RU2580107C1 - Method of producing 4-methoxybiphenyl by suzuki-miyaura reaction - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4-methoxy biphenyl using Suzuki-Miyaura reaction and can be used in chemical and pharmaceutical industries for producing bi-aryls, which are important intermediate products in synthesis of pharmaceutical preparations, ligands and polymers. Method involves reaction of 4-bromanizol and phenylboronic acid in solvent in presence of base and Pd/MN100 synthesized by impregnation of over above cross-linked polystyrene of MN100 grade with precursor, heating reaction mixture in gas atmosphere in molar excess of phenylboronic acid in relation to 4-bromanizol 1.5. At that, for process of impregnation precursor used is solution (CH₃CN)₂PdCl₂ in tetrahydrofurane impregnation is carried out at temperature from 20°C to 40°C, wherein content of palladium in catalyst ranges from 0.5 to 2 wt% using preliminarily milled MN100, amount of catalyst ranges from 0.5 to 1.5 mol% with respect to 4-bromanizol, as reaction solvent mixture of ethanol/water at ratio of 1:0 to 1:2 is used and, as base is NaOH, K₂CO₃ and Na₂CO₃ in amount of 1-2 mmol at temperature from 50 to 75°C for 10 min to 1 h in gas atmosphere of nitrogen or air.

EFFECT: proposed method allows to efficiently obtain end product with high technological effectiveness of process.

1 cl, 6 dwg, 7 tbl, 7 ex

Description

The invention relates to fine organic synthesis and can be used in the chemical and pharmaceutical industries for the production of biaryls, which are important intermediates in the synthesis of pharmaceuticals, ligands and polymers.

The invention describes a process for the synthesis of 4-methoxybiphenyl using the Suzuki-Miyaura cross-coupling reaction using a palladium catalyst based on hypercrosslinked polystyrene (ATP) functionalized with amino groups.

The Suzuki-Miyaura reaction is carried out at a temperature of from 10 to 200 ° C and a pressure of up to 100 bar (most often the pressure varies from atmospheric to 40 bar (US 20120116118, class C07C 51/353, C07C 51/363, C07C 51/377, 10.05 .2012).

Primary, secondary and tertiary amines (for example, alkylamines, dialkylamines, trialkylamines), which may be cyclic or open, are used as bases; alkali and alkaline earth metal salts of aliphatic and / or aromatic carboxylic acids (for example, acetates, propionates or benzoates); carbonates of alkali and alkaline earth metals, bicarbonates, phosphates, hydrophosphates and / or hydroxides; metal alkoxides (especially alkoxides of alkali and alkaline earth metals, such as sodium methoxide, sodium ethoxide, potassium methoxide, magnesium methoxide, calcium ethoxide, etc.). Preference is given to carbonates, hydroxides or phosphates of lithium, sodium, potassium, calcium, magnesium or cesium, in particular NaOH, KOH, K ₂ CO ₃ and Na ₂ CO ₃ . Also, fluorides, for example, CaF, NaF, KF, LiF, CsF, etc. (US 20120116118, class C07C 51/353, C07C 51/363, C07C 51/377, 05/10/2012) can be added to the reaction mixture.

The choice of solvent is important. Particular preference is given to the following solvents and mixtures thereof: tetrahydrofuran, dioxane, diethyl ether, diglyme, methyl tert-butyl ether, methyl tert-amyl ether, dimethyl ether, 2-methyltetrahydrofuran, acetonitrile, butyronitrile, toluene, xylene, anisole, these , isopropyl acetate, methanol, ethanol, propanol, butanol, ethylene glycol, ethylene carbonate, propylene carbonate, N, N-dimethylacetamide (DMA), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), water (US 20030181748, cl .S07B 37/04 09/25/2003). It is preferable to use organic solvent / water mixtures in ratios ranging from 2: 3 to 20: 1 depending on the type of catalyst and the reaction conditions (US 20030181748, CL C07B 37/04, 09/25/2003; Liu C, Ni Q., Bao F., Qiu J., Green chemistry, 13 (2011) 1260; Heidenreich RG, Kohler K., Krauter JGE, Pietsch J., Synlett, 7 (2002) 1118; US 20040254066, CL C07C 13/28, C07C 25/18, C07C 49/84, B01J 31/18, B01J 35/08, 12/16/2004; US 20090227740, class C08F 226/06, 09/10/2009; Phan NTS, Brown DH, Styring P., Tetrahedron Letters, 45 (2004) 7915; US 20040192542.cl. C07C 15/54, C07B 61/00, B01J 23/44, C07C 15/14, 09/30/2004; Choi K.-H., Shokouhimehr M., Sung Y.- E., Bulletin of the Korean Chemical Society, 34 (2013) 1477). From the point of view of ensuring the environmental safety of production, the preferred solvent is water (Huang L., Chen F., Wang Y., Wong PK, Physical chemistry, 3 (2013) 21), as well as its mixtures with ethanol, preferably in a 1: 1 ratio (Colacot TJ, Gore ES, Kuber A., Organometallics, 21 (2002) 3301; US 20130211106, CL B01J 23/44, 08/15/2013; Shokouhimehr M., Lee JE, Han SI, Hyeon T., Chemical Communications, 49 (2013) 4779).

To create an inert atmosphere, to prevent the destruction of the catalyst during the reaction, nitrogen or argon is used (US 20030181748, CL C07B 37/04, 09/25/2003).

Palladium complexes containing ligands based on phosphorus and nitrogen compounds, Pd salts (palladium acetate, palladium propionate, palladium acetylacetonate, palladium chloride, palladium bromide, palladium nitrate, bis (dibenzylideneacetone) palladium, tris (dibenzylidene) can be used as a source of palladium. , bis (acetonitrile) palladium dichloride, bis (benzonitrile) palladium dichloride, lithium tetrachloropalladate (II), palladium hydroxide. In this case, a ligand can be added to the salt (“Pd + ligand” system). Such a system can be obtained previously, shortly before the reaction, or the ligand is added separately directly to the reaction mixture (US 20120116118, class C07C 51/353, C07C 51/363, C07C 51/377, 05/10/2012).

In the absence of ligands, it is customary to speak of ligandless catalytic systems (Pan C. [et al.], Catalysis communication, 9 (2008) 321). Most often, Pd / C is used for the Suzuki-Miyaura reaction in industry (Sołoducho J. [et al.], Advances in Chemical Engineering and Science, 3 (2013) 19).

A known method of carrying out the Suzuki-Miyaura reaction using commercial Pd / C (E 105 O / W 5 wt.% Pd, Degussa-Hüls AG). The reaction is carried out in toluene, NMP, DMA, as well as in a toluene / water mixture (1: 1), at a temperature of 120 ° C, NaOH is used as a base, and bromobenzene is used as a substrate, the reaction time is 1 h, the catalyst concentration is 0.2 mol .%. The conversion is 2-95% (US 20030181748, CL C07B 37/04, 09/25/2003).

The disadvantage of this method is the high palladium content in the catalyst and the complete loss of the initial structure of the catalyst after a single use, which makes it impossible to reuse it in the Suzuki-Miyaura reaction.

A known method of carrying out the cross-coupling reaction of 4-bromotoluene and phenylboronic acid in the presence of a Pd / C-LSS catalyst (5.4 wt.% Pd). Reaction conditions: inert atmosphere (nitrogen), DMF solvent, temperature 95 ° C, base K ₂ CO ₃ , pH 10.6, reaction time 6 min, catalyst concentration 1 mol.%. The conversion of 4-bromotoluene is at least 95% (US 2013289321, CL C07C 1/26, 10/30/2013).

The disadvantage of this method is the high palladium content in the catalyst.

A known method of carrying out the cross-coupling reaction of bromobenzene and phenylboronic acid using a Pd (II) / MgO catalyst. Reaction conditions: solvent, DMA / water mixture (1: 1), temperature 50 ° C, inert atmosphere (argon), reaction time 1 h, catalyst concentration 0.2 mol%. The conversion is more than 80% in the first four reaction cycles (Huang L., Chen F., Wang Y., Wong P.K., Physical chemistry, 3 (2013) 21).

The disadvantage of this method is the low conversion of bromobenzene (not more than 88%).

A known method of carrying out the Suzuki-Miyaura reaction using Pd / TiO ₂ (5.2 wt.% Pd), synthesized by the method of impregnation. Reaction conditions: substrate - 4-bromotoluene, inert atmosphere (nitrogen), DMF solvent, K ₂ CO ₃ base, temperature 95 ° C, pH 10.6, stirring speed 210 rpm, reaction time 10 min, catalyst concentration 1 mol.% . The conversion of 4-bromotoluene is 100% (US 2014163283, CL C07C 1/32, 05/14/2014).

The disadvantage of this method is the high palladium content in the catalyst.

The prototype of the claimed invention is a method for producing 4-methoxybiphenyl by the Suzuki-Miyaura reaction between 4-bromoanisole and phenylboronic acid in the presence of a Pd / MN100 catalyst (3.75 wt.% Pd). The catalyst was synthesized by the method of impregnation of supercrosslinked polystyrene of the MN100 brand with an aqueous solution of PdCl ₂ precrocor followed by treatment with a solution of the base when heated to 80 ° C to precipitate palladium nanoparticles. The amount of catalyst is 2 mol% with respect to 4-bromoanisole. This reaction is carried out in a gaseous atmosphere of argon at a temperature of 100 ° C. The molar excess of phenylboronic acid with respect to 4-bromoanisole is 1.5. The reaction time is 5 hours. N, N-dimethylformamide (DMF), toluene or water are used as solvents. A phase transfer agent, tetra-n-butylammonium bromide (Bu ₄ NBr), is added to the reaction mixture. The base used is K ₃ PO ₄ or CS ₂ CO ₃ (1 mmol). The highest conversion of 4-bromoanisole (99%) is achieved in the case of DMF solvent and K ₃ PO ₄ base, as well as H ₂ O solvent and Cs ₂ CO ₃ base (Lyubimov SE [et al.], Reactive and Functional Polymers, 69 ( 2009) 755).

The main disadvantages of the prototype are the high reaction time at high temperature and a high percentage of catalyst relative to 4-bromoanisole, a high palladium content in the catalyst, and the need to use a phase transfer agent.

The objective of the invention is to develop a method for producing 4-methoxybiphenyl by the Suzuki-Miyaura reaction between 4-bromoanisole and phenylboronic acid in the presence of a Pd / MN100 catalyst, which reduces the reaction temperature, reduces the reaction time, reduces the percentage of catalyst relative to 4-bromanisole, and reduces palladium in the catalyst and the absence of the need for a phase transfer agent.

The technical result of the invention is to increase the manufacturability and efficiency of the process for producing 4-methoxybiphenyl.

The problem and the technical result are achieved by the fact that in the method for producing 4-methoxybiphenyl by the Suzuki-Miyaura reaction, comprising the interaction of 4-bromoanisole and phenylboronic acid in a solvent in the presence of a base and a Pd / MN100 catalyst synthesized by the method of impregnation of supercrosslinked polystyrene of the MN100 brand with a precursor, heating the reaction mixture in a gas atmosphere with a molar excess of phenylboronic acid with respect to 4-bromoanisole 1.5, according to the invention, for the impregnation process as a precursor a solution of (CH ₃ CN) ₂ PdCl ₂ in tetrahydrofuran is used, impregnation is carried out at a temperature of from 20 to 40 ° C, while the palladium content in the catalyst is from 0.5 to 2 wt.% using MN100, pre-ground, the amount of catalyst is from 0.5 to 1.5 mol% with respect to 4-bromoanisole, ethanol / water mixture in a ratio of 1: 0 to 1: 2 is used as a solvent for the Suzuki-Miyaura reaction, and NaOH, K ₂ CO ₃ and Na _{2 are used} as a base CO ₃ in an amount of from 1 to 2 mM at a temperature of from 50 to 75 ° C for 10 minutes to 1 hour in a nitrogen gas atmosphere or air.

The use of (CH ₃ CN) ₂ PdCl ₂ is due to the high affinity of this compound for the polymer matrix MN100 compared to PdCl ₂ . The combination of the precursor (CH ₃ CN) ₂ PdCl ₂ and the impregnation temperature from 20 to 40 ° C allows one to avoid the formation of nanoparticles and use the Pd / MN100 catalyst in the Suzuki-Miyaura reaction immediately after the impregnation. In the case of preliminary reduction of the catalyst in a stream of hydrogen at temperatures from 250 to 300 ° C, leading to the formation of palladium nanoparticles, the activity of the catalyst decreases, the reaction time increases by 1.5 times.

Pre-grinding of the MN100 before impregnation is necessary to increase the surface area of the catalyst available to the reagents and to remove intra-diffusion restrictions.

With a decrease in the palladium content in the catalyst of less than 0.5 wt.%, A sharp decrease in the degree of conversion of 4-bromoanisole occurs (the conversion is less than 60% for more than 5 hours of reaction), and an increase in the palladium content above 2 wt.% Is impractical, since it does not significantly increase the degree of 4-bromoanisole conversion during the reaction (from 10 minutes to 1 hour).

The amount of catalyst less than 0.5 mol.% Also leads to an increase in the duration of the reaction and a sharp decrease in the degree of conversion of 4-bromoanisole. Increasing the concentration of the catalyst more than 1.5 mol.% Is impractical.

When the reaction time is reduced to less than 10 minutes, the conversion of 4-bromoanisole is reduced to less than 70%, while an increase in the reaction time more than 1 hour is not required, since after this time the reaction practically stops (4-bromoanisole conversion remains almost constant).

With a decrease in temperature of less than 50 ° C, a decrease in the conversion of 4-bromoanisole is observed. A temperature above 75 ° C is unacceptable, since the process is carried out at atmospheric pressure, and the boiling point of ethanol is 78.4 ° C.

The use of K ₂ CO ₃ , Na ₂ CO ₃ or NaOH as bases in an amount of from 1 to 2 mmol leads to the achievement of the degree of conversion of 4-bromoanisole above 75%. It is preferable to use NaOH in an amount of 1.5 mmol, which allows to achieve the conversion of 4-bromoanisole above 97%. A decrease in the amount of NaOH below 1 mmol leads to a decrease in the degree of conversion of 4-bromoanisole to 79%. An increase in the amount of NaOH to 2 mmol is impractical, since it does not lead to a further increase in the degree of conversion of 4-bromoanisole in comparison with the amount of NaOH 1.5 mmol.

The invention is illustrated by drawings, where in FIG. 1 shows the time dependence of 4-bromoanisole conversion with varying nature of the base; FIG. 2 shows the time dependence of the conversion of 4-bromoanisole with varying reaction temperatures; FIG. 3 - time-dependent conversion of 4-bromoanisole with varying catalyst concentration, FIG. 4 shows the time dependence of 4-bromoanisole conversion with varying base concentration, FIG. 5 shows the time dependence of 4-bromoanisole conversion with varying gas phase composition; FIG. 6 - dependence of the conversion of 4-bromoanisole on time with varying solvent composition.

The method for producing 4-methoxybiphenyl by the Suzuki-Miyaura reaction is illustrated by the following examples.

Example 1

The Suzuki-Miyaura reaction between 4-bromoanisole (1 mmol) and phenylboronic acid (1.5 mmol) using Pd (II) / MN100 (2 wt% Pd) as a catalyst, synthesized by the method of impregnation of pre-ground supercrosslinked polystyrene of brand MN100 with a solution (CH ₃ CN) ₂ PdCl ₂ in tetrahydrofuran at a temperature of from 20 to 40 ° C, followed by treatment with an aqueous solution of the base. In a thermostatic reactor, 50 mg of catalyst was introduced, which corresponds to 1 mol.% Concentration with respect to 4-bromoanisole, 30 ml of an ethanol / water mixture at a ratio of 5: 1, as well as K ₂ CO ₃ , Na ₂ CO ₃ or NaOH in an amount of 1.5 mmol. The reaction mixture was heated in a nitrogen gas atmosphere at a temperature of 70 ° C. The reaction time was 55 minutes.

In table 1 and in FIG. Figure 1 shows data on the time dependence of 4-bromoanisole conversion with varying nature of the base.

Based on table 1 and FIG. 1 it can be concluded that with an increase in base strength, an increase in the degree of conversion of 4-bromoanisole occurs. The maximum degree of conversion of 4-bromoanisole (97.1%) is achieved during the reaction time of 55 min in the case of using NaOH as the base.

This is explained by the fact that the base plays a multiple role, accelerating two limiting stages (trans-metallization and reductive elimination) and, at the same time, limiting the formation of unreactive anions. Thus, increasing the concentration of OH ^- , you can increase the completeness of the conversion of 4-bromoanisole.

Thus, the use of a strong base (NaOH) allows under milder conditions (70 ° C) using a half-concentration of the catalyst with a lower palladium content compared with the prototype in a relatively short time to achieve a degree of 4-bromanisole conversion of more than 97%.

Example 2

The example was carried out similarly to the above example, but the palladium content in the catalyst was varied from 0.5 to 2.0% (the amount of catalyst was 50 mg in all cases). As the base, Na ₂ CO _{3 was} added in an amount of 1.5 mmol.

Table 2 shows the data on the conversion of 4-bromoanisole with varying palladium content in the catalyst.

Based on table 2, we can conclude that with an increase in the palladium content, the degree of conversion of 4-bromoanisole increases.

Example 3

The example was carried out similarly to the above example, but the temperature was varied from 50 to 75 ° C. 1.5 mmol Na ₂ CO _{3 was} added as a base, and Pd (II) / MN100 (2 wt% Pd) as a catalyst.

In table 3 and in FIG. 2 shows data on the effect of temperature on the degree of conversion of 4-bromoanisole to 4-methoxybiphenyl.

Based on table 3 and FIG. 2, we can conclude that with a decrease in temperature to 50 ° C, a noticeable decrease in the degree of conversion of 4-bromoanisole is observed, while an increase in temperature to 60 ° C and higher allows a conversion of> 95% to be achieved during a reaction time of 55 min. Moreover, the behavior of the catalyst in the selected temperature range of 60-75 ° C remains virtually unchanged, which allows us to recommend 60 ° C as the optimum temperature (the degree of 4-bromanisole conversion equal to 96.5% is achieved).

Thus, the use of the synthesized catalyst Pd (II) / MN100 (2 wt.% Pd) provides the technical result of the invention by reducing the reaction temperature of the synthesis of 4-methoxybiphenyl by 40 ° C compared with the prototype.

Example 4

The example was carried out similarly to the above example, but the reaction was carried out at a temperature of 60 ° C. The concentration of the catalyst ranged from 0.5 to 1.5 mol% with respect to 4-bromoanisole.

In table 4 and in FIG. 3 shows data on the effect of catalyst concentration on the degree of conversion of 4-bromoanisole to 4-methoxybiphenyl.

Based on table 4 and FIG. 3, we can conclude that with an increase in the concentration of the catalyst from 0.5 to 1 mol%, an increase in the degree of conversion of 4-bromoanisole is observed from 94% to 95.5%. A further increase in the concentration of the catalyst to 1.5 mol.% Does not lead to an increase in the degree of conversion of 4-bromoanisole and therefore is not advisable.

Thus, a two-fold decrease in the concentration of the catalyst is achieved in comparison with the prototype, which fully meets the objectives of the invention.

Example 5

The example was carried out similarly to the above example, but NaOH in an amount of 1 to 2 mmol was added as the base. The concentration of the catalyst was 1 mol.% In relation to 4-bromoanisole.

In table 5 and in FIG. 4 shows data on the effect of NaOH concentration on the degree of conversion of 4-bromoanisole to 4-methoxybiphenyl.

Based on table 5 and FIG. 4, we can conclude that with a decrease in the amount of NaOH from 1.5 to 1.0 mmol, a decrease in the degree of conversion of 4-bromoanisole from 98.1% to 79.3% is observed. An increase in the amount of NaOH to 2 mmol does not cause a significant increase in the conversion rate of 4-bromoanisole. Thus, 1.5 mmol of NaOH can be considered the optimal amount.

Example 6

The example was carried out similarly to the above example, but the composition of the atmosphere was varied: nitrogen, hydrogen, air were used. As the base, NaOH was added in an amount of 1.5 mmol.

In table 6 and in FIG. 5 shows data on the effect of the composition of the gas atmosphere on the degree of conversion of 4-bromoanisole to 4-methoxybiphenyl.

Based on table 6 and FIG. 5, we can conclude that when replacing an inert atmosphere of nitrogen with air, there is a slight decrease in the degree of conversion of 4-bromoanisole from 98.1% to 96.3%. Whereas the use of a reducing atmosphere of hydrogen leads to a sharp decrease in the degree of conversion of 4-bromoanisole by almost 4 times compared with an inert atmosphere. This is due to the fact that the use of hydrogen leads to the rapid reduction of palladium and its deposition in the form of nanoparticles, i.e., to a decrease in the stability in solution of molecular forms of palladium formed in situ, which are responsible for the observed catalytic activity in the synthesis of 4-methoxybiphenyl.

Example 7

The example was carried out similarly to the above example, but the solvent composition was varied. The solvent used was a mixture of ethanol / water in a ratio of from 1: 0 to 1: 2. The reaction was carried out in an inert atmosphere (nitrogen).

In table 7 and in FIG. 6 shows data on the effect of solvent composition on the degree of conversion of 4-bromoanisole to 4-methoxybiphenyl.

Based on table 7 and FIG. 6 we can conclude that the use of pure ethanol as a solvent leads to a sharp decrease in the degree of conversion of 4-bromoanisole, while the addition of water in an insignificant amount (ethanol / water ratio = 5: 1) allows to increase the degree of conversion of 4-bromoanisole to 98.1%. Moreover, a further increase in the water content in the mixture negatively affects the degree of conversion of 4-bromoanisole. It is important to note that water and its mixtures with ethanol are preferable from the point of view of ensuring the environmental safety of production. In addition, the use of a mixed solvent avoids the need to add a phase transfer agent to the reaction mixture.

The presented examples of the implementation of the proposed method confirm that the proposed method for producing 4-methoxybiphenyl by the Suzuki-Miyaura reaction can improve the manufacturability and efficiency of the process for producing 4-methoxybiphenyl by halving the concentration of the catalyst at a lower palladium content in it, and lowering the temperature of the synthesis reaction by 40 ° C a significant reduction in the time of the process (5 times) compared with the prototype with almost the same values of the degree of conversion of 4-bromoanisole. In addition, a decrease in the metal content in the catalyst and the possibility of its multiple use leads to a reduction in the cost of the resulting product.

Currently, the method is at the stage of laboratory experiments.

Claims (1)

A method for producing 4-methoxybiphenyl by the Suzuki-Miyaura reaction, comprising reacting 4-bromoanisole and phenylboronic acid in a solvent in the presence of a base and a Pd / MN100 catalyst synthesized by impregnation of supercrosslinked polystyrene of the MN100 grade with a precursor, heating the reaction mixture in a gas atmosphere with a molar excess of phenylboron acid relative to 4-bromoanisole 1.5, characterized in that for impregnation process as a precursor, a solution (CH ₃ CN) ₂ PdCl ₂ in THF, impregnation is carried out at temperature from 20 to 40 ° C, while the palladium content in the catalyst is from 0.5 to 2 wt.% using MN100, pre-crushed, the amount of catalyst is from 0.5 to 1.5 mol.% in relation to 4-bromoanisole, as a reaction solvent Suzuki Miyaura use a mixture of ethanol / water in a ratio of 1: 0 to 1: 2, and NaOH, K ₂ CO ₃ and Na ₂ CO ₃ in an amount of 1 to 2 mmol at a temperature of 50 to 75 ° C as the base. for 10 minutes to 1 hour in a gaseous atmosphere of nitrogen or air.

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