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CN107382885B - Preparation method of 1H-1,2, 3-triazole - Google Patents

Preparation method of 1H-1,2, 3-triazole Download PDF

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CN107382885B
CN107382885B CN201710623099.4A CN201710623099A CN107382885B CN 107382885 B CN107382885 B CN 107382885B CN 201710623099 A CN201710623099 A CN 201710623099A CN 107382885 B CN107382885 B CN 107382885B
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triazole
sodium nitrite
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CN107382885A (en
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杨栽根
晏金华
魏海鹏
李喜
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Fuxiang Shandong New Materials Co ltd
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Weifang Aotong Pharmaceutical Co ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/041,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

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Abstract

本发明公开了一种1H‑1,2,3‑三氮唑的制备方法,包括:化合物A与亚硝酸钠在溶剂I中的反应;所述化合物A为1,2‑二氨基乙烯、1,2‑二氨基乙烯的盐或上述两者的混合物。与现有生产技术相比,本发明的有益效果体现在:(1)本发明的生产路线短,目标产物的转化率高、原子利用率高、原子经济非常好。(2)摩尔收率高,总摩尔收率为90%以上。(3)溶剂均可回收套用,废水的排放量很低。(4)生产过程安全可控。The invention discloses a preparation method of 1H-1,2,3-triazole, comprising: the reaction of compound A and sodium nitrite in solvent I; the compound A is 1,2-diaminoethylene, 1 , 2-diaminoethylene salt or a mixture of the above two. Compared with the existing production technology, the beneficial effects of the present invention are reflected in: (1) the production route of the present invention is short, the conversion rate of the target product is high, the atom utilization rate is high, and the atom economy is very good. (2) The molar yield is high, and the total molar yield is more than 90%. (3) All solvents can be recycled and applied, and the discharge of waste water is very low. (4) The production process is safe and controllable.

Description

Preparation method of 1H-1,2, 3-triazole
Technical Field
The invention belongs to the technical field of preparation of intermediates of an antibiotic β -lactamase inhibitor drug, and particularly relates to a preparation method of 1H-1,2, 3-triazole.
Background
After the invention of the antibiotic drugs, a large number of lives are saved clinically, and huge welfare is created for the health of human beings. Meanwhile, with the large-scale application of antibiotics, the immunity (drug resistance) of pathogenic bacteria to the antibiotics is stronger and more, so that a large number of antibiotic varieties are clinically eliminated or the dosage is greatly increased.
Later scientists discovered that a key factor contributing to resistance in pathogenic bacteria was the development by the pathogenic bacteria of an enzyme (e.g., β -lactamase) that degrades the antibiotic, which breaks down the antibiotic before it kills the pathogenic bacteria, thereby rendering the antibiotic ineffective or partially ineffective.
The tazobactam is an irreversible competitive β -lactamase inhibitor, and the sodium salt of the tazobactam is combined with certain antibiotics such as penicillins and cephalosporins to greatly improve the drug effect, mainly the tazobactam sodium effectively inhibits the activity of β -lactamase in pathogenic bacteria, so that the tazobactam sodium does not degrade the antibiotics any more.
1H-1,2, 3-triazole is a constituent of the key active group of tazobactam. In the traditional tazobactam synthesis process, more reaction steps are needed for constructing the active group, and the raw materials such as acetylene and methanesulfonic acid are adopted, so that potential safety production hazards and the risk of residual genotoxic impurities in the product exist.
Patent document JP 101104607(16Jan 2008) discloses a technique for preparing "1H-1, 2, 3-triazole" from "o-phenylenediamine" as a starting material, wherein the synthetic route is as shown in formula 1 below, and the total molar yield is 60%. Because a large amount of potassium permanganate is used as a ring-opening oxidant of a benzene ring and thermal decomposition decarboxylation is carried out at 150 ℃, a large amount of dangerous solid wastes are generated, the production safety is ensured, and the like.
Figure BDA0001362151500000021
The literature "Science of Synthesis" (13, 415-601; 2004) reports the technique of one-step Synthesis with "acetylene" and "sodium azide" in a total molar yield of 70%. Because the mixed system of benzene and concentrated sulfuric acid is adopted, and the reaction temperature of 100 ℃ and the reaction time of 60 hours are adopted, the problems of serious production safety risk, low production efficiency and the like exist.
Disclosure of Invention
The invention provides a novel preparation method of 1H-1,2, 3-triazole, which is safe and controllable, generates less hazardous waste and has higher yield.
A preparation method of 1H-1,2, 3-triazole comprises the following steps: reacting the compound A with sodium nitrite in a solvent I; the compound A is 1, 2-diaminoethylene, a salt of 1, 2-diaminoethylene or a mixture of the two.
More preferably, the method comprises the following specific steps:
(1) reacting the compound A with sodium nitrite in a solvent I;
(2) after the reaction in the step (1) is completed, distilling and recovering a solvent I;
(3) after the solvent I is distilled and recovered, adding a water-insoluble solvent II, and adjusting the pH value to be more than 8 by using alkali; then, layering and separating out a water layer, and concentrating an organic layer to recover a solvent II;
(4) and (4) after the step (3) is finished, rectifying the concentrated solution to obtain the 1H-1,2, 3-triazole.
By adopting the method, the solvent I and the solvent II can be recovered by a simple distillation process, and the whole route is economic and environment-friendly and is suitable for industrial mass production.
For step (2): preferably, the temperature for distilling and recovering the solvent B is 50 to 120 ℃, and more preferably, the solvent B is concentrated under reduced pressure at 50 to 70 ℃.
In step (3), the base can be selected from conventional bases or aqueous solutions of bases, for example, the base is selected from one or more of the following bases: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and the like. Preferably, the pH value is more preferably 8 to 10. In the step (3), the residue obtained after the distillation recovery of the solvent I may be subjected to pH adjustment, and then the water-insoluble solvent II may be added. In the step, water can be added in advance, the residue after the solvent I is distilled and recovered is diluted, and then alkali or an alkali water solution is used for adjusting the pH value; the pH can also be adjusted directly with an aqueous alkali solution.
In the step (4), the rectification can adopt the following conditions: collecting fractions at 90-95 ℃ under an absolute pressure of less than or equal to 5 mmHg; by adopting the rectification condition, the purity of the product can be ensured to be more than 99 percent, and the overall molar yield is ensured to be more than 90 percent.
In the present invention, the compound a is selected from at least one of the following compounds:
Figure BDA0001362151500000031
in the present invention, the salt of 1, 2-diaminoethylene is selected from at least one of the following compounds:
Figure BDA0001362151500000032
wherein B is an inorganic acid.
Preferably, B is selected from at least one of the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid.
More preferably, the compound A is the sequential-type-1, 2-diaminoethylene hydrochloride; taking the formula-1, 2-diaminoethylene hydrochloride as a starting material, the chemical reaction equation is as follows:
Figure BDA0001362151500000033
in the invention, the solvent I is selected from one or more of water, C1-C4 carboxylic acid, DMSO and DMF. Preferably, the solvent I is selected from a mixture of water and one or more of acetic acid, formic acid, propionic acid, DMSO and DMF. The invention selects the mixture solution of water and organic solvent, which is beneficial to the dissolution of raw materials and ensures the smooth operation of the reaction. Further preferred is a mixture of water and acetic acid.
Preferably, solvent B is selected from water and organic solvents in a ratio of 1: (0.1 to 10), more preferably 1 (1 to 3).
In the present invention, the sodium nitrite may be added in the form of a pre-prepared aqueous solution, or may be added to the solvent I system in which the 1, 2-diaminoethylene or its salt is dissolved, or may be added to the reaction solvent in portions of the 1, 2-diaminoethylene or its salt and sodium nitrite. In the process of adding sodium nitrite, the temperature of the system needs to be kept at-10 ℃. After the sodium nitrite is added, the compound A and the sodium nitrite are firstly reacted for 10 to 40 minutes at the temperature of minus 10 to 10 ℃; then heating to 10-80 ℃ for complete reaction, wherein the temperature is preferably 40-80 ℃, and the temperature is preferably 50-60 ℃; the second-stage reaction time is preferably 1-5 h.
When the 1, 2-diamino ethylene or the salt thereof reacts with the sodium nitrite, the invention adopts stage temperature rise, thereby further avoiding the occurrence of side reaction and ensuring the yield and the purity of the target product.
In the present invention, preferably, the water-insoluble solvent II is one or more selected from C1-C3 halogenated alkanes, C1-C3 alcohol esters of C1-C3 acids, toluene, benzene, methyl tert-butyl ether and diethyl ether. More preferably dichloromethane or ethyl acetate.
Preferably, the molar ratio of the compound a to the sodium nitrite is 1: (0.9-5), and more preferably 1: (0.9-3). As a still further preference, the molar ratio of compound a to sodium nitrite is 1: (1-1.5).
Compared with the prior art, the invention has the beneficial effects that:
(1) the method has the advantages of short production route, high conversion rate of the target product, high atom utilization rate and good atom economy.
(2) The preparation method has high molar yield, and the total molar yield is more than 90%.
(3) The solvent used in the preparation process can be recycled and reused, and the discharge amount of the waste water is low.
(4) The production process of the invention is safe and controllable.
Drawings
FIG. 1 is a C13 nuclear magnetic spectrum of the product prepared in the example;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the product prepared in example.
Detailed Description
In order to make the technical solution and advantages of the present invention clearer, preferred embodiments of the present invention are described in further detail below, and the present invention includes, but is not limited to, the following embodiments.
Example 1:
dissolving 80.0g of sodium nitrite (MW69.00, 1.16mol) in 250g of purified water, stirring at 30-40 ℃ for dissolving, and cooling to 0-5 ℃ to obtain a sodium nitrite aqueous solution for later use.
94.5g of 1, 2-diaminoethylene hydrochloride (1.00mol) is added into 250g of glacial acetic acid, stirred, dissolved and clarified, cooled to-10-0 ℃, 330.0g of sodium nitrite solution prepared in advance is added dropwise, and the temperature is controlled to-5 ℃. After dripping, stirring and reacting for 20 minutes at 0-5 ℃, slowly heating to 70-80 ℃, and keeping the temperature for reacting for 1 hour.
After the reaction is finished, decompressing and concentrating to recover acetic acid, cooling to 0-5 ℃, adjusting the pH value to 8-9 by using 10% alkali liquor (sodium carbonate aqueous solution), extracting by using 800mL dichloromethane in batches, combining organic layers, and concentrating to obtain 68g crude triazole oil.
Then 68g of crude triazole oil is transferred into a 100mL circular rectification flask for rectification in a high vacuum tower, and fractions at 90-95 ℃ (the absolute pressure is less than or equal to 5mmHg) are collected to obtain 63g of 1H-1,2, 3-triazole in colorless transparent liquid, wherein the purity is more than 99.0%, and the boiling point is 200 ℃. The molar yield was 91.2%. Collecting front fraction and back fraction, and repeating after accumulationRectifying and recovering crude triazole oil.1H-NMR(400MHz,CDCl3,ppm):δ7.86(s,2H,C2H2),δ14.96(s,1H,NH);13C-NMR(100MHz,CDCl3,ppm):δ131.04(C-4,C-5)。
C13 nuclear magnetic spectrum (13C-NMR(100MHz,CDCl3Ppm)) is shown in FIG. 1.
Nuclear magnetic hydrogen spectrum diagram (1H-NMR(400MHz,CDCl3Ppm)) is shown in FIG. 2.
Example 2:
94.5g of 1, 2-diamino ethylene hydrochloride (1.00mol) is added into a mixed solution of 100g of water and 300g of glacial acetic acid, the mixed solution is stirred, dissolved and cleared, the temperature is reduced to minus 10 to minus 5 ℃, 85.0g of sodium nitrite (MW69.00, 1.23mol) is added in batches, and the temperature is controlled to minus 10 to 0 ℃. After the addition is finished, stirring and reacting for 30 minutes at the temperature of minus 10 to minus 5 ℃, slowly heating to 40 to 50 ℃, and reacting for 2 hours in a heat preservation way.
After the reaction is finished, after acetic acid is recovered by vacuum concentration, 100g of water is added, the pH value is adjusted to 9-10 by using 10% alkali liquor, the mixture is extracted by 1000mL of ethyl acetate in portions, organic layers are combined, and the mixture is concentrated to obtain 69.5g of crude triazole oil.
Then transferring 69.5g of crude triazole oil into a 100mL circular rectification flask, carrying out high vacuum column rectification, collecting 90-95 ℃ fractions (the absolute pressure is less than or equal to 5mmHg), and obtaining 64.5g of 1H-1,2, 3-triazole as colorless transparent liquid, wherein the purity is more than 99.0%, and the boiling point is 200 ℃. The molar yield was 93.3%. The collected front fraction and back fraction can be rectified again to recover crude triazole oil after accumulation. The test data were the same as in example 1.
Example 3
200g of water and 200g of glacial acetic acid are mixed, 85.0g of sodium nitrite (MW69.00, 1.23mol) is added under stirring, and after dissolution and clarification, the mixture is cooled to-10 to-5 ℃. Then, 94.5g of 1, 2-diaminoethylene hydrochloride (1.00mol) is added into the reaction solution in a small amount in batches, the temperature is controlled to be 0-5 ℃, and the feeding time is controlled to be 0.5-1.0 h. After the addition is finished, stirring and reacting for 15 minutes at 0-5 ℃, slowly heating to 50-60 ℃, and reacting for 2 hours in a heat preservation way.
After the reaction is finished, the acetic acid is firstly concentrated under reduced pressure and recovered, then the pH value is adjusted to 9-10 by using 10% alkali liquor, the mixture is extracted by 1000mL dichloromethane in a fractional manner, organic layers are combined, and the concentration is carried out to obtain 69.0g triazole crude oil.
Then transferring 69.0g of crude triazole oil into a 100mL circular rectification flask, carrying out high vacuum column rectification, collecting 90-95 ℃ fractions (the absolute pressure is less than or equal to 5mmHg), and obtaining 66.0g of 1H-1,2, 3-triazole as colorless transparent liquid, wherein the purity is more than 99.0%, and the boiling point is 200 ℃. The molar yield was 95.5%. The collected front fraction and back fraction can be rectified again to recover crude triazole oil after accumulation. The test data were the same as in example 1.

Claims (5)

1. A preparation method of 1H-1,2, 3-triazole is characterized by comprising the following steps: reacting the compound A with sodium nitrite in a solvent I; the compound A is 1, 2-diaminoethylene, a salt of 1, 2-diaminoethylene or a mixture of the two; the method comprises the following specific steps:
(1) reacting the compound A with sodium nitrite in a solvent I;
(2) after the reaction in the step (1) is completed, distilling and recovering a solvent I;
(3) after the solvent I is distilled and recovered, adding a water-insoluble solvent II, and adjusting the pH value to be more than or equal to 8.0 by using alkali; then, layering and separating out a water layer, and concentrating an organic layer to recover a solvent II;
(4) after the step (3) is finished, rectifying the concentrated solution to obtain 1H-1,2, 3-triazole;
when the compound A is reacted with sodium nitrite, the reaction is carried out for 10-40 minutes at-10 ℃, and then the reaction is completed at 50-60 ℃;
the solvent I is selected from one or more of water, C1-C4 carboxylic acid, DMSO and DMF;
the water-insoluble solvent II is one or more selected from C1-C3 halogenated alkane, C1-C3C 1-C3 alcohol ester, toluene, benzene, methyl tert-butyl ether and diethyl ether;
the molar ratio of the compound A to the sodium nitrite is 1: (0.9-5).
2. The preparation method of 1H-1,2, 3-triazole according to claim 1, wherein the compound A is at least one of the following compounds:
Figure FDA0002316808140000011
3. the preparation method of 1H-1,2, 3-triazole according to claim 1, wherein the salt of 1, 2-diaminoethylene is selected from at least one of the following compounds:
Figure FDA0002316808140000012
wherein B is an inorganic acid.
4. The preparation method of 1H-1,2, 3-triazole according to claim 3, wherein B is selected from at least one of the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid.
5. The preparation method of 1H-1,2, 3-triazole according to claim 1, wherein the molar ratio of the compound A to sodium nitrite is 1: (1-1.5).
CN201710623099.4A 2017-07-27 2017-07-27 Preparation method of 1H-1,2, 3-triazole Active CN107382885B (en)

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CN102516186A (en) * 2011-12-19 2012-06-27 张家港舒马克电梯安装维修服务有限公司镀锌分公司 Preparation method for electroplating additive 5-chloro-benzotriazole
CN105237488A (en) * 2015-11-13 2016-01-13 如皋市金陵化工有限公司 Synthesis method of benzotriazole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516186A (en) * 2011-12-19 2012-06-27 张家港舒马克电梯安装维修服务有限公司镀锌分公司 Preparation method for electroplating additive 5-chloro-benzotriazole
CN105237488A (en) * 2015-11-13 2016-01-13 如皋市金陵化工有限公司 Synthesis method of benzotriazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
六烷基胍TADC含能离子液体的合成与表征;甘志勇等;《火炸药学报》;20120229;第35卷(第1期);第19-22、31页 *

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