KR20220132979A - Preparation method of biphenyl derivatives with a high yield - Google Patents

Abstract

The present invention relates to a method for producing biphenyl derivatives in high yield and high purity. The method for producing biphenyl derivatives according to the present invention comprises a process of removing a metal catalyst used in a homo-coupling reaction using an acidic solution, and thus a biphenyl derivative can be produced with better yield and selectivity compared to conventional methods, and safety problems can be solved by using a solvent with low risk during a nitration reaction.

Description

Method for preparing biphenyl derivatives in high yield {Preparation method of biphenyl derivatives with a high yield}

To a method for producing a biphenyl derivative in high yield, and to a method capable of producing a biphenyl derivative with high yield and selectivity by further comprising the step of removing a metal catalyst used in the preparation of the biphenyl derivative.

2,2-Bis(trifluoromethyl)benzidine (TFMB), which is used as a key raw material for polyimide films, is attracting attention as a material suitable for manufacturing transparent flexible displays. The preparation method is known as a benzidine rearrangement pathway. As a method for preparing the TFMB, conventionally, NiCl ₂ /Zn (JP 1994-094430 B2), CoBr ₂ /Mn (Chemistry-A European Journal, 2009, 15(19), 4770-4774), Cu (JP 2003- 044355 A) using a homo-coupling (Homo-coupling) method for producing a biphenyl derivative reacting has been reported, but there are problems such as intense reaction or hazardous waste is generated, yield and selectivity are low. In addition, a method for preparing a biphenyl derivative in which a Grignard reagent is produced using Mg and a metal catalyst (Fe derivative) is used for a coupling reaction as a catalyst has also been reported (JP 2008-255037), but this also yields There are problems in the improvement and refinement process.

In addition, the manufacturing method provided in JP 2008-255037 A includes a process of generating a Grignard reagent, which requires a separate initiator and has a fundamentally low reproducibility of Mg activation. In addition, when the -CF ₃ substituent is substituted on the phenyl group, an exothermic phenomenon due to the interaction between Mg and the -CF ₃ substituent has been reported (Organic Process Research & Development, 2006, 10(6), 1258), The reaction system is non-uniform due to the reaction between the Mg residue and the metal catalyst (Fe derivative), and there is a high possibility of problems such as stirring and filtration.

On the other hand, as a method for producing a nitro-biphenyl derivative, JP 2008-255037 A discloses a method of nitration using 1,2-dichloropropane (1,2-DCP). However, since 1,2-DCP is a hazardous substance with confirmed carcinogenicity and is a substance subject to legal regulations, its use in actual compound synthesis is limited, and high-risk fuming nitric acid is used to introduce nitro There is a problem that

The present invention solves the problems of the conventional biphenyl derivative production method as described above by confirming that the distillation purification yield can be significantly lowered if the residual catalyst is not easily removed after the homo-coupling reaction using a metal catalyst (Fe derivative) In the course of research for this purpose, it was confirmed that a production method capable of producing a biphenyl derivative in high yield and high purity and with low risk was found.

One object of the present invention is to provide a method for preparing a biphenyl derivative in high yield and high purity in a homo-coupling reaction through a Grignard reaction using a metal catalyst.

Another object of the present invention is to provide a method for preparing a nitro-biphenyl derivative using a low-risk solvent in order to solve the existing safety problem with respect to the solvent used for the nitration reaction of the biphenyl derivative. will do

In order to achieve the above object,

One aspect of the present invention is

After reacting the compound represented by Formula 1 with a Grignard reagent, homo-coupling under a metal catalyst to form a dimer represented by Formula 2; and

It provides a method for preparing a biphenyl derivative represented by Formula 2, including; removing the residual catalyst after the homo-coupling reaction.

[Formula 1]

,

,

[Formula 2]

,

,

wherein R ¹ is hydrogen or C _1-5 alkyl, wherein _one or more hydrogens substituted for the C _1-5 alkyl _may be substituted with halogen; and

wherein X is I, Br, Cl, or F.

Another aspect of the present invention is

The biphenyl derivative represented by Formula 2 prepared by the above method,

It provides a method for producing a biphenyl derivative represented by the following formula (3), comprising the step of nitration (Nitration) in DCM (Dicholoromethane) solvent.

[Formula 3]

Wherein R ¹ is as defined above.

The method for producing a biphenyl derivative according to the present invention further comprises a process of removing a metal catalyst used for a homo-coupling reaction using an acidic solution, thereby providing a biphenyl derivative with superior yield and selectivity than the conventional method. A phenyl derivative can be prepared, and since a solvent with low risk is used during the nitration reaction, the safety problem can be solved.

Hereinafter, the present invention will be described in detail.

On the other hand, the embodiment of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, "including" a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

The existing method for preparing biphenyl derivatives had limitations in low yield and high purification cost, and there was a problem of safety in that a solvent identified as a hazardous substance was used when introducing a nitro group. On the other hand, since the method for producing a biphenyl derivative provided in the present invention provides homo-coupling using a Grignard-Halide exchange reaction, the separate production process of the Grignard reagent is Since it is not necessary and further includes a process of removing the metal catalyst, a biphenyl derivative can be prepared in high yield and high purity, and 60% nitric acid with low risk is used for nitro group introduction, and at least instead of 1,2-DCP Using DCM (Dichloromethane) of DCM (Dichloromethane) can be used to prepare nitro-biphenyl derivatives while lowering the risk of the entire process.

One aspect of the present invention is

As a method for producing a biphenyl derivative in high yield and high purity

forming a dimer represented by Formula 2 by reacting the compound represented by the following Chemical Formula 1 with a Grignard reagent, followed by a homo-coupling reaction under a metal catalyst; and

It provides a method for preparing a biphenyl derivative represented by Formula 2, including; removing the residual catalyst after the homo-coupling reaction.

[Formula 1]

,

,

[Formula 2]

,

,

In this case, R ¹ may be hydrogen or C _{1-5 alkyl} , wherein at least one hydrogen substituted for the C _1-5 alkyl _may be substituted with halogen; and

X may be I, Br, Cl, or F.

In this case, R ¹ may be a straight-chain or branched C _1-5 alkyl, C _1-4 alkyl, _{C 1-3 alkyl} , _{C 1-2 alkyl ,} or C ₁ alkyl, _and the straight-chain or branched alkyl One or more hydrogens substituted in may be substituted with halogen.

The substitution of at least one hydrogen substituted for the alkyl with a halogen may be understood as meaning that a CH bond included in the alkyl may be substituted with a C-halogen bond. For example, in the present invention, through an embodiment, when R ¹ is C ₁ alkyl, all -H of C ₁ alkyl is substituted with -F (fluoro group), that is, when -CF ₃ is, the biphenyl derivative is high It was confirmed that it was prepared in yield and high purity.

The metal catalyst is not particularly limited as long as it is a metal catalyst that can be used in a homo-coupling reaction using a Grignard reagent, but for example, Fe, Al, Cr, Co, Ti, W, Si, Ir, Rh, Pt, Pd , Ru, Th, Ni, Cu, V, Au, Re, Zr or Mo. The metal catalyst may be used in a form combined with other atoms in a form that can be appropriately adopted and used by those skilled in the art.

The step of removing the residual catalyst,

The method may include adding and stirring an acidic solution to the dimer formed by the homo-coupling reaction, and then removing the aqueous layer.

In this case, the acidic solution may be nitric acid, sulfuric acid, citric acid, phosphoric acid, phosphonic acid, thiomalic acid, thiosalicylic acid, or 2,2'-dithiosalicylic acid, and as an acidic solution, it is not limited as long as it is a solution that removes the residual catalyst .

The concentration of the acidic solution may be 0.1 wt% to 10 wt%, for example, 0.5 wt% to 8 wt%, 1 wt% to 8 wt%, 0.5 wt% to 7 wt%, 1 wt% to 6 wt% %, 3 wt% to 7 wt%, 1 wt% to 5 wt% or 4 wt% to 6 wt%.

In addition, the step of removing the residual catalyst

It is not intended to be limited as long as it is a method capable of improving the yield and purity of the biphenyl derivative by removing the residual metal catalyst. The step of removing the catalyst may include filtering the homo-coupling reaction mixture, and the filtering step may include passing the reaction mixture through a pad or bed of adsorbent. In this case, a suitable adsorbent may be a chromatography gel or a finely ground silicon and/or aluminum oxide (including silicates, aluminates and/or aluminosilicates), or a membrane having a pore size of a certain size. It may be allowed to pass through or pass through a metal filter and/or a purification filter and/or resin. Alternatively, it may include a chemical treatment or the use of an iron remover. The method using the acidic solution may be understood as an example of the chemical treatment method.

In addition, after the step of removing the aqueous layer, the step of distilling under reduced pressure under the conditions of 100 ℃ to 200 ℃, 5 mbar to 20 mbar may be further included.

The reduced pressure distillation temperature condition may be 120 °C to 180 °C, 130 °C to 170 °C, 140 °C to 160 °C, or about 150 °C, and the present invention effectively removes residual iron at about 150 °C through an embodiment By doing so, it was confirmed that the biphenyl derivative can be prepared in high yield and high purity.

The reduced pressure distillation pressure condition may be 5 mbar to 18 mbar, 5 mbar to 15 mbar, 7 mbar to 13 mbar, 8 mbar to 12 mbar, or about 10 mbar, and the present invention is about 10 mbar through one embodiment It was confirmed that the biphenyl derivative can be prepared in high yield and high purity by effectively removing residual iron from

In the reaction solution after removing the residual catalyst, the metal catalyst may be present in an amount of 0.1 ppm or less. That is, the removal of the metal catalyst is not used in the sense of completely removing the metal catalyst present in the reaction solution. For example, the metal catalyst is about 5 ppm or less, 3 ppm or less in the reaction solution after the metal catalyst removal step. , 1 ppm or less, 0.1 ppm or less, 0.05 ppm or less, 0.005 ppm or less, or 0.001 ppm or less. In addition, the metal catalyst remaining in the reaction solution may be completely removed through the metal catalyst removal reaction.

Another aspect of the present invention is

The biphenyl derivative represented by Formula 2, prepared by the method according to the above,

It provides a method for preparing a biphenyl derivative represented by Formula 3, comprising the step of nitration in DCM (Dicholoromethane) solvent:

[Formula 3]

Wherein R ¹ is as defined above.

That is, the present invention provides a solvent that can replace 1,2-DCP, which is a previously used hazardous substance.

The biphenyl derivative represented by Formula 3 may be prepared by reducing the -NO ₂ group to -NH ₂ by a well-known reduction reaction after the nitration reaction.

The nitric acid used in the nitration reaction may have a concentration of about 80% or less, 75% or less, 70% or less, preferably 65% or less, and most preferably 60% or less.

The compound represented by Formula 3 may be TFMB (2,2'-Bis(trifluoromethyl)benzidine).

Hereinafter, Examples and Experimental Examples of the present invention will be specifically illustrated and described below. However, the Examples and Experimental Examples to be described below are merely illustrative of a part of the present invention, and the present invention is not limited thereto.

< Example 1> Homo-coupling (H omo -coupling) through the reaction biphenyl Method for producing derivatives in high yield

[Scheme 1]

Step 1: Homo-coupling reaction step

While maintaining a nitrogen atmosphere, 306 mL (0.61 mol) of 2M i-PrMgCl in THF (tetrahydrofuran, Tetrahydrofuran) was put into a double jacketed glass reactor of 2 L size at 10 ° C. was put in. 76 mL (125 g, 0.56 mol) of 2-bromobenzotrifluoride was slowly added while maintaining the temperature inside the reactor at 15°C. After stirring for 2 hours, FeCl ₃ in THF 325 mL (0.02 mol) was added to the inside of the reactor at room temperature. The reaction was terminated by stirring at an internal temperature of the reactor at 50 °C for 2 hours. Then, after cooling to 5 °C, 250 mL of 0.5 N HCl aqueous solution was slowly added, and then 250 mL of toluene and 250 mL of water were added, the layers were separated, the aqueous layer was discarded, washed twice with water, and then the organic layer was concentrated. .

Step 2: Removal of Residual Iron Catalyst

100 mL of aqueous phosphoric acid solution was added to the concentrated organic layer prepared in step 1 and stirred for 30 minutes. Then, the layer was separated, the aqueous layer was discarded, and the water washing process was repeated twice, and then distilled under reduced pressure at 150° C./10 mbar to obtain 44.3 g of a biphenyl derivative compound as a product. At this time, instead of using the aqueous phosphoric acid solution, biphenyl derivatives were prepared in the same manner by using each acidic solution having the concentration conditions according to Table 1 below, and the yield and purity of the prepared compound are shown in Table 1 below.

< comparative example 1>

From the concentrated organic layer prepared in the same manner as in Step 1 of Example 1, distillation was performed under reduced pressure to obtain 25.0 g of a biphenyl derivative compound as a product. The yield and purity of the prepared compound are shown in Table 1 below.

division Concentration (wt%) transference number (%) Purity (%) Comparative Example 1 - 31 48 Example 1 nitric acid
(Nitric acid) 1.0 35 60 5.0 37 65 sulfuric acid
(Sulfuric acid) 1.0 34 72 5.0 38 78 citric acid
(Citric acid) 1.0 42 88 5.0 45 92 phosphoric acid
(Phosphoric acid) 1.0 48 97 5.0 55 98 phosphonic acid
(Phosphonic acid) 1.0 45 95 5.0 54 95 Thiomalic acid
(Thomalic acid) 1.0 34 79 5.0 38 80 Thiosalicylic acid
(Thiosalicylic acid) 1.0 35 76 5.0 39 77 2,2'-dithiosalicylic acid
(2,2'-Dithiosalicylic acid) 1.0 40 81 5.0 41 80

As can be seen in Table 1, when the iron catalyst removal process was not included in Comparative Example 1 as in the prior art, the distillation purification yield was as low as about 31%, but according to Example 1, nitric acid, sulfuric acid, citric acid, phosphoric acid, phosphonic acid In the case of distillation under reduced pressure using an acidic solution such as phonic acid, thiomalic acid, thiosalicylic acid, or 2,2'-dithiosalicylic acid, all yields increased to about 35% or more, and in particular, citric acid, phosphoric acid, phosphonic acid, 2,2' -When dithiosalicylic acid was used, the yield was excellently increased to 40% or more, and when the concentration of phosphoric acid and phosphonic acid was increased to 5.0 wt%, it can be seen that the yield increased remarkably to about 55% or more.

Purity was also very low at 48% when the iron catalyst was not removed in Comparative Example 1 as before, but when an acidic solution was used according to Example 1, the purity was mostly increased to 70% or more, especially citric acid, When phosphoric acid and phosphonic acid were used, the purity was significantly increased to about 90% or more.

Through this, it was confirmed that when the iron catalyst was removed using an acidic solution, the purity and yield of the biphenyl derivative prepared through a homo-coupling reaction were significantly increased.

< Example 2> DCM under solvent nitrate (Nitration) Method for preparing nitro-biphenyl derivatives through reaction

[Scheme 2]

72 g of 60% nitric acid was added to a 500 mL round-bottom flask, cooled to 15 °C or less, and 253 g of 95% sulfuric acid was slowly added thereto, taking care not to exceed 25 °C, to prepare a mixed acid. After 15 mL of dichloromethane (DCM) was added to the mixed acid product, 50 g (0.17 mol) of the biphenyl derivative prepared in Example 1 was slowly added for 1 hour. After the addition, the temperature of the reactant was maintained at 25 °C and stirred for 1 hour, and then the temperature of the reactant was raised to 40 °C and stirred for 8 hours. When the reaction was completed, 200 mL of dichloromethane was added, stirred for 30 minutes, and the residual acid was removed through layer separation. The organic layer was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was removed. After removing dichloromethane by pesticides, it was crystallized with ethanol to obtain 46 g of a nitrobiphenyl derivative compound (yield 70%).

< comparative example 2> 1,2- DCP under solvent nitrate Nitro through reaction biphenyl Method for producing derivatives

36 g of a nitro-biphenyl derivative compound was obtained in the same manner as in Example 2, except that 1,2-dichloropropane (1.2-DCP) was used instead of dichloromethane (yield 55%).

As a result, it was confirmed that a nitrobiphenyl derivative could be prepared in a much superior yield when DCM (Example 2) was used than when 1,2-DCP (Comparative Example 2) was used as a solvent for the nitration reaction. could In addition, since 1,2-DCP is a compound that is legally regulated as a hazardous substance with confirmed carcinogenicity, it is more effective to use DCM as a solvent, which can produce nitrobiphenyl derivatives in a safer and higher yield. Able to know.

As mentioned above, although the present invention has been described in detail through preferred embodiments, the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (11)

forming a dimer represented by Formula 2 by reacting the compound represented by Formula 1 with a Grignard reagent and then performing a homo-coupling reaction under a metal catalyst; and
Removing the residual catalyst after the homo-coupling reaction; Method for producing a biphenyl derivative represented by Formula 2, including:
[Formula 1]

,
[Formula 2]

,

wherein R ¹ is hydrogen or C _1-5 alkyl, wherein _one or more hydrogens substituted for the C _1-5 alkyl _may be substituted with halogen; and
wherein X is I, Br, Cl, or F.
According to claim 1,
Wherein R ¹ is C _{1-2 alkyl} , wherein at least one hydrogen substituted for _the C _1-2 alkyl may be substituted with halogen.
According to claim 1,
The metal catalyst is selected from the group consisting of Fe, Al, Cr, Co, Ti, W, Si, Ir, Rh, Pt, Pd, Ru, Th, Ni, Cu, V, Au, Re, Zr and Mo A method for producing a biphenyl derivative comprising one or more metals.
According to claim 1,
The step of removing the residual catalyst,
After stirring by adding an acidic solution to the dimer formed by the homo-coupling reaction, the method for producing a biphenyl derivative comprising the step of removing the aqueous layer.
5. The method of claim 4,
The acidic solution is at least one selected from the group consisting of nitric acid, sulfuric acid, citric acid, phosphoric acid, phosphonic acid, thiomalic acid, thiosalicylic acid and 2,2'-dithiosalicylic acid, the method for producing a biphenyl derivative.
5. The method of claim 4,
The concentration of the acidic solution is 0.1 wt% to 10 wt%, the method for producing a biphenyl derivative.
5. The method of claim 4,
After removing the aqueous layer,
The method for producing a biphenyl derivative, further comprising the step of distillation under reduced pressure under conditions of 100 ℃ to 200 ℃, 5 mbar to 20 mbar.
According to claim 1,
The method for producing a biphenyl derivative, wherein the metal catalyst is present in 0.1 ppm or less in the reaction solution after the step of removing the residual catalyst.
The biphenyl derivative represented by Formula 2 prepared by the method according to claim 1,
Method for producing a biphenyl derivative represented by Formula 3, comprising the step of nitration in DCM (Dicholoromethane) solvent:
[Formula 3]

Wherein R ¹ is as defined in claim 1.
10. The method of claim 9,
Wherein R ¹ is C _{1-2 alkyl} , wherein at least one hydrogen substituted for _the C _1-2 alkyl may be substituted with halogen.
10. The method of claim 9,
A method for producing a biphenyl derivative, wherein the compound represented by Formula 3 is TFMB (2,2'-Bis(trifluoromethyl)benzidine).