JPH0720937B2 - Process for producing 2-aryl-5-halogenopyridine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a 2-aryl-5-halogenopyridine derivative.

[Prior Art] Conventionally, as a method for producing a 2-aryl-5-halogenopyridine derivative, a reaction between an aryllithium derivative and pyridine is carried out, There is known a method for producing (see, for example, JP-A-63-174973).

[Problems to be Solved by the Invention] However, the above-mentioned production method has problems that the synthesis route is long and the yield is not high.

[Means for Solving the Problems] The present inventors have solved the above problems and obtained a 2-aryl-5-halogenopyridine derivative in high yield with a shorter synthetic route than conventional methods. As a result of intensive studies aimed at, the present invention has been achieved.

That is, the present invention has the general formula [In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, Represents a 2,5-pyridylene group] and a general formula RYA-Mg-X ¹ (2) [wherein, R represents an alkyl group having 1 to 18 carbon atoms (the alkyl group). 1 or 2 CH ₂ is an O atom, an S atom or -CH
2 O atoms or S atoms may be replaced by those not directly bonded to each other by a group selected from the group consisting of = CH-), X ¹ is a chlorine atom, a bromine atom or an iodine atom. , A is a 1,4-phenylene group or 4,4′-biphenylene group in which some or all of the hydrogen atoms of the aromatic ring may be substituted with fluorine atoms or chlorine atoms,
Y represents -O-, -S-, -C≡C- or a direct bond] with a compound represented by a formula (I) in the presence of a zero-valent or divalent palladium catalyst or a zero-valent or divalent nickel catalyst. General formula characterized by ringing [In the formula, R is an alkyl group having 1 to 18 carbon atoms (in the alkyl group, 1 or 2 CH ₂ is an O atom, an S atom, and -CH
Two O atoms or S atoms may be replaced by those selected from the group consisting of = CH- as not directly bonded to each other), Is a 2,5-pyridylene group, X is a chlorine atom, a bromine atom or an iodine atom, and A is a hydrogen atom of an aromatic ring, part or all of which may be substituted with a fluorine atom or a chlorine atom.
-Phenylene group or 4,4'-biphenylene group, Y is-
O-, -S-, -C [identical to] C- or a direct bond] is a process for producing a 2-aryl-5-halogenopyridine derivative.

The compound represented by the general formula (1) is not particularly limited, but preferred are 2,5-dibromopyridine,
2,5-dichloropyridine and the like can be mentioned.

In the general formulas (2) and (3), the number of carbon atoms showing R is 1 to 18
Examples of the alkyl group include ethyl group, n-propyl group, n
-Butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tetradecyl group, n -Hexadecyl group, n-octadecyl group and the like.

Of these, preferred is an alkyl group having 2 to 14 carbon atoms.

Among the 1,4-phenylene group or 4,4'-biphenylene group in which some or all of the hydrogen atoms of the aromatic ring represented by A may be substituted with a fluorine atom or a chlorine atom, preferred is 1 of the aromatic ring. Hydrogen atom is a 1,4-phenylene group or 4,4'-biphenylene group optionally substituted with fluorine atoms.

Specific examples of the compound represented by the general formula (2) are shown in Table-
Examples thereof include compounds having a group as shown in 1.

Specific examples of the compound represented by the general formula (3) are shown in Table-
Examples thereof include compounds having a group as shown in 2.

In Table-1 and Table-2, each symbol represents the following groups.

BUT; nC ₄ H ₉ -HEX; nC ₆ H ₁₃ -OCT; nC ₈ H ₁₇ -The compound contained in the general formula (2) can be synthesized, for example, through the following steps (wherein X ¹ , Y, A and R are the same as in the case of the general formula (2)).

 When Y is a direct bond.

That is, the compound of the general formula (2a) can be obtained by reacting the compound of the general formula (4) with magnesium metal.

 When Y is -O- or -S-.

That is, the compound of general formula (5) is reacted with an alkylating agent of general formula (6) (for example, an alkyl halide) in the presence of a base (for example, sodium hydroxide) to obtain a compound of general formula (7).

The compound of general formula (2b) can be obtained by reacting the compound of general formula (7) with magnesium metal.

 When Y is -C≡C-.

That is, by reacting the compound of the general formula (8) with the compound of the general formula (9) in triethylamine under an inert gas atmosphere using a zero-valent or divalent palladium catalyst and copper iodide, The compound of 10) is obtained.

The compound of general formula (2c) can be obtained by reacting the compound of general formula (10) with magnesium metal.

By cross-coupling the compound of general formula (1) and the compound of general formula (2) in the presence of a zero-valent or divalent palladium catalyst or a zero-valent or divalent nickel catalyst, The compound 2-aryl-5
A halogenopyridine derivative is obtained.

In the present invention, the cross coupling reaction is usually performed in the presence of a solvent. Examples of the solvent used in this reaction include aprotic solvents such as diethyl ether, tetrahydrofuran, dioxane, glyme and diglyme. Of these, preferred are diethyl ether and tetrahydrofuran.

The amount of the solvent used is 2 to 100 times by weight, preferably 3 to 20 times by weight that of the compound of the general formula (2).

The zero-valent or divalent palladium catalyst or the zero-valent or divalent nickel catalyst used in this cross-coupling reaction can be represented by the following general formula.

L ₂ M (2) Q ₂ , L ² M (2) Q ₂ , L ₄ M (0) orM (2) Q ₂ (11) [wherein M (2) is divalent palladium or divalent Nickel and M (0) represents zero-valent palladium or zero-valent nickel. L represents a ligand having one Z '(phosphorus atom, arsenic atom or antimony atom) in one molecule, and L ² represents a ligand having ^two Z'in one molecule. Q is chlorine atom, bromine atom, iodine atom, -OOCCH
₃ groups, -OOCC ₂ H ₅ group, -OOCC ₃ H ₇ group, -OOCC ₄ H ₉ group or -OC (CH ₃ = CHCOCH ₃ group. In the reaction system, L ₂ M (2) Q ₂ or L If even a small amount of ² M (2) Q ₂ is formed, L and M (2) Q ₂ or L ² and M (2) Q ₂ can be added separately and at an arbitrary ratio. L + M (2) Q ₂ or L ² + M (2) Q ₂ ) is also L ₂
It has the same meaning as M (2) Q ₂ or L ² M (2) Q ₂ . In the palladium catalyst or nickel catalyst represented by the above general formula, palladium is preferable among M.

Examples of the ligand L include (CH ₃ ) ₃ P, (C ₂ H ₅ ) ₃ P, (CH ₂ = CHCH ₂ ) ₃ P, (C ₃ H ₇ ) ₃ P, (C ₄ H ₉ ) ₃ P, (C ₅ H ₁₁ ) ₃ P, (C ₆ H ₁₃ ) ₃ P, (C ₇ H ₁₅ ) ₃ P, (C ₈ H ₁₇ ) ₃ P, (C ₆ H ₁₁ ) ₃ P, (C _{6 H 5) 3 P, (CH} 3 C 6 H 4) 3 P, (ClC 6 H 4) 3 P, (CH 3 OC 6 H 4) 3 P, (C 6 H 5 CH 2) 3 P, (C ₄ H ₉ ) ₂ (C ₆ H ₅ ) P, (C ₄ H ₉ ) (C ₆ H ₅ ) ₂ P, (CH ₃ OC ₆ H ₄ ) (C ₆ H ₅ ) ₂ P, (CH ₃ O) ₃ P, (C ₂ H ₅ O) ₃ P, (C ₅ H ₁₁ O) ₃ P, (C ₈ H ₁₇ O) ₃ P, (C ₆ H ₅ CH ₂ O) ₃ P, (C ₆ H ₅ O) ₃ P, (CH ₃ C ₆ H ₄ O) ₃ P, (ClC ₆ H ₄ O) ₃ P, (CH ₃ OC ₆ H ₄ O) ₃ P, (CH ₃ O) (C ₆ H ₅ ) ₂ P, (C ₄ H ₉ O) ₂ (C ₆ H ₅ ) P, (CH ₃ C ₆ H ₄ O) (C ₆ H ₅ ) ₂ P, (C ₄ H ₉ O) (C ₆ H ₅ O ) ₂ P and other phosphorus compounds, (CH ₃ ) ₃ As, (C ₂ H ₅ ) ₃ As, (CH ₂ = CHCH ₂ ) ₃ As, (C ₃ H ₇ ) ₃ As, (C ₄ H ₉ ) _{3 As, (C 6 H 13)} 3 As, (C 8 H 17) 3 As, (C 6 H 5 CH 2) 3 As, (C 6 H 5) 3 As, (CH 3 C 6 H 4) 3 As _{, (CH 3 OC 6 H 4} ) 3 As, (ClC 6 H 4) 3 As, such as Containing _{compound, (CH 3) 3 Sb,} (C 2 H 5) 3 Sb, (CH 2 = CHCH 2) 3 Sb, (C 3 H 7) 3 Sb, (C 4 H 9) 3 Sb, (C 6 H ₁₃ ) ₃ Sb, (C ₈ H ₁₇ ) ₃ Sb, (C ₆ H ₅ CH ₂ ) ₃ Sb, (C ₆ H ₅ ) ₃ Sb, (CH ₃ C ₆ H ₄ ) ₃ Sb, (CH ₃ OC Examples thereof include antimony compounds such as ₆ H ₄ ) ₃ Sb and (ClC ₆ H ₄ ) ₃ Sb.

The ligand L ^2, for example _{(C 6 H 5) 2 PCH} 2 CH 2 P (C 6 H 5) 2, (C 6 H 5) 2 PCH 2 CH 2 CH 2 P (C 6 H 5) 2 , Phosphorus compounds, such as Arsenic compounds, such as And antimony compounds.

Of these ligands L or L ² , preferred are phosphorus compounds, and particularly preferred are (C ₆ H ₅ ) ₃ P and (C ₆ H ₅ ) ₂ PCH ₂ CH ₂ P (C ₆ H ₅ ) ₂ , (C ₆ H ₅ ) ₂ PCH ₂ CH ₂ CH ₂ P (C ₆ H ₅ ) ₂ , and Is.

Preferred among Q are chlorine atom, bromine atom, iodine atom, -OOCCH ₃ group, -OOCC ₂ H ₅ group and -OOCC ₃ H ₇ group,
Particularly preferred are chlorine atom, bromine atom, -OOCCH ₃ group and -OOCC ₂ H ₅ group.

The amount of the palladium catalyst or nickel catalyst used may be usually 0.1 to 20 mol% with respect to the compound of the general formula (2),
It is particularly preferably 0.1 to 5%, but not limited to this.

The molar ratio of the compound of the general formula (1) to the compound of the general formula (2) is usually 10: 1 to 1:10, preferably 10: 7 to 10:15.

The reaction temperature of this coupling reaction is usually −20 to 100 ° C., preferably −10 to 40 ° C., and if the temperature is too high, the catalyst is deactivated, which is not preferable.

The reaction time of this coupling reaction is not particularly limited, and the time point when the starting material, 2,5-dihalogenopyridine, disappears can be the end point of the reaction. The end point of the reaction can be confirmed using gas chromatography or the like.

After completion of the reaction, the desired 2-aryl-5-halogenopyridine derivative represented by the general formula (3) can be isolated from the reaction mixture by a usual separation means such as extraction, washing, and concentration. It can be purified by recrystallization, column chromatography and the like.

The 2-aryl-5-halogenopyridine derivative produced by the method of the present invention is useful as an intermediate for various liquid crystal compounds, and can also be used as an intermediate for medicines, agricultural chemicals and the like.

For example, the following liquid crystal compound can be obtained by using the 2-aryl-5-halogenopyridine derivative produced by the method of the present invention as an intermediate.

Of the above compounds, compounds (12), (13) and (14)
Is a compound described in the literature, and hitherto a method obtained from β-chlorovinyl ketone and an enamine [eg, JP-A-62-223
171] Method obtained from phenylacetic acid derivative and ketone body [eg JP-A-63-250365], Method obtained by reaction of aryl lithium derivative with pyridine and alkyl bromide [eg JP-A-63-174973] Has been synthesized by. On the other hand, by using the compound obtained by the method of the present invention as an intermediate, it became possible to obtain it easily and in high yield by a short synthetic route.

Further, the compound (11) was a compound that could not be synthesized by the above-mentioned conventional method, and it was possible to synthesize the compound (11) only by using the compound obtained by the method of the present invention as an intermediate.

Table 3 shows the phase transition temperatures of the compounds (11) to (14) as indices of usefulness as liquid crystals.

In Table 3, each symbol represents the following phase.

Cr; Crystal phase S ₁ ; Unidentified smectic phase S _C ; Smectic C phase S _A ; Smectic A phase N; Nematic phase I; Isotropic liquid phase [Examples] Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to this.

Example-1 Production of Compound (15) 30.0 g of o-fluoro-p-iodophenol was dissolved in 150 ml of dimethyl sulfoxide, and an aqueous solution of sodium hydroxide (10.1 g / 35 ml) and 1-bromohexane 2 were added.
5.0 g was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was extracted with hexane and washed 3 times with water. Hexane was distilled off to obtain 34.6 g of oily pn-hexyloxy-m-fluoroiodobenzene.

pn-hexyloxy-m-fluoroiodobenzene 15.0 g and 120 ml ether solution of Grignard reagent prepared from magnesium, and 2,5-dibromopyridine 13.2
120 ml of a dry tetrahydrofuran solution of g and 338 mg of dichlorobisdiphenylphosphinobutane palladium as a catalyst.
Was used for 5 hours at room temperature in a nitrogen atmosphere. The reaction was stopped with water, the reaction mixture was extracted with ether, washed successively with 1N hydrochloric acid and water, and then the ether was distilled off. By recrystallizing the obtained solid from methanol, 10.0 g of the compound (15) of the present invention was obtained. The structure of the compound is NMR
(Nuclear magnetic resonance spectrum analysis), MS (mass spectrometry), IR
(Infrared absorption spectrum analysis) and elemental analysis confirmed. The IR spectrum, H-NMR spectrum and F-NMR spectrum of the above compound are shown in FIG. 1, FIG. 2 and FIG. 3, respectively.

Elemental analysis value: Theoretical value (%) Actual value (%) C: 57.97 C: 57.88 H: 5.44 H: 5.49 F: 5.39 F: 5.33 N: 3.98 N: 4.03 Example-2 Preparation of the following compound (16) 30.0 g of o-fluoro-p-iodophenol was dissolved in 150 ml of dimethyl sulfoxide, and an aqueous solution of sodium hydroxide (10.1 g / 35 ml) and 1-bromoheptane 2 were added to the solution.
7.2 g was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was extracted with hexane and washed 3 times with water. Hexane was distilled off to obtain 36.5 g of oily pn-heptyloxy-m-fluoroiodobenzene.

p-n-heptyloxy-m-fluoroiodobenzene (15.7 g) and magnesium solution of 120 ml of Grignard reagent prepared from magnesium, and 2,5-dibromopyridine (13.2 g).
120 ml of a dry tetrahydrofuran solution of g and 338 mg of dichlorobisdiphenylphosphinobutane palladium as a catalyst.
Was used for 5 hours at room temperature in a nitrogen atmosphere. The reaction was stopped with water, the reaction mixture was extracted with ether, washed successively with 1N hydrochloric acid and water, and then the ether was distilled off. By recrystallizing the obtained solid from methanol, 10.5 g of compound (16), which is the compound of the present invention, was obtained. The elemental analysis values of the compound (16) are shown below.

Elemental analysis value: Theoretical value (%) Actual value (%) C: 59.03 C: 58.91 H: 5.78 H: 5.77 F: 5.19 F: 5.22 N: 3.82 N: 3.80 Example-3 Production of the following compound (17) 30.0 g of o-fluoro-p-iodophenol was dissolved in 150 ml of dimethyl sulfoxide, and an aqueous solution of sodium hydroxide (10.1 g / 35 ml) and 1-bromooctane 2 were dissolved in this solution.
9.2 g was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was extracted with hexane and washed 3 times with water. Hexane was distilled off to obtain 37.6 g of oily pn-octyloxy-m-fluoroiodobenzene.

p-n-octyloxy-m-fluoroiodobenzene 16.3 g and 120 ml ether solution of Grignard reagent prepared from magnesium, and 2,5-dibromopyridine 13.2
120 ml of a dry tetrahydrofuran solution of g and 338 mg of dichlorobisdiphenylphosphinobutane palladium as a catalyst.
Was used for 5 hours at room temperature in a nitrogen atmosphere. The reaction was stopped with water, the reaction mixture was extracted with ether, washed successively with 1N hydrochloric acid and water, and the combined product was extracted with ether, washed successively with IN hydrochloric acid and water, and then the ether was distilled off. The obtained solid was recrystallized from methanol to obtain 10.2 g of the compound (17) of the present invention. The elemental analysis values of the compound (17) are shown below.

Elemental analysis value: Theoretical value (%) Actual value (%) C: 60.01 C: 59.92 H: 6.10 H: 6.15 F: 5.00 F: 5.02 N: 3.68 N: 3.66 Example-4 Production of following compound (18) 25.0 g of p-iodophenol was dissolved in 200 ml of dimethyl sulfoxide, and an aqueous solution of sodium hydroxide (9.0
g / 30 ml) and 17.8 g of 1-bromohexane were added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was extracted with hexane and washed 3 times with water. By distilling off hexane, an oily p-
31.0 g of n-hexyloxy-iodobenzene was obtained.

p-n-Hexyloxy-iodobenzene 15.0 g and an ether solution of Grignard reagent prepared from magnesium 120 ml, and a solution of 2,5-dibromopyridine 14.0 g in dry tetrahydrofuran 120 ml were used as catalysts and dichlorobisdiphenylphosphinobutane palladium 357 mg. Using,
The reaction was carried out at room temperature under a nitrogen atmosphere for 5 hours. The reaction was stopped with water, the reaction mixture was extracted with ether, washed successively with 1N hydrochloric acid and water, and then the ether was distilled off. The obtained solid was recrystallized from methanol to obtain 8.9 g of the compound (18) of the present invention. The structure of the compound was confirmed by NMR (nuclear magnetic resonance spectrum analysis), MS (mass spectrometry), IR (infrared absorption spectrum analysis) and elemental analysis. The IR spectrum and 1 H-NMR spectrum of the above compound are shown in FIGS. 4 and 5, respectively.

Elemental analysis value: Theoretical value (%) Actual measurement value (%) C: 61.09 C: 61.00 H: 6.03 H: 6.08 N: 4.19 N: 4.20 [Effect of the invention] According to the method of the present invention, a high synthetic route 2-in yield
An aryl-5-halogenopyridine derivative can be obtained. The pyridine derivative thus produced is useful as an intermediate for various liquid crystal compounds, and can also be used as an intermediate for medicines, agricultural chemicals and the like.

[Brief description of drawings]

1, 2 and 3 show the IR, H-NMR and F-NMR spectra of the compound obtained in Example-1, respectively, and FIGS. 4 and 5 show it in Example-4. The IR and 1 H-NMR spectra of the obtained compound are shown.

Claims (1)

[Claims] 1. A general formula [In the formula, X represents a chlorine atom, a bromine atom or an iodine atom, Represents a 2,5-pyridylene group] and a general formula RYA-Mg-X ¹ (2) [wherein, R represents an alkyl group having 1 to 18 carbon atoms (the alkyl group). 1 or 2 CH ₂ is an O atom, an S atom or -CH
2 O atoms or S atoms may be replaced by those not directly bonded to each other by a group selected from the group consisting of = CH-), X ¹ is a chlorine atom, a bromine atom or an iodine atom. , A is a 1,4-phenylene group or 4,4′-biphenylene group in which some or all of the hydrogen atoms of the aromatic ring may be substituted with fluorine atoms or chlorine atoms,
Y represents -O-, -S-, -C≡C- or a direct bond] with a compound represented by a formula (I) in the presence of a zero-valent or divalent palladium catalyst or a zero-valent or divalent nickel catalyst. General formula characterized by ringing [In the formula, R is an alkyl group having 1 to 18 carbon atoms (in the alkyl group, 1 or 2 CH ₂ is an O atom, an S atom, and -CH
Two O atoms or S atoms may be replaced by those not directly bonded to each other by one selected from the group consisting of = CH-), Is a 2,5-pyridylene group, X is a chlorine atom, a bromine atom or an iodine atom, and A is a hydrogen atom of an aromatic ring, part or all of which may be substituted with a fluorine atom or a chlorine atom.
-Phenylene group or 4,4'-biphenylene group, Y is-
O-, -S-, -C≡C- or represents a direct bond].