JP4601274B2 - Method for producing γ-ketoacetals - Google Patents

Description

The present invention relates to a method for producing γ-ketoacetals.

  γ-ketoacetal (compound having the following general formula (A)) is known as an intermediate of a 4-methyl-1,2-diarylpyrrole derivative (see Patent Document 1), and 4-methyl-1,2 -Diarylpyrrole derivatives are known to be useful as analgesics (see Patent Document 2).

（上式中、Ａｒ¹は置換されていてもよいアリール基を示し、Ｒ¹及びＲ²はそれぞれ低級アルキル基を示すか、或いは、Ｒ¹及びＲ²は一緒になってトリメチレン等を示す。）
当該γ−ケトアセタール類の製造方法としては、ニトロメタン（ＣＨ₃ＮＯ₂）と塩基を用いた方法が知られている（特許文献３）。しかしながら、ニトロメタンは爆発しやすい化合物であるので取り扱いに非常に注意を要し、そのため、その製造方法によってγ−ケトアセタール類を製造する場合、特に大量に製造する場合には、操作が煩雑になるという問題があった。

特開２０００−８００７８号（段落［００３０］及び［００４８］乃至［００５２］） 米国特許第５９０８８５８号明細書（ＡＢＳＴＲＡＣＴ） 特開２０００−８００７８号（請求項２）

(In the above formula, Ar ¹ represents an optionally substituted aryl group, R ¹ and R ² each represent a lower alkyl group, or R ¹ and R ² together represent trimethylene and the like. )
As a method for producing the γ-ketoacetals, a method using nitromethane (CH ₃ NO ₂ ) and a base is known (Patent Document 3). However, since nitromethane is an explosive compound, it needs to be handled with great care. Therefore, when γ-ketoacetals are produced by the production method thereof, especially when they are produced in large quantities, the operation becomes complicated. There was a problem.

JP 2000-80078 (paragraphs [0030] and [0048] to [0052]) US Pat. No. 5,908,858 (ABSTRACT) JP 2000-80078 (Claim 2)

As a result of intensive studies on a method for producing γ-ketoacetals, the present inventors have found that, by using an enamine derivative, γ-keto having a high yield and high purity can be obtained by a simple operation without using nitromethane. The inventors have found that acetals can be obtained and completed the present invention.

The present invention
(1) General formula (2)

（式中、ＡｒはＣ₆−Ｃ₁₀アリール基、又は置換基群αから選択される基で置換されたＣ₆−Ｃ₁₄アリール基を示し、置換基群αはハロゲン原子、Ｃ₁−Ｃ₆アルキル基、ハロゲン化Ｃ₁−Ｃ₆アルキル基、水酸基、Ｃ₁−Ｃ₆アルコキシ基、Ｃ₁−Ｃ₆アルキルチオ基、メルカプト基、Ｃ₁−Ｃ₆アルキルスルホニル基及びスルファモイル基からなる群を示し、Ｘはハロゲン原子を示す。）と一般式（３）

(In the formula, Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from the substituent group α, wherein the substituent group α is a halogen atom, C ₁ -C _A group consisting of ₆ alkyl groups, halogenated C ₁ -C ₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, mercapto groups, C ₁ -C ₆ alkylsulfonyl groups and sulfamoyl groups X represents a halogen atom) and general formula (3)

（式中、Ｒ^a及びＲ^bは、同一若しくは異なって、それぞれ、Ｃ₁−Ｃ₆アルキル基、Ｃ₁−Ｃ₆アルコキシで置換されたＣ₁−Ｃ₆アルキル基、又はＣ₃−Ｃ₆シクロアルキル基を示すか、或いは、Ｒ^a及びＲ^bは、一緒になって、Ｃ₄−Ｃ₈アルキレン基を示す。）を有する化合物とを不活性溶媒中で反応させ、酸で加水分解させて、一般式（４）

(In the formula, R ^a and R ^b are the same or different and are each a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group substituted with C ₁ -C ₆ alkoxy, or C ₃ -C _{6, respectively.} A cycloalkyl group or R ^a and R ^{b taken} together represent a C ₄ -C ₈ alkylene group) and reacted with an acid in an inert solvent and hydrolyzed with an acid. General formula (4)

（式中、Ａｒは前記と同意義を示す。）を有する化合物を製造し、次いで、酸の存在下、一般式（４）を有する化合物と一般式（５）
ＨＯ−Ｗ−ＯＨ （５）
（式中、ＷはＣ₁−Ｃ₆アルキレン基を示す。）を有する化合物とを反応させることを特徴とする、一般式（１）

(Wherein Ar has the same meaning as described above), and then in the presence of an acid, the compound having the general formula (4) and the general formula (5)
HO-W-OH (5)
(Wherein W represents a C ₁ -C ₆ alkylene group) and a compound having the general formula (1)

（式中、Ａｒ及びＷは前記と同意義を示す。）を有する化合物の製造方法に関する。

上記のうち、好適な方法は、
（２） Ａｒがフェニル、又は置換基群αから選択される基で置換されたフェニルである方法、
（３） Ａｒがフェニル基、又はメチル、メトキシ、エトキシ及びメチルチオから選択される基で置換されたフェニル基である方法、
（４） Ａｒが４−メチルフェニル、３−メチルフェニル、４−メトキシフェニル、４−エトキシフェニル、４−メチルチオフェニル、３，４−ジメチルフェニル又は３，４−ジメトキシフェニル基である方法、
（５） Ｘが臭素原子又はヨウ素原子である方法、
（６） Ｘが臭素原子である方法、
（７） Ｒ^a及びＲ^bが、同一若しくは異なって、それぞれ、Ｃ₂−Ｃ₅アルキル基、Ｃ₁−Ｃ₄アルコキシで置換されたＣ₂−Ｃ₅アルキル基、又はＣ₄−Ｃ₆シクロアルキル基である方法、
（８） Ｒ^a及びＲ^bが、同一若しくは異なって、それぞれ、イソプロピル、イソブチル、イソペンチル、２−メトキシエチル、３−メトキシプロピル、２−エトキシエチル、シクロペンチル又はシクロヘキシル基である方法、
（９） Ｒ^a及びＲ^bがそれぞれイソブチル基である方法、
（１０） Ｗが、Ｃ₃−Ｃ₅直鎖若しくは分枝鎖アルキレン基である方法、
（１１） Ｗが、Ｃ₃−Ｃ₅直鎖アルキレン基である方法、及び
（１２） Ｗが、２−メチルトリメチレン又は２，２−ジメチルトリメチレン基である方法である。

また、本発明は、
（１３） 一般式（２）

(Wherein Ar and W are as defined above).

Among the above, the preferred method is
(2) The method wherein Ar is phenyl or phenyl substituted with a group selected from the substituent group α,
(3) The method wherein Ar is a phenyl group or a phenyl group substituted with a group selected from methyl, methoxy, ethoxy and methylthio,
(4) the method wherein Ar is 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 3,4-dimethylphenyl or 3,4-dimethoxyphenyl;
(5) A method wherein X is a bromine atom or an iodine atom,
(6) The method wherein X is a bromine atom,
(7) R ^a and R ^b are the same or different and each represents a C ₂ -C ₅ alkyl group, a C ₂ -C ₅ alkyl group substituted with C ₁ -C ₄ alkoxy, or C ₄ -C ₆ cyclo A method which is an alkyl group,
(8) R ^a and R ^b are the same or different and are each an isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, cyclopentyl or cyclohexyl group,
(9) The method wherein R ^a and R ^b are each an isobutyl group,
(10) The method wherein W is a C ₃ -C ₅ linear or branched alkylene group,
(11) A method in which W is a C ₃ -C ₅ linear alkylene group, and (12) a method in which W is a 2-methyltrimethylene or 2,2-dimethyltrimethylene group.

The present invention also provides:
(13) General formula (2)

（式中、ＡｒはＣ₆−Ｃ₁₀アリール基、又は置換基群αから選択される基で置換されたＣ₆−Ｃ₁₄アリール基を示し、置換基群αはハロゲン原子、Ｃ₁−Ｃ₆アルキル基、ハロゲン化Ｃ₁−Ｃ₆アルキル基、水酸基、Ｃ₁−Ｃ₆アルコキシ基、Ｃ₁−Ｃ₆アルキルチオ基、メルカプト基、Ｃ₁−Ｃ₆アルキルスルホニル基及びスルファモイル基からなる群を示し、Ｘはハロゲン原子を示す。）と一般式（３）

(In the formula, Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from the substituent group α, wherein the substituent group α is a halogen atom, C ₁ -C _A group consisting of ₆ alkyl groups, halogenated C ₁ -C ₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, mercapto groups, C ₁ -C ₆ alkylsulfonyl groups and sulfamoyl groups X represents a halogen atom) and general formula (3)

（式中、Ｒ^a及びＲ^bは、同一若しくは異なって、それぞれ、Ｃ₁−Ｃ₆アルキル基、Ｃ₁−Ｃ₆アルコキシで置換されたＣ₁−Ｃ₆アルキル基、又はＣ₃−Ｃ₆シクロアルキル基を示すか、或いは、Ｒ^a及びＲ^bは、一緒になって、Ｃ₄−Ｃ₈アルキレン基を示す。）を有する化合物とを不活性溶媒中で反応させ、酸で加水分解させて、一般式（４）

(Wherein, R ^a and R ^b are the same or different and each represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group substituted with C ₁ -C ₆ alkoxy, or C ₃ -C _6). A cycloalkyl group or R ^a and R ^{b taken} together represent a C ₄ -C ₈ alkylene group) and reacted with an acid in an inert solvent and hydrolyzed with an acid. General formula (4)

（式中、Ａｒは前記と同意義を示す。）を有する化合物を製造する工程；及び
酸の存在下、一般式（４）を有する化合物と一般式（５）
ＨＯ−Ｗ−ＯＨ （５）
（式中、ＷはＣ₁−Ｃ₆アルキレン基を示す。）を有する化合物とを反応させて一般式（１）

(Wherein Ar is as defined above), and in the presence of an acid, the compound having the general formula (4) and the general formula (5)
HO-W-OH (5)
(Wherein W represents a C ₁ -C ₆ alkylene group) and a compound having the general formula (1)

（式中、Ａｒ及びＷは前記と同意義を示す。）を製造する工程
を包含することを特徴とする、一般式（７）

(Wherein Ar and W have the same meaning as described above).

［式中、ＡｒはＣ₆−Ｃ₁₀アリール基、又は置換基群αから選択される基で置換されたＣ₆−Ｃ₁₄アリール基を示し、置換基群αはハロゲン原子、Ｃ₁−Ｃ₆アルキル基、ハロゲン化Ｃ₁−Ｃ₆アルキル基、水酸基、Ｃ₁−Ｃ₆アルコキシ基、Ｃ₁−Ｃ₆アルキルチオ基、メルカプト基、Ｃ₁−Ｃ₆アルキルスルホニル基及びスルファモイル基からなる群を示し、Ｙは、メチル又はアミノ基を示す（Ｙは、好適には、アミノ基である）。］を有する化合物の製造方法、及び、
（１４） 一般式（２）

[Wherein Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from substituent group α, wherein substituent group α is a halogen atom, C ₁ -C _A group consisting of ₆ alkyl groups, halogenated C ₁ -C ₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, mercapto groups, C ₁ -C ₆ alkylsulfonyl groups and sulfamoyl groups Y represents a methyl or amino group (Y is preferably an amino group). And a method for producing a compound having
(14) General formula (2)

（式中、ＡｒはＣ₆−Ｃ₁₀アリール基、又は置換基群αから選択される基で置換されたＣ₆−Ｃ₁₄アリール基を示し、置換基群αはハロゲン原子、Ｃ₁−Ｃ₆アルキル基、ハロゲン化Ｃ₁−Ｃ₆アルキル基、水酸基、Ｃ₁−Ｃ₆アルコキシ基、Ｃ₁−Ｃ₆アルキルチオ基、メルカプト基、Ｃ₁−Ｃ₆アルキルスルホニル基及びスルファモイル基からなる群を示し、Ｘはハロゲン原子を示す。）と一般式（３）

(In the formula, Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from the substituent group α, wherein the substituent group α is a halogen atom, C ₁ -C _A group consisting of ₆ alkyl groups, halogenated C ₁ -C ₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, mercapto groups, C ₁ -C ₆ alkylsulfonyl groups and sulfamoyl groups X represents a halogen atom) and general formula (3)

（式中、Ｒ^a及びＲ^bは、同一若しくは異なって、それぞれ、Ｃ₁−Ｃ₆アルキル基、Ｃ₁−Ｃ₆アルコキシで置換されたＣ₁−Ｃ₆アルキル基、又はＣ₃−Ｃ₆シクロアルキル基を示すか、或いは、Ｒ^a及びＲ^bは、一緒になって、Ｃ₄−Ｃ₈アルキレン基を示す。）を有する化合物とを不活性溶媒中で反応させ、酸で加水分解させて、一般式（４）

(Wherein, R ^a and R ^b are the same or different and each represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group substituted with C ₁ -C ₆ alkoxy, or C ₃ -C _6). A cycloalkyl group or R ^a and R ^{b taken} together represent a C ₄ -C ₈ alkylene group) and reacted with an acid in an inert solvent and hydrolyzed with an acid. General formula (4)

（式中、Ａｒは前記と同意義を示す。）を有する化合物を製造し、次いで、酸の存在下、一般式（４）を有する化合物と一般式（５）
ＨＯ−Ｗ−ＯＨ （５）
（式中、ＷはＣ₁−Ｃ₆アルキレン基を示す。）を有する化合物とを反応させて一般式（１）

(Wherein Ar is as defined above), and then in the presence of an acid, the compound having the general formula (4) and the general formula (5)
HO-W-OH (5)
(Wherein W represents a C ₁ -C ₆ alkylene group) and a compound having the general formula (1)

（式中、Ａｒ及びＷは前記と同意義を示す。）を製造し、更に、一般式（１）の化合物と一般式（６）

(Wherein Ar and W are as defined above), and the compound of general formula (1) and general formula (6)

［式中、Ｙは、メチル又はアミノ基を示す（Ｙは、好適には、アミノ基である）。］有する化合物とを反応させて、一般式（７）

[Wherein Y represents a methyl or amino group (Y is preferably an amino group). And a compound having the general formula (7)

［式中、ＡｒはＣ₆−Ｃ₁₀アリール基、又は置換基群αから選択される基で置換されたＣ₆−Ｃ₁₄アリール基を示し、置換基群αはハロゲン原子、Ｃ₁−Ｃ₆アルキル基、ハロゲン化Ｃ₁−Ｃ₆アルキル基、水酸基、Ｃ₁−Ｃ₆アルコキシ基、Ｃ₁−Ｃ₆アルキルチオ基、メルカプト基、Ｃ₁−Ｃ₆アルキルスルホニル基及びスルファモイル基からなる群を示し、Ｙは、メチル又はアミノ基を示す（Ｙは、好適には、アミノ基である）。］を有する化合物を製造する方法
を提供する。

本発明を特定するために用いられている、「Ｃ₆−Ｃ₁₀アリール基」、「ハロゲン原子」、「Ｃ₁−Ｃ₆アルキル基」、「ハロゲン化Ｃ₁−Ｃ₆アルキル基」、「Ｃ₁−Ｃ₆アルコキシ基」、「Ｃ₁−Ｃ₆アルキルチオ基」、「Ｃ₁−Ｃ₆アルキルスルホニル基」、「Ｃ₃−Ｃ₆シクロアルキル基」、「Ｃ₄−Ｃ₈アルキレン基」及び「Ｃ₁−Ｃ₆アルキレン基」の語は、それぞれ以下のように定義される。

[Wherein Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from substituent group α, wherein substituent group α is a halogen atom, C ₁ -C _A group consisting of ₆ alkyl groups, halogenated C ₁ -C ₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, mercapto groups, C ₁ -C ₆ alkylsulfonyl groups and sulfamoyl groups Y represents a methyl or amino group (Y is preferably an amino group). A method for producing a compound having the formula:

“C ₆ -C ₁₀ aryl group”, “halogen atom”, “C ₁ -C ₆ alkyl group”, “halogenated C ₁ -C ₆ alkyl group”, “ “C ₁ -C ₆ alkoxy group”, “C ₁ -C ₆ alkylthio group”, “C ₁ -C ₆ alkylsulfonyl group”, “C ₃ -C ₆ cycloalkyl group”, “C ₄ -C ₈ alkylene group” And the term “C ₁ -C ₆ alkylene group” are respectively defined as follows.

Ar in the definition of "C ₆ -C ₁₀ aryl group" moiety of the "C ₆ -C ₁₀ aryl group" and "substituted with a group selected from Substituent group α a C ₆ -C ₁₀ aryl group" is, It can be a phenyl or naphthyl group, and is preferably a phenyl group.

The “C ₆ -C ₁₀ aryl group” may be condensed with C ₃ -C ₁₀ cycloalkyl (preferably C ₅ -C ₆ cycloalkyl), for example, 5-indanyl. obtain.

The “C ₆ -C ₁₀ aryl group substituted with a group selected from substituent group α” in the definition of Ar is preferably substituted with 1 to 4 groups selected from substituent group α. A C ₆ -C ₁₀ aryl group, more preferably a C ₆ -C ₁₀ aryl group substituted with 1 to 3 groups selected from the substituent group α, and even more preferably A C ₆ -C ₁₀ aryl group substituted with one or two groups selected from the substituent group α.

The “halogen atom” in the definition of the substituent groups α and X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the substituent group α, a fluorine atom, a chlorine atom or a bromine atom is preferable, and a fluorine atom or a chlorine atom is more preferable. As X, a bromine atom or an iodine atom is preferable, and a bromine atom is particularly preferable.

Substituent group alpha, "C ₁ -C ₆ alkyl group" in the definitions of R ^a and R ^b, as well as, C ₁ -C ₆ alkyl substituted with "C ₁ -C ₆ alkoxy in the definitions of R ^a and R ^b The alkyl part of “group” is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl. , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl , 2,3-dimethylbutyl or 2-ethylbutyl group can be a linear or branched alkyl group, and the substituent group α is preferably A C ₁ -C ₄ straight or branched chain alkyl group, more preferably a methyl, ethyl, propyl, isopropyl or butyl group, particularly preferably a methyl, ethyl or propyl group, Most preferred is a methyl group. R ^a and R ^b are preferably a C ₂ -C ₅ linear or branched alkyl group, more preferably an ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl group, and particularly preferred. Is an isopropyl, isobutyl or isopentyl group, and most preferably an isobutyl group.

The “halogenated C ₁ -C ₆ alkyl group” in the definition of the substituent group α is such that one or more hydrogen atoms of the “C ₁ -C ₆ alkyl group” are substituted with the “halogen atom”. Group, preferably a halogenated C ₁ -C ₄ alkyl group, more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloro Ethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl group, and more preferably trifluoromethyl, trichloromethyl, difluoromethyl. Or a fluoromethyl group, and most preferably a trifluoromethyl group.

"C ₁ -C ₆ alkoxy group" in the definition of Substituent group alpha, and alkoxy moiety of the "C ₁ -C ₆ C ₁ -C ₆ alkyl group substituted with an alkoxy" in the definitions of R ^a and R ^b , A group in which an oxygen atom is bonded to the “C ₁ -C ₆ alkyl group”, preferably a C ₁ -C ₄ linear or branched alkoxy group, more preferably methoxy, ethoxy, A propoxy, isopropoxy or butoxy group, particularly preferably a methoxy, ethoxy or propoxy group. The substituent group α is most preferably an ethoxy group.

The “C ₁ -C ₆ alkylthio group” in the definition of the substituent group α is a group in which a sulfur atom is bonded to the above “C ₁ -C ₆ alkyl group”, preferably a C ₁ -C ₄ straight chain or A branched alkylthio group, more preferably a methylthio, ethylthio, propylthio, isopropylthio or butylthio group, and particularly preferably a methylthio, ethylthio or propylthio group.

The “C ₁ -C ₆ alkylsulfonyl group” in the definition of the substituent group α is a group in which sulfonyl (—SO ₂ —) is bonded to the above “C ₁ -C ₆ alkyl group”, preferably C ₁ -C ₄ a linear or branched alkylsulfonyl group, more preferably a methylsulfonyl, ethylsulfonyl, propyl sulfonyl, isopropylsulfonyl or butylsulfonyl group, particularly preferably a methylsulfonyl, ethylsulfonyl or propyl A sulfonyl group, and most preferably a methylsulfonyl group.

The “C ₃ -C ₆ cycloalkyl group” in the definition of R ^a and R ^b can be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a C ₄ -C ₆ cycloalkyl group, more preferably Is a cyclopentyl or cyclohexyl group.

“C ₄ -C ₈ alkylene group” represented by R ^a and R ^{b taken} together is tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,1 -Dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene, hexamethylene, 2-methylpentamethylene, heptamethylene or 2,4-dimethylpentamethylene group, preferably C _{A 4-} C ₆ straight chain or branched alkylene group, more preferably a tetramethylene or pentamethylene group, and particularly preferably a tetramethylene group.

“C ₁ -C ₆ alkylene group” in the definition of W means methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1, It may be a linear or branched alkylene group such as 1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene or a hexamethylene group, preferably a C ₃ -C ₅ straight chain. A chain or branched alkylene group, more preferably a trimethylene, 2-methyltrimethylene or 2,2-dimethyltrimethylene group, and particularly preferably a trimethylene or 2,2-dimethyltrimethylene group. And most preferably a 2,2-dimethyltrimethylene group.

Ar, X, W, and the substituent group α each represent a group as defined above. Among them, preferred groups are as follows.

  Ar is preferably a phenyl group or a phenyl group substituted with a group selected from the substituent group α, and more preferably a phenyl group or a group selected from methyl, methoxy, ethoxy and methylthio More preferably a phenyl group substituted with a group selected from methyl, methoxy, ethoxy and methylthio, particularly preferably 4-methylphenyl, 3-methylphenyl 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 3,4-dimethylphenyl or 3,4-dimethoxyphenyl, most preferably 4-ethoxyphenyl or 3,4-dimethylphenyl .

  X is preferably a bromine atom or an iodine atom, and particularly preferably a bromine atom.

W is preferably a C ₃ -C ₅ linear or branched alkylene group, more preferably a C ₃ -C ₅ linear alkylene group, still more preferably trimethylene, 2-methyl. It is a trimethylene or 2,2-dimethyltrimethylene group, particularly preferably a trimethylene or 2,2-dimethyltrimethylene group, and most preferably a 2,2-dimethyltrimethylene group.

Substituent group α is preferably composed of a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group and a C ₁ -C ₄ alkylthio group, and more preferably from a methyl, methoxy, ethoxy and methylthio group. Particularly preferably consisting of methyl and ethoxy groups.

The manufacturing method of (gamma) -ketoacetals of this invention is implemented as follows.

（上記式中、Ａｒ、Ｒ^a、Ｒ^b、Ｘ及びＷは前記と同意義を示す。）
工程１ａは、フェナシルハライド化合物（２）とエナミン化合物（３）とを、不活性溶媒中、塩基の存在下又は非存在下で反応させ、次いで反応混合物に酸を加えて加水分解させて、ジオキソ化合物（４）を製造する工程である。

(In the above formula, Ar, R ^a , R ^b , X and W are as defined above.)
In step 1a, the phenacyl halide compound (2) and the enamine compound (3) are reacted in an inert solvent in the presence or absence of a base, and then the reaction mixture is hydrolyzed by adding an acid. In this step, the dioxo compound (4) is produced.

  Inert solvents used are, for example, aliphatic hydrocarbons such as pentane, hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogens such as dichloromethane, chloroform, carbon tetrachloride or dichloroethane Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol or t-butanol; N, N-dimethyl Aprotic polar solvents such as formamide, N, N-dimethylacetamide or dimethylsulfoxide; nitriles such as acetonitrile; or esters such as methyl acetate or ethyl acetate; The suitable, aprotic polar solvents or nitriles, and particularly preferably, N, is N- dimethylacetamide or acetonitrile.

  The base used can be, for example, an organic amine such as pyridine, picoline, 4- (N, N-dimethylamino) pyridine, triethylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, preferably triethylamine, Tributylamine or diisopropylethylamine.

  The reaction temperature is −30 ° C. to 200 ° C. (preferably 0 ° C. to 100 ° C.), and the reaction time is usually 30 minutes to 30 hours (preferably 1 hour to 20 hours), depending on the reaction temperature and the like. .

  After completion of the addition reaction of the phenacyl halide compound (2) and the enamine compound (3), the dioxo compound (4) is produced by adding an acid to the reaction mixture. The acids used are, for example, inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid; or acetic acid, formic acid, succinic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid or It can be an organic acid such as trifluoromethanesulfonic acid, preferably sulfuric acid, hydrogen chloride or paratoluenesulfonic acid.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

  For example, the reaction mixture can be cooled and precipitated as crystals, or neutralized as appropriate, and if insolubles are present, removed by filtration, then added with water and extracted with an immiscible organic solvent such as toluene. It is obtained by washing with water or the like, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

  If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

The dioxo compound (4) produced in this step may be used in the next step (step 1b) without purification.

In step 1b, the dioxo compound (4) and the glycol compound are mixed with an acid (same as described in step 1a) in the presence of an inert solvent (same as described in step 1a). Used to produce compound (1).

  The reaction temperature is usually −70 ° C. to 100 ° C., preferably −30 ° C. to 60 ° C. The reaction time is usually 10 minutes to 20 hours, preferably 30 minutes to 2 hours.

  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

  For example, the reaction mixture can be cooled and precipitated as crystals, or neutralized as appropriate, and if insolubles are present, removed by filtration, then added with water and extracted with an immiscible organic solvent such as toluene. It is obtained by washing with water or the like, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

  If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

Compound (2), compound (3) and compound (5) which are starting materials in the method of the present invention are known compounds, and compound (2) and compound (3) are disclosed, for example, in US Pat. No. 5,908,858.

The 4-methyl-1,2-diarylpyrrole derivative (7) can be produced by carrying out the following reaction using the compound (1) produced as described above.

（式中、Ａｒ及びＷは前記と同意義を示し、Ｙは、メチル又はアミノ基を示す。）
第２工程は、化合物（１）とアニリン化合物（６）とを、不活性溶媒中、酸存在下若しくは非存在下、脱水縮合させて閉環し、１，２−ジアリールピロール化合物（７）を製造する工程である。

(In the formula, Ar and W are as defined above, and Y represents a methyl or amino group.)
In the second step , compound (1) and aniline compound (6) are subjected to dehydration condensation in an inert solvent in the presence or absence of an acid to cyclize to produce 1,2-diarylpyrrole compound (7). It is a process to do.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane or petroleum ether; benzene, toluene or xylene Aromatic hydrocarbons such as; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; methanol, ethanol, propanol, isopropanol or Alcohols such as butanol; nitriles such as acetonitrile; organic acids such as formic acid, acetic acid or propionic acid; or water, any one of which may be used alone or a mixture of liquids may be used It is done. Preferably, an alcohol-water mixed solvent, more preferably, a mixed solvent of propanol and water is used.

  The acids used are, for example, inorganic acids such as hydrochloric acid or sulfuric acid; or organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid or trifluoromethanesulfonic acid, preferably organic acids It is. More preferred is acetic acid or paratoluenesulfonic acid, and particularly preferred is paratoluenesulfonic acid. The amount of acid used is 0.01 equivalents to 50 equivalents, preferably 0.05 equivalents to 20 equivalents, and more preferably 0.1 equivalents to 10 equivalents.

  The amount of the aniline compound (6) used is 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to 1 equivalent of the compound (1).

  The reaction temperature varies depending on the solvent used, but is usually 0 ° C to 200 ° C, preferably room temperature to 150 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 30 minutes to 15 hours.

  The reaction may be carried out while removing water generated during the reaction, but usually the reaction proceeds sufficiently without such operation.

  After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method.

  For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, and then water is added to extract an immiscible organic solvent such as ethyl acetate, and the extract is washed with water. It is obtained by distilling off the solvent after drying over anhydrous magnesium sulfate or the like.

If necessary, the obtained target product can be separated and purified by a conventional method such as recrystallization, reprecipitation, or silica gel column chromatography.

According to the production method of the present invention, γ-ketoacetals with high yield and high purity can be obtained by a simple operation without using nitromethane.

  The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

[Example 1]

3- (5,5-Dimethyl-1,3-dioxan-2-yl) -1- (4-ethoxyphenyl) butan-1-one in 20 L of acetonitrile under a nitrogen stream, 2-bromo-1- (4-ethoxy Phenyl) -ethane-1-one (5.0 kg) and N, N-bis (2-methylpropyl) -1-propenylamine (5.1 kg) were added, and the mixture was stirred at about 50 ° C. for 1.5 hours. To the reaction mixture, 20 L of water, 5.0 kg of concentrated sulfuric acid, 3.2 kg of neopentyl glycol and 0.5 kg of paratoluenesulfonic acid were sequentially added, followed by stirring at about 50 ° C. for 1.5 hours. After cooling to room temperature, the precipitated crystals were collected by filtration to obtain 4.3 kg (yield 71%) of the target compound as white crystals.
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.71 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.18 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H), 2.42-2.52 (m, 1H), 2.78 (dd, J = 16.6Hz, J = 8.5Hz, 1H), 3.25 (dd, J = 16.6Hz, J = 4.6Hz, 1H), 3.41 (dd, J = 11.0Hz, J = 3.7Hz, 2H), 3.57-3.63 (m, 2H), 4.10 (q, J = 7.0Hz, 2H), 4.38 (d, J = 3.7Hz, 1H), 6.91 (d, J = 8.7Hz, 2H), 7.96 (d, J = 8.7Hz, 2H).

[Example 2]

3- (5,5-Dimethyl-1,3-dioxan-2-yl) -1- (4-ethoxyphenyl) butan-1-one In a nitrogen stream, 16 mL of dimethylacetamide was added to 2-bromo-1- (4- Ethoxyphenyl) -ethane-1-one (4.0 g) and N, N-bis (2-methylpropyl) -1-propenylamine (4.0 g) were added, and the mixture was stirred at 50 to 55 ° C. for 2 hours. To the reaction mixture, 1.6 g of paratoluenesulfonic acid and 2.1 g of neopentyl glycol were sequentially added and reacted at 50-60 ° C. for 3 hours. After adding 8 mL of water, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain 3.7 g (yield 74%) of the target compound as white crystals.

^{The 1} H-nuclear magnetic resonance spectrum was substantially the same as the ¹ H-nuclear magnetic resonance spectrum in Example 1.

[Example 3]

3- (5,5-Dimethyl-1,3-dioxan-2-yl) -1- (4-ethoxyphenyl) butan-1-one In a nitrogen stream, 16 mL of dimethylformamide was added to 2-bromo-1- (4- Ethoxyphenyl) -ethane-1-one (4.0 g) and N, N-bis (2-methylpropyl) -1-propenylamine (4.0 g) were added, and the mixture was stirred at 50 to 55 ° C. for 2 hours. To the reaction mixture, 1.6 g of paratoluenesulfonic acid and 2.1 g of neopentyl glycol were sequentially added, followed by stirring at 50-60 ° C. for 3 hours. After adding 8 mL of water, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain 3.7 g (yield 72%) of the target compound as white crystals.

^{The 1} H-nuclear magnetic resonance spectrum was substantially the same as the ¹ H-nuclear magnetic resonance spectrum in Example 1.

[Example 4]

3- (5,5-Dimethyl-1,3-dioxan-2-yl) -1- (3,4-dimethylphenyl) butan-1-one In a nitrogen stream, 990 mL of dimethylformamide was added to 2-bromo-1- ( 3,4-Dimethylphenyl) -ethan-1-one (220 g) and N, N-bis (2-methylpropyl) -1-propenylamine (249 g) were added, and the mixture was stirred at about 50 ° C. for 2 hours. After cooling to about 10 ° C., 990 mL of water, 170 g of neopentyl glycol and 173 g of concentrated sulfuric acid were sequentially added, and the mixture was stirred at about 60 ° C. for 2 hours. After cooling to room temperature, the precipitated crystals were collected by filtration to obtain 262 g (yield 83%) of the target compound as white crystals.
¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.71 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H), 1.18 (s, 3H), 2.31 (s, 6H), 2.43- 2.53 (m, 1H), 2.81 (dd, J = 16.8Hz, J = 8.5Hz, 1H), 3.26 (dd, J = 16.7Hz, J = 4.8Hz, 1H), 3.41 (dd, J = 11.1Hz, J = 4.3Hz, 2H), 3.58-3.63 (m, 2H), 4.39 (d, J = 3.4Hz, 1H), 7.20 (d, J = 7.6Hz, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.76 (s, 1H).

[Example 5]

3- (5,5-Dimethyl-1,3-dioxan-2-yl) -1- (3,4-dimethylphenyl) butan-1-one In a nitrogen stream, 2-bromo-1- (3 , 4-Dimethylphenyl) -ethane-1-one (6.2 g) and N, N-bis (2-methylpropyl) -1-propenylamine (6.8 g) were added, and the mixture was stirred at about 50 ° C. for 4 hours. After cooling to about 10 ° C., 25 mL of water, 4.3 g of neopentyl glycol, 6.2 g of concentrated sulfuric acid and 0.62 g of paratoluenesulfonic acid were added and stirred at about 60 ° C. for 1 hour. After cooling to room temperature, the precipitated crystals were collected by filtration to obtain 6.6 g (yield 84%) of the target compound as white crystals.

^{The 1} H-nuclear magnetic resonance spectrum was substantially the same as the ¹ H-nuclear magnetic resonance spectrum in Example 4.

  According to the production method of the present invention, γ-ketoacetals with high yield and high purity can be obtained by a simple operation without using nitromethane.

Claims (13)

General formula (2)

(In the formula, Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from the substituent group α, wherein the substituent group α is a halogen atom, C ₁ -C _A group consisting of a ₆ alkyl group, a halogenated C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, a mercapto group, a C ₁ -C ₆ alkylsulfonyl group and a sulfamoyl group X represents a halogen atom) and general formula (3)

(Wherein, ^{R a} and ^{R b} are the same or different, _{respectively,} C 1 -C ₆ alkyl _{group, C} 1 -C ₆ alkyl group substituted by C 1 -C ₆ alkoxy or _C 3 -C _6, A cycloalkyl group or R ^a and R ^{b taken} together represent a C ₄ -C ₈ alkylene group) and reacted with an acid in an inert solvent and hydrolyzed with an acid. General formula (4)

(Wherein Ar is as defined above), and then in the presence of an acid, the compound having the general formula (4) and the general formula (5)
HO-W-OH (5)
(Wherein W represents a C ₁ -C ₆ alkylene group) and a compound having the general formula (1)

(Wherein Ar and W are as defined above). The method according to claim 1, wherein Ar is phenyl or phenyl substituted with a group selected from substituent group α. The process according to claim 1, wherein Ar is a phenyl group or a phenyl group substituted with a group selected from methyl, methoxy, ethoxy and methylthio. 2. Ar according to claim 1, wherein Ar is a 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 3,4-dimethylphenyl or 3,4-dimethoxyphenyl group. Method. The method according to any one of claims 1 to 4, wherein X is a bromine atom or an iodine atom. The method according to any one of claims 1 to 4, wherein X is a bromine atom. R ^a and R ^b are the same or different and each represents a C ₂ -C ₅ alkyl group, a C ₂ -C ₅ alkyl group substituted with C ₁ -C ₄ alkoxy, or a C ₄ -C ₆ cycloalkyl group. 7. A method according to any one of claims 1 to 6 selected from: R ^a and R ^b are the same or different and are each selected from isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, cyclopentyl, or cyclohexyl groups. The method described in any one of the above. The method according to any one of claims 1 to 6, wherein R ^a and R ^b are each an isobutyl group. METHOD W is a C ₃ -C ₅ straight or branched chain alkylene group, as described in item 1 one selected from claims 1 to 9. METHOD W is a C ₃ -C ₅ straight chain alkylene group, as described in item 1 one selected from claims 1 to 9. The method according to any one of claims 1 to 9, wherein W is a 2-methyltrimethylene or 2,2-dimethyltrimethylene group. General formula (2)

(In the formula, Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from the substituent group α, wherein the substituent group α is a halogen atom, C ₁ -C _A group consisting of a ₆ alkyl group, a halogenated C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, a mercapto group, a C ₁ -C ₆ alkylsulfonyl group and a sulfamoyl group X represents a halogen atom) and general formula (3)

(Wherein, ^{R a} and ^{R b} are the same or different, _{respectively,} C 1 -C ₆ alkyl _{group, C} 1 -C ₆ alkyl group substituted by C 1 -C ₆ alkoxy or _C 3 -C _6, A cycloalkyl group or R ^a and R ^{b taken} together represent a C ₄ -C ₈ alkylene group) and reacted with an acid in an inert solvent and hydrolyzed with an acid. General formula (4)

(Wherein Ar is as defined above), and then in the presence of an acid, the compound having the general formula (4) and the general formula (5)
HO-W-OH (5)
(Wherein W represents a C ₁ -C ₆ alkylene group) and a compound having the general formula (1)

(Wherein Ar and W are as defined above), and the compound of general formula (1) and general formula (6)

(Wherein Y represents a methyl or amino group) is reacted with a compound having the general formula (7)

(In the formula, Ar represents a C ₆ -C ₁₀ aryl group or a C ₆ -C ₁₄ aryl group substituted with a group selected from the substituent group α, wherein the substituent group α is a halogen atom, C ₁ -C _A group consisting of a ₆ alkyl group, a halogenated C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, a mercapto group, a C ₁ -C ₆ alkylsulfonyl group and a sulfamoyl group And Y represents a methyl or amino group).