CN110590597A - A kind of preparation method of aryl triazene compound - Google Patents

Abstract

The invention discloses a preparation method of aryl triazene compounds, belonging to the technical field of organic synthesis. The aryl triazene compound is 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl) triazene-1-ene, and its preparation method is as follows: to replace the aniline raw material, acidic diazotization under the action of sodium nitrite, another substituted aniline was added under alkaline conditions for reaction, TLC was monitored until the reaction was completed, and the reaction liquid was separated and purified to obtain aryl triazene compounds. The present invention adopts the above-mentioned technology and uses cheap and easy-to-obtain substituted anilines as raw materials to synthesize 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene , the method has mild reaction conditions, low raw material prices, and good industrialization prospects.

Description

A kind of preparation method of aryl triazene compound

technical field

The invention belongs to the technical field of organic synthesis, in particular to the preparation of 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triazene-1-ene, an aryl triazene compound method.

Background technique

Triazene refers to an organic compound containing three nitrogen atom structural units -N=N-N- in the molecule, and is also called a diazoamino compound. In the molecular structure of this type of compound, three nitrogen atoms are conjugated to each other, thus exhibiting unique physical and chemical properties. The research on triazene can be traced back to the 19th century when Griess first reported the synthesis of triazene in 1862. Since then, this type of compound has gradually been widely used in industries such as medicine, dyes, and food additives.

Aryltriazenes are widely used in protecting groups for natural product synthesis, combinatorial chemistry, synthesis of polymers and oligomers, synthesis of heterocyclic compounds, and research on anticancer activity.

For example, Shang Xiaobo of Zhejiang University and others studied the application of aryl triazenes in organic synthesis.

For example, CN 102424657 A introduces novel triazene compounds for treating cancer.

At present, there are many preparation methods for triazene compounds. For example, in 2010, Nahkai, A. et al. reported the reaction of aryl azides with Grignard reagents to generate triazene in a stable configuration through 1,3 proton transfer. Compound; in 2011, Wang Yang et al. added a certain amount of concentrated hydrochloric acid to the ethanol solution of amine compounds, fully protonated at room temperature, and then slowly added an aqueous solution of sodium nitrite dropwise at -10°C until the diazotization reaction was complete. Add ethanol solution of secondary amine and sodium carbonate solid, react for a period of time to obtain triazene compounds; aryl azide reacts with Grignard reagent or organolithium reagent to prepare aryl triazene and other methods, but there are certain problems , such as catalysts are expensive and difficult to recycle.

Contents of the invention

In view of the above-mentioned problems existing in the prior art, the object of the present invention is to provide aryltriazene compound namely 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triazine-1- The preparation method of alkene is synthesized through a series of reaction sequences and the control of reaction conditions to synthesize aryltriazene compounds. The method has mild conditions, low raw material prices, and has good industrialization prospects.

The preparation method of a kind of aryl triazene compound is characterized in that it comprises the following steps:

1) Under acidic conditions, add a certain amount of sodium nitrite aqueous solution dropwise to the 3,4-dichloroaniline solution shown in formula (I) at a temperature of -5 to 5°C, and react with stirring for 1-3 hours after dropping Obtain 3,4-dichloroaniline diazonium salt solution;

2) Under the condition of ice-water bath, slowly drop the 3,4-dichloroaniline diazonium salt obtained in step 1) into the alkaline solution within 30 minutes, and continue to stir for 5-30 minutes to obtain the compound shown in formula (II) 3,4-Dichloroaniline diazonium salt solution;

3) Add the 3,4-dichloroaniline diazonium salt solution shown in formula (II) obtained in step 2) into the preheated p-fluoroaniline shown in formula (III), at 60 to 80 React at ℃ for 0.5-3h to generate a coupling product. After the reaction, the reaction solution is post-treated to obtain 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl) as shown in formula (IV). ) triazine-1-ene, its reaction equation is as follows:

The preparation method of the described 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene is characterized in that the acid used in the acidic condition in step 1) is sulfuric acid, One or more mixtures of hydrochloric acid or phosphoric acid, preferably hydrochloric acid.

The preparation method of the described 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene is characterized in that the alkali in the alkaline solution in step 1) is One or more mixtures of sodium hydroxide, potassium hydroxide and sodium ethylate, preferably sodium hydroxide.

The method for preparing aryltriazene compounds is characterized in that the molar ratio of 3,4-dichloroaniline to base shown in step 2) is 1:4-8.

The preparation method of a kind of aryl triazene compound is characterized in that the molar ratio of 3,4-dichloroaniline and sodium nitrite in step 1) is 1:1～1.3, preferably 1: 1.05.

The method for preparing aryltriazene compounds is characterized in that the reaction temperature is controlled at -5 to 5°C, preferably 0 to 5°C when sodium nitrite is added in step 1).

The method for preparing aryltriazene compounds is characterized in that the preheating temperature of p-fluoroaniline represented by formula (III) in step 3) is 60-80°C, preferably 65-75°C.

The preparation method of a kind of aryltriazene compound is characterized in that the post-treatment process of the reaction solution in step 3) is as follows: the reaction solution is cooled to room temperature, ethyl acetate is added for extraction, and the organic phase is separated, and water is added. Washed 2 to 3 times, the organic phase was concentrated under reduced pressure to remove the solvent, and the obtained concentrate was separated by column chromatography to obtain the target product 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)tri Nitrogen-1-ene.

The preparation method of a kind of aryl triazene compound is characterized in that the eluent separated by column chromatography is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether and ethyl acetate is 4-8 :1, preferably 6:1.

Beneficial effects of the present invention: the method has mild reaction conditions, low raw material prices, and is suitable for industrial production. 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triazine-1 of the present invention -ene, as an aryltriazene compound, is widely used in medicine, dyestuff, food additive and other industries.

Detailed ways

The present invention will be further described below in conjunction with the examples, but the protection scope of the present invention is not limited thereto.

Embodiment 1 (the influence of diazotization process temperature on yield)

Add 1.36g (0.01mmol) of 3,4-dichloroaniline and 1mL distilled water into a 50mL flask, heat to 75°C, and after it dissolves, add 5.5mL of concentrated hydrochloric acid with a mass fraction of 36%, add 5mL of distilled water after vigorous stirring, Heat and stir intermittently until it dissolves completely, add 15mL of water after cooling naturally to room temperature, stir to form a uniform white milky suspension, place the flask in an ice-water bath at -5-5°C, and add sodium nitrite aqueous solution dropwise (5mL, 0.0105mol, 2.1M), and continued to stir for 2h to obtain 3,4-dichloroaniline diazonium salt aqueous solution.

Add aqueous sodium hydroxide solution (15mL, 0.06mol, 4M) into a 100mL beaker, bathe in ice water, and when the solution drops to -5~5°C, slowly add 3,4-dichloroaniline dropwise within 30min under vigorous stirring For the diazonium salt solution, after the dropwise addition, the stirring was continued in an ice-water bath for 5 min to obtain an aqueous solution of 3,4-dichloroaniline diazonium salt.

Weigh 11.1g (0.1mol) of p-fluoroaniline in a 100mL beaker, stir vigorously and add the above-mentioned 3,4-dichlorobenzenediazonium salt aqueous solution dropwise when heated to 70°C, stir at constant temperature for 40min after the addition is completed, TLC Monitor until the end of the reaction, stop the reaction. The reaction solution was extracted with ethyl acetate, precipitated, and the concentrated solution was separated by column chromatography (petroleum ether/ethyl acetate=6:1, V/V) to obtain a yellow powder, the product 1-(3,4-dichlorobenzene yl)-3-(4-fluorophenyl)triaze-1-ene. The above reaction formula is as follows:

The ¹ H NMR of 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene is as follows:

1H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.27-7.05 (m, 7H).

Table 2 Effect of temperature on yield in diazotization process temperature

Reaction temperature/℃ Yield/% -5 53 0 53 5 50

Embodiment 2 (the influence of the mol ratio of substituted aniline and sodium nitrite on productive rate)

Add 1.36g (0.01mol) of 3,4-dichloroaniline and 1mL of distilled water into a 50mL flask, heat to 75°C, and after it dissolves, add 5.5mL of concentrated hydrochloric acid with a mass fraction of 36%, add 5mL of distilled water after vigorous stirring , heated and stirred intermittently until it was completely dissolved, cooled naturally to room temperature, added 15 mL of water, stirred to form a uniform white milky suspension, placed the flask in an ice-water bath at 0-5°C, repeated the above experiment three times, and Add dropwise 5.0mL, 5.7mL, 6.2mL of 2.1M sodium nitrite aqueous solution (that is, the amount of sodium nitrite is 0.0105, 0.012, 0.013mol respectively), and continue to stir for 2h to obtain three parts of 3,4-di Chloroaniline diazonium salt solution, and coded as a, b, c;

Take three 100mL beakers and add aqueous sodium hydroxide solution (15ml, 0.06mol, 4M) to each, and put them in an ice-water bath. When the solution drops to 0-5°C, slowly add the above-mentioned a and b respectively within 30 minutes under vigorous stirring. , c aqueous solution, after the dropwise addition, continue to stir in the ice-water bath for 5 minutes to obtain three parts of 3,4-dichloroaniline diazonium salt aqueous solution, and numbered as a', b', c';

Weigh three portions of 11.1g (0.1mmol) p-fluoroaniline into three 100mL beakers, stir vigorously and add the above aqueous solutions of a', b', and c' dropwise when heated to 70°C, and stir at constant temperature for 40min after the dropwise addition is completed , TLC monitoring until the end of the reaction, stop the reaction. The reaction solution was extracted with ethyl acetate, precipitated, and the concentrated solution was separated by column chromatography (petroleum ether/ethyl acetate=6:1, V/V) to obtain a yellow powder, the product 1-(3,4-dichlorobenzene yl)-3-(4-fluorophenyl)triaze-1-ene.

The above reaction formula is as follows:

The ¹ H NMR of 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene is as follows:

¹ H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.27-7.05 (m, 7H).

Table 1 The influence of the molar ratio of substituted aniline and sodium nitrite on the yield

Embodiment 3 (the influence of reactant (Ⅲ) preheating temperature on yield)

Add 1.36g (0.01mmol) of 3,4-dichloroaniline and 1mL of distilled water into a 50mL flask, heat to 75°C, add 5.5mL of concentrated hydrochloric acid with a mass fraction of 36% dropwise after it dissolves, add 5mL of distilled water after stirring vigorously, Heat and stir intermittently until it dissolves completely, add 15mL of water after natural cooling to room temperature, stir to form a uniform white milky suspension, place the flask in an ice-water bath at 0-5°C, add sodium nitrite aqueous solution ( 5mL, 0.0105mol, 2.1M), and continued stirring for 2h to obtain an aqueous solution of 3,4-dichloroaniline diazonium salt.

Add aqueous sodium hydroxide solution (15mL, 0.06mol, 4M) into a 100mL beaker, take an ice-water bath, and when the solution drops to 0-5°C, slowly add 3,4-dichloroaniline weight dropwise within 30min under vigorous stirring. Nitrogen salt solution, after the dropwise addition, continue to stir in an ice-water bath for 5 minutes to obtain an aqueous solution of 3,4-dichloroaniline diazonium salt.

Weigh 11.1g (0.1mol) of p-fluoroaniline into a 100mL beaker, stir vigorously and add the above-mentioned 3,4-dichlorobenzenediazonium salt aqueous solution dropwise when heated to 60-80°C, and stir at constant temperature for 40min after the addition is completed , TLC monitoring until the end of the reaction, stop the reaction. The reaction solution was extracted with ethyl acetate, precipitated, and the concentrated solution was separated by column chromatography (petroleum ether/ethyl acetate=6:1, V/V) to obtain a yellow powder, the product 1-(3,4-dichlorobenzene yl)-3-(4-fluorophenyl)triaze-1-ene. The above reaction formula is as follows:

The ¹ H NMR of 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene is as follows:

1H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.27-7.05 (m, 7H).

Table 2 Effect of reactant (Ⅲ) preheating temperature on yield

Reaction temperature/℃ Yield/% 60 48 70 53 80 45

Embodiment 4 (the influence of the mol ratio of substituted aniline and alkali on productive rate)

Add 1.36g (0.01mmol) of 3,4-dichloroaniline and 1mL distilled water into a 50mL flask, heat to 75°C, add 5.5mL of 36% concentrated hydrochloric acid dropwise after it dissolves, add 5mL distilled water after vigorous stirring, heat and intermittently Stir until it is completely dissolved, add 15 mL of water after natural cooling to room temperature, and stir to form a uniform white milky suspension. mol, 2.1M), continued to stir for 2h, repeated the above experiment three times to obtain three aqueous solutions of 3,4-dichloroaniline diazonium salt.

Add 10mL, 15mL, and 20mL of 4M potassium hydroxide aqueous solution into three different 100mL beakers, and put them in an ice-water bath. When the solution drops to 0-5°C, slowly add the above-mentioned solution dropwise within 30 minutes under vigorous stirring. 3,4-Dichloroaniline diazonium salt solution, after the dropwise addition, continue to stir in an ice-water bath for 5 minutes to obtain 3,4-dichloroaniline diazonium salt aqueous solution, and numbered as d, e, f.

Weigh three parts of 11.1g (0.1mol) of p-fluoroaniline into three 100mL beakers, stir vigorously and add the above aqueous solutions of d, e and f respectively dropwise when heated to 70°C. After the dropwise addition is completed, stir at constant temperature for 40min, TLC Monitor until the end of the reaction, stop the reaction. The reaction solution was extracted with ethyl acetate, precipitated, and the concentrated solution was separated by column chromatography (petroleum ether/ethyl acetate=6:1, V/V) to obtain a yellow powder, the product 1-(3,4-dichlorobenzene yl)-3-(4-fluorophenyl)triaze-1-ene. The above reaction formula is as follows:

The ¹ H NMR of 1-(3,4-dichlorophenyl)-3-(4-fluorophenyl)triaze-1-ene is as follows:

1H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.27-7.05 (m, 7H).

Table 3 The influence of the molar ratio of substituted aniline and base on the yield

The content described in this specification is only an enumeration of the implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as limited to the specific forms stated in the embodiments. Equivalent technical means conceivable by the invention concept.

Claims (9)

1. A preparation method of an aryltriazene compound is characterized by comprising the following steps:

1) under the acidic condition, dropwise adding a certain amount of sodium nitrite aqueous solution into a 3, 4-dichloroaniline solution shown in the formula (I) at the temperature of-5 ~ 5 ℃, and carrying out heat preservation and stirring reaction for 1-3h after dropwise adding to obtain a 3, 4-dichloroaniline diazonium salt solution;

2) slowly dripping the 3, 4-dichloroaniline diazonium salt obtained in the step 1) into an alkaline solution within 30min under the ice-water bath condition, and continuously stirring for 5-30min to obtain a 3, 4-dichloroaniline diazonium salt solution shown in a formula (II);

3) adding the 3, 4-dichloroaniline diazoate solution shown in the formula (II) obtained in the step 2) into preheated para-fluoroaniline shown in the formula (III), reacting at 60 ~ 80 ℃ for 0.5-3h to generate a coupling product, and after the reaction is finished, carrying out post-treatment on the reaction solution to obtain 1- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) trinitron-1-ene shown in the formula (IV), wherein the reaction equation is as follows:

。

2. the method for preparing aryltriazenes according to claim 1, wherein the acid used in the acidic condition in step 1) is one or more of sulfuric acid, hydrochloric acid or phosphoric acid, preferably hydrochloric acid.

3. The method for preparing aryltriazenes according to claim 1, wherein the alkali in the alkaline solution in step 1) is one or more of sodium hydroxide, potassium hydroxide and sodium ethoxide, preferably sodium hydroxide.

4. The process for producing aryltriazenes according to claim 1, wherein the molar ratio of 3, 4-dichloroaniline to base in step 2) is 1: 4 ~ 8.

5. The method for preparing aryltriazenes according to claim 1, characterized in that the molar ratio of 3, 4-dichloroaniline to sodium nitrite in step 1) is 1:1 ~ 1.3.3, preferably 1: 1.05.

6. The method for preparing aryltriazenes according to claim 1, wherein the reaction temperature is controlled to-5 ~ 5 ℃, preferably 0 ~ 5 ℃ when adding sodium nitrite in step 1).

7. The process for producing aryltriazenes according to claim 1, wherein the preheat temperature of para-fluoroaniline of formula (III) in step 3) is 60 ~ 80 ℃, preferably 65 ~ 75 ℃.

8. The preparation method of the aryltriazenes compound according to claim 1, characterized in that the post-treatment process of the reaction liquid in the step 3) is that the reaction liquid is cooled to room temperature, ethyl acetate is added for extraction, then the organic phase is separated, water is added for washing for 2 ~ 3 times, the organic phase is decompressed and concentrated to remove the solvent, and the obtained concentrate is separated by column chromatography to obtain the target product 1- (3, 4-dichlorophenyl) -3- (4-fluorophenyl) triazo-1-ene.

9. The method for preparing aryltriazenes according to claim 8, wherein the eluent for column chromatography is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 4 ~ 8:1, preferably 6: 1.