CN115536529B - Synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene - Google Patents
Synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene Download PDFInfo
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Abstract
The application relates to the technical field of organic synthesis, in particular to a method for synthesizing 3, 5-di (2-cyano-isopropyl) -toluene. A synthetic method of 3, 5-di (2-cyano-isopropyl) -toluene comprises the following steps: firstly, taking a compound 1 as a raw material, and carrying out esterification reaction with methanol in sulfuric acid to obtain a compound 2; secondly, performing condensation reaction on the compound 2 and a Grignard reagent in 2-methyltetrahydrofuran to obtain a compound 3; and thirdly, carrying out cyanation reaction on the compound 3 and trimethylcyano silane in boron trifluoride diethyl ether to obtain a target product 3, 5-di (2-cyano-isopropyl) -toluene. The synthesis method of the application avoids methylation reaction in the prior art and adopts trimethylcyano silane to replace virulent cyanide for cyanation reaction, thus having the characteristics of simple synthesis steps, low raw material cost and safe synthesis method and being more beneficial to industrial production.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a method for synthesizing 3, 5-di (2-cyano-isopropyl) -toluene.
Background
The anastrozole is clinically used for treating advanced breast cancer of postmenopausal women, and has the advantages of high selectivity, strong effect, good curative effect, light side effect, convenient administration and the like. Among the reported synthetic methods of anastrozole, 3, 5-bis (2-cyano-isopropyl) -toluene is an important synthetic intermediate.
There have been many reports on a method for synthesizing intermediate 3, 5-bis (2-cyano-isopropyl) -toluene. One of the synthetic methods is as follows: m-trimethylbenzene is used as a raw material, the raw material is subjected to bromination reaction in the first step, potassium cyanide is adopted to carry out cyanation reaction in the second step, methyl iodide is adopted to carry out methylation reaction in the third step, and 3, 5-di (2-cyano-isopropyl) -toluene can be synthesized.
The synthetic route of the synthetic method is shown in the following chart:
Another synthesis method comprises the following steps: taking 5-methyl-1, 3-phthalic acid (9 in the following route) as a raw material, and carrying out esterification, reduction and bromination on the raw material in the first step to obtain a brominated product (5 in the following route); and then, carrying out cyanation reaction on the brominated product by adopting sodium cyanide or potassium cyanide to obtain a cyanated product (6 in the following route), and finally, carrying out methylation reaction by adopting methyl tosylate to synthesize the 3, 5-di (2-cyano-isopropyl) -toluene (2 in the following route).
The synthetic route of the synthetic method is shown in the following chart:
however, in the cyanation reaction of the two synthesis methods, potassium cyanide with extremely toxicity is used, so that the synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene is dangerous and is not beneficial to industrial production. Therefore, a safe synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene, which is beneficial to industrial production, is needed.
Disclosure of Invention
In order to improve the safety of synthesizing 3, 5-di (2-cyano-isopropyl) -toluene, the application provides a method for synthesizing 3, 5-di (2-cyano-isopropyl) -toluene.
The application provides a synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene, which adopts the following technical scheme:
A synthetic method of 3, 5-di (2-cyano-isopropyl) -toluene comprises the following steps:
firstly, taking a compound 1 as a raw material, and carrying out esterification reaction with methanol in strong acid to obtain a compound 2;
Secondly, performing condensation reaction on the compound 2 and a Grignard reagent in 2-methyltetrahydrofuran to obtain a compound 3;
Thirdly, carrying out cyanation reaction on the compound 3 and trimethylcyano silane in boron trifluoride diethyl ether to obtain a target product 3, 5-di (2-cyano-isopropyl) -toluene;
The reaction formula of the steps is as follows:
By adopting the technical scheme, 5-methyl-1, 3-phthalic acid is used as a raw material, and after esterification, grignard reagent is used for addition reduction, so that methylation reaction in the prior art is avoided, steps are simplified, expensive potassium iodide reagent is avoided, and cost is reduced. Meanwhile, under the reaction condition of the third step, trimethylcyano silane is adopted to replace virulent cyanide to react with the compound 3 to prepare the product 3, 5-di (2-cyano-isopropyl) -toluene, so that the safety of the synthesis method is improved. Therefore, the synthesis method has the characteristics of simple synthesis steps, low raw material cost and safe synthesis method, and is more beneficial to industrial production.
Preferably, in the first step, the feed ratio of the compound 1, methanol and concentrated sulfuric acid is 1mol (43.59-46.47) mol (1.94-2.53).
Preferably, in the first step, the reaction temperature is 50-60 ℃ and the reaction time is 20-25h.
By adopting the technical scheme, the compound 1, the methanol and the concentrated sulfuric acid are subjected to esterification reaction under the above feeding ratio and reaction conditions, the yield and purity of the obtained compound 2 are higher, and the use amount of the concentrated sulfuric acid is proper, so that the safety of the synthesis reaction is further improved.
Preferably, in the first step, after the esterification reaction is finished, a reaction solution is obtained, the reaction solution is cooled to 40-50 ℃, then is added into a sodium carbonate aqueous solution in a dropwise manner, after stirring for 1-2 hours, the mixture is filtered, and the solid is collected and dried to obtain the compound 2.
By adopting the technical scheme, the post-treatment of the first-step reaction is simple and convenient to operate, and the high-purity compound 2 can be obtained by only cooling the reaction liquid, then neutralizing acid and alkali, filtering and drying. Meanwhile, the reaction liquid is cooled and then is dripped into the sodium carbonate aqueous solution for acid-base neutralization, so that the exothermic phenomenon of the reaction during acid-base neutralization is weakened, and the safety of the synthesis reaction is further improved.
Preferably, in the second step, the feed ratio of the compound 2, the Grignard reagent and the 2-methyltetrahydrofuran is 1mol (6.67-7.67) mol (11.67-13.67) mol.
Preferably, in the second step, a mixed solution of the compound 2 and 2-methyltetrahydrofuran is added to methyl magnesium bromide having a temperature lower than 20 ℃, and then the reaction is stirred at 40-50 ℃ for 20-24 hours.
Preferably, the grignard reagent comprises methyl magnesium bromide or methyl magnesium chloride.
By adopting the technical scheme, the compound 2, the 2-methyltetrahydrofuran and the Grignard reagent are subjected to condensation reaction under the above feeding ratio and reaction conditions, so that the yield of the obtained compound 3 is further improved. Meanwhile, the reaction condition of the application is room temperature reaction, which is convenient to control and is beneficial to industrial production.
Preferably, in the second step, after the condensation reaction is finished, a reaction solution is obtained, the reaction solution is cooled to be less than 20 ℃, then the reaction solution is added into a citric acid aqueous solution to be quenched, then the solution is separated, and an organic phase is collected; petroleum ether is added into the organic phase, white solid is separated out, and the separated white solid is dried to obtain the compound 3.
By adopting the technical scheme, the reaction liquid obtained in the second step is subjected to post-treatment according to the steps, and the obtained compound 3 has higher purity and yield. Meanwhile, since the post-treatment step does not employ purification methods such as column chromatography purification, compound 3 of high purity is also obtained. Therefore, the steps of the synthesis process are further simplified, and the industrial production is facilitated.
Preferably, in the third step, the feeding ratio of the compound 3 and the trimethylcyano silane is 1mol (4.8-5.5 mol).
Preferably, in the third step, the trimethylcyano silane is added into the dichloromethane mixed solution of the compound 3 with the temperature of (-70) - (-60), then the dichloromethane mixed solution of boron trifluoride-diethyl ether is added, then the mixture is stirred and reacted for 1-2h at the temperature of (-70) - (-60), then the mixture is stirred and reacted for 0.5-1h at the temperature of (-30) - (-20), and finally the mixture is stirred and reacted for 20-24h at the temperature of 20-25 ℃.
By adopting the technical scheme, as the compound 3 and the trimethylcyano silane are subjected to cyanation reaction under the above feeding ratio and reaction conditions, the raw materials react more completely, which is beneficial to improving the yield of the obtained 3, 5-di (2-cyano-isopropyl) -toluene.
In summary, the application has the following beneficial effects:
The synthesis process of the application uses 5-methyl-1, 3-phthalic acid as raw material, esterifies the raw material first, then uses Grignard reagent to carry out addition reduction, thereby avoiding methylation reaction in the prior art, simplifying steps, avoiding expensive potassium iodide reagent and reducing raw material cost; meanwhile, in the cyanation reaction, trimethylcyano silane is adopted to replace highly toxic cyanide, so that the safety of the synthesis method is improved; therefore, the synthesis method has the characteristics of simple synthesis steps, low raw material cost and safe synthesis method, and is more beneficial to industrial production.
Drawings
FIG. 1 is a high performance liquid chromatogram of 3, 5-bis (2-cyano-isopropyl) -toluene in example 1 of the present application.
Detailed Description
The application is described in further detail below with reference to the drawings and examples.
The raw materials used in the examples and comparative examples of the present application are all commercially available.
Examples
Example 1
A synthetic method of 3, 5-di (2-cyano-isopropyl) -toluene comprises the following synthetic routes:
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
Firstly, adding concentrated sulfuric acid (32.6 g,0.33 mol) dropwise to a mixture of compound 1 (30 g,0.17 mol) and methanol (300 mL,7.41 mol) at a temperature lower than 40 ℃, and then carrying out reflux stirring reaction at 50 ℃ for 23h to obtain a reaction solution; the reaction solution was cooled to 40℃and then added dropwise to a 10% aqueous sodium carbonate solution (362 mL), after stirring for 1h, the solid was collected by filtration, and dried at 55-65 (55℃in the present example) for 24-36h (36 h in the present example) to give 32.0g of a white solid.
The white solid was detected as compound 2 in 92.2% yield, HPLC: purity 99.8%, 1 H NMR (400 MHz, CDCl 3): δ8.48 (s, 1H), δ8.04 (s, 2H), δ3.93 (s, 6H), δ2.45 (s, 3H).
In the second step, to methyl magnesium bromide (66.2 mL,0.20 mol) having a temperature lower than 20℃was added a mixed solution of compound 2 (7 g,0.03 mol) and 2-methyltetrahydrofuran (35 mL,0.35 mol), followed by stirring at 40℃for 20 hours to obtain a reaction solution.
In the examples of the present application, the grignard reagent is exemplified by methyl magnesium bromide (MeMgBr) only, but does not affect the application of methyl magnesium chloride in the present application.
Cooling the reaction solution to be less than 20 ℃, adding the reaction solution into 10% citric acid aqueous solution (125 mL) for quenching, separating the solution, collecting an organic phase, extracting the residual aqueous phase once by using ethyl acetate (70 mL), merging the organic phases, and concentrating the organic phase until no organic solvent remains, thus obtaining a concentrate.
Petroleum ether (100 mL) was added to the concentrate, white solids precipitated, filtered, the white solids collected, and the white solids were dried at 50-60℃for 24h (50℃in the present example) to give 5.9g of white solids.
The white solid is compound 3, the yield is 84%, the water content is 0.48%, the purity is HPLC 99.8％,1H NMR(400MHz,CDCl3):(δ7.44(s,1H),δ7.17(s,2H),δ2.37(s,3H),δ1.95(br,2H),δ1.57(s,12H),LCMS:M/Z＝191.2(M-18).
Thirdly, adding trimethylcyanosilane (4.8 g,0.048 mol) to a mixed solution of a compound 3 (2 g,0.01 mol) at (-70) DEG C and dichloromethane (10 mL) to obtain a mixture; adding a mixed solution of boron trifluoride-diethyl etherate (2.5 g,0.018 mol) and dichloromethane (10 mL) under the condition that the internal temperature of the mixture is lower than (-60) DEG C, stirring and reacting for 1h at (-70) DEG C, stirring and reacting for 0.5h at (-30) DEG C, and stirring and reacting for 20h at 20-25 ℃ to obtain a reaction solution.
The reaction solution was added dropwise to a 2mol/L aqueous sodium hydroxide solution (20 mL) to obtain a mixed solution, and the temperature of the mixed solution was controlled to be not more than 20℃during the addition. After the completion of the dropwise addition, the mixture was allowed to stand until the mixture was layered, the aqueous phase was extracted twice with methylene chloride (10 mL), the organic phases were combined, and the organic phase was extracted twice with water (20 mL), and concentrated until no methylene chloride remained after being collected with a camera, to obtain a concentrate.
Ethyl acetate (4 mL) was added to the concentrate, followed by dropwise addition of petroleum ether (40 mL) at 0-10deg.C, precipitation of a white solid, filtration, collection of the white solid, and drying of the white solid at 40-50deg.C (50℃in the present example) for 24 hours, to give 1.4g of a white solid.
The white solid was detected as the target product 3, 5-bis (2-cyano-isopropyl) -toluene in a yield of 64.5% and a moisture content of 0.48%, purity 99.76%, 1HNMR(400MHz,CDCl3, see FIG. 1: δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
Example 2
A synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene was carried out in the same way as in example 1.
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
Firstly, dropwise adding concentrated sulfuric acid (38.25 g,0.39 mol) into a mixed solution of a compound 1 (30 g,0.17 mol) and methanol (310 mL,7.65 mol) with a temperature lower than 40 ℃, and then carrying out reflux stirring reaction for 20h at 55 ℃ to obtain a reaction solution;
The reaction solution was cooled to 45℃and then added dropwise to a 10% aqueous sodium carbonate solution, after stirring for 1.5 hours, the solid was filtered, collected and dried at 65℃for 24 hours to give 31.0g of a white solid.
The white solid was detected as compound 2 in 89.4% yield, 99.7% purity, 1H NMR(400MHz,CDCl3): δ8.48 (s, 1H), δ8.04 (s, 2H), δ3.93 (s, 6H), δ2.45 (s, 3H).
In the second step, to MeMgBr (72.58 mL,0.21 mol) having a temperature lower than 20℃was added a mixed solution of compound 2 (7 g,0.03 mol) and 2-methyltetrahydrofuran (37.93 mL,0.38 mol), followed by stirring at 45℃for 22 hours to obtain a reaction solution.
Cooling the reaction solution to be less than 20 ℃, adding the reaction solution into 10% citric acid aqueous solution (125 mL) for quenching, separating the solution, collecting an organic phase, extracting the residual aqueous phase once by using ethyl acetate (70 mL), merging the organic phases, and concentrating the organic phase until no organic solvent remains, thus obtaining a concentrate.
Petroleum ether (100 mL) was added to the concentrate, white solids precipitated, filtered, the white solids collected, and the white solids dried at 60℃for 25h to give 5.7g of white solids.
The white solid is compound 3, the yield is 81.4%, the water content is 0.36% and the purity is detected 99.6％,1H NMR(400MHz,CDCl3):(δ7.44(s,1H),δ7.17(s,2H),δ2.37(s,3H),δ1.95(br,2H),δ1.57(s,12H),LCMS:M/Z＝191.2(M-18).
Thirdly, adding trimethylcyanosilane (4.96 g,0.05 mol) to a mixed solution of compound 3 (2 g,0.01 mol) at (-65) DEG C and dichloromethane (10 mL) to obtain a mixture; adding a mixed solution of boron trifluoride-diethyl etherate (2.8 g,0.02 mol) and dichloromethane (10 mL) under the condition that the internal temperature of the mixture is lower than (-60) DEG C, stirring and reacting for 1.5h at (-65) DEG C, stirring for 0.75h at (-25) DEG C, and stirring and reacting for 22h at 20-25 ℃ to obtain a reaction solution.
The reaction solution was added dropwise to a 2mol/L aqueous sodium hydroxide solution (20 mL) to obtain a mixed solution, and the temperature of the mixed solution was controlled to be not more than 20℃during the addition. After the completion of the dropwise addition, the mixture was allowed to stand until the mixture was layered, the aqueous phase was extracted twice with methylene chloride (10 mL), the organic phases were combined, and the organic phase was extracted twice with water (20 mL), and concentrated until no methylene chloride remained after being collected with a camera, to obtain a concentrate.
Ethyl acetate (4 mL) was added to the concentrate, petroleum ether (40 mL) was then added dropwise at 0-10℃with a white solid precipitated, the white solid was filtered, and the white solid was collected and dried at 40℃for 24 hours to give 1.3g of a white solid.
The white solid was detected as the target product 3, 5-bis (2-cyano-isopropyl) -toluene in 59.8% yield, 0.34% moisture, 99.5% purity, 1HNMR(400MHz,CDCl3): δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
Example 3
A synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene was carried out in the same way as in example 1.
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
Firstly, dropwise adding concentrated sulfuric acid (42.17 g,0.43 mol) into a mixed solution of a compound 1 (30 g,0.17 mol) and methanol (320 mL,7.90 mol) with a temperature lower than 40 ℃, and then carrying out reflux stirring reaction for 25 hours at 60 ℃ to obtain a reaction solution;
The reaction solution was cooled to 50℃and then added dropwise to a 10% aqueous sodium carbonate solution, after stirring for 2 hours, the solid was filtered, collected and dried at 60℃to give 32.5g of a white solid.
The white solid was detected as compound 2 in 93.7% yield, 99.7% purity, 1H NMR(400MHz,CDCl3): δ8.48 (s, 1H), δ8.04 (s, 2H), δ3.93 (s, 6H), δ2.45 (s, 3H).
In the second step, to MeMgBr (79.51 mL,0.23 mol) having a temperature lower than 20℃was added a mixed solution of compound 2 (7 g,0.03 mol) and 2-methyltetrahydrofuran (40.92 mL,0.41 mol), followed by stirring at 50℃for reaction for 24 hours to give a reaction solution.
Cooling the reaction solution to be less than 20 ℃, adding the reaction solution into 10% citric acid aqueous solution (125 mL) for quenching, separating the solution, collecting an organic phase, extracting the residual aqueous phase once by using ethyl acetate (70 mL), merging the organic phases, and concentrating the organic phase until no organic solvent remains, thus obtaining a concentrate.
Petroleum ether (100 mL) was added to the concentrate, white solids precipitated, filtered, the white solids collected, and the white solids dried at 55deg.C for 23h to give 5.8g of white solids.
The white solid is compound 3, the yield is 82.9%, the water content is 0.37% and the purity is detected 99.87％,1H NMR(400MHz,CDCl3):(δ7.44(s,1H),δ7.17(s,2H),δ2.37(s,3H),δ1.95(br,2H),δ1.57(s,12H),LCMS:M/Z＝191.2(M-18).
Thirdly, adding trimethylcyanosilane (5.46 g,0.055 mol) to a mixed solution of a compound 3 (2 g,0.01 mol) at (-60) DEG C and methylene chloride (10 mL) to obtain a mixture; adding a mixed solution of boron trifluoride and diethyl etherate (3.0 g,0.021 mol) and dichloromethane (10 mL) under the condition that the internal temperature of the mixture is lower than (-60) DEG C, stirring and reacting for 2 hours at (-60) DEG C, stirring for 1 hour at (-20) DEG C, and stirring and reacting for 24 hours at 20-25 ℃ to obtain a reaction solution.
The reaction solution was added dropwise to a 2mol/L aqueous sodium hydroxide solution (20 mL) to obtain a mixed solution, and the temperature of the mixed solution was controlled to be not more than 20℃during the addition. After the completion of the dropwise addition, the mixture was allowed to stand until the mixture was layered, the aqueous phase was extracted twice with methylene chloride (10 mL), the organic phases were combined, and the organic phase was extracted twice with water (20 mL), and concentrated until no methylene chloride remained after being collected with a camera, to obtain a concentrate.
Ethyl acetate (4 mL) was added to the concentrate, petroleum ether (40 mL) was then added dropwise at 0-10℃with a white solid precipitated, the white solid was filtered, and the white solid was collected and dried at 45℃for 25 hours to give 1.25g of a white solid.
The white solid was detected as the target product 3, 5-bis (2-cyano-isopropyl) -toluene in 57.5% yield, 0.33% moisture, 99.6% purity, 1HNMR(400MHz,CDCl3): δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
Example 4
A synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene was carried out in the same way as in example 1.
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
The first step: the same as in example 1.
And a second step of: the same as in example 1.
And a third step of: to a mixture of compound 3 (20.8 g,0.1 mol) at (-70) deg.c and methylene chloride (100 mL), trimethylcyanosilane (54.6 g,0.55 mol) was added to obtain a mixture; adding a mixed solution of boron trifluoride-diethyl etherate (30.0 g,0.21 mol) and dichloromethane (100 mL) under the condition that the internal temperature of the mixture is lower than (-60) DEG C, stirring and reacting for 2 hours at (-60) DEG C, stirring for 1 hour at (-20) DEG C, and stirring and reacting for 24 hours at 20-25 ℃ to obtain a reaction solution.
The reaction solution was added dropwise to a 2mol/L aqueous sodium hydroxide solution (20 mL) to obtain a mixed solution, and the temperature of the mixed solution was controlled to be not more than 20℃during the addition. After the completion of the dropwise addition, the mixture was allowed to stand until the mixture was layered, the aqueous phase was extracted twice with methylene chloride (200 mL), the organic phases were combined, and the organic phase was extracted twice with water (200 mL), and concentrated until no methylene chloride remained after being collected with a camera, to obtain a concentrate.
To the concentrate was added ethyl acetate (40 mL), followed by dropwise addition of petroleum ether (40 0 mL) at 0-10℃to precipitate a white solid, filtration, collection of the white solid, and drying of the white solid at 50℃for 24 hours to give 15.0g of a white solid.
The white solid was detected as the target product 3, 5-bis (2-cyano-isopropyl) -toluene in 66.3% yield, 0.37% moisture, 99.4% purity, 1HNMR(400MHz,CDCl3): δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
Comparative example
Comparative example 1
A method for synthesizing 3, 5-bis (2-cyano-isopropyl) -toluene, which is different from example 1 in that the synthetic route of the third step is as follows:
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
The first step: the same as in example 1.
And a second step of: the same as in example 1.
And a third step of: compound 3 (20.8 g,0.1 mol) and a solution of 20% acetyl chloride in methylene chloride (100 mL) were reacted at room temperature (20-25 ℃ C.) for 12h. Then, most of the solvent was concentrated under reduced pressure (the comparative example of the present application was concentrated under reduced pressure to half of the solvent), and xylene (100 mL) was added, followed by concentration under reduced pressure to obtain a xylene solution of Compound 4.
The xylene solution of compound 4 was used directly in the next reaction without purification.
Fourth step: cuCN (19.8 g) and Cu 2 O (2.8 g) were added to the xylene solution of Compound 4 obtained in the third step, followed by reaction at 130-140℃for 16-20 hours to obtain a reaction solution.
The reaction solution was cooled to room temperature (20-25 ℃), filtered, the filtrate was concentrated to no solvent residue, then ethyl acetate (40 mL) was added, and petroleum ether (400 mL) was slowly added dropwise at 0-10 ℃ with white solid precipitated, filtered, and the collected white solid was dried at 40-50 ℃ for 24 hours to give 9.5g of off-white product.
Upon detection, 3, 5-bis (2-cyano-isopropyl) -toluene was obtained as a white solid in a yield of 42.0%, moisture of 0.36%, purity of 99.2%, 1HNMR(400MHz,CDCl3): δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
Comparative example 2
A synthesis method of 3, 5-bis (2-cyano-isopropyl) -toluene was different from example 1 in the synthesis step of the third step.
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
The first step: the same as in example 1.
And a second step of: the same as in example 1.
And a third step of: compound 3 (20.8 g,0.1 mol) was dissolved in toluene (140 mL), then InCl 3 (8.8 g) was added thereto, and after stirring at room temperature (20-25 ℃ C.) for 0.5-1h, trimethylchlorosilane (29.8 g) was added dropwise thereto, and then stirred at 40-50 ℃ C.) for reaction for 8-16h, to obtain a reaction solution.
The reaction solution was quenched into 20% aqueous potassium hydroxide (200 mL), allowed to stand for delamination, the organic phase was washed three times with water (100 mL), and the organic phase was concentrated to no solvent residue. Ethyl acetate (40 mL) was then added, petroleum ether (400 mL) was slowly added dropwise at 0-10deg.C, off-white solid precipitated, filtered, and the off-white solid was dried at 40-50deg.C for 24h to give 10.4g of off-white solid.
The white solid was detected as the target product 3, 5-bis (2-cyano-isopropyl) -toluene in 46% yield, 0.41% moisture, 99.1% purity, 1HNMR (400 MHz, CDCl 3): δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
Comparative example 3
A synthesis method of 3, 5-bis (2-cyano-isopropyl) -toluene was different from example 1 in the synthesis step of the third step.
The 3, 5-bis (2-cyano-isopropyl) -toluene described above, comprising the steps of:
The first step: the same as in example 1.
And a second step of: the same as in example 1.
And a third step of: compound 3 (20.8 g,0.1 mol) was dissolved in methylene chloride (210 mL), then trimethylcyanosilane (49.6 g) was added, and 40mL of a 1mol/L SnCl 4/methylene chloride solution was added dropwise at 0-5℃and then reacted at room temperature (20-25 ℃) with stirring for 24 hours to give a reaction solution.
The post-treatment steps of the reaction liquid are as follows: the reaction solution was quenched into 10% aqueous potassium carbonate (500 mL), allowed to stand for delamination, the organic phase was washed three times with water (100 mL), and the organic phase was concentrated to no solvent residue. Ethyl acetate (40 mL) was then added, petroleum ether (400 mL) was slowly added dropwise at 0-10deg.C, off-white solid precipitated, filtered, and the off-white solid was dried at 40-50deg.C for 24h to give 9.9g of off-white solid.
The white solid was detected as the target product 3, 5-bis (2-cyano-isopropyl) -toluene in 44% yield, 0.37% moisture, 99.3% purity, 1 HNMR (400 MHz, CDCl 3): δ7.32 (s, 1H), δ7.25 (s, 2H), δ2.41 (s, 3H), δ1.73 (s, 12H).
As a result of analysis of the synthesis methods of 3, 5-bis (2-cyano-isopropyl) -toluene in examples 1 to 4 and comparative examples 1 to 3 according to the present application, the yield of 3, 5-bis (2-cyano-isopropyl) -toluene synthesized in examples 1 to 4 according to the present application was 57.5 to 66.3%, and the yield of 3, 5-bis (2-cyano-isopropyl) -toluene synthesized in comparative examples 1 to 3 was 42 to 46%. Therefore, the method has the characteristics of simple synthesis steps, low raw material cost and safe synthesis method, is more favorable for industrial production, and can also improve the yield of a target product.
Meanwhile, compared with the two synthesis methods using 3, 5-dimethyl methyl benzoate or 5-methyl-1, 3-phthalic acid as raw materials in the prior art, the synthesis method of 3, 5-di (2-cyano-isopropyl) -toluene in the embodiments 1-4 of the application improves the safety of the synthesis method and is more beneficial to industrial production because the use of cyanide with extremely toxicity is avoided.
The present embodiment is only for explanation of the present application and is not to be construed as limiting the present application, and modifications to the present embodiment, which may not creatively contribute to the present application as required by those skilled in the art after reading the present specification, are all protected by patent laws within the scope of claims of the present application.
Claims (5)
1. A method for synthesizing 3, 5-di (2-cyano-isopropyl) -toluene, which is characterized by comprising the following steps:
firstly, taking a compound 1 as a raw material, and carrying out esterification reaction with methanol in strong acid to obtain a compound 2;
Secondly, performing condensation reaction on the compound 2 and a Grignard reagent in 2-methyltetrahydrofuran to obtain a compound 3;
thirdly, carrying out cyanation reaction on the compound 3 and trimethylcyano silane in boron trifluoride diethyl ether to obtain a target product 3, 5-di (2-cyano-isopropyl) -toluene;
The reaction formula of the steps is as follows:
；
in the third step, the feeding ratio of the compound 3 and the trimethylcyano silane is 1 mol (4.8-5.5) mol;
In the third step, adding trimethylcyanosilane into a dichloromethane mixed solution of a compound 3 with the temperature of (-70) - (-60), adding boron trifluoride-diethyl ether into the dichloromethane mixed solution, stirring and reacting for 1-2h at the temperature of (-70) - (-60), stirring and reacting for 0.5-1h at the temperature of (-30) - (-20), and stirring and reacting for 20-24h at the temperature of 20-25 ℃;
In the second step, the feeding ratio of the compound 2, the Grignard reagent and the 2-methyltetrahydrofuran is 1mol (6.67-7.67) mol (11.67-13.67) mol;
In the second step, adding a mixed solution of the compound 2 and 2-methyltetrahydrofuran into a Grignard reagent with the temperature lower than 20 ℃, and then stirring and reacting for 20-24 hours at 40-50 ℃;
The grignard reagent is methyl magnesium bromide.
2. The method for synthesizing 3, 5-bis (2-cyano-isopropyl) -toluene according to claim 1, wherein: in the first step, the feeding ratio of the compound 1, the methanol and the concentrated sulfuric acid is 1mol (43.59-46.47) mol (1.94-2.53) mol.
3. The method for synthesizing 3, 5-bis (2-cyano-isopropyl) -toluene according to claim 1, wherein: in the first step, the reaction temperature is 50-60 ℃ and the reaction time is 20-25h.
4. The method for synthesizing 3, 5-bis (2-cyano-isopropyl) -toluene according to claim 1, wherein: in the first step, after the esterification reaction is finished, a reaction liquid is obtained, the reaction liquid is cooled to 40-50 ℃, then is dripped into a sodium carbonate aqueous solution, is stirred for 1-2 hours, is filtered, and is collected and dried to obtain the compound 2.
5. The method for synthesizing 3, 5-bis (2-cyano-isopropyl) -toluene according to claim 1, wherein: in the second step, after the condensation reaction is finished, a reaction liquid is obtained, the reaction liquid is cooled to be less than 20 ℃, then the reaction liquid is added into a citric acid aqueous solution to quench, then liquid separation is carried out, and an organic phase is collected; petroleum ether is added into the organic phase, white solid is separated out, and the separated white solid is dried to obtain the compound 3.
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