CN111393382A - Preparation method of 1-tetrazole acetate - Google Patents
Preparation method of 1-tetrazole acetate Download PDFInfo
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- CN111393382A CN111393382A CN202010262980.8A CN202010262980A CN111393382A CN 111393382 A CN111393382 A CN 111393382A CN 202010262980 A CN202010262980 A CN 202010262980A CN 111393382 A CN111393382 A CN 111393382A
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- aminotetrazole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 26
- ULRPISSMEBPJLN-UHFFFAOYSA-N 2h-tetrazol-5-amine Chemical compound NC1=NN=NN1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000001816 cooling Methods 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 22
- 239000000243 solution Substances 0.000 claims abstract description 18
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940106681 chloroacetic acid Drugs 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- VPIXQGUBUKFLRF-UHFFFAOYSA-N 3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N-methyl-1-propanamine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCNC)C2=CC=CC=C21 VPIXQGUBUKFLRF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 13
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 12
- 238000010992 reflux Methods 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000004321 preservation Methods 0.000 description 5
- 150000003536 tetrazoles Chemical class 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical compound OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 238000007126 N-alkylation reaction Methods 0.000 description 3
- 229960002449 glycine Drugs 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- UXSGOQPTHCMKFT-UHFFFAOYSA-N 2-aminoacetic acid;2h-tetrazole Chemical compound C1=NN=NN1.NCC(O)=O UXSGOQPTHCMKFT-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- PBTHJVDBCFJQGG-UHFFFAOYSA-N methyl azide Chemical compound CN=[N+]=[N-] PBTHJVDBCFJQGG-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- -1 tetrazole acetate Chemical class 0.000 description 2
- YMRIDJQAEZFTSC-UHFFFAOYSA-N 2,3-dihydro-1h-tetrazole Chemical compound N1NC=NN1 YMRIDJQAEZFTSC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 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
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- HJMZMZRCABDKKV-UHFFFAOYSA-M cyanoformate Chemical compound [O-]C(=O)C#N HJMZMZRCABDKKV-UHFFFAOYSA-M 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 239000002837 defoliant Substances 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000002466 imines Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000003911 water pollution Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis, and discloses a preparation method of 1-tetrazole acetate, which comprises the following steps: 1) taking aminoguanidine carbonate as a raw material, adjusting the pH value to be acidic by using an acid solution, then dropping a sodium nitrite aqueous solution after cooling, adjusting the pH value to be alkaline, and refluxing and ring closing to generate 5-aminotetrazole; 2) reacting 5-aminotetrazole with chloroacetic acid under an alkaline condition to synthesize 1-acetic acid-5-aminotetrazole; 3) finally, reducing by using a reducing agent to remove amino to obtain the 1-tetrazole acetate. Compared with the prior art, the method is safer and more environment-friendly, and the obtained product has high yield and purity.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of 1-tetrazole acetate.
Background
The 1-tetrazole acetate is mainly used for synthesizing cephalosporin antibiotics, and downstream products of the cephalosporin antibiotics are cefazolin, ceftezole and the like. The currently known process route mainly adopts flammable and explosive sodium azide as a starting material, and comprises the following steps:
in patent CN106831628, formic acid and glycine are condensed, and then ring closure is carried out, and then reaction with sodium azide is carried out.
However, the process adopts chloroformate and cyano formate, and the product is regulated according to the regulation information of safety regulations on dangerous chemicals, and the compounds are hypertoxic and are regulated by the public security department. Meanwhile, according to the experimental condition, the time consumption of the ring closing process is found to be large. Not belonging to the green chemical category of energy conservation and emission reduction.
In patent CN201310404058, cyanoacetic acid, sodium azide, a solvent and a catalyst are stirred and heated to reflux, the solvent is concentrated after the reaction is finished, the pH value is adjusted by acid, and the product 5-tetrazole acetic acid is obtained after concentration and treatment. In patent CN104292178, sodium azide is used to react with cyano group to obtain tetrazole, and then N-alkylation reaction is carried out to obtain tetrazole acetate. In patent CN 102351805, the N-alkylation of 5-aminotetrazole with chloroacetic acid to obtain the amino-acetic acid tetrazole is directly mentioned. Patent CN102382071 mentions that amino is removed from amino by reduction of tetrazole glycine to obtain tetrazole acetic acid. In the fine chemical engineering P472-474 of No. 4 of volume 30 of 2013, hydrazine hydrate and cyanamide are used as starting materials, and 5-aminotetrazole is synthesized with the yield of 85%; then, carrying out deamination reduction reaction to obtain 1H-tetrazole with the yield of 95%; finally, nucleophilic substitution reaction is carried out on the product and chloroacetic acid under the alkaline condition, and the 1H-tetrazoleacetic acid is synthesized with the yield of 81.7%.
However, the above synthetic route has the disadvantage that the adopted raw materials are dangerous to some extent or are not environment-friendly enough, so that a safe and green synthetic process for preparing the 1-tetrazole acetate still needs to be found.
Disclosure of Invention
Compared with the prior art, the method is safer and more environment-friendly, and the obtained product has high yield and purity.
The specific technical scheme of the invention is as follows: a preparation method of 1-tetrazole acetate comprises the following steps:
1) taking aminoguanidine carbonate as a raw material, regulating the pH value to be acidic by using a hydrochloric acid solution, then dropping a sodium nitrite aqueous solution after cooling, regulating the pH value to be alkaline, and refluxing and ring closing to generate 5-aminotetrazole;
2) reacting 5-aminotetrazole with chloroacetic acid to synthesize 1-acetic acid-5-aminotetrazole;
3) finally, reducing by using a reducing agent to remove amino to obtain the 1-tetrazole acetate.
The method comprises the steps of taking aminoguanidine carbonate as a raw material, regulating acid with hydrochloric acid, cooling, dropwise adding a sodium nitrite aqueous solution, regulating the pH value to be alkaline with sodium carbonate, refluxing and ring closing to generate 5-aminotetrazole, reacting with chloroacetic acid to synthesize aminotetrazole, and reducing to remove amino to obtain the 1-tetrazole acetate.
In the step 1), the raw material aminoguanidine carbonate for industrial production is directly adopted, compared with the prior art that 30% cyanamide aqueous solution, 50% hydrazine hydrate aqueous solution or about 30% hydrochloric acid aqueous solution is adopted, the reaction can greatly reduce the generation of waste water and has low toxicity, meanwhile, the cyanamide aqueous solution is used as a defoliant and a nontoxic insecticide for fruit trees abroad, the serious water pollution can be caused by leakage, and the use of a high-toxicity compound hydrazine hydrate (L D50 is 129mg/kg) is avoided.
In the step 2), 5-amino tetrazole and chloroacetic acid are refluxed under an alkaline condition to perform N alkylation reaction to obtain amino acetic acid tetrazole. The research of the team of the invention discovers that tetrazole is shown in a pKa: 4.9 is a resonance type, resulting in 1 position, 2 position substituted material chance is approximately equal, selectivity is poor, therefore obtain purity higher 1 position substituted material difficulty, and need many times of purification, high yield. By changing the reaction sequence, the pKa value of the N atom on the heterocyclic ring is changed by utilizing the electron donating effect of the substituent group, so that the selectivity is higher. Before optimization, the selectivity of the step 2) is about 50%, after optimization, the selectivity can be improved to about 75%, and the remaining 25% is isomer impurities.
Preferably, in step 1): the molar ratio of the aminoguanidine carbonate to the sodium nitrite is 1: 1-1: 1.05.
Preferably, in step 1): and adjusting the pH to 5-6 by using hydrochloric acid solution. The pH was adjusted to above 9 with sodium carbonate.
In step 1), it is critical to adjust the pH to a value greater than 9 with sodium carbonate, so that the maximum precipitation of the first product is possible.
Preferably, the step 1) specifically comprises the steps of dissolving aminoguanidine carbonate in a hydrochloric acid solution, cooling to below 10 ℃, dropwise adding a sodium nitrite aqueous solution within 1h, carrying out heat preservation reaction for 20-40min, then adjusting the pH to be higher than 9 by using sodium carbonate, heating to 80-90 ℃, reacting for 2-4h, tracking T L C until the raw material reaction is finished, cooling to room temperature, adding hydrochloric acid to adjust the pH to be 4.5-5.5, separating out solids, then continuously cooling to-15 to-10 ℃, stirring, crystallizing overnight, filtering, thermally pulping by using methanol, filtering, and drying to obtain 5-aminotetrazole.
Preferably, in step 2): the molar ratio of the 5-aminotetrazole to the chloroacetic acid is 1: 1.1-1: 1.2.
Preferably, the step 2) specifically comprises the steps of mixing 5-aminotetrazole, water, sodium bicarbonate and chloroacetic acid, stirring and heating to reflux, reacting overnight, stopping heating when T L C tracing reaction is completed until the raw materials react, cooling to room temperature, filtering to obtain white powder, adding water soluble solution, adjusting the pH to be less than 2, cooling to-10-5 ℃, crystallizing, recrystallizing with methanol, filtering, and drying to obtain the 1-acetic acid-5-aminotetrazole.
Preferably, in step 3): the molar ratio of the 1-acetic acid-5-aminotetrazole to the reducing agent is 1: 1-1: 1.2.
Preferably, in step 3): the reducing agent is selected from methanol, ethanol and hypophosphorous acid.
Preferably, the step 3) specifically comprises the steps of mixing 1-acetic acid-5-aminotetrazole, concentrated sulfuric acid and water, stirring to dissolve, cooling to 0-5 ℃, dropwise adding a reducing agent, reacting for 2-4 hours after dropwise adding is completed within 2 hours, keeping the temperature, carrying out T L C tracing until the raw materials react completely, adding ethyl acetate for extraction for multiple times, and concentrating an organic phase to obtain a final product.
Compared with the prior art, the invention has the beneficial effects that: compared with the prior art, the method is safer and more environment-friendly, and the obtained product has high yield and purity.
Detailed Description
The present invention will be further described with reference to the following examples.
General examples
A preparation method of 1-tetrazole acetate comprises the following steps:
1) dissolving aminoguanidine carbonate in a hydrochloric acid solution to enable the pH value to be 5-6, cooling to below 10 ℃, dropwise adding a sodium nitrite aqueous solution within 1h, carrying out heat preservation reaction for 20-40min, then adjusting the pH value to be more than 9 by using sodium carbonate, heating to 80-90 ℃, reacting for 2-4h, tracking T L C until the raw material reaction is finished, cooling to room temperature, adding hydrochloric acid to adjust the pH value to be 4.5-5.5, separating out solids, then continuously cooling to-15 to-10 ℃, stirring for crystallization overnight, filtering, carrying out hot pulping by using methanol, filtering, and drying to obtain 5-aminotetrazole, wherein the molar ratio of aminoguanidine carbonate to sodium nitrite is 1: 1-1: 1.05.
2) Mixing 5-aminotetrazole, water, sodium bicarbonate and chloroacetic acid, stirring and heating to reflux, reacting overnight, performing T L C tracing reaction until the raw materials react completely, stopping heating, cooling to room temperature, filtering to obtain white powder, adding water soluble clear, adjusting the pH to be less than 2, cooling to-10 to-5 ℃, crystallizing, recrystallizing with methanol, filtering, and drying to obtain 1-acetic acid-5-aminotetrazole.3), and finally reducing with a reducing agent to remove amino to obtain 1-acetic acid tetrazole, wherein the molar ratio of the 5-aminotetrazole to chloroacetic acid is 1: 1.1-1: 1.2.
3) Mixing 1-acetic acid-5-aminotetrazole, concentrated sulfuric acid and water, stirring and dissolving, cooling to 0-5 ℃, dropwise adding a reducing agent, finishing dropwise adding within 2h, then carrying out heat preservation reaction for 2-4h, tracking T L C until the reaction is complete, adding ethyl acetate for multiple times for extraction, and concentrating an organic phase to obtain a final product, wherein the molar ratio of the 1-acetic acid-5-aminotetrazole to the reducing agent is 1: 1-1: 1.2, and the reducing agent is selected from methanol, ethanol and hypophosphorous acid.
Example 1
The first step is as follows: synthesis of 5-aminotetrazole
13.63g (0.1mol) of aminoguanidine carbonate is dissolved in 73g (0.3mol) of hydrochloric acid solution (15%), the temperature is reduced to below 10 ℃, 7.245g (0.105mol) of sodium nitrite solution (30%) is dripped in 1 hour, the heat preservation reaction is carried out for 30min, then 25g of sodium carbonate is used for adjusting the pH value to be more than 9, the temperature is initially increased to about 85 ℃, the reaction is carried out for 3 hours, T L C is traced that the raw material reaction is finished, the temperature is reduced to the room temperature, 11.5g of hydrochloric acid (30%) is added, the pH value is adjusted to about 5, solids are separated out, then the temperature is continuously reduced to-15 ℃, the stirring crystallization is carried out overnight, the obtained is filtered to obtain 8.7g, then 30g of methanol is used for hot pulping, the filtration and the drying are carried out, the obtained is H' NMR (450MHz, DMSO), 6.52 (s: 2H), 14.33(s, 1H), L C-MS [ M + H ]: 86, the yield is 97.
The second step is that: synthesis of 1-acetic acid-5-aminotetrazole
50g (0.59mol) of 5-aminotetrazole, 700g of water, 238g (2.83mol) of sodium bicarbonate and 60g (63.5mol) of chloroacetic acid are stirred and heated to reflux, the reaction is carried out overnight, T L C tracks the reaction, when the raw materials are reacted, heating is stopped, the temperature is reduced to room temperature, filtration is carried out to obtain 90.4g of white powder, 250g of water soluble clear solution is added, the pH is adjusted to be less than 2, the temperature is reduced to-10 ℃, crystallization is carried out to obtain 75.7g of white powder, then 100g of methanol is used for recrystallization, filtration and drying are carried out to obtain 62.2g of white powder, the yield is 74%, the HP L C content is 95%, H' NMR (400MHz, DMSO-d6), 6.77(s, 2H), 5.04(s, 1H) and L C-MS (M + H) 144.
The third step: synthesis of 1-tetrazole acetate
14.3g (0.1mol) of 1-acetic acid-5-aminotetrazole, 10.78g (0.11mol) of concentrated sulfuric acid and 43g of water are stirred and dissolved, the temperature is reduced to 2 ℃, 26.4 g of 50% hypophosphorous acid solution (2mol) is dripped, the dripping is completed within 2 hours, then the reaction is kept for 3 hours, T L C tracks the raw materials until the reaction is completed, 100g of ethyl acetate is added for extraction for three times, the organic phase is concentrated to obtain 10.3g of products, the yield is 78.2%, the melting point is 127-129 ℃, H' NMR (400MHz and DMSO-),: 5.38(s, 2H), 9.22(s, 1H), 13.67(s, 1H) and L C-MS (M + H): 129.
Example 2
The first step is as follows: synthesis of 5-aminotetrazole
Aminoguanidine carbonate 13.63g (0.1mol), dissolved in 73g (0.3mol) of hydrochloric acid solution (15%), cooled to below 10 ℃, 7.245g (0.105mol) of sodium nitrite solution (30%) is added dropwise within 1 hour, the reaction is kept for 30min, then 25g of sodium carbonate is used for adjusting the pH value to be more than 9, the temperature is raised to about 85 ℃, the reaction is carried out for 3 hours, T L C is traced that the raw material reaction is finished, the temperature is reduced to the room temperature, 11.5g of hydrochloric acid (30%) is added, the pH value is adjusted to about 5, solid is separated out, then the temperature is continuously reduced to-15 ℃, stirred and crystallized overnight, the mixture is filtered to obtain 8.7g, then the mixture is thermally pulped by 30g of methanol, filtered and dried to obtain 8.3g of dry product, H' NMR (400MHz, DMSO), 6.52(s, 2H), 14.33(s, 1H), L C-MS [ M + H ]: 86, the yield is 97.6%, and the liquid phase purity is.
The second step is that: synthesis of 1-acetic acid-5-aminotetrazole
50g (0.59mol) of 5-aminotetrazole, 700g of water, 238g (2.83mol) of sodium bicarbonate and 60g (63.5mol) of chloroacetic acid are stirred and heated to reflux, the reaction is carried out overnight, T L C tracks the reaction, when the raw materials are reacted, heating is stopped, the temperature is reduced to room temperature, filtration is carried out to obtain 90.4g of white powder, 250g of water soluble clear solution is added, the pH is adjusted to be less than 2, the temperature is reduced to-10 ℃, crystallization is carried out to obtain 75.7g of white powder, then 100g of methanol is used for recrystallization, filtration and drying are carried out to obtain 62.2g of white powder, the yield is 74%, the HP L C content is 95%, H' NMR (400MHz, DMSO) is 6.77(s, 2H), and 5.04(s, 1H) L C-MS [ M + H ]: 144.
The third step: synthesis of 1-tetrazole acetate
14.3g (0.1mol) of 1-acetic acid-5-amino tetrazole, 10.78g (0.11mol) of concentrated sulfuric acid and 43g of water are stirred and dissolved, the temperature is reduced to 3 ℃, diazo compounds are dropwise added into 40 ℃ and 200g of methanol solution within 4 hours, the reaction is finished for 3 hours under the condition of heat preservation, T L C tracks the raw materials until the reaction is complete, yellow viscous oily substances are obtained by concentration, 100g of ethyl acetate is added for three times for extraction, the organic phase is concentrated, 125ml of ethyl acetate is used for recrystallization to obtain 9.43g of products, the yield is 73.7%, the melting point is 127-129 ℃, H' NMR (400MHz, DMSO) is 5.38(s, 2H), 9.22(s, 1H), 13.67(s, 1H) and L C-MS (M + H) is 129.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (9)
1. The preparation method of the 1-tetrazole acetate is characterized by comprising the following steps:
1) taking aminoguanidine carbonate as a raw material, adjusting the pH value to be acidic by using an acid solution, then dropping a sodium nitrite aqueous solution after cooling, adjusting the pH value to be alkaline, and refluxing and ring closing to generate 5-aminotetrazole;
2) reacting 5-aminotetrazole with chloroacetic acid under an alkaline condition to synthesize 1-acetic acid-5-aminotetrazole;
3) finally, reducing by using a reducing agent to remove amino to obtain the 1-tetrazole acetate.
2. The method of claim 1, wherein in step 1): the molar ratio of the aminoguanidine carbonate to the sodium nitrite is 1: 1-1: 1.05.
3. The method of claim 2, wherein in step 1):
adjusting the pH value to 5-6 by using an acid solution; and/or
And dropwise adding sodium nitrite aqueous solution to adjust the pH value to be more than 9.
4. The preparation method according to claim 3, wherein the step 1) specifically comprises the steps of dissolving aminoguanidine carbonate in hydrochloric acid solution, cooling to below 10 ℃, dropwise adding sodium nitrite aqueous solution within 1 hour, keeping the temperature for reaction for 20-40min, then adjusting the pH to be higher than 9, heating to 80-90 ℃, reacting for 2-4 hours, cooling to room temperature after T L C tracks that the raw material reaction is finished, adding acid to adjust the pH to be 4.5-5.5, separating out solids, then continuing cooling to-15 ℃ to-10 ℃, stirring for crystallization overnight, filtering, thermally pulping with methanol, filtering, and drying to obtain 5-aminotetrazole.
5. The method according to claim 1 or 4, wherein in step 2): the molar ratio of the 5-aminotetrazole to the chloroacetic acid is 1: 1.1-1: 1.2.
6. The preparation method according to claim 5, wherein the step 2) specifically comprises mixing 5-aminotetrazole, water, an alkaline substance and chloroacetic acid, stirring and heating to reflux, reacting overnight, stopping heating when T L C tracks the reaction until the raw materials are reacted, cooling to room temperature, filtering to obtain white powder, adding water to dissolve the white powder, adjusting the pH to be less than 2, cooling to-10 to-5 ℃, crystallizing, recrystallizing with methanol, filtering, and drying to obtain the 1-acetic acid-5-aminotetrazole.
7. The method of claim 1, wherein in step 3): the molar ratio of the 1-acetic acid-5-aminotetrazole to the reducing agent is 1: 1-1: 1.2.
8. the method of claim 1 or 7, wherein in step 3): the reducing agent is selected from methanol, ethanol and hypophosphorous acid.
9. The preparation method according to claim 1 or 7, wherein the step 3) specifically comprises the steps of mixing 1-acetic acid-5-aminotetrazole, concentrated sulfuric acid and water, stirring to dissolve, cooling to 0-5 ℃, dropwise adding a reducing agent, reacting for 2 hours after dropwise adding is completed, keeping the temperature for 2-4 hours, tracking T L C until the reaction is completed, adding ethyl acetate for multiple times to extract, and concentrating an organic phase to obtain a final product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112142681A (en) * | 2020-10-23 | 2020-12-29 | 浙江拓普药业股份有限公司 | Production process of 5-aminotetrazole |
| CN116023361A (en) * | 2022-12-22 | 2023-04-28 | 北京四环科宝制药股份有限公司 | Preparation method of 3-amino-2- (1H-tetrazole-5-yl) -ethyl acrylate and analogues thereof |
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| CS190055B1 (en) * | 1977-01-11 | 1979-05-31 | Josef Arient | Method of preparing 5-amonitetrazole |
| CN102351805A (en) * | 2011-09-19 | 2012-02-15 | 山东省化工研究院 | Method for preparing, separating and refining 5-amino-1H-tetrazol-1-ylacetic acid |
| CN102382071A (en) * | 2011-09-19 | 2012-03-21 | 山东艾孚特科技有限公司 | Technology for preparing 1H-tetrazoleacetic acid with deamination reduction method |
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| CS190055B1 (en) * | 1977-01-11 | 1979-05-31 | Josef Arient | Method of preparing 5-amonitetrazole |
| CN102351805A (en) * | 2011-09-19 | 2012-02-15 | 山东省化工研究院 | Method for preparing, separating and refining 5-amino-1H-tetrazol-1-ylacetic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112142681A (en) * | 2020-10-23 | 2020-12-29 | 浙江拓普药业股份有限公司 | Production process of 5-aminotetrazole |
| CN116023361A (en) * | 2022-12-22 | 2023-04-28 | 北京四环科宝制药股份有限公司 | Preparation method of 3-amino-2- (1H-tetrazole-5-yl) -ethyl acrylate and analogues thereof |
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