Synthesis process of 5-phenyltetrazole

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of 5-phenyltetrazole, which comprises the following steps: in an inert atmosphere, in the presence of K2CO3 and a zeolite-loaded composite palladium catalyst, carrying out reflux one-pot reaction on arylboronic acid, KCN and NaN3, and carrying out post-treatment to obtain the target product 5-phenyltetrazole. According to the one-pot method for preparing the 5-phenyltetrazole, the raw materials are easy to obtain, the technological process is simple and convenient, toxic organic solvents are not used, the production cost is remarkably reduced, the palladium catalyst can be recycled, activated and reused, the technological yield is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a synthesis process of 5-phenyltetrazolyl. Background Art

[0002] Phenyltetrazolyl, also known as 5-phenyl-1H-tetrazolyl, is an important pharmaceutical intermediate, especially widely used in the synthesis of new generation cephalosporin antibiotics. Almost all domestic and foreign manufacturers use organic solvents such as ethyl acetate, DMF, DMSO as the reaction system solvent, and obtain 5-phenyltetrazolyl salt through multiple extractions, distillations, separations and other complex processes under the action of phase transfer catalysts, and then obtain 5-phenyltetrazolyl products through acidification and refining. The traditional synthesis method of 5-phenyltetrazolyl compounds is to obtain them under high temperature reaction conditions in an inert solvent using benzocyanate and azide compounds as raw materials. This method has many by-products, low yield, complicated post-processing and difficult purification.

[0003] CN105481786A relates to a method for synthesizing 5-phenyltetrazolyl. The method comprises the following steps: adding benzonitrile and sodium azide in a raw material ratio of 1:1 to 1:1.5 and a certain amount of catalyst into a three-necked flask, adding a solvent, heating the flask to 60 to 180°C under mechanical stirring, keeping the temperature for reaction for 1 to 48 hours, cooling the flask, filtering the flask to recover the catalyst, distilling the filtrate under reduced pressure to recover the solvent, adjusting the pH value of the residual liquid to 2 to 3 with hydrochloric acid having a mass concentration of 10%, precipitating a crude product, filtering the flask, washing the flask with water, recrystallizing the flask, and drying the 5-phenyltetrazolyl.

[0004] CN104910089A discloses a method for preparing 5-phenyltetrazolyl, which relates to the technical field of organic synthesis. N,N-dimethylformamide is used as a reaction solvent, benzonitrile is used as a raw material, and a 5-phenyltetrazolyl crude product is obtained by reaction with sodium azide and ammonium chloride. Anhydrous ethanol is then added for refining. After centrifugation and drying, a 5-phenyltetrazolyl finished product is obtained, but the product yield is not high. Summary of the invention

[0005] The invention aims to develop a synthesis process of 5-phenyltetrazolyl with short route flow, high yield and purity and high environmental benefit.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A synthesis process of 5-phenyltetrazolyl comprises the following steps: reacting an arylboronic acid with KCN and NaN3 in the presence of K2CO3 and a supported zeolite composite palladium catalyst under an inert atmosphere, and performing a one-pot reflux reaction, followed by post-treatment to obtain the target product 5-phenyltetrazolyl.

[0008] The reaction equation is:

[0009]

[0010] The specific steps are:

[0011] (1) under an inert atmosphere, adding an aromatic boronic acid, KCN, NaN3, K2CO3 and a supported zeolite composite palladium catalyst into a reaction solvent, and refluxing the reaction in one pot to obtain a reaction solution;

[0012] (2) The reaction solution is extracted with a mixture of water and DMF, the organic phase is dried, and vacuum concentrated to obtain a crude residual oil; potassium carbonate and unreacted trace amounts of potassium cyanide, sodium azide and other inorganic salts are dissolved in water, and the product is dissolved in DMF.

[0013] (3) The crude residue oil is added to a chromatography column, and 5-phenyltetrazolyl is obtained by column chromatography using a mixture of petroleum ether and DMF as an eluent.

[0014] In step (1), the reaction solvent is a mixture of ethanol and water, with a mass ratio of ethanol:water = 1:1 to 1:2.0, which can better dissolve the aromatic boronic acid.

[0015] In step (1), the supported zeolite composite palladium catalyst is rhodium-palladium-zeolite (0.10 mol% Pd). The present invention uses Xunkai PMCAT series catalyst, wherein the palladium is 0.10 mol% and the rhodium is 0.03-0.05 mol%.

[0016] In step (1), the molar ratio of aryl boronic acid: KCN: NaN3: K2CO3 is 1: (3.0-3.3): (3.0-3.3): 2.

[0017] In step (1), the reaction time is controlled at 0.5 h to 1 h.

[0018] In step (1), the volume molar ratio of the reaction solvent to the arylboronic acid is 4 mL:1 mmol.

[0019] In step (2), the volume ratio of water to DMF is 1:1.

[0020] In step (3), the volume ratio of petroleum ether to DMF is 5:1.

[0021] Compared with the prior art, the one-pot method for preparing 5-phenyltetrazolyl has readily available raw materials, a simple process flow, no toxic organic solvents, and significantly reduced production costs. The palladium catalyst can be recycled and activated for reuse, and the process yield is high, which is suitable for industrial production. DETAILED DESCRIPTION

[0022] The present invention is further described below in conjunction with embodiments. It should be noted that the following description is only for explaining the present invention and does not limit its contents.

[0023] Example 1

[0024] (1) Under an inert atmosphere, 4 mL of a reaction solvent, arylboronic acid (1 mmol), KCN (3 mmol), NaN3 (3 mmol), K2CO3 (2 mmol) and 4 mg of a rhodium-palladium-zeolite (palladium content 0.1 mol%, rhodium content 0.03 mol%) catalyst were added to a reaction kettle, and the mixture was refluxed for 0.5 h. The reaction process was monitored by TLC analysis. After the reaction was completed, a reaction solution was obtained; the reaction solvent was a mixture of ethanol and water, and the mass ratio of ethanol to water was 1:1.

[0025] (2) The reaction solution was extracted with a mixture of water and DMF (3×50 mL) to remove inorganic impurities from the mixture. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude residual oil; in a volume ratio, water:DMF=1:1.

[0026] (3) The crude residue oil was added to a chromatography column, and a mixture of petroleum ether and DMF was used as an eluent. 139.1 mg of 5-phenyltetrazolyl was obtained by column chromatography. The melting point of the product was 218° C., the yield was 95.18%, and the content was 99.1%. Among them, the volume ratio of petroleum ether:DMF was 5:1.

[0027] Example 2

[0028] (1) Under an inert atmosphere, 4 mL of a reaction solvent, arylboronic acid (1 mmol), KCN (3.2 mmol), NaN3 (3.2 mmol), K2CO3 (2 mmol) and 4 mg of a rhodium-palladium-zeolite (palladium content 0.1 mol%, rhodium content 0.05 mol%) catalyst were added to a reaction kettle, and the mixture was refluxed for 1 h. The reaction process was monitored by TLC analysis. After the reaction was completed, a reaction solution was obtained; the reaction solvent was a mixture of ethanol and water, and the mass ratio of ethanol to water was 1:1.

[0029] (2) The reaction solution was extracted with a mixture of water and DMF (3×50 mL) to remove inorganic impurities from the mixture. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude residual oil; in a volume ratio, water:DMF=1:1.

[0030] (3) The crude residue oil was added to a chromatography column, and a mixture of petroleum ether and DMF was used as an eluent. 139.2 mg of 5-phenyltetrazolyl was obtained by column chromatography. The melting point of the product was 217° C., the yield was 95.24%, and the content was 99.2%. Among them, the volume ratio of petroleum ether to DMF was 5:1.

[0031] Example 3

[0032] (1) Under an inert atmosphere, 4 mL of a reaction solvent, arylboronic acid (1 mmol), KCN (3.3 mmol), NaN3 (3.3 mmol), K2CO3 (2 mmol) and 4 mg of a rhodium-palladium-zeolite (palladium content 0.1 mol%, rhodium content 0.03 mol%) catalyst were added to a reaction kettle, and the mixture was refluxed for 0.5 h. The reaction process was monitored by TLC analysis. After the reaction was completed, a reaction solution was obtained; the reaction solvent was a mixture of ethanol and water, and the mass ratio of ethanol to water was 1:1 to 1:2.0.

[0033] (2) The reaction solution was extracted with a mixture of water and DMF (3×50 mL) to remove inorganic impurities from the mixture. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude residual oil; in a volume ratio, water:DMF=1:1.

[0034] (3) The crude residue oil was added to a chromatography column, and a mixture of petroleum ether and DMF was used as an eluent. 139.7 mg of 5-phenyltetrazolyl was obtained by column chromatography. The melting point of the product was 219° C., the yield was 95.59%, and the content was 99.3%. Among them, the volume ratio of petroleum ether to DMF was 5:1.

[0035] Example 4

[0036] (1) Under an inert atmosphere, 5 mL of a reaction solvent, arylboronic acid (1 mmol), KCN (3 mmol), NaN3 (3 mmol), K2CO3 (2 mmol) and 4 mg of a rhodium-palladium-zeolite (palladium content 0.1 mol%, rhodium content 0.04 mol%) catalyst were added to a reaction kettle, and the mixture was refluxed for 1 h. The reaction process was monitored by TLC analysis. After the reaction was completed, a reaction solution was obtained; the reaction solvent was a mixture of ethanol and water, and the mass ratio of ethanol to water was 1:2.

[0037] (2) The reaction solution was extracted with a mixture of water and DMF (3×50 mL) to remove inorganic impurities from the mixture. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude residual oil; in a volume ratio, water:DMF=1:1.

[0038] (3) The crude residue oil was added to a chromatography column, and a mixture of petroleum ether and DMF was used as an eluent. 140.0 mg of 5-phenyltetrazolyl was obtained by column chromatography. The melting point of the product was 217° C., the yield was 95.79%, and the content was 99.0%. Among them, the volume ratio of petroleum ether:DMF was 4:1.

[0039] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

Claims

1. A synthesis process for 5-phenyltetrazolyl, characterized in that, Under an inert atmosphere, aromatic boronic acid reacts with KCN and NaN3 in the presence of K2CO3 and a supported zeolite composite palladium catalyst under reflux in one pot and post-treated to obtain the target product 5-phenyltetrazolyl.

2. A synthesis process for 5-phenyltetrazolyl according to claim 1, characterized in that, The specific steps are: (1) under an inert atmosphere, adding an aromatic boronic acid, KCN, NaN3, K2CO3 and a supported zeolite composite palladium catalyst into a reaction solvent, and refluxing the reaction in one pot to obtain a reaction solution; (2) extracting the reaction solution with a mixture of water and DMF, drying the organic phase, and concentrating in vacuo to obtain a crude residual oil; (3) The crude residue oil is added to a chromatography column, and 5-phenyltetrazolyl is obtained by column chromatography using a mixture of petroleum ether and DMF as an eluent.

3. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (1), the reaction solvent is a mixture of ethanol and water, with a mass ratio of ethanol:water = 1:1 to 1:2.

0.

4. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (1), the supported zeolite composite palladium catalyst is a rhodium-palladium-zeolite catalyst.

5. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (1), the molar ratio of aryl boronic acid: KCN: NaN3: K2CO3 is 1: (3.0-3.3): (3.0-3.3):

2.

6. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (1), the reaction time is controlled at 0.5 h to 1 h.

7. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (1), the volume molar ratio of the reaction solvent to the arylboronic acid is a mass ratio of (4-5) mL:1 mmol.

8. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (2), the volume ratio of water to DMF is 1:

1.

9. A synthesis process for 5-phenyltetrazolyl according to claim 2, characterized in that, In step (3), the volume ratio of petroleum ether:DMF=(4-5):1.

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