JP2009215259A - Production method of 3-halogeno-4-hydrocarbyloxy-nitrobenzene compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for selectively producing a 3-halogeno-4-hydrocarbyloxy-nitrobenzene compound from a 3,4-dihalgeno-nitrobenzene compound under a mild condition using a weak base without establishing a specific reaction condition. <P>SOLUTION: The 3-halogeno-4-hydrocarbyloxy-nitrobenzene compound represented by general formula (3) (wherein X<SP>2</SP>is F, Cl, Br, or I, and an arbitrary hydrogen atom may be substituted by an alkyl, alkenyl, cycloalkyl, aralkyl, aryl or heteroaryl) is obtained by reacting the 3,4-dihalgeno-nitrobenzene compound with a hydroxyl compound represented by general formula (2) (wherein R is an alkyl, alkenyl, cycloalkyl or aralkyl) in the presence of an alkali metal carbonate. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound from a 3,4-dihalogenonitrobenzene compound. A 3-halogeno-4-hydrocarbyloxynitrobenzene compound is a useful compound as a synthetic intermediate such as a protein tyrosine kinase enzyme inhibitor (see, for example, Patent Document 1).

Conventionally, as a method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound from a 3,4-dihalogenonitrobenzene compound, for example, 3-chloro-4-fluoronitrobenzene and benzyl alcohol are used in the presence of sodium hydride. A method of obtaining 4-benzyloxy-3-chloronitrobenzene by reacting in acetonitrile is disclosed (for example, see Patent Document 1). However, this method has a problem that it is necessary to use a strong base sodium hydride (water-free strong base) which is complicated to handle.
Furthermore, a method is disclosed in which 3-fluoro-4-chloronitrobenzene and methanol are reacted to obtain a mixture of 4-methoxy-3-chloronitrobenzene and 3-fluoro-4-methoxynitrobenzene (for example, non-patented). Reference 1). This method has a problem in that the regioselectivity cannot be controlled, and the product must be separated by excessive post-treatment.
In addition, in the reaction using alcohols having a low acidity (for example, alkyl alcohol and aralkyl alcohol), the nucleophilic substitution reaction can be performed only in the presence of a strong base such as an alkali metal hydride or alkali metal hydroxide. There has been a problem that it does not proceed and a coupling reaction and a substitution reaction with a hydroxy group of a halogen atom that cannot be avoided.
US Patent Publication No. 2006/0059678 Tetrahedoron, No. 52, Vol. 7, 2557 (1996)

  The object of the present invention is to select 3-halogeno-4-hydrocarbyloxynitrobenzene selectively from a 3,4-dihalogenonitrobenzene compound under mild conditions using a weak base without setting any special reaction conditions. It is to provide a method for producing a compound.

  In the presence of alkali metal carbonate, general formula (1)

(In the formula, X ¹ represents a fluorine atom, a chlorine atom or a bromine atom, X ² represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and X ¹ and X ² may be the same or different. Any hydrogen atom on the benzene ring may be substituted with an alkyl group, alkenyl group, cycloalkyl group, aralkyl group, aryl group or heteroaryl group.
3,4-dihalogenonitrobenzene compound represented by the general formula (2)

(In the formula, R represents an alkyl group, an alkenyl group, a cycloalkyl group, or an aralkyl group.)
And a hydroxy compound represented by the general formula (3)

(In the formula, X ² represents a halogen atom, and any hydrogen atom on the benzene ring may be substituted with an alkyl group, an alkenyl group, a cycloalkyl group, an aralkyl group, an aryl group, or a heteroaryl group.)
This is solved by a method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound represented by the following formula.

  According to the present invention, a 3-halogeno-4-hydrocarbyloxynitrobenzene compound is selectively produced from a 3,4-dihalogenonitrobenzene compound under mild conditions using a weak base without setting special reaction conditions. A method can be provided.

The 3,4-dihalogenonitrobenzene compound used in the reaction of the present invention is represented by the above general formula (1). In the general formula (1), X ¹ represents a fluorine atom, chlorine atom or bromine atom, X ² represents a fluorine atom, chlorine atom, bromine atom or iodine atom, and X ¹ and X ² are the same or different. May be. Further, any hydrogen atom on the benzene ring may be substituted with an alkyl group, alkenyl group, cycloalkyl group, aralkyl group, aryl group or heteroaryl group shown in paragraph No. 0006.

  The hydroxy compound used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R is an alkyl group, an alkenyl group, or a cycloalkyl group. For example, an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group; a vinyl group , An alkenyl group such as an allyl group, a propenyl group, a cyclopropenyl group, a cyclobutenyl group, and a cyclopentenyl group; and a cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

  In addition, these groups may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom.

  Examples of the substituent formed through the carbon atom include alkyl groups such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclo group. Cycloalkyl groups such as heptyl group; Alkenyl groups such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group; quinolyl group, pyridyl group, pyrrolidyl group, pyrrolyl group, furyl group, thienyl group, etc. An aryl group such as phenyl group, tolyl group, fluorophenyl group, xylyl group, biphenylyl group, naphthyl group, anthryl group, phenanthryl group; acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, Benzoyl group, naphthoyl Group, acyl group such as toluoyl group (may be acetalized); carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; trifluoromethyl group and the like A halogenated alkyl group; and a cyano group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, and a benzyloxyl group; a phenoxyl group And aryloxyl groups such as toluyloxyl group and naphthyloxyl group. These groups include various isomers.

  Examples of the substituent formed through the nitrogen atom include dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, methylethylamino group, methylpropylamino group, methylbutylamino group, diphenylamino group, N- Secondary amino groups such as methyl-N-methanesulfonylamino group; heterocyclic amino groups such as morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group and indolyl group; imino group. These groups include various isomers.

  Examples of the substituent formed through the sulfur atom include a thioalkoxyl group such as a thiomethoxyl group, a thioethoxyl group, and a thiopropoxyl group; a thioaryl group such as a thiophenoxyl group, a thiotoluyloxyl group, and a thionaphthyloxyl group. An oxyl group etc. are mentioned. These groups include various isomers.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and a chlorine atom.

  Examples of the alkali metal carbonate used in the reaction of the present invention include sodium carbonate, potassium carbonate and cesium carbonate, preferably sodium carbonate, potassium carbonate and cesium carbonate, more preferably sodium carbonate and potassium carbonate, particularly preferably. Potassium carbonate is used. In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the alkali metal carbonate used is preferably 0.5 to 10 mol, more preferably 0.6 to 8.0 mol, and particularly preferably 0.7 to 5.0 mol with respect to 1 mol of the 3,4-dihalonitrobenzene compound.

  The solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide and N-methylpyrrolidone; Ureas such as N, N'-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Nitriles such as acetonitrile and propionitrile; Diethyl ether , Ethers such as diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene, and the like, preferably sulfoxides and amides, more preferably dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N- Methyl pyrrolidone, particularly preferably dimethyl sulfoxide is used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is preferably 0.1 to 100 ml, more preferably 0.5 to 80 ml, and particularly preferably 1 to 50 ml with respect to 1 g of the 3,4-dihalogenonitrobenzene compound.

  The reaction of the present invention is carried out, for example, by a method of mixing a 3,4-dihalogenonitrobenzene compound, a hydroxy compound, an alkali metal carbonate and a solvent and reacting them with stirring. The reaction temperature at that time is preferably 50 to 200 ° C, more preferably 70 to 180 ° C, particularly preferably 80 to 150 ° C, and the reaction pressure is not particularly limited.

  As a preferred embodiment of the reaction of the present invention, 3,4-dihalogenonitrobenzene compound is added dropwise (mixed as a solution dissolved in a solvent if necessary) while mixing and stirring the alkali metal carbonate, hydroxy compound and solvent. You may).

  A 3-halogeno-4-hydrocarbyloxynitrobenzene compound is obtained by the reaction of the present invention. After completion of the reaction, for example, general methods such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc. Can be isolated and purified by various methods.

  In order to adjust the reactivity of the present invention, a quaternary ammonium salt such as tetrabutylammonium bromide, crown ethers or the like may be added.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Example 1 (X ¹ = X ² = chlorine atom, R = benzyl group; synthesis of 3-chloro-4-benzyloxynitrobenzene)
To a glass container with an internal volume of 100 ml equipped with a stirrer, add 5.0 g (26.0 mmol) of 3,4-dichloronitrobenzene, 8.45 g (78.1 mmol) of benzyl alcohol, 8.99 g (65.1 mmol) of potassium carbonate and 30 ml of dimethyl sulfoxide. The reaction was carried out at 130 ° C. for 1 hour with stirring. After completion of the reaction, water was added to the reaction solution, followed by extraction with 200 ml of ethyl acetate, and the extract was concentrated under reduced pressure. The precipitated solid was filtered, and the residue was washed with hexane to obtain 5.0 g of 3-chloro-4-benzyloxynitrobenzene as beige crystals (isolated yield: 72.8%).
The physical properties of 3-chloro-4-benzyloxynitrobenzene were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 5.25 (2H, s), 7.00 to 7.03 (1H, m), 7.34 to 7.45 (5H, m), 8.07 to 8.11 (1H, m), 8.27 to 8.28 (1H, m)
CI-MS; 264 (M + 1)

Example 2 (X ¹ = X ² = chlorine atom, R = 3-fluorobenzyl group; synthesis of 3-chloro-4- (3-fluorobenzyloxy) nitrobenzene)
In a 100 ml glass container equipped with a stirrer, 5.0 g (26.0 mmol) of 3,4-dichloronitrobenzene, 9.85 g (78.1 mmol) of 3-fluorobenzyl alcohol, 8.99 g (65.1 mmol) of potassium carbonate and dimethyl sulfoxide 10 ml was added and reacted at 130 ° C. for 1 hour with stirring. After completion of the reaction, water was added to the reaction solution, followed by extraction with 200 ml of ethyl acetate, and the extract was concentrated under reduced pressure. The concentrated liquid was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 (volume ratio)) to obtain 4.34 g of 3-chloro-4- (3-fluorobenzyloxy) nitrobenzene as beige crystals ( Isolated yield; 59.2%).
The physical properties of 3-chloro-4- (3-fluorobenzyloxy) nitrobenzene were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 5.27 (2H, s), 7.01 to 7.41 (5H, m), 8.10 to 8.13 (1H, m), 8.29 to 8.30 (1H, m)
CI-MS; 282 (M + 1)

Example 3 (X ¹ = X ² = chlorine atom, R = 2-pyridylmethyl group; synthesis of 3-chloro-4- (2-pyridylmethoxy) nitrobenzene)
In a glass container with an internal volume of 30 ml equipped with a stirrer, 3,4-dichloronitrobenzene 1.0 g (5.2 mmol), 2-pyridinemethanol 2.66 g (15.6 mmol), potassium carbonate 1.8 g (13.0 mmol) and dimethyl sulfoxide 5 ml And the reaction was carried out at 130 ° C. for 4 hours with stirring. After completion of the reaction, water was added to the reaction solution, followed by extraction with 50 ml of ethyl acetate, and the extract was concentrated under reduced pressure. The concentrated liquid was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 (volume ratio)) to obtain 0.60 g of 3-chloro-4- (2-pyridylmethoxy) nitrobenzene as beige crystals (single (Separation yield; 44.0%).
The physical properties of 3-chloro-4- (2-pyridylmethoxy) nitrobenzene were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 5.46 (2H, s), 7.37 to 7.41 (1H, m), 7.46 to 7.49 (1H, m), 7.56 to 7.58 (1H, m), 7.86 to 7.92 (1H, m), 8.21-8.25 (1H, m), 8.35-8.36 (1H, m), 8.60-8.61 (1H, m)
CI-MS; 265 (M + 1)

  The present invention relates to a method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound from a 3,4-dihalogenonitrobenzene compound. A 3-halogeno-4-hydrocarbyloxynitrobenzene compound is a useful compound as a synthetic intermediate such as a protein tyrosine kinase enzyme inhibitor.

Claims (6)

In the presence of alkali metal carbonate, general formula (1)

(In the formula, X ¹ represents a fluorine atom, a chlorine atom or a bromine atom, X ² represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and X ¹ and X ² may be the same or different. Any hydrogen atom on the benzene ring may be substituted with an alkyl group, alkenyl group, cycloalkyl group, aralkyl group, aryl group or heteroaryl group.
3,4-dihalogenonitrobenzene compound represented by the general formula (2)

(In the formula, R represents an alkyl group, an alkenyl group, a cycloalkyl group, or an aralkyl group.)
And a hydroxy compound represented by the general formula (3)

(In the formula, X ² represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and any hydrogen atom on the benzene ring represents an alkyl group, an alkenyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl. It may be substituted with a group.)
A method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound represented by the formula: The method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound according to claim ^1, wherein X ¹ and X ² are the same. The method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound according to claim 1 or 2, wherein X ¹ and X ² are both chlorine atoms.   The method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound according to claim 1, wherein R is an aralkyl group.   5. The method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound according to claim 1, wherein R is a 3-fluorobenzyl group.   The method for producing a 3-halogeno-4-hydrocarbyloxynitrobenzene compound according to claim 1, wherein the alkali metal carbonate is potassium carbonate.