JP2002284768A - Method for producing phenylpyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method for obtaining a 2-phenylpyrimidine derivative in good yield. SOLUTION: The 2-phenylpyrimidine derivate can inpexpensively be produced in a high yield by reacting a pyrimidine compound having a leaving group at the 2-position and optionally a substituent, with a phenylboronic acid optionally having a substituent in a solvent consisting essentially of an alcoholic solvent in the presence of a palladium-based or nickel-based catalyst and a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the production of 2-phenylpyrimidine derivatives useful as electronic materials and functional materials such as liquid crystal display materials and the like, as medicines, agrochemicals, fragrances, various additives and synthetic intermediates thereof.

[0002]

2. Description of the Related Art 2-Phenylpyrimidine derivatives are useful as electronic materials and functional materials such as liquid crystal display materials, as well as medicines, agricultural chemicals, fragrances, various additives and synthetic intermediates thereof.
A liquid crystal material having a 2-phenylpyrimidine skeleton is important because it exhibits characteristic physical properties. As a method for synthesizing a pyrimidine compound, the following method is generally known.
(Seniwa Sorin, liquid crystal material, p235, Kodansha)

[0003]

Embedded image However, this synthesis method has many steps and the yield is not high. Therefore, a method using 2-halogenopyrimidines as a raw material has come to be used at present. For example, a 5-alkyl-2-phenylpyrimidine can be obtained by reacting a 5-alkyl-2-chloropyrimidine with an aryl Grignard reagent in the presence of a palladium or nickel catalyst. However, the yield is not high, only around 60%. Therefore, a method using a phenylboric acid reagent instead of an aryl Grignard reagent is also being studied, but under general conditions, that is, as a solvent, a mixed solvent of toluene, ethanol and 2N
Potassium carbonate solution (NMAli et al., Tetra
hedron, 48 , 8117) did not improve the yield, and higher production conditions were required.

[0004]

An object of the present invention is to provide a low-yield, high-yield production method for obtaining a 2-phenylpyrimidine derivative.

[0005]

Means for Solving the Problems As a result of diligent studies to solve the above-mentioned problems, the present invention has found that a chlorine atom at the 2-position which may have a substituent in a solvent mainly containing an alcohol solvent. A pyrimidine compound having a leaving group such as an atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group and a phenylboric acid which may have a substituent are reacted in the presence of a palladium-based or nickel-based catalyst and a base. By doing so, they found that a 2-phenylpyrimidine derivative could be produced in good yield and at low cost, and completed the present invention.

[0006]

DETAILED DESCRIPTION OF THE INVENTION As described above, for the production of a 2-phenylpyrimidine derivative, the reaction can be carried out under the following conditions.

In this reaction, an alcohol-based solvent is mainly used as a reaction solvent, and the organic solvent is methanol, ethanol, 1-propanol, 2-propanol, or 1-propanol.
Butanol and 2-butanol are preferred, and these alcohol solvents can be used alone or as a mixture, but ethanol is particularly preferred. The content is preferably 60 to 100% by mass based on the whole solvent, particularly 90% by mass.
It is preferred that the content be at least 50% by mass. Other solvents include water or 1,2-dichloroethane, a halogenated solvent such as 1,1,1-trichloroethane, methyl-t-butyl ether,
Ethers such as tetrahydrofuran and 1,4-dioxane,
Esters such as ethyl acetate, methyl acetate, and butyl acetate;
Saturated hydrocarbons such as pentane, hexane, heptane, and octane; benzenes such as benzene, toluene, xylene, and chlorobenzene; and amides such as N, N-dimethylformamide and N, N-dimethylacetamide alone or in combination. Although it can be used, water, tetrahydrofuran, toluene or xylene is preferred.

The base used in this reaction is not particularly limited, but inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate and the like are preferable. Sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide are more preferred, and sodium carbonate or potassium carbonate is particularly preferred.

The catalyst used in this reaction is tetrakis
(Triphenylphosphine) palladium, dichlorobis
(Triphenylphosphine) palladium, dichloro [bis
(Diphenylphosphino) ethane] palladium, dichloro
[Bis (diphenylphosphino) propane] palladium, dichloro [bis (diphenylphosphino) butane] palladium, dichloro [bis (diphenylphosphino) ferrocene]
Palladium complexes such as palladium, tetrakis (triphenylphosphine) nickel, dichlorobis (triphenylphosphine) nickel, dichloro [bis (diphenylphosphino) ethane] nickel, dichloro [bis (diphenylphosphino) propane] nickel, dichloro [bis ( Nickel complexes such as diphenylphosphino) butane] nickel and dichloro [bis (diphenylphosphino) ferrocene] nickel can be mentioned, but palladium complexes are preferred.

In the pyrimidine compound which may have a substituent and has a leaving group at the 2-position, the substituent is not particularly limited, but the compound represented by the general formula (II)

Embedded image Is preferably represented by In the general formula (II), ^Ra is an alkyl group having 1 to 20 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms or an alkenyloxy group having 2 to 20 carbon atoms. Represents an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms or 2 to carbon atoms.
10 alkenyloxy groups are preferred, especially 1 carbon atom
Alkyl group of 6 to 6, alkoxyl group having 1 to 6 carbon atoms,
An alkenyl group having 2 to 6 carbon atoms or an alkenyloxy group having 2 to 6 carbon atoms is preferred. Y represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group, preferably a chlorine atom or a bromine atom.

The phenylboric acid which may have a substituent is not particularly limited, but may be represented by the general formula (III)

[0012]

Embedded image Is preferably represented by In the general formula (III), R ^b
Represents an alkyl group having 1 to 20 carbon atoms,
-20 alkoxyl group, C2-20 alkenyl group, C2-20 alkenyloxy group, cyano group which may be protected, trifluoromethyl group, trifluoromethoxy group, difluoromethoxy group, Represents a 2,2,2-trifluoroethoxy group, a hydroxy group which may be protected, a carboxyl group which may be protected, a fluorine atom, a chlorine atom or a hydrogen atom, and has 1 to 10 carbon atoms.
An alkoxyl group, an alkenyl group having 2 to 10 carbon atoms,
An alkenyloxy group having 2 to 10 carbon atoms, an optionally protected cyano group, a trifluoromethyl group, a trifluoromethoxy group, a difluoromethoxy group, a 2,2,2-trifluoroethoxy group, which may be protected; Good hydroxy group,
A carboxyl group which may be protected, a fluorine atom, a chlorine atom or a hydrogen atom is preferable, particularly an alkoxyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an alkenyloxy having 2 to 6 carbon atoms. Preferred are a group, an optionally protected cyano group, a trifluoromethyl group, a trifluoromethoxy group, a difluoromethoxy group, a fluorine atom or a hydrogen atom. R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, preferably a hydrogen atom. X ¹ , X ² and X ³ each independently represent a hydrogen atom or a fluorine atom,
Preferably, ¹ is a fluorine atom, and particularly preferably, X ¹ and X ² are both fluorine atoms. A is a single bond, 1,4
Represents a cyclohexylene group or a 1,4-phenylene group which may be substituted by 1 to 4 fluorine atoms, preferably a single bond.

Thus, a 2-phenylpyrimidine derivative can be obtained.

Embedded image

Preferably, in the general formula (I),

Embedded image (In the formula, R ^c and R ^d represent an alkyl group having 1 to 6 carbon atoms.) The compounds represented by (I-1) to (I-9) are preferable.

[0015]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Synthesis of 5-propyl-2- (3,5-difluorophenyl) pyrimidine 79 g of 2-chloro-5-propylpyrimidine and 104 g of 3,5-difluorophenylboric acid were dissolved in 320 ml of ethanol. , 105 g of anhydrous potassium carbonate and 12 g of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated under reflux for 8 hours. The solvent was distilled off under reduced pressure, 400 ml of toluene was added, and water and
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: toluene) to obtain 116 g of 5-propyl-2- (3,5-difluorophenyl) pyrimidine (98% yield).

Comparative Example 1 Synthesis of 5-propyl-2- (3,5-difluorophenyl) pyrimidine (Example using Grignard reagent) 13.5 g of magnesium was suspended in 27 ml of tetrahydrofuran, and 3,5-difluoro A solution of 117 g of 1-bromobenzene in 450 ml of tetrahydrofuran was added dropwise at a rate at which tetrahydrofuran was gently refluxed, and the mixture was further stirred at room temperature for 1 hour to prepare a Grignard reagent. 79 g of 2-chloro-5-propylpyrimidine was dissolved in 320 ml of tetrahydrofuran, 12 g of tetrakis (triphenylphosphine) palladium (0) was added, and the Grignard reagent prepared above was added dropwise at room temperature.
The mixture was further heated to reflux for 8 hours. 90 ml of 10% hydrochloric acid and 300 ml of water
Was added, extracted with 400 ml of toluene, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: toluene) to obtain 74 g of 5-propyl-2- (3,5-difluorophenyl) pyrimidine (yield: 63%).

(Comparative Example 2) Synthesis of 5-propyl-2- (3,5-difluorophenyl) pyrimidine (general synthesis example using phenylboric acid) 79 g of 2-chloro-5-propylpyrimidine and 3,5- 104 g of difluorophenylboric acid in 160 ml of ethanol and toluene 3
Dissolved in 20 ml, added 320 ml of 2N aqueous potassium carbonate solution and 12 g of tetrakis (triphenylphosphine) palladium (0)
The mixture was heated to reflux for 8 hours. Cool to room temperature, toluene 200ml
Was added, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent: toluene).
80 g of 2- (3,5-difluorophenyl) pyrimidine (68% yield)
I got

[0019]

According to the manufacturing method provided by the present invention, an electronic material such as a liquid crystal display material, a functional material, a medical and agricultural chemical, a fragrance,
Compounds having a 2-phenylpyrimidine skeleton, which are useful as various additives and synthetic intermediates thereof, can be produced in good yield and at low cost.

Claims (5)

[Claims] 1. A pyrimidine compound optionally having a substituent, a leaving group at the 2-position, and a phenylboric acid optionally having a substituent in a solvent mainly comprising an alcohol solvent. Is reacted in the presence of a transition metal catalyst and a base, to produce a 2-phenylpyrimidine derivative. 2. A compound of the general formula (I) (Wherein, ^Ra is an alkyl group having 1 to 20 carbon atoms,
Represents an alkoxyl group having 1 to 20, an alkenyl group having 2 to 20 carbon atoms or an alkenyloxy group having 2 to 20 carbon atoms, R
^b is an alkyl group having 1 to 20 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkenyloxy group having 2 to 20 carbon atoms, optionally protected cyano Group, trifluoromethyl group, trifluoromethoxy group, difluoromethoxy group, 2,2,2-trifluoroethoxy group, optionally protected hydroxy group, optionally protected carboxyl group, fluorine atom, chlorine atom Or represents a hydrogen atom, X ¹ , X ² , X ³ each independently represents a hydrogen atom or a fluorine atom, A is a single bond, 1,4-
Represents a cyclohexylene group or a 1,4-phenylene group which may be substituted with 1 to 4 fluorine atoms. A method for producing a compound represented by the general formula (II): (Wherein, ^Ra represents the same meaning as in the general formula (I), and Y represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group) and a compound of the general formula (II
I) (Wherein, R ^b and A represent the same meaning as in the general formula (I), and R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.) 2. The production method according to claim 1, wherein the reaction is carried out in a solvent mainly containing an alcohol solvent in the presence of a base. 3. The method according to claim 1, wherein the transition metal catalyst is palladium or nickel. 4. An alcohol-based solvent as the solvent.
4. The production method according to claim 1, wherein the content is 100% by mass. 5. The method according to claim 1, wherein ethanol is used as the alcohol solvent.