东化工.2009,(第12期),7-9. * |
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