CN118047736A - A method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds - Google Patents

Abstract

The invention discloses a method for synthesizing 2,2', 6' -tetrafluoro- [1,1' -biphenyl ] compounds, which comprises the following steps: preparing a compound shown in a formula I, and preparing the compound shown in the formula I into organic zincate shown in a formula II in an inert gas atmosphere; under the action of palladium catalyst and organophosphorus ligand, the organic zincate shown in the formula II and the compound shown in the formula IV are subjected to coupling reaction to obtain the 2,2', 6' -tetrafluoro- [1,1' -biphenyl ] compound shown in the formula V. The invention has the advantages that: the method has the advantages of simple operation, easily obtained raw materials, greatly reduced consumption of raw materials and catalysts, low cost and high yield, and the obtained 2,2', 6' -tetrafluoro- [1,1' -biphenyl ] compound has higher quality, and the scale of the synthesis method can be enlarged to hundred kilograms, so that intermediate products with high quality and low price can be provided for industries such as biological medicine, synthetic chemistry and the like, thereby solving the problems of unstable raw materials, large catalyst consumption, high price, unsuitable mass production and the like in the prior art.

Description

A method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds

Technical Field

The invention relates to the technical field of intermediate preparation, in particular to a preparation technology of 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds.

Background technique

2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds are very important pharmaceutical intermediates and liquid crystal compound intermediates, and are widely used in the fields of medicine, petrochemicals, microelectronics manufacturing, machinery manufacturing, and aerospace.

Usually, the synthesis of this type of compound is carried out through the Suzuki coupling reaction, which requires the use of an organic boron compound. The organic boron compound is not very stable under the reaction conditions, so an excess of substrate and an equivalent amount of catalyst need to be used. These factors will greatly increase the cost, making it impossible to industrialize the reaction, limiting the promotion and application of this type of high practical value compound.

Therefore, it is extremely important to develop a green, environmentally friendly, cheap, efficient and easy-to-produce method to synthesize 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds.

Summary of the invention

The purpose of the present invention is to provide a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound and a synthesis method thereof, so as to solve the problems of high cost, difficulty in industrialization and limited promotion of the synthesis method in the prior art.

In order to achieve the above object, the present invention adopts the following technical solutions:

A method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds, the process comprising:

(1) firstly reacting 1,3,5-trifluorobenzene with a raw material _R1 to prepare a compound represented by formula I;

(2) Under an inert gas atmosphere, preparing the compound represented by formula III into the compound represented by formula IV;

(3) Under an inert gas atmosphere, preparing the compound represented by formula I into an organic zinc ester represented by formula II;

(4) Under the action of a palladium catalyst and an organic phosphorus ligand, the organic zinc ester represented by Formula II and the compound represented by Formula IV undergo a coupling reaction to obtain a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound represented by Formula V. The reaction process is as follows:

;

Wherein R ₁ is one of the following substituents:

;

_R2 is substituted by one of the following compounds or substituents: methyl formate, ethyl formate, isopropyl formate, acetyl, nitro, cyano, dimethylformamide, diethylformamide;

The compound shown in formula IV is one of the following:

.

Further, the process includes:

(1) adding _R1 raw material, 1,3,5-trifluorobenzene and potassium carbonate to a first solvent, heating and refluxing to prepare a compound represented by formula I;

(2) Under an inert gas atmosphere, add the compound represented by formula III to the second solvent, cool down, add alkyl lithium, keep warm and stir, add liquid bromine, raise the temperature after the addition, and add saturated sulfurous acid aqueous solution dropwise until the reaction system turns light yellow to obtain the compound represented by formula IV;

(3) Under an inert gas atmosphere, dissolving the compound represented by formula I in a second solvent, cooling to a low temperature, adding alkyl lithium to maintain the temperature for reaction, then adding zinc pivalate and heating to react to obtain the compound represented by formula II;

(4) Adding the compound represented by formula IV, a palladium catalyst and an organophosphorus ligand to the system obtained in step (3), and heating the mixture to react; after the reaction is completed, purifying the mixture to obtain the compound represented by formula V, i.e., a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound.

Furthermore, the purification process includes: quenching the reaction with acid water, extracting with an organic solvent, combining the organic phases, and concentrating under reduced pressure to remove the solvent to obtain a crude product of 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds; and performing recrystallization purification on the crude product.

Furthermore, the acid water is a hydrochloric acid aqueous solution, and the system is adjusted to 5-6.

Furthermore, the recrystallization solvent includes one or a mixture of two or more of petroleum ether, n-hexane, and isopropyl ether.

Further, the compound represented by formula V is one of the following:

; /> ; /> ;

; /> .

Further, the first solvent is acetonitrile;

The second solvent is one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether and toluene;

The alkyl lithium is any one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium and lithium diisopropylamide.

Furthermore, in the step (1), the molar ratio of the _R1 raw material, 1,3,5-trifluorobenzene and potassium carbonate is 1.0: (1.0-1.5): (1.0-2.0);

The temperature was raised to reflux for 9 hours.

Furthermore, in the step (2), the amount of the second solvent used is 8 to 18 times the weight of the compound represented by formula III in terms of mL/g; the temperature is lowered to -65°C; the amount of alkyl lithium used is 1 to 3 times the molar number of the compound represented by formula III; the amount of liquid bromine used is 1 to 3 times the molar number of the compound represented by formula III; and the temperature is raised to 0°C.

Furthermore, in the step (3), the volume of the second solvent is 8 to 18 times the weight of the compound represented by formula I, measured in mL/g, and the temperature is lowered to -78°C to -40°C; the amount of alkyl lithium used is 1 to 2 equivalents of the compound represented by formula I, the amount of zinc pivalate used is 1 to 2 equivalents of the structural compound represented by formula I, and the temperature is raised to 20 to 25°C and reacted for 30 minutes.

Furthermore, in the step (3), the amount of alkyl lithium used is 1 to 1.2 equivalents of the compound represented by formula I.

Furthermore, the dosage of the zinc pivalate is 1 to 1.2 equivalents of the compound of the structure shown in formula I.

Further, the palladium catalyst is any one of Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , and PdCl ₂ ;

The amount of the palladium catalyst used is 0.05 to 0.5 equivalents of the compound represented by formula II.

Furthermore, the amount of the palladium catalyst used is 0.05 to 0.2 equivalents of the compound represented by formula II.

Further, the organophosphorus ligand is any one of X-Phos, S-Phos, Ru-Phos, John-Phos, Cy-JohnPhos, and Me-Phos;

The amount of the organophosphorus ligand used is 0.1 to 1 equivalent of the compound represented by formula II.

Furthermore, the amount of the organophosphorus ligand used is 0.1 to 0.4 equivalents of the compound represented by formula II.

Furthermore, based on molar ratio, the amount of the compound represented by formula I is 2-4 times the amount of the compound represented by formula VI.

Furthermore, the temperature-raising reaction in step (4) is carried out at a temperature of 50-60°C.

The advantages of the invention include: simple operation, easy availability of raw materials, greatly reduced usage of raw materials and catalysts, low cost and high yield, the obtained 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds have high quality, the synthesis method can be scaled up to hundreds of kilograms, and can provide high-quality and low-cost intermediate products for industries such as biomedicine and synthetic chemistry, thereby solving the current problems of unstable raw materials, large usage of catalysts, high prices, and unsuitability for large-scale production in the production of such compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings described herein are used to provide a further understanding of the present invention, constitute a part of the present application, and do not constitute an improper limitation of the present invention. In the drawings:

FIG1 is a one-dimensional H-NMR spectrum of the product of Example 1;

Fig. 2 is a mass spectrum of the product of Example 1;

FIG. 3 is a high performance liquid chromatogram of the product of Example 1.

Detailed ways

The present invention will be described in detail below in conjunction with the accompanying drawings and specific embodiments. The exemplary embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention.

The raw materials used in the present invention are all commercially available raw materials.

Unless otherwise specified, the reagents used in the present invention are all commonly used reagents purchased from the market, and the operating temperatures involved are all carried out at room temperature unless otherwise specified.

Example 1

The present embodiment provides a method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds, comprising the following steps: adding 3.0 L of acetonitrile to a reaction bottle 1, adding 174.2 g of morpholine, 290 g of 1,3,5-trifluorobenzene and 414 g of potassium carbonate in sequence under stirring, heating to reflux, reacting for 9 hours, filtering to remove insoluble matter, concentrating the filtrate to remove acetonitrile, and obtaining 302 g of 3,5-difluorophenylmorpholine with a yield of 76%.

Under an inert gas atmosphere, add 2.4 L of anhydrous tetrahydrofuran to reaction bottle 2, add 174 g of methyl 2,4-difluorobenzoate under stirring, cool to -65 °C, and drop 600 mL of 2.5 M n-butyl lithium for 2 hours. After the addition is complete, continue stirring at -65 °C for 1 hour. Then drop 256 g of liquid bromine, and the reaction temperature is maintained at -65 °C during the addition process. After the addition is complete, heat to zero degrees and drop saturated sulfurous acid aqueous solution until the reaction system is light yellow. Concentrate the reaction mixture to remove the solvent, extract the aqueous phase twice with 1.2 L of ethyl acetate, and concentrate to obtain 162 g of methyl 2,4-difluoro-3-bromobenzoate with a yield of 65%.

Under an inert gas atmosphere, add 1.8 L of anhydrous tetrahydrofuran to the reaction bottle 3, add 184 g of 3,5-difluorophenylmorpholine, cool to -55 ~ -65 °C, add 250 g of 2.5 M n-butyl lithium dropwise, keep warm for 1 hour after the addition is complete, add 220 g of zinc pivalate, raise the temperature to 20 ~ 25 °C and react for 30 min. After the reaction is qualified in the control, continue to add 113 g of methyl 2,4-difluoro-3-bromobenzoate, 5 g of Pd ₂ (dba) ₃ , and 9 g of X-Phos, raise the temperature to 50 ~ 60 °C and react. After the reaction is complete, add 460 g of ethyl acetate, 670 g of water, and 264 g of 2 M hydrochloric acid solution to the reaction solution, adjust the pH to 5 ~ 6, and add 460 g of ethyl acetate × 2 after phase separation for extraction. The organic phase is washed with 1000 g of saturated brine, 90 g anhydrous sodium sulfate, and concentrated under reduced pressure to distill off the solvent to obtain a solid crude product, which was purified by recrystallization from isopropyl ether to obtain 269.5 g of a pure product with a yield of 79%. ¹ H NMR (400 MHz, DMSO-d ⁶ ) δ 8.07 (td, J = 8.6, 6.5 Hz, 1H), 7.41 (td, J = 8.7, 1.2Hz, 1H), 6.91 – 6.80 (m, 2H), 3.87 (s, 3H), 3.77 – 3.69 (m, 4H), 3.28 (dd, J= 5.8, 4.0 Hz, 4H). MS: (m/z) 370[M+1]+, 411[M+MeCN+1]*

The molecular structure of the product is as follows:

.

As shown in Figure 1, it is a one-dimensional H-NMR spectrum of the product; as shown in Figure 2, it is a mass spectrum of the product; as shown in Figure 3, it is a high performance liquid chromatogram of the product.

Example 2

This embodiment provides a method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound, comprising the following steps:

The synthesis of N,N-dimethyl-3,5-difluoroaniline was carried out by referring to the synthesis method of 3,5-difluorophenylmorpholine in Example 1. The difference was that the starting material morpholine was changed to dimethylamine. The other reaction conditions were the same.

Under an inert gas atmosphere, add 2 L of anhydrous tetrahydrofuran to the reaction bottle 1, add 157 g of N,N-dimethyl-3,5-difluoroaniline, cool to -55 ~ -65 °C, add 2.5 M n-butyl lithium 271 g, keep warm for 1 hour after the addition, add 233 g of zinc pivalate, raise the temperature to 20 ~ 25 °C and react for 30 min. After the reaction is qualified, continue to add 121 g of methyl 2,4-difluoro-3-bromobenzoate, 5.2 g of Pd ₂ (dba) ₃ , 9.9 g of X-Phos, raise the temperature to 50 ~ 60 °C and react. After the reaction is completed, add 500 g of ethyl acetate, 700 g of water, and 270 g of 2 M hydrochloric acid solution to the reaction solution, adjust the pH to 5 ~ 6, and add ethyl acetate 500 g × 2 after phase separation for extraction. The organic phase is washed with 1000 g of saturated brine, 90 The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent to obtain a solid crude product, which was purified by recrystallization from isopropyl ether to obtain 219.3 g of a pure product with a yield of 67%.

The molecular structure of the product is as follows:

.

Example 3

This embodiment provides a method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound, comprising the following steps:

The synthesis of N,N-diethyl-3,5-difluoroaniline was carried out according to the synthesis method of 3,5-difluorophenylmorpholine in Example 1. The difference was that the starting material morpholine was changed to diethylamine. The other reaction conditions were the same.

Under an inert gas atmosphere, add 1.9 L of anhydrous tetrahydrofuran to the reaction bottle 1, add 185 g of N,N-diethyl-3,5-difluoroaniline, cool to -55~-65℃, add 280 g of 2.5 M n-butyl lithium dropwise, keep warm for 1 hour after the addition, add 267 g of zinc pivalate, raise the temperature to 20~25℃ and react for 30 min. After the reaction is qualified, continue to add 125 g of methyl 2,4-difluoro-3-bromobenzoate, 6.25 g of _Pd2 (dba) ₃ , and 11.8 g of X-Phos, raise the temperature to 50~60℃ and react. After the reaction is completed, add 500 g of ethyl acetate, 700 g of water, and 283 g of 2 M hydrochloric acid solution to the reaction solution, adjust the pH to 5~6, and add 500 g of ethyl acetate × 2 after phase separation for extraction. The organic phase is washed with 1000 g of saturated brine, 90 The crude product was purified by recrystallization from isopropyl ether to obtain 252 g of a pure product with a yield of 71%.

The molecular structure of the product is as follows:

.

Example 4

This embodiment provides a method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound, comprising the following steps:

The synthesis of 3,5-difluorophenylthiomorpholine is carried out in accordance with the method for synthesizing 3,5-difluorophenylmorpholine in Example 1. The difference is that the starting material morpholine is replaced with thiomorpholine. The other reaction conditions are the same.

Under an inert gas atmosphere, add 1.9 L of anhydrous tetrahydrofuran to the reaction bottle 1, add 215 g of 3,5-difluorophenylthiomorpholine, cool to -55 ~ -65 °C, add 292 g of 2.5 M n-butyl lithium dropwise, keep warm for 1 hour after the addition is complete, add 267 g of zinc pivalate, raise the temperature to 20 ~ 25 °C and react for 30 min. After the reaction is qualified in the control, continue to add 122 g of methyl 2,4-difluoro-3-bromobenzoate, 5 g of Pd ₂ (dba) ₃ , and 9 g of X-Phos, raise the temperature to 50 ~ 60 °C and react. After the reaction is complete, add 500 g of ethyl acetate, 700 g of water, and 271 g of 2 M hydrochloric acid solution to the reaction solution, adjust the pH to 5 ~ 6, and add 500 g of ethyl acetate × 2 after phase separation for extraction. The organic phase is washed with 1000 g of saturated brine, 88 The crude product was purified by recrystallization from isopropyl ether to obtain 289 g of a pure product with a yield of 75%.

The molecular structure of the product is as follows:

.

Example 5

This embodiment provides a method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound, comprising the following steps:

The synthesis of 2,4-difluoro-3-bromobenzophenone was carried out according to the synthesis method of methyl 2,4-difluoro-3-bromobenzoate in Example 1. The starting materials methyl 2,4-difluorobenzoate and n-butyl lithium were replaced with 2,4-difluoroacetophenone and lithium diisopropylamide, respectively. The other reaction conditions were the same.

Under an inert gas atmosphere, add 1.8 L of anhydrous tetrahydrofuran to the reaction bottle 1, add 184 g of 3,5-difluorophenylmorpholine, cool to -55 ~ -65 ° C, add 250 g of 2.5 M n-butyl lithium, keep warm for 1 hour after the addition, add 220 g of zinc pivalate, raise the temperature to 20 ~ 25 ° C and react for 30 min. After the reaction is qualified, continue to add 107 g of 2,4-difluoro-3-bromobenzophenone, 4.7 g of Pd ₂ (dba) ₃ , and 8.6 g of X-Phos, raise the temperature to 50 ~ 60 ° C and react. After the reaction is completed, add 450 g of ethyl acetate, 650 g of water, and 255 g of 2 M hydrochloric acid solution to the reaction solution, adjust the pH to 5 ~ 6, and add 450 g of ethyl acetate × 2 after phase separation for extraction. The organic phase is washed with 900 g of saturated brine. g, dried over 80 g of anhydrous sodium sulfate, concentrated under reduced pressure to distill off the solvent, and obtained a solid crude product. The crude product was recrystallized from isopropyl ether to obtain 205 g of a pure product with a yield of 58%.

The molecular structure of the product is as follows:

.

The technical solutions provided by the embodiments of the present invention are introduced in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the embodiments of the present invention. The description of the above embodiments is only applicable to help understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, according to the embodiments of the present invention, there will be changes in the specific implementation methods and application scopes. In summary, the content of this specification should not be understood as limiting the present invention.

Claims (10)

1. A method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds, characterized in that: The process includes: (1) firstly reacting 1,3,5-trifluorobenzene with a raw material _R1 to prepare a compound represented by formula I; (2) Under an inert gas atmosphere, preparing the compound represented by formula III into the compound represented by formula IV; (3) Under an inert gas atmosphere, preparing the compound represented by formula I into an organic zinc ester represented by formula II; (4) Under the action of a palladium catalyst and an organic phosphorus ligand, the organic zinc ester represented by Formula II and the compound represented by Formula IV undergo a coupling reaction to obtain a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound represented by Formula V. The reaction process is as follows: ; Wherein R ₁ is one of the following substituents: ; _R2 is substituted by one of the following compounds or substituents: methyl formate, ethyl formate, isopropyl formate, acetyl, nitro, cyano, dimethylformamide, diethylformamide; The compound shown in formula IV is one of the following: . 2. A method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to claim 1, characterized in that: The process includes: (1) adding _R1 raw material, 1,3,5-trifluorobenzene and potassium carbonate to a first solvent, heating and refluxing to prepare a compound represented by formula I; (2) Under an inert gas atmosphere, add the compound represented by formula III to the second solvent, cool down, add alkyl lithium, keep warm and stir, add liquid bromine, raise the temperature after the addition, and add saturated sulfurous acid aqueous solution dropwise until the reaction system turns light yellow to obtain the compound represented by formula IV; (3) Under an inert gas atmosphere, dissolving the compound represented by formula I in a second solvent, cooling to a low temperature, adding alkyl lithium to maintain the temperature for reaction, then adding zinc pivalate and heating to react to obtain the compound represented by formula II; (4) Adding the compound represented by formula IV, a palladium catalyst and an organic phosphorus ligand to the system obtained in step (3), and heating the mixture to react; after the reaction is completed, purifying the mixture to obtain the compound represented by formula V, i.e., a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound. 3. A method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to claim 2, characterized in that: The compound represented by formula V is one of the following: ; /> ; /> ; ; /> . 4. The method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to claim 2, characterized in that: The first solvent is acetonitrile; The second solvent is one or a mixture of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether and toluene; The alkyl lithium is any one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium and lithium diisopropylamide. 5. The method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to claim 2, characterized in that: In the step (1), the molar ratio of the _R1 raw material, 1,3,5-trifluorobenzene and potassium carbonate is 1.0: (1.0-1.5): (1.0-2.0); The temperature was raised to reflux for 9 hours. 6. A method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds according to claim 2, characterized in that: In the step (2), the amount of the second solvent used is 8 to 18 times the weight of the compound represented by formula III in terms of mL/g, the temperature is lowered to -65°C; the amount of alkyl lithium used is 1 to 3 times the molar number of the compound represented by formula III; the amount of liquid bromine used is 1 to 3 times the molar number of the compound represented by formula III; and the temperature is raised to 0°C. 7. The method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to claim 2, characterized in that: In the step (3), the volume of the second solvent is 8 to 18 times the weight of the compound represented by formula I, measured in mL/g, and the temperature is lowered to -78°C to -40°C; the amount of alkyl lithium used is 1 to 2 equivalents of the compound represented by formula I, the amount of zinc pivalate used is 1 to 2 equivalents of the compound represented by formula I, and the temperature is raised to 20 to 25°C for reaction for 30 minutes. 8. A method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to any one of claims 1 to 7, characterized in that: The palladium catalyst is any one of Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , and PdCl ₂ ; The amount of the palladium catalyst used is 0.05 to 0.5 equivalents of the compound represented by formula II; The organophosphorus ligand is any one of X-Phos, S-Phos, Ru-Phos, John-Phos, Cy-JohnPhos, and Me-Phos; The amount of the organophosphorus ligand used is 0.1 to 1 equivalent of the compound represented by formula II. 9. A method for synthesizing a 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compound according to any one of claims 1 to 7, characterized in that: In terms of molar ratio, the amount of the compound represented by formula I is 2-4 times the amount of the compound represented by formula VI. 10. The method for synthesizing 2,2',6,6'-tetrafluoro-[1,1'-biphenyl] compounds according to claim 2, characterized in that: The temperature-raising reaction in step (4) is to raise the temperature to 50-60°C for reaction.