CN111848535A - Process for synthesizing 1H-tetrazole acetic acid - Google Patents
Process for synthesizing 1H-tetrazole acetic acid Download PDFInfo
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- CN111848535A CN111848535A CN202010720905.1A CN202010720905A CN111848535A CN 111848535 A CN111848535 A CN 111848535A CN 202010720905 A CN202010720905 A CN 202010720905A CN 111848535 A CN111848535 A CN 111848535A
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- acetic acid
- ester hydrochloride
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- 238000000034 method Methods 0.000 title claims abstract description 37
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical compound OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 65
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000004471 Glycine Substances 0.000 claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003513 alkali Substances 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008213 purified water Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000002390 rotary evaporation Methods 0.000 claims description 14
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- -1 glycine ester Chemical class 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 16
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- DZMVCVMFETWNIU-LDYMZIIASA-N ceftezole Chemical compound O=C([C@@H](NC(=O)CN1N=NN=C1)[C@H]1SC2)N1C(C(=O)O)=C2CSC1=NN=CS1 DZMVCVMFETWNIU-LDYMZIIASA-N 0.000 description 1
- 229960004366 ceftezole Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- MSMGXWFHBSCQFB-UHFFFAOYSA-N ethyl cyanoformate Chemical compound CCOC(=O)C#N MSMGXWFHBSCQFB-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- 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 new process for synthesizing 1H-tetrazole acetic acid. Glycine ester hydrochloride, triethyl orthoformate, sodium azide and the like are adopted as raw materials to synthesize the 1H-tetrazole acetic acid in ethanol solution by a one-pot method. And (2) dropwise adding alkali into an ethanol solution of glycine ester hydrochloride, triethyl orthoformate and sodium azide, reacting the generated glycine ester with triethyl orthoformate and sodium azide in the system, dropwise adding concentrated sulfuric acid and purified water into the reaction solution after the reaction is finished, and closing a ring and hydrolyzing to prepare the 1H-tetrazole acetic acid. The solvent ethanol used in the invention can be recycled, can inhibit the hydrolysis of triethyl orthoformate, improve the reaction progress, effectively reduce the cost, has the advantages of simple synthesis process route, wide application range and lower 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 repeatability are high, and the industrial production is facilitated.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a novel synthesis process of 1H-tetrazole acetic acid.
Background
The tetrazoleacetic acid compound is an important organic intermediate and has the effects of resisting bacteria, diminishing inflammation, regulating plant growth and the like. The 1H-tetrazole acetic acid is an important intermediate for producing penicillin and cephalosporin, and downstream products of the 1H-tetrazole acetic acid are cefazolin, ceftezole and the like. With the rapid increase of the demand of penicillin and cephalosporin antibiotic drugs, the development and the demand of 1H-tetrazole acetic acid are promoted.
At present, the synthesis method of 1H-tetrazole acetic acid mainly comprises four methods: (1) the triazole is obtained by condensation and hydrolysis of tetrazole and ethyl bromoacetate under the catalytic action of triethylamine, and in the method, the tetrazole serving as a raw material is difficult to obtain; (2) the sodium azide and the ethyl isocyanoacetate are subjected to cyclization and hydrolysis to prepare the compound, and in the method, 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, has the advantages of long reaction time, complex process, high required cost, easy generation of virulent cyanide and prominent environmental protection pressure on the three wastes; (4) the method is directly obtained by one-pot method of glycine, sodium azide and triethyl orthoformate, and has the defects that solvent glacial acetic acid is difficult to recover, the product crystallization rate is low, and the safety coefficient is low. Due to the sudden medical and health events, the demand of cephalosporin antibiotics is increased rapidly, so that the 1H-tetrazole acetic acid is difficult to obtain in the market. Meanwhile, under the pressure of technical bottleneck and environmental protection, a manufacturer is in a production stop state or a semi-production stop state.
Therefore, the method has very important practical significance for finding a new synthesis process route of the 1H-tetrazole acetic acid, which has high safety coefficient, small environmental pollution, low production cost and simple operation and conforms to the modern green chemical industry.
Disclosure of Invention
The invention aims to overcome the defects and technical problems of the existing process route, and therefore provides a new process route for synthesizing 1H-tetrazole acetic acid.
In order to achieve the purpose, the invention adopts the following technical scheme:
a process for synthesizing tetrazole acetic acid is prepared by taking glycine ester hydrochloride, triethyl orthoformate and sodium azide as raw materials, and comprises the following steps:
the process for synthesizing the 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 reacting for 3-5 h under heat preservation;
(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 2-4H after dropwise adding, ending the reaction, recovering ethanol from the reaction liquid by rotary evaporation, extracting with ethyl acetate, recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain the 1H-tetrazole acetic acid.
Preferably, the glycine ester hydrochloride in the step (1) is selected from glycine ethyl ester hydrochloride or glycine methyl ester hydrochloride;
preferably, the solvent in the step (1) is ethanol, and the molar ratio of glycine ester 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 the 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 the glycine ester hydrochloride to the 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 the glycine ester hydrochloride to the purified water in the step (2) is 1: 1-1.2
The beneficial results of the invention are as follows:
according to the invention, glycine ethyl ester hydrochloride is used as a raw material, alkali is slowly added dropwise in an ethanol system, the glycine ethyl ester hydrochloride generates glycine ethyl ester along with the addition of the alkali, and amino groups of the glycine ethyl ester react with triethyl orthoformate and sodium azide 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 new process for synthesizing the tetrazoleacetic 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 an ethanol solution of glycine ester hydrochloride, triethyl orthoformate and sodium azide to generate an azido intermediate; and dropwise adding concentrated sulfuric acid into the system, heating to reflux, and performing ring closing and hydrolysis on the reaction liquid to obtain the 1H-tetrazoleacetic acid.
The new synthetic process route of the invention takes ethanol as a solvent, can effectively inhibit the hydrolysis of triethyl orthoformate, can recycle the ethanol solvent, and simultaneously improves the safety coefficient of the reaction process, the yield of the product and reduces the production cost; the hydrochloride of the glycine ester and the alkali are used as raw materials, and the progress of the reaction can be effectively controlled in the process of adding the alkali. Slowly dropwise adding alkali into the reaction system, and dissociating glycine ethyl ester after the added alkali reacts with hydrochloric acid of glycine ethyl ester hydrochloride, so as to promote the reaction of glycine ethyl ester, sodium azide and triethyl orthoformate. The addition speed is controlled in the alkali adding process to keep the proper pH value of the system, the alkalinity of the system is too strong to facilitate the reaction when the addition speed is too high, 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 requirements of modern green chemical industry are 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 convenience for industrial production.
Drawings
FIG. 1 is a tetrazoleacetic acid nuclear magnetic diagram
Detailed Description
The present invention will be further illustrated by the following examples, which are intended to be merely illustrative and not limitative.
Example 1:
69.79g (0.5mol) of glycine ethyl ester hydrochloride, 74.10g (0.5mol) of triethyl orthoformate, 32.51g (0.5mol) of sodium azide and 230.0g (5mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is increased to 45 ℃, 50.60g (0.5mol) of triethylamine is dropwise added into the reaction system, and the reaction is continued for heat preservation for 4 hours after the dropwise addition is finished. And then heating the reaction system to reflux, simultaneously dropwise adding 25.0g (0.25mol) of 98% concentrated sulfuric acid and 9.0g (0.5mol) of purified water into the reaction solution, and continuing to react for 3 hours after the dropwise adding is finished, wherein the reaction is finished. And (2) recovering ethanol from the rotary evaporation reaction liquid, extracting reaction solids by using ethyl acetate, then 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 ℃.
Example 2:
62.79g (0.5mol) of glycine methyl ester hydrochloride, 74.10g (0.5mol) of triethyl orthoformate, 32.51g (0.5mol) of sodium azide and 207.05g (4.5mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is raised to 55 ℃, 22.99g (0.51mol) of ethanol solution containing dimethylamine is dripped into the reaction system, and the heat preservation reaction is continued for 3 hours after the dripping is finished. And then heating the reaction system to reflux, simultaneously dropwise adding 25.0g (0.25mol) of 98% concentrated sulfuric acid and 10.8g (0.6mol) of purified water into the reaction solution, and continuing to react for 4 hours after the dropwise adding is finished, wherein the reaction is finished. And (2) recovering ethanol from the rotary evaporation reaction liquid, extracting reaction solids by using ethyl acetate, then 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 ℃.
Example 3:
62.79g (0.5mol) of glycine ethyl ester hydrochloride, 74.10g (0.5mol) of triethyl orthoformate, 32.51g (0.5mol) of sodium azide and 184.04g (4.0mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is raised to 55 ℃, 20.8g (0.52mol) of ethanol solution containing sodium hydroxide is dropwise added into the reaction system, and the heat preservation reaction is continued for 5 hours after the dropwise addition is finished. And then heating the reaction system to reflux, simultaneously dropwise adding 20.0g (0.20mol) of 98% concentrated sulfuric acid and 10.8g (0.6mol) of purified water into the reaction solution, and continuing to react for 2 hours after the dropwise adding is finished, wherein the reaction is finished. And (3) recovering ethanol from the rotary evaporation reaction liquid, extracting reaction solids 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 ℃.
Example 4
62.79g (0.5mol) of glycine ethyl ester hydrochloride, 59.28g (0.4mol) of triethyl orthoformate, 26.0g (0.4mol) of sodium azide and 230.05g (5.0mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is increased to 35 ℃, 50.5g (0.5mol) of ethanol solution of triethylamine is dropwise added into the reaction system, and the reaction is continued for 5 hours after the dropwise addition is finished. And then heating the reaction system to reflux, simultaneously dropwise adding 15.0g (0.15mol) of 98% concentrated sulfuric acid and 10.8g (0.6mol) of purified water into the reaction solution, and continuing to react for 3 hours after the dropwise adding is finished, wherein the reaction is finished. And (3) recovering ethanol from the rotary evaporation reaction liquid, extracting reaction solids by using ethyl acetate, then recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain 41.77g of 1H-tetrazole acetic acid, wherein the yield is as follows: 81.27%, content 99.6% (HPLC), melting point: 126-128 ℃.
Example 5:
69.79g (0.5mol) of glycine ethyl ester hydrochloride, 74.10g (0.5mol) of triethyl orthoformate, 32.51g (0.5mol) of sodium azide and 230.0g (5mol) of absolute ethyl alcohol are weighed and placed in a reaction flask, the temperature is increased to 45 ℃, 52.61g (0.525mol) of triethylamine is dropwise added into the reaction system, and the reaction is continued for 4 hours under heat preservation after the dropwise addition is finished. And then heating the reaction system to reflux, simultaneously dropwise adding 25.0g (0.25mol) of 98% concentrated sulfuric acid and 10.80g (0.6mol) of purified water into the reaction solution, and continuing to react for 3 hours after the dropwise adding is finished, wherein the reaction is finished. And (2) recovering ethanol from the rotary evaporation reaction liquid, extracting reaction solids by using ethyl acetate, then 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 to 129 ℃.
Claims (10)
1. The process for synthesizing the tetrazole acetic acid is characterized by being prepared from glycine ester hydrochloride, triethyl orthoformate and sodium azide as raw materials, and specifically comprises the following steps:
2. the process for synthesizing tetrazole acetic acid as claimed in claim 1, wherein the process for synthesizing tetrazole acetic acid comprises the following steps:
(1) adding glycine ester hydrochloride, triethyl orthoformate and sodium azide into a solvent, heating, adding alkali into a system, and reacting for 3-5 h under heat preservation;
(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 2-4H after dropwise adding, ending the reaction, recovering ethanol from the reaction liquid by rotary evaporation, extracting with ethyl acetate, recovering ethyl acetate by rotary evaporation, separating out crystals, and drying to obtain the 1H-tetrazole acetic acid.
3. The process for synthesizing tetrazoleacetic acid according to claim 2, wherein the glycine ester hydrochloride in the step (1) is selected from glycine ethyl ester hydrochloride or glycine methyl ester hydrochloride.
4. The process for synthesizing tetrazole acetic acid of claim 2, wherein the solvent in step (1) is ethanol, and the molar ratio of glycine ester hydrochloride to ethanol is 1: 8-10.
5. The process for synthesizing tetrazole acetic acid of claim 2, wherein the base in step (1) is dimethylamine, triethylamine, sodium hydroxide, sodium bicarbonate, and the molar ratio of glycine ester hydrochloride to base is 1: 1-1.05.
6. The process for synthesizing tetrazole acetic acid of claim 2, wherein the molar ratio of glycine ester hydrochloride to triethyl orthoformate in step (1) is 1: 0.8-1.0.
7. The process for synthesizing tetrazole acetic acid of claim 2, wherein the molar ratio of glycine ester hydrochloride to sodium azide in step (1) is 1: 0.8-1.0.
8. The process for synthesizing tetrazole acetic acid of claim 2, wherein the temperature in step (1) is 35-55 ℃.
9. The process for synthesizing tetrazole acetic acid of claim 2, wherein the molar ratio of glycine ester hydrochloride to 98% concentrated sulfuric acid in step (2) is 1: 0.3-0.5.
10. The process for synthesizing tetrazole acetic acid of claim 2, wherein the molar ratio of glycine ester hydrochloride to purified water in step (2) is 1: 1-1.2.
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| 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 |
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