CN108129258B - Synthesis process of 4-bromo-4' -propylbiphenyl - Google Patents
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Abstract
The invention discloses a synthesis process of 4-bromo-4' -propylbiphenyl, relates to the technical field of medicine synthesis, and solves the problems of harsh reaction conditions and low total yield of the existing process. The invention avoids the ultra-high temperature reaction condition required by Huang Minlon reaction reduction or the ultra-low temperature reaction condition required by halogen lithium exchange reaction, does not use carcinogenic compound iodopropane, has mild reaction condition, easier control of synthesis process condition, easy operation and simple post-treatment; the synthesis process has high atom economy of chemical reaction, and compared with the total yield of 20-30% in the prior art, the total yield of the process reaches 57%, and the product yield is obviously improved; the invention uses cheap and easily available biphenyl as a starting raw material, thereby reducing the cost.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthesis process of 4-bromo-4' -propylbiphenyl.
Background
4-bromo-4 '-propylbiphenyl is an important organic synthesis intermediate, and 4-propylbiphenyl boric acid prepared by reacting the 4-bromo-4' -propylbiphenyl with boric acid ester is used as a liquid crystal monomer and widely applied to synthesis of liquid crystal materials. Meanwhile, 4-bromo-4' -propylbiphenyl can generate various coupling reactions through metal catalysis, and is an important framework structure in the pharmaceutical industry. Through literature research, the synthesis of 4-bromo-4' -propylbiphenyl has the following routes.
Firstly, through Friedel-Crafts acylation reaction (Journal of Material Chemistry: C, Material for Optical and Electronic Devices,2014,2,891-900), the intermediate obtained in the Chinese invention patent with the publication number of CN1876622A is reduced by a Huang Minlon reaction, and the synthetic route is shown as the reaction formula 1. However, it is known that the Huang Minlon reaction reduction generally requires the high temperature of 150-200 reaction, which is a great challenge for industrialization, has high requirements for plant equipment, and also has great potential safety hazard.
In addition, the synthetic route in patent PCT2002035580 is shown as reaction 2, and after halogen lithium exchange is carried out on dibromobiphenyl and butyl lithium, 4-bromo-4' -propylbiphenyl can be prepared by reacting with iodopropane. However, this route also has significant drawbacks. Firstly, bromine atoms and iodine atoms are replaced in the reaction, and the atom economy of the chemical reaction is not high due to the large atomic weight ratio of the bromine atoms and the iodine atoms, and the total yield is only 20-30%. Secondly, the lithium halide exchange reaction is usually carried out at a temperature below-78 ℃ and is difficult to achieve in many plants. Finally, iodine is easily eliminated under alkaline conditions, resulting in a large excess of iodopropane, which is a carcinogenic agent and also requires strict protective measures in industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a synthesis process of 4-bromo-4 '-propylbiphenyl, which takes biphenyl which is a very cheap industrial chemical as a starting raw material, introduces propionyl through Friedel-Crafts acylation reaction, performs elimination reaction under the catalysis of p-toluenesulfonic acid after reduction by sodium borohydride to obtain a compound 4, does not undergo separation, performs hydrogenation reaction on the compound 4 under the catalysis of palladium to obtain a compound 5, and performs bromination reaction to obtain the 4-bromo-4' -propylbiphenyl. The process has the advantages of simple operation, mild reaction conditions, no need of high-temperature heating, no use of highly toxic chemicals such as hydrazine hydrate and iodopropane, and safe operation.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthesis process of 4-bromo-4' -propylbiphenyl comprises the following steps:
step one, synthesis of a compound 2: sequentially adding biphenyl, a first organic solvent and propionyl chloride into a reaction bottle, fully stirring, cooling, starting to slowly add aluminum chloride when the temperature is reduced to 5-10 ℃, stirring at room temperature for 4-6 hours after adding, then cooling to 0-10 ℃, dropwise adding water to quench reaction, standing for layering, separating out a water phase, stirring and washing the organic phase with water twice, spin-drying the organic phase, recrystallizing with a second organic solvent after spin-drying, and drying to obtain a compound 2;
step two, synthesis of compound 3: adding the compound 2 and a third organic solvent into a reaction bottle, stirring, cooling to 10-15 ℃, starting to dropwise add a sodium borohydride aqueous solution, stirring at room temperature for 2-4 hours after the addition is finished, adding ethyl acetate, water and concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing the organic phase twice with water, removing the water phase, and spin-drying the organic phase to obtain a compound 3;
step three, synthesizing a compound 4: adding the compound 3, a fourth organic solvent and p-toluenesulfonic acid into a reaction bottle in sequence, fully stirring, heating to 80-90 ℃ and maintaining the reaction for 3-6 hours, cooling to 15-30 ℃, adding ethyl acetate and water, stirring, standing for layering, separating out a water phase, washing the organic phase with water twice, removing the water phase, and directly using the organic phase for the next reaction;
step four, synthesis of compound 5: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding palladium carbon for hydrogenation, heating, keeping the temperature at 35-45 ℃, stirring for 10-15 hours, cooling to 15-30 ℃ after the reaction is finished, carrying out suction filtration, leaching a filter cake with ethyl acetate, spin-drying the filtrate after the filtration is finished to obtain a crude compound 5, and recrystallizing with methanol to obtain a white solid, namely the compound 5;
step five, synthesis of compound 6: adding the compound 5, a fifth organic solvent and ferric chloride into a reaction bottle in sequence, fully stirring, slowly adding liquid bromine, keeping the temperature at 20-30 ℃ and maintaining the reaction for 15-20 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 10% -20% to quench the reaction, stirring, standing for layering, washing the organic phase with water twice, removing the water phase, carrying out spin drying on the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6;
the synthesis process is carried out according to the following reaction formula:
more preferably, the first organic solvent is any one of dichloroethane, dichloromethane, chlorobenzene, and toluene.
More preferably, the second organic solvent is any one combination of ethyl acetate/petroleum ether, ethyl acetate/n-heptane, and isopropyl acetate/n-heptane.
More preferably, the third organic solvent is any one of tetrahydrofuran, acetonitrile, dichloroethane and dioxane;
the fourth organic solvent is any one of toluene, ethyl acetate, acetonitrile and tetrahydrofuran.
More preferably, the fifth organic solvent is any one of dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, N-dimethylformamide, and acetic acid.
More preferably, the first step specifically comprises the synthesis of compound 2: adding 1 equivalent of biphenyl, a first organic solvent and 1.0-1.15 equivalents of propionyl chloride into a reaction bottle in sequence, wherein the weight ratio of the first organic solvent to the biphenyl is 3-5:1, fully stirring, cooling, slowly adding 1.05-1.3 equivalents of aluminum chloride when the temperature is reduced to 5-10 ℃, stirring for 4-6 hours at room temperature after the addition is finished, cooling to 0-10 ℃, dropwise adding water to quench and react, standing for layering, separating out a water phase, stirring and washing the organic phase twice with water, spin-drying the organic phase, recrystallizing with a second organic solvent after spin-drying, and drying to obtain a compound 2.
More preferably, the second step specifically comprises synthesis of compound 3: adding 1 equivalent of compound 2 and a third organic solvent into a reaction bottle, wherein the weight ratio of the third organic solvent to the compound 2 is 3-5:1, stirring, cooling to 10-15 ℃, starting to dropwise add a sodium borohydride aqueous solution, wherein the sodium borohydride aqueous solution consists of 0.5-0.6 equivalent of sodium borohydride and 0.5-1 equivalent of water, stirring at room temperature for 2-4 hours after the addition is finished, adding 5-7 equivalent of ethyl acetate, 3-4 equivalent of water and 1.5 equivalent of concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing an organic phase twice with water, removing a water phase, and spin-drying the organic phase to obtain a compound 3.
More preferably, the third step specifically includes synthesis of compound 4: adding the compound 3, a fourth organic solvent and 0.1-0.2 equivalent of p-toluenesulfonic acid into a reaction bottle in sequence, wherein the adding amount of the fourth organic solvent is 3-6 times of the weight of the compound 2, fully stirring, heating to 80-90 ℃, maintaining the reaction for 3-6 hours, cooling to 15-30 ℃, adding 3-5 equivalent of ethyl acetate and 3-4 equivalent of water, stirring, standing for layering, separating out a water phase, washing the organic phase twice with water, removing the water phase, and directly using the organic phase for the next reaction.
More preferably, the fourth step specifically comprises the synthesis of compound 5: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding 0.05-0.2 equivalent of palladium carbon for hydrogenation, heating and raising the temperature, keeping the temperature at 35-45 ℃, stirring for 10-15 hours, cooling to 15-30 ℃ after the reaction is finished, carrying out suction filtration, leaching a filter cake with ethyl acetate, carrying out spin drying on the filtrate after the reaction is finished to obtain a crude compound 5, and carrying out recrystallization with methanol to obtain a white solid, namely the compound 5.
More preferably, the fifth step specifically comprises synthesis of compound 6: adding 1 equivalent of the compound 5, a fifth organic solvent and 0.1-0.3 equivalent of ferric chloride into a reaction bottle in sequence, wherein the weight ratio of the fifth organic solvent to the compound 5 is 4-6: 1, fully stirring, slowly adding 1.1-1.2 equivalent of liquid bromine, keeping the temperature at 20-30 ℃ and reacting for 15-20 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 10-20% to quench the reaction, stirring, standing for layering, washing an organic phase twice with water, removing an aqueous phase, carrying out spin drying on the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention avoids the ultra-high temperature reaction condition required by Huang Minlon reaction reduction or the ultra-low temperature reaction condition required by halogen lithium exchange reaction, does not use carcinogenic compound iodopropane, has mild reaction condition, easier control of synthesis process condition, easy operation and simple post-treatment;
(2) the synthesis process has high atom economy of chemical reaction, and compared with the total yield of 20-30% in the reaction formula 1, the total yield of the process reaches 57%, and the product yield is obviously improved;
(3) the invention uses cheap and easily available biphenyl as a starting raw material, thereby reducing the cost.
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
Detailed Description
The invention is described in detail below with reference to the figures and examples. Unless otherwise specified, the reagents and apparatus used in the following examples are commercially available products and laboratory-standard apparatus.
Example 1: a synthesis process of 4-bromo-4' -propylbiphenyl is shown in a reaction formula of figure 1, and specifically comprises the following steps:
step one, synthesis of a compound 2: sequentially adding 1 equivalent of biphenyl, a first organic solvent and 1.0 equivalent of propionyl chloride into a clean 100mL three-necked bottle, wherein the first organic solvent is dichloroethane, the weight ratio of the first organic solvent to the biphenyl is 3:1, fully stirring, cooling, slowly adding 1.05 equivalent of aluminum chloride when the temperature is reduced to 5 ℃, stirring at room temperature for 4 hours after the addition is finished, cooling to 0 ℃, dropwise adding water to quench and react, standing for layering, separating out a water phase, stirring and washing the organic phase twice with water, spin-drying the organic phase, recrystallizing with a second organic solvent after spin-drying, wherein the second organic solvent is ethyl acetate/petroleum ether (10mL/30mL), and drying to obtain a compound 2 with the yield of 84%;
step two, synthesis of compound 3: adding 1 equivalent of compound 2 and a third organic solvent, wherein the third organic solvent is tetrahydrofuran, and the weight ratio of the third organic solvent to the compound 2 is 3:1, stirring, cooling to 10 ℃, starting to dropwise add a sodium borohydride aqueous solution, wherein the sodium borohydride aqueous solution consists of 0.5 equivalent of sodium borohydride and 0.5 equivalent of water, stirring at room temperature for 2 hours after the addition is finished, adding 5 equivalents of ethyl acetate, 3 equivalents of water and 1.5 equivalents of concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing an organic phase twice with water, removing a water phase, and spin-drying the organic phase to obtain a compound 3;
step three, synthesizing a compound 4: adding a compound 3, a fourth organic solvent and 0.2 equivalent of p-toluenesulfonic acid into a reaction bottle in sequence, wherein the fourth organic solvent is toluene, the adding amount of the fourth organic solvent is 6 times of the weight of the compound 2, fully stirring, heating to 90 ℃, maintaining the reaction for 6 hours, cooling to 30 ℃, adding 5 equivalent of ethyl acetate and 4 equivalent of water, stirring, standing for layering, separating out an aqueous phase, washing the organic phase twice with water, removing the aqueous phase, and directly using the organic phase for the next reaction;
step four, synthesis of compound 5: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding 0.2 equivalent of palladium carbon for hydrogenation, heating and raising the temperature, keeping the temperature at 45 ℃, stirring for 15 hours, cooling to 30 ℃ after the reaction is finished, carrying out suction filtration, leaching a filter cake with ethyl acetate, spin-drying the filtrate after the reaction is finished to obtain a crude compound 5, and recrystallizing with methanol to obtain a white solid, namely the compound 5, wherein the yield is 87%;
step five, synthesis of compound 6: adding 1 equivalent of the compound 5, a fifth organic solvent and 0.2 equivalent of ferric chloride into a reaction bottle in sequence, wherein the fifth organic solvent is dichloromethane, and the weight ratio of the fifth organic solvent to the compound 5 is 5:1, fully stirring, slowly adding 1.15 equivalent of liquid bromine, keeping the temperature at 25 ℃ and reacting for 18 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 15% to quench the reaction, stirring, standing for layering, washing an organic phase twice with water, removing a water phase, spin-drying the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6, wherein the yield is 77%.
In fig. 1, the standard name of compound 2 is 4-propionyl-biphenyl, the standard name of compound 3 is 1-biphenyl-4-yl-1-propanol, the standard name of compound 4 is 4-propenyl-biphenyl, the standard name of compound 5 is 4-propyl-biphenyl, the standard name of compound 6 is 4-bromo-4 '-propylbiphenyl, and the CAS number of 4-bromo-4' -propylbiphenyl is 58743-81-0.
Example 2: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step one specifically comprises the synthesis of a compound 2: adding 1 equivalent of biphenyl, a first organic solvent and 1.1 equivalents of propionyl chloride into a clean three-necked bottle of 100mL in sequence, wherein the first organic solvent is dichloroethane, the weight ratio of the first organic solvent to the biphenyl is 4:1, fully stirring, cooling, slowly adding 1.15 equivalents of aluminum chloride when the temperature is reduced to 8 ℃, stirring at room temperature for 5 hours after the addition is finished, cooling to 5 ℃, dropwise adding water to quench and react, standing for layering, separating out a water phase, stirring and washing the organic phase twice with water, spin-drying the organic phase, then recrystallizing with a second organic solvent, wherein the second organic solvent is ethyl acetate/petroleum ether (10mL/30mL), and drying to obtain a compound 2.
Example 3: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step one specifically comprises the synthesis of a compound 2: adding 1 equivalent of biphenyl, a first organic solvent and 1.15 equivalents of propionyl chloride into a clean three-necked bottle of 100mL in sequence, wherein the first organic solvent is dichloroethane, the weight ratio of the first organic solvent to the biphenyl is 5:1, fully stirring, cooling, slowly adding 1.3 equivalents of aluminum chloride when the temperature is reduced to 10 ℃, stirring at room temperature for 6 hours after the addition is finished, cooling to 10 ℃, dropwise adding water to quench and react, standing for layering, separating out a water phase, stirring and washing the organic phase twice with water, spin-drying the organic phase, then recrystallizing with a second organic solvent, wherein the second organic solvent is ethyl acetate/petroleum ether (10mL/30mL), and drying to obtain a compound 2.
Example 4: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the synthesis process of example 1 is that the second step specifically comprises the synthesis of a compound 3: adding 1 equivalent of compound 2 and a third organic solvent, wherein the third organic solvent is tetrahydrofuran, and the weight ratio of the third organic solvent to the compound 2 is 4:1, stirring, cooling to 12 ℃, starting to dropwise add a sodium borohydride aqueous solution, wherein the sodium borohydride aqueous solution consists of 0.55 equivalent of sodium borohydride and 0.8 equivalent of water, stirring at room temperature for 3 hours after the addition is finished, adding 6 equivalent of ethyl acetate, 3.5 equivalent of water and 1.5 equivalent of concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing an organic phase twice with water, removing an aqueous phase, and spin-drying the organic phase to obtain a compound 3.
Example 5: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the synthesis process of example 1 is that the second step specifically comprises the synthesis of a compound 3: adding 1 equivalent of compound 2 and a third organic solvent, wherein the third organic solvent is tetrahydrofuran, and the weight ratio of the third organic solvent to the compound 2 is 5:1, stirring, cooling to 15 ℃, starting to dropwise add a sodium borohydride aqueous solution, wherein the sodium borohydride aqueous solution consists of 0.6 equivalent of sodium borohydride and 1 equivalent of water, stirring at room temperature for 4 hours after the addition is finished, adding 7 equivalents of ethyl acetate, 4 equivalents of water and 1.5 equivalents of concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing an organic phase twice with water, removing a water phase, and spin-drying the organic phase to obtain a compound 3.
Example 6: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step three specifically comprises the synthesis of a compound 4: adding a compound 3, a fourth organic solvent and 0.15 equivalent of p-toluenesulfonic acid into a reaction bottle in sequence, wherein the fourth organic solvent is toluene, the adding amount of the fourth organic solvent is 4.5 times of the weight of the compound 2, fully stirring, heating to 85 ℃, maintaining the reaction for 4.5 hours, cooling to 22 ℃, adding 4 equivalent of ethyl acetate and 3.5 equivalent of water, stirring, standing for layering, separating out an aqueous phase, washing the organic phase twice with water, removing the aqueous phase, and directly using the organic phase for the next reaction.
Example 7: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step three specifically comprises the synthesis of a compound 4: adding a compound 3, a fourth organic solvent and 0.1 equivalent of p-toluenesulfonic acid into a reaction bottle in sequence, wherein the fourth organic solvent is toluene, the adding amount of the fourth organic solvent is 3 times of the weight of the compound 2, fully stirring, heating to 80 ℃, maintaining the reaction for 3 hours, cooling to 15 ℃, adding 3 equivalents of ethyl acetate and 3 equivalents of water, stirring, standing for layering, separating out an aqueous phase, washing the organic phase twice with water, removing the aqueous phase, and directly using the organic phase for the next reaction.
Example 8: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step four specifically comprises the synthesis of a compound 5: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding 0.1 equivalent of palladium carbon for hydrogenation, heating and raising the temperature, keeping 40 ℃ and stirring for 13 hours, after the reaction is finished, cooling to 20 ℃, carrying out suction filtration, leaching a filter cake with ethyl acetate, spin-drying the filtrate after the suction is dried to obtain a crude compound 5, and recrystallizing with methanol to obtain a white solid, namely the compound 5.
Example 9: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step four specifically comprises the synthesis of a compound 5: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding 0.05 equivalent of palladium carbon for hydrogenation, heating and raising the temperature, keeping the temperature at 35 ℃, stirring for 10 hours, cooling to 15 ℃ after the reaction is finished, carrying out suction filtration, leaching a filter cake with ethyl acetate, spin-drying the filtrate after the suction is dried to obtain a crude compound 5, and recrystallizing with methanol to obtain a white solid, namely the compound 5.
Example 10: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step five specifically comprises the synthesis of a compound 6: adding 1 equivalent of the compound 5, a fifth organic solvent and 0.1 equivalent of ferric chloride into a reaction bottle in sequence, wherein the fifth organic solvent is dichloromethane, and the weight ratio of the fifth organic solvent to the compound 5 is 4:1, fully stirring, slowly adding 1.1 equivalent of liquid bromine, keeping the temperature at 20 ℃ and reacting for 20 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 10% to quench the reaction, stirring, standing for layering, washing an organic phase twice with water, removing a water phase, spin-drying the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6.
Example 11: the difference between the synthesis process of 4-bromo-4' -propylbiphenyl and the example 1 is that the step five specifically comprises the synthesis of a compound 6: adding 1 equivalent of the compound 5, a fifth organic solvent and 0.3 equivalent of ferric chloride into a reaction bottle in sequence, wherein the fifth organic solvent is dichloromethane, and the weight ratio of the fifth organic solvent to the compound 5 is 6: 1, fully stirring, slowly adding 1.2 equivalents of liquid bromine, keeping the temperature at 30 ℃ and reacting for 15 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 20% to quench the reaction, stirring, standing for layering, washing an organic phase twice with water, removing a water phase, spin-drying the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6.
Example 12: a process for the synthesis of 4-bromo-4' -propylbiphenyl, which differs from example 1 in that the first organic solvent is dichloromethane and the second organic solvent is ethyl acetate/n-heptane.
Example 13: a process for the synthesis of 4-bromo-4' -propylbiphenyl, which differs from example 1 in that the first organic solvent is chlorobenzene and the second organic solvent is isopropyl acetate/n-heptane.
Example 14: a process for the synthesis of 4-bromo-4' -propylbiphenyl, different from example 1 in that the first organic solvent is toluene.
Example 15: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the third organic solvent is acetonitrile and the fourth organic solvent is ethyl acetate.
Example 16: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the third organic solvent is dichloroethane and the fourth organic solvent is acetonitrile.
Example 17: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the third organic solvent is dioxane and the fourth organic solvent is tetrahydrofuran.
Example 18: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the fifth organic solvent is tetrahydrofuran.
Example 19: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the fifth organic solvent is dioxane.
Example 20: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the fifth organic solvent is dimethyl sulfoxide.
Example 21: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the fifth organic solvent is N, N-dimethylformamide.
Example 22: a process for synthesizing 4-bromo-4' -propylbiphenyl, which is different from example 1 in that the fifth organic solvent is acetic acid.
The overall yields of examples 1-22 are shown in Table 1. As can be seen from Table 1, the synthesis process of the present invention has high atom economy of chemical reaction, and compared with the total yield of 20-30% in the reaction formula 1, the total yield of the process reaches more than 56%, and the total yield of the product is significantly improved.
TABLE 1 Total yield of examples 1-22
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (10)
1. A synthesis process of 4-bromo-4' -propylbiphenyl is characterized by comprising the following steps:
step one, synthesis of a compound 2: sequentially adding biphenyl, a first organic solvent and propionyl chloride into a reaction bottle, fully stirring, cooling, starting to slowly add aluminum chloride when the temperature is reduced to 5-10 ℃, stirring at room temperature for 4-6 hours after adding, then cooling to 0-10 ℃, dropwise adding water to quench reaction, standing for layering, separating out a water phase, stirring and washing the organic phase with water twice, spin-drying the organic phase, recrystallizing with a second organic solvent after spin-drying, and drying to obtain a compound 2;
step two, synthesis of compound 3: adding the compound 2 and a third organic solvent into a reaction bottle, stirring, cooling to 10-15 DEGoC, beginning to dropwise add a sodium borohydride aqueous solution, stirring at room temperature for 2-4 hours after the addition is finished, adding ethyl acetate, water and concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing the organic phase twice with water, removing the water phase, and spin-drying the organic phase to obtain a compound 3;
step three, synthesizing a compound 4: adding the compound 3, the fourth organic solvent and the p-toluenesulfonic acid into a reaction bottle in sequence, fully stirring, heating to 80-90 DEGoC, maintaining the reaction for 3 to 6 hours, cooling to 15 to 30 DEGoC, adding ethyl acetate and water, stirring, standing for layering, removing a water phase, washing an organic phase twice with water, removing the water phase, and directly using the organic phase for the next reaction;
step four, synthesis of compound 5: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding palladium carbon for hydrogenation, heating and raising the temperature, and keeping the temperature for 35-45 DEGoC, stirring for 10-15 hours, cooling to 15-30 ℃ after the reaction is finishedoC, performing suction filtration, leaching a filter cake with ethyl acetate, spin-drying the filtrate after suction drying to obtain a crude compound 5, and recrystallizing with methanol to obtain a white solid, namely the compound 5;
step five, synthesis of compound 6: adding the compound 5, the fifth organic solvent and ferric chloride into a reaction bottle in sequence, fully stirring, slowly adding liquid bromine, and keeping the temperature at 20-30 DEGoC is combined with vitaminAfter the reaction lasts for 15-20 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 10% -20% to quench the reaction, stirring, standing for layering, washing the organic phase twice with water, removing the water phase, spin-drying the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6;
the synthesis process is carried out according to the following reaction formula:
2. the process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the first organic solvent is any one of dichloroethane, dichloromethane, chlorobenzene, and toluene.
3. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the second organic solvent is any one combination of ethyl acetate/petroleum ether, ethyl acetate/n-heptane, and isopropyl acetate/n-heptane.
4. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the third organic solvent is any one of tetrahydrofuran, acetonitrile, dichloroethane, and dioxane;
the fourth organic solvent is any one of toluene, ethyl acetate, acetonitrile and tetrahydrofuran.
5. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the fifth organic solvent is any one of dichloromethane, tetrahydrofuran, dioxane, dimethyl sulfoxide, N-dimethylformamide, and acetic acid.
6. The process for the synthesis of 4-bromo-4' -propylbiphenyl according to claim 1, wherein the first step specifically comprises the synthesis of compound 2: adding 1 equivalent of biphenyl, a first organic solvent and 1.0-1.15 equivalents of propionyl chloride into a reaction bottle in sequence, wherein the weight ratio of the first organic solvent to the biphenyl is 3-5:1, fully stirring, cooling, slowly adding 1.05-1.3 equivalents of aluminum chloride when the temperature is reduced to 5-10 ℃, stirring for 4-6 hours at room temperature after the addition is finished, cooling to 0-10 ℃, dropwise adding water to quench and react, standing for layering, separating out a water phase, stirring and washing the organic phase twice with water, spin-drying the organic phase, recrystallizing with a second organic solvent after spin-drying, and drying to obtain a compound 2.
7. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the second step specifically comprises the synthesis of compound 3: adding 1 equivalent of compound 2 and a third organic solvent into a reaction bottle, wherein the weight ratio of the third organic solvent to the compound 2 is 3-5:1, stirring, cooling to 10-15 DEGoAnd C, beginning to dropwise add an aqueous solution of sodium borohydride, wherein the aqueous solution of sodium borohydride consists of 0.5-0.6 equivalent of sodium borohydride and 0.5-1 equivalent of water, stirring at room temperature for 2-4 hours after the addition is finished, adding 5-7 equivalents of ethyl acetate, 3-4 equivalents of water and 1.5 equivalents of concentrated hydrochloric acid after the reaction is finished, standing for layering after the stirring, washing the organic phase twice with water, removing the water phase, and spin-drying the organic phase to obtain the compound 3.
8. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the step three specifically comprises the synthesis of compound 4: adding the compound 3, a fourth organic solvent and 0.1-0.2 equivalent of p-toluenesulfonic acid into a reaction bottle in sequence, wherein the adding amount of the fourth organic solvent is 3-6 times of the weight of the compound 2, fully stirring, heating to 80-90 DEG CoC, maintaining the reaction for 3 to 6 hours, cooling to 15 to 30 DEGoAnd C, adding 3-5 equivalent of ethyl acetate and 3-4 equivalent of water, stirring, standing for layering, removing a water phase, washing an organic phase twice with water, removing the water phase, and directly using the organic phase for the next reaction.
9. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the process comprisesIn step four, the synthesis of compound 5 specifically comprises: transferring the organic phase obtained in the third step into a hydrogenation kettle, adding 0.05-0.2 equivalent of palladium carbon for hydrogenation, heating and raising the temperature, and keeping the temperature at 35-45 DEGoC, stirring for 10-15 hours, cooling to 15-30 ℃ after the reaction is finishedoAnd C, performing suction filtration, leaching a filter cake with ethyl acetate, spin-drying the filtrate after suction drying to obtain a crude compound 5, and recrystallizing with methanol to obtain a white solid, namely the compound 5.
10. The process for synthesizing 4-bromo-4' -propylbiphenyl according to claim 1, wherein the step five specifically comprises the synthesis of compound 6: adding 1 equivalent of the compound 5, a fifth organic solvent and 0.1-0.3 equivalent of ferric chloride into a reaction bottle in sequence, wherein the weight ratio of the fifth organic solvent to the compound 5 is 4-6: 1, fully stirring, slowly adding 1.1-1.2 equivalent of liquid bromine, and keeping the temperature at 20-30oAnd C, after maintaining the reaction for 15-20 hours, adding a sodium hydroxide aqueous solution with the mass concentration of 10% -20% to quench the reaction, stirring, standing for layering, washing the organic phase twice with water, removing the water phase, spin-drying the organic phase to obtain a crude product of the compound 6, pulping in methanol, cooling, filtering, precipitating and drying to obtain a white solid, namely the compound 6.
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