WO2002048089A1 - Process for producing mononitrated aromatic ether compound - Google Patents
Process for producing mononitrated aromatic ether compound Download PDFInfo
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- WO2002048089A1 WO2002048089A1 PCT/JP2001/010874 JP0110874W WO0248089A1 WO 2002048089 A1 WO2002048089 A1 WO 2002048089A1 JP 0110874 W JP0110874 W JP 0110874W WO 0248089 A1 WO0248089 A1 WO 0248089A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
Definitions
- the present invention relates to a method for producing an aromatic ether compound by converting an aromatic ether compound into a ditoxin.
- Mononitrated aromatic ether compounds are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like. Background art
- An object of the present invention is to solve the above-mentioned problems and to obtain a monodito-aromatic aromatic ether compound from an aromatic ether compound in a high yield by a simple method without the need for complicated post-treatment.
- An object of the present invention is to provide a method for producing an industrially suitable mononitrated aromatic ether compound which can be produced. Summary of the Invention
- the present invention provides a compound represented by the general formula (1):
- Z represents an oxygen atom, a methylene group or an imino group
- X represents a hydrogen atom, a formyl group, a cyano group, a carbonyl group or an ester group
- R 1 and R 2 are the same or different Represents an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group or an acyl group, which may have a substituent, and R 1 and R 2 may be linked to form a ring.
- the aromatic ether compound used in the reaction of the present invention is a compound represented by the above general formula (1).
- Z is an oxygen atom, a methylene group or an imino group, and preferably represents an oxygen atom.
- X represents a hydrogen atom, a formyl group, a cyano group, a propyloxyl group or an ester group.
- the ester group include a carboxylate group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, and the like).
- R 1 and R 2 may be the same or different, Represents an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group or an acyl group which may have a substituent.
- R 1 and R 2 may be linked to form a ring. Examples of the group that forms a ring by linking include an alkylene group and the like.
- the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like.
- these groups include various isomers.
- a cycloalkyl group having 3 to 8 carbon atoms is particularly preferable, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Note that these groups include various isomers.
- the alkenyl group is particularly preferably an alkenyl group having 2 to 8 carbon atoms.
- Examples thereof include a linear or branched alkenyl group such as a vinyl group, an aryl group and an isopropyl group, a cyclopropenyl group, a cyclobutenyl group and a cyclopentenyl group.
- a cycloalkenyl group such as a group.
- these groups include various isomers.
- the aryl group is preferably an aryl group having 6 to 20 carbon atoms, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group and a phenanthryl group. In addition, these groups include various isomers.
- an acyl group having 2 to 20 carbon atoms is particularly preferable. And the like. In addition, these groups include various isomers.
- the above-mentioned alkyl group, cycloalkyl group, alkenyl group, aryl group or acyl group may have a substituent.
- substituents 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 a methyl group, an ethyl group, Alkyl groups such as propyl group, butyl group, pentyl group and hexyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cyclobutyl group; vinyl group, aryl group, propenyl group, Alkenyl groups such as cyclopropenyl group, cyclobutenyl group and cyclopentenyl group; heterocyclic alkenyl groups such as pyrrolidyl group, pyrrolyl group, furyl group and phenyl group; phenyl group, tolyl group, xylyl group, biphenyl group, Aryl groups such as naphthyl, anthryl, and phenanthryl; acetyl groups such as formyl, acetyl, propion
- Examples of the substituent formed through the oxygen atom include: a hydroxy group; an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexoxy group, and a heptyloxy group; an aralkyl group such as a benzyloxy group. And an aryloxy group such as a phenoxy group, a tolyloxy group and a naphthyloxy group. In addition, these groups include various isomers.
- Examples of the substituent formed through the nitrogen atom include: a primary amino group such as a methylamino group, an ethylamino group, a butylamino group, a cyclohexylamino group, a phenylamino group, a naphthylamino group; a dimethylamino group, a acetylamino group; Secondary amino groups such as dibutylamino group, methylethylamino group, methylbutylamino group, diphenylamino group; heterocyclic rings such as morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group, indolyl group, etc.
- Formula amino groups; and imino groups include various isomers.
- Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxy group such as a thiomethoxy group, a thioethoxy group, and a thiopropoxy group; And thioaryloxy groups.
- these groups include various isomers.
- Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- nitric acid is used in a molar amount of 1 to 2 times the amount of the raw material aromatic ether compound.
- an aqueous solution having a higher concentration is suitably used, and an aqueous solution having a concentration of 50% or more is particularly preferably used.
- the amount of sulfuric acid used in the reaction of the present invention is not particularly limited as long as it is not less than a catalytic amount, and is preferably 0.01 to 20 times mol, more preferably 0.05 to 10 times mol, with respect to the nitric acid. Particularly preferably, it is 0.1 to 5 moles.
- the organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction.
- Examples thereof include carboxylic acids such as acetic acid and propionic acid; and halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane. And acetic acid and 1,2-dichloroethane are preferably used.
- the amount of the organic solvent used is appropriately adjusted so that the solution is easily stirred and uniform, and preferably 0.5 to 20 ml, more preferably 0.5 to 1 (kl) with respect to the aromatic ether compound lg. These solvents may be used alone or in combination of two or more.
- the reaction of the present invention is carried out, for example, by mixing an aromatic ether compound, nitric acid, sulfuric acid and an organic solvent in an amount of 1 to 2 moles per mole of the aromatic ether compound in an inert gas atmosphere such as nitrogen, helium, or argon. This is performed by a method such as stirring.
- the reaction temperature at that time is preferably 0 to 100 ° C, more preferably 10 to 5 (TC, and the reaction pressure is not particularly limited.
- the mononitrified aromatic ether compound obtained by the reaction of the present invention is generally subjected to recrystallization, distillation, column chromatography, etc. after completion of the reaction, followed by treatment such as neutralization, extraction, and concentration. And purification by various methods.
- Example 1 The mononitrified aromatic ether compound obtained by the reaction of the present invention is generally subjected to recrystallization, distillation, column chromatography, etc. after completion of the reaction, followed by treatment such as neutralization, extraction, and concentration. And purification by various methods.
- Example 1 Synthesis of methyl 6-dito-3,4-dimethoxybenzoate
- a 25 ml glass three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with a nitrogen atmosphere.
- methyl 3,4-dimethoxybenzoate l.OOg (5.10 t) and 3 ml of acetic acid were added, and the mixture was cooled to 5 to 10 in an ice bath.
- Example 1 As described in Table 1, the reaction was carried out in the same manner as in Example 1 except that the aromatic ether compound, the amount of nitric acid, the amount of sulfuric acid, the amount of the organic solvent and the amount used, the reaction temperature, and the reaction time in Example 1 were changed. went. The results are shown in Table 1.
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Abstract
Description
明 細 書 モノ二卜口化芳香族エーテル化合物の製造法 技術分野 Description Process for producing mono-nitrogenated aromatic ether compounds
本発明は、 芳香族エーテル化合物を二ト口化してモノ二ト口化芳香族エーテル 化合物を製造する方法に関する。 モノニトロ化芳香族エーテル化合物は、 医薬や 農薬等の合成中間体として有用な化合物である。 背景技術 The present invention relates to a method for producing an aromatic ether compound by converting an aromatic ether compound into a ditoxin. Mononitrated aromatic ether compounds are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like. Background art
従来、 芳香族エーテル化合物を二ト口化してモノ二ト口化芳香族エーテル化合 物を製造する方法としては、 一般的に、 原料に対して過剰の硝酸及び硫酸の混合 酸を使用して反応させることが行われている。 しかしながら、 この方法では、 目 的物との分離が困難な位置異性体ゃジニト口化合物が副生物として生成してしま レ 目的物の収率が低いという問題があった。 又、 反応終了後に、 過剰の混合酸 を多量の塩基で中和した後に有機溶媒で目的物を抽出しなければならない等、 後 処理が極めて煩雑となるという問題もあった。 一方、 反応液に多量の水を添カロし て目的物を結晶として得る方法もあるが、 この方法では、 多量の硝酸廃液が残 り、 工業的製造法としては不利であった。 Conventionally, as a method for producing an aromatic ether compound by converting an aromatic ether compound into a ditoxin, a reaction is generally performed using an excess of a mixed acid of nitric acid and sulfuric acid with respect to the raw material. Let it be done. However, this method has a problem in that the regioisomer ゃ dinit-mouth compound, which is difficult to separate from the target substance, is produced as a by-product. The yield of the target substance is low. In addition, there is also a problem that the post-treatment is extremely complicated, for example, after the reaction, the excess mixed acid must be neutralized with a large amount of base, and then the target substance is extracted with an organic solvent. On the other hand, there is a method in which a large amount of water is added to the reaction solution to obtain the desired product as crystals, but this method is disadvantageous as an industrial production method because a large amount of nitric acid waste liquid remains.
本発明め目的は、 上記問題点を解決し、 簡便な方法によって、 繁雑な後処理を 必要とすることなく、 芳香族エーテル化合物からモノ二ト口化芳香族エーテル化 合物を高収率で製造することが出来る、 工業的に好適なモノニトロ化芳香族エー テル化合物の製造法を提供することである。 発明の要旨 An object of the present invention is to solve the above-mentioned problems and to obtain a monodito-aromatic aromatic ether compound from an aromatic ether compound in a high yield by a simple method without the need for complicated post-treatment. An object of the present invention is to provide a method for producing an industrially suitable mononitrated aromatic ether compound which can be produced. Summary of the Invention
本発明は、 一般式 （1 ) ：
式中、 Zは、 酸素原子、 メチレン基又はイミノ基を表し、 Xは、 水素原子、 ホルミル基、 シァノ基、 力ルポキシル基又はエステル基を表し、 また、 R1 及び R2は、 同一或いは異なっていても良く、 置換基を有していても良い、 アルキル基、 シクロアルキル基、 アルケニル基、 ァリール基又はァシル基を 表し、 R 1と R2は、 連結して環を形成していても良い、 In the formula, Z represents an oxygen atom, a methylene group or an imino group, X represents a hydrogen atom, a formyl group, a cyano group, a carbonyl group or an ester group, and R 1 and R 2 are the same or different Represents an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group or an acyl group, which may have a substituent, and R 1 and R 2 may be linked to form a ring. good,
で示される芳香族エーテル化合物に、 芳香族エーテル化合物に対して 1〜 2倍モ ルの硝酸を、 硫酸の存在下、 有機溶媒中で反応させることを特徴とする、 一般式 ( 2 ) ： A reaction of an aromatic ether compound represented by the formula with nitric acid in an amount of 1 to 2 times that of the aromatic ether compound in an organic solvent in the presence of sulfuric acid; a general formula (2):
式中、 Z、 X、 R1及び R2は、 前記と同義である、 Wherein Z, X, R 1 and R 2 are as defined above,
で示されるモノニトロ化芳香族エーテル化合物の製造法に関する。 発明を実施するための最良の形態 And a method for producing a mononitrated aromatic ether compound represented by the formula: BEST MODE FOR CARRYING OUT THE INVENTION
本発明の反応において使用する芳香族エーテル化合物は、 前記の一般式 （1 ) で示される化合物である。 その一般式 （1 ) において、 Zは、 酸素原子、 メチレ ン基又はイミノ基であるが、 好ましくは酸素原子を表す。 Xは、 水素原子、 ホル ミル基、 シァノ基、 力ルポキシル基又はエステル基を表す。 エステル基として は、 カルボン酸エステル基 （例えば、 メトキシカルポニル基、 エトキシカルポ二 ル基等） が挙げられる。 また、 R 1及び R2は、 同一或いは異なっていても良く、 置換基を有していても良い、 アルキル基、 シクロアルキル基、 アルケニル基、 ァ リール基又はァシル基を表す。 なお、 R 1と R2は、 連結して環を形成してレても 良い。 連結して環を形成する基としては、 例えば、 アルキレン基等があげられ る。 The aromatic ether compound used in the reaction of the present invention is a compound represented by the above general formula (1). In the general formula (1), Z is an oxygen atom, a methylene group or an imino group, and preferably represents an oxygen atom. X represents a hydrogen atom, a formyl group, a cyano group, a propyloxyl group or an ester group. Examples of the ester group include a carboxylate group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, and the like). Also, R 1 and R 2 may be the same or different, Represents an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group or an acyl group which may have a substituent. R 1 and R 2 may be linked to form a ring. Examples of the group that forms a ring by linking include an alkylene group and the like.
俞記アルキル基としては、 特に炭素数 1 ~ 8のアルキル基が好ましく、 例え ば、 メチル基、 ェチル基、 プロピル基、 ブチル基、 ペンチル基、 へキシル基、 へ プチル基、 ォクチル基等が挙げられる。 なお、 これらの基は、 各種異性体を含 む。 The alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. Can be In addition, these groups include various isomers.
前記シクロアルキル基としては、 特に炭素数 3〜 8のシクロアルキル基が好ま しく、 例えば、 シクロプロピル基、 シクロブチル基、 シクロペンチル基、 シクロ へキシル基、 シクロへプチル基、 シクロォクチル基等が挙げられる。 なお、 これ らの基は、 各種異性体を含む。 As the cycloalkyl group, a cycloalkyl group having 3 to 8 carbon atoms is particularly preferable, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Note that these groups include various isomers.
前記アルケニル基としては、 特に炭素数 2〜 8のアルケニル基が好ましく、 例 えば、 ビニル基、 ァリル基、 イソプロぺニル基等の直鎖又は分岐アルケニル基、 シクロプロぺニル基、 シクロブテニル基、 シクロペンテニル基等のシクロアルケ ニル基等が挙げられる。 なお、 これらの基は、 各種異性体を含む。 The alkenyl group is particularly preferably an alkenyl group having 2 to 8 carbon atoms. Examples thereof include a linear or branched alkenyl group such as a vinyl group, an aryl group and an isopropyl group, a cyclopropenyl group, a cyclobutenyl group and a cyclopentenyl group. And a cycloalkenyl group such as a group. In addition, these groups include various isomers.
前記ァリール基としては、 特に炭素数 6〜 2 0のァリール基が好ましく、 例え ば、 フエニル基、 トリル基、 キシリル基、 ビフエ二ル基、 ナフチル基、 アントリ ル基、 フエナントリル基等が挙げられる。 なお、 これらの基は、 各種異性体を含 む。 The aryl group is preferably an aryl group having 6 to 20 carbon atoms, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group and a phenanthryl group. In addition, these groups include various isomers.
前記ァシル基としては、 特に炭素数 2〜2 0のァシル基が好ましく、 例えば、 ァセチル基、 プロピオニル基、 ビバロイル基、 シクロへキシルカルポニル基等の 脂肪族ァシル基、 ベンゾィル基、 ナフトイル基、 トルオイル基等の芳香族ァシル 基等が挙げられる。 なお、 これらの基は、 各種異性体を含む。 As the above-mentioned acyl group, an acyl group having 2 to 20 carbon atoms is particularly preferable. And the like. In addition, these groups include various isomers.
前記のアルキル基、 シクロアルキル基、 アルケニル基、 ァリール基又はァシル 基は置換基を有していても良い。 その置換基としては、 例えば、 炭素原子を介し て出来る置換基、 酸素原子を介して出来る置換基、 窒素原子を介して出来る置換 基、 硫黄原子を介して出来る置換基、 ハロゲン原子等が挙げられる。 The above-mentioned alkyl group, cycloalkyl group, alkenyl group, aryl group or acyl group 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. .
前記炭素原子を介して出来る置換基としては、 例えば、 メチル基、 ェチル基、 プロピル基、 ブチル基、 ペンチル基、 へキシル基等のアルキル基；シクロプロピ ル基、 シクロブチル基、 シクロペンチル基、 シクロへキシル基、 シクロブチル基 等のシクロアルキレ基； ビニル基、 ァリル基、 プロぺニル基、 シクロプロぺニル 基、 シクロブテニル基、 シクロペンテニル基等のアルケニル基； ピロリジル基、 ピロリル基、 フリル基、 チェニル基等の複素環式アルケニル基；フエニル基、 ト リル基、 キシリル基、 ビフエ二ル基、 ナフチル基、 アントリル基、 フエナントリ ル基等のァリール基；ホルミル基、 ァセチル基、 プロピオニル基、 ビバロイル 基、 シクロへキシルカルポニル基、 ベンゾィル基、 ナフトイル基、 トルオイル基 等のァシル基 (ァセタール化されていても良い) ；カルボキシル基；メトキシカ ルポニル基、 エトキシカルボニル基等のアルコキシ力ルポニル基；フエノキシ力 ルポニル基等のァリールォキシ力ルポニル基； トリフルォロメチル基等のハロゲ ン化アルキル基；シァノ基が挙げられる。 なお、 これらの基は、 各種異性体を含 む。 Examples of the substituent formed through the carbon atom include a methyl group, an ethyl group, Alkyl groups such as propyl group, butyl group, pentyl group and hexyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cyclobutyl group; vinyl group, aryl group, propenyl group, Alkenyl groups such as cyclopropenyl group, cyclobutenyl group and cyclopentenyl group; heterocyclic alkenyl groups such as pyrrolidyl group, pyrrolyl group, furyl group and phenyl group; phenyl group, tolyl group, xylyl group, biphenyl group, Aryl groups such as naphthyl, anthryl, and phenanthryl; acetyl groups such as formyl, acetyl, propionyl, bivaloyl, cyclohexylcarbonyl, benzoyl, naphthoyl, and toluoyl; Carboxyl group; methoxy It includes Shiano group; halogen alkyl group such as a triflate Ruo Russia methyl; Ariruokishi force Ruponiru group such as phenoxy force Ruponiru group; mosquito Ruponiru group, an alkoxy force Ruponiru group such as methoxycarbonyl group and ethoxycarbonyl group. In addition, these groups include various isomers.
前記酸素原子を介して出来る置換基としては、 例えば、 ヒドロキシ基；メトキ シ基、 エトキシ基、 プロポキシ基、 ブトキシ基、 ペンチルォキシ基、 へキシルォ キシ基、 ヘプチルォキシ基等のアルコキシ基；ベンジルォキシ基等のァラルキル ォキシ基； フエノキシ基、 トルィルォキシ基、 ナフチルォキシ基等のァリールォ キシ基が挙げられる。 なお、 これらの基は、 各種異性体を含む。 Examples of the substituent formed through the oxygen atom include: a hydroxy group; an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexoxy group, and a heptyloxy group; an aralkyl group such as a benzyloxy group. And an aryloxy group such as a phenoxy group, a tolyloxy group and a naphthyloxy group. In addition, these groups include various isomers.
前記窒素原子を介して出来る置換基としては、 例えば、 メチルァミノ基、 ェチ ルァミノ基、 プチルァミノ基、 シクロへキシルァミノ基、 フエニルァミノ基、 ナ フチルァミノ基等の第一級ァミノ基；ジメチルァミノ基、 ジェチルァミノ基、 ジ プチルァミノ基、 メチルェチルァミノ基、 メチルブチルァミノ基、 ジフエニルァ ミノ基等の第二級ァミノ基；モルホリノ基、 ピペリジノ基、 ピペラジニル基、 ピ ラゾリジニル基、 ピロリジノ基、 インドリル基等の複素環式ァミノ基；イミノ基 が挙げられる。 なお、 これらの基は、 各種異性体を含む。 Examples of the substituent formed through the nitrogen atom include: a primary amino group such as a methylamino group, an ethylamino group, a butylamino group, a cyclohexylamino group, a phenylamino group, a naphthylamino group; a dimethylamino group, a acetylamino group; Secondary amino groups such as dibutylamino group, methylethylamino group, methylbutylamino group, diphenylamino group; heterocyclic rings such as morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group, indolyl group, etc. Formula amino groups; and imino groups. In addition, these groups include various isomers.
前記硫黄原子を介して出来る置換基としては、 例えば、 メルカプト基；チオメ トキシ基、 チォエトキシ基、 チォプロポキシ基等のチォアルコキシ基；チォフエ ノキシ基、 チオトルイルォキシ基、 チォナフチルォキシ基等のチオアリールォキ シ基等が挙げられる。 なお、 これらの基は、 各種異性体を含む。 前記ハロゲン原子としては、 フッ素原子、 塩素原子、 臭素原子、 ヨウ素原子が 挙げられる。 Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxy group such as a thiomethoxy group, a thioethoxy group, and a thiopropoxy group; And thioaryloxy groups. In addition, these groups include various isomers. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
本発明の反応において硝酸は、 原料の芳香族エーテル化合物に対して 1〜 2倍 モル使用する。 該硝酸は、 より高濃度の水溶液が好適に用いられ、 特に好ましく は 50%以上の濃度の水溶液が使用される。 In the reaction of the present invention, nitric acid is used in a molar amount of 1 to 2 times the amount of the raw material aromatic ether compound. As the nitric acid, an aqueous solution having a higher concentration is suitably used, and an aqueous solution having a concentration of 50% or more is particularly preferably used.
本発明の反応において使用する硫酸の量は、 触媒量以上であれば特に制限され ず、 前記硝酸に対して、 好ましくは 0. 01〜20倍モル、 更に好ましくは 0. 05〜10倍 モル、 特に好ましくは 0. 1〜5倍モルである。 The amount of sulfuric acid used in the reaction of the present invention is not particularly limited as long as it is not less than a catalytic amount, and is preferably 0.01 to 20 times mol, more preferably 0.05 to 10 times mol, with respect to the nitric acid. Particularly preferably, it is 0.1 to 5 moles.
本発明の反応において使用する有機溶媒としては、 反応を阻害しないものなら ば特に限定されず、 例えば、 酢酸、 プロピオン酸等のカルボン酸類；塩化メチレ ン、 1， 2-ジクロロェタン等のハロゲン化炭化水素類が挙げられ、 好ましくは酢 酸、 1, 2-ジクロロェタンが使用される。 The organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. Examples thereof include carboxylic acids such as acetic acid and propionic acid; and halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane. And acetic acid and 1,2-dichloroethane are preferably used.
前記有機溶媒の使用量は、 溶液が攪拌しやすく、 均一となるように適宜調節 し、 芳香族エーテル化合物 l gに対して、 好ましくは 0. 5〜20ml、 更に好ましくは 0. 5〜l(klである。 なお、 これらの溶媒は、 単独又は二種以上を混合して使用し ても良い。 The amount of the organic solvent used is appropriately adjusted so that the solution is easily stirred and uniform, and preferably 0.5 to 20 ml, more preferably 0.5 to 1 (kl) with respect to the aromatic ether compound lg. These solvents may be used alone or in combination of two or more.
本発明の反応は、 例えば、 窒素、 ヘリウム、 アルゴン等の不活性ガス雰囲気に て、 芳香族エーテル化合物、 芳香族エーテル化合物に対して 1〜 2倍モルの硝 酸、 硫酸及び有機溶媒を混合して攪拌する等の方法によって行われる。 その際の 反応温度は、 好ましくは 0〜100°C、 更に好ましくは 10〜5(TCであり、 反応圧力は 特に限定されない。 The reaction of the present invention is carried out, for example, by mixing an aromatic ether compound, nitric acid, sulfuric acid and an organic solvent in an amount of 1 to 2 moles per mole of the aromatic ether compound in an inert gas atmosphere such as nitrogen, helium, or argon. This is performed by a method such as stirring. The reaction temperature at that time is preferably 0 to 100 ° C, more preferably 10 to 5 (TC, and the reaction pressure is not particularly limited.
本発明の反応によって得られるモノニト口化芳香族ェ一テル化合物は、 反応終 了後、 中和、 抽出、 濃縮等の処理を行った後、 再結晶、 蒸留、 カラムクロマトグ ラフィ一等による一般的な方法によって分離 ·精製される。 実施例 The mononitrified aromatic ether compound obtained by the reaction of the present invention is generally subjected to recrystallization, distillation, column chromatography, etc. after completion of the reaction, followed by treatment such as neutralization, extraction, and concentration. And purification by various methods. Example
以下に、 実施例を挙げて本発明を具体的に説明するが、 本発明の範囲はこれら に限定されるものではない。 実施例 1 (6-二ト口- 3, 4-ジメトキシ安息香酸メチルの合成） 攪拌装置、 温度計、 還流冷却器及び滴下漏斗を備えた内容積 25mlのガラス製三 つ口フラスコに、 窒素雰囲気下、 3, 4-ジメトキシ安息香酸メチル l. OOg (5. 10 腿 ol)及び酢酸 3mlを加え、 氷浴中で 5〜10でに冷却した。 次いで、 96%硫酸 1. 00g (10. 20廳 ol)、 69%硝酸 0. 47g (5. 15匪 ol)の順でゆるやかに滴下した。 滴下 後、 反応液を 25°Cまでゆるやかに昇温し、 同温度で 30分間反応させた。 反応終了 後、 氷水 50mlを加えた後、 更に 8mol/l水酸化ナトリゥム水溶液 2. 6ml (20. 80腿 ol) を加えて中和した。 反応液を 1， 2-ジクロロェタン 65mlで 2回抽出した後、 有機層 (1, 2-ジクロロェタン層） を分離し、 高速液体クロマトグラフィー （内部標準 法） により分析したところ、 3， 4-ジメトキシ安息香酸メチルは完全に消費されて おり、 6-ニトロ- 3， 4-ジメトキシ安息香酸メチルが 1. 20g生成していた (反応収率 97. 8 Hereinafter, the present invention will be described specifically with reference to Examples, but the scope of the present invention is not limited thereto. Example 1 (Synthesis of methyl 6-dito-3,4-dimethoxybenzoate) A 25 ml glass three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with a nitrogen atmosphere. Below, methyl 3,4-dimethoxybenzoate l.OOg (5.10 t) and 3 ml of acetic acid were added, and the mixture was cooled to 5 to 10 in an ice bath. Next, 1.00 g of 96% sulfuric acid (10.20 ol) and 0.47 g of 69% nitric acid (5.15 ol) were slowly dropped in this order. After the dropwise addition, the temperature of the reaction solution was gradually raised to 25 ° C, and the reaction was carried out at the same temperature for 30 minutes. After the reaction was completed, 50 ml of ice water was added, and then 2.6 ml (20.80 tmol) of an 8 mol / l aqueous sodium hydroxide solution was further added for neutralization. After extracting the reaction solution twice with 65 ml of 1,2-dichloroethane, the organic layer (1,2-dichloroethane layer) was separated and analyzed by high performance liquid chromatography (internal standard method). Methyl acid was completely consumed, and 1.20 g of methyl 6-nitro-3,4-dimethoxybenzoate was produced (reaction yield 97.8).
実施例 2〜 7 Examples 2 to 7
表 1に記載されたように、 実施例 1における芳香族エーテル化合物、 硝酸量、 硫酸量、 有機溶媒及びその使用量、 反応温度、 反応時間を変えた以外は、 実施例 1と同様に反応を行った。 その結果を表 1に示す。 As described in Table 1, the reaction was carried out in the same manner as in Example 1 except that the aromatic ether compound, the amount of nitric acid, the amount of sulfuric acid, the amount of the organic solvent and the amount used, the reaction temperature, and the reaction time in Example 1 were changed. went. The results are shown in Table 1.
a)：芳香族エーテル類に対する比。 b) ：確酸に対する比。 a): Ratio to aromatic ethers. b): ratio to acetic acid.
c) ：芳香族エーテルに対する量。 c): Amount based on aromatic ether.
産業上の利用可能性 Industrial applicability
本発明により、 簡便な方法によって、 繁雑な後処理を必要とすることなく、 芳 香族エーテル化合物からモノ二ト口化芳香族エーテル化合物を高収率で製造する ことが出来る、 工業的に好適なモノニトロ化芳香族エーテル化合物の製造法を提 供することが出来る。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to produce a mononitrated aromatic ether compound from an aromatic ether compound in a high yield by a simple method without complicated post-treatment, which is industrially suitable. A method for producing a mononitrated aromatic ether compound can be provided.
Claims
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| AU2002222606A AU2002222606A1 (en) | 2000-12-12 | 2001-12-12 | Process for producing mononitrated aromatic ether compound |
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| JP2000377132 | 2000-12-12 | ||
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7705145B2 (en) | 2002-09-13 | 2010-04-27 | Astrazeneca Ab | Process for the preparation of 4-(3′-chloro-4′-fluoroanilino) -7-methoxy-6-(3-morpholinopropoxy) quinazoline |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5740447A (en) * | 1980-08-22 | 1982-03-06 | Mitsubishi Chem Ind Ltd | Preparation of 3-nitro-4- lower alkoxy aniline |
| EP0312931A2 (en) * | 1987-10-19 | 1989-04-26 | The Dow Chemical Company | Process for the preparation of amino-1,3 benzenediol |
| EP0368008A1 (en) * | 1988-10-24 | 1990-05-16 | Bayer Ag | Fluorine-containing phenols |
-
2001
- 2001-12-12 AU AU2002222606A patent/AU2002222606A1/en not_active Abandoned
- 2001-12-12 WO PCT/JP2001/010874 patent/WO2002048089A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5740447A (en) * | 1980-08-22 | 1982-03-06 | Mitsubishi Chem Ind Ltd | Preparation of 3-nitro-4- lower alkoxy aniline |
| EP0312931A2 (en) * | 1987-10-19 | 1989-04-26 | The Dow Chemical Company | Process for the preparation of amino-1,3 benzenediol |
| EP0368008A1 (en) * | 1988-10-24 | 1990-05-16 | Bayer Ag | Fluorine-containing phenols |
Non-Patent Citations (1)
| Title |
|---|
| WISSNER A. ET AL.: "4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors", J. MED. CHEM., vol. 43, no. 17, 2000, pages 3244 - 3256, XP002909029 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7705145B2 (en) | 2002-09-13 | 2010-04-27 | Astrazeneca Ab | Process for the preparation of 4-(3′-chloro-4′-fluoroanilino) -7-methoxy-6-(3-morpholinopropoxy) quinazoline |
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