JP2010006787A - Method for producing malonic acid ester derivative or keto acid ester derivative and new compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for easily and efficiently producing a malonic acid ester derivative or a keto acid ester derivative and to provide a new compound. <P>SOLUTION: The method for producing a malonic acid ester derivative or a keto acid ester derivative comprises the light exposure of a compound of formula R<SP>1</SP>C(O)CC(O)R<SP>2</SP>in a solvent expressed by ROH (methanol, ethanol, propanol, etc.) in the presence of oxygen and a catalyst comprising a bivalent metal iodide (CaI<SB>2</SB>, MgI<SB>2</SB>, NiI<SB>2</SB>, etc.) and/or a catalyst comprising a bivalent metal hydroxide [Ca(OH)<SB>2</SB>, Ni(OH)<SB>2</SB>, Co(OH)<SB>2</SB>, etc.] and iodine to produce the malonic acid ester derivative or a keto acid ester derivative [ROC(O)C(R<SP>1</SP>)(OH)C(O)R<SP>3</SP>]. The method for producing a malonic acid derivative comprises a step of producing an intermediate which is a new compound. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a malonic ester derivative or a keto ester derivative and a novel compound. More specifically, the present invention relates to a simple and efficient method for producing a malonic ester derivative or a keto ester derivative and a novel compound.

Malonic acid ester derivatives or keto acid ester derivatives have ester sites that can be converted into various functional groups, and are thus produced in large quantities as various chemical products and pharmaceutical raw materials. In particular, malonic acid derivatives are compounds useful for organic synthesis in the fields of medicine and agricultural chemicals, and are widely used in the pharmaceutical industry, particularly as a raw material for sleeping agents.
The active methylene group sandwiched between the malonic acid diester groups is easily deprotonated in the presence of a base to generate an anionic species, so various electrophiles can be introduced. It is synthesized.
However, there is a problem that a base is required in the production process, and it is difficult to introduce an aromatic ring such as benzene which is an important functional group.
Here, the manufacturing method which synthesize | combines a malonic acid derivative from malonic acid dialkyl ester is disclosed (for example, refer patent document 1).
According to this production method, a malonic acid derivative can be produced by reacting a malonic acid dialkyl ester with an alkali metal salt and then reacting with a polyfluoroalkyl iodide.

JP 11-246480 A

However, the above production method is not an efficient production method because it requires a step of once converting to an alkali metal salt.
Furthermore, a method for producing a malonic acid derivative containing an aromatic ring that is particularly important for pharmaceuticals is not disclosed.

  The present invention solves the above-described conventional problems, and an object thereof is to provide a simple and efficient method for producing a malonic ester derivative or a keto ester derivative, and a novel compound.

〔一般式（２）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕

〔一般式（３）において、Ｒは炭素数１〜５のアルキル基を示し、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^３は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕
２．上記一般式（２）で表される化合物１モルに対して、上記触媒が、０．１５〜０．４モルである上記１．に記載のマロン酸エステル誘導体又はケト酸エステル誘導体の製造方法。
３．上記溶媒が、メタノール、エタノール及びプロパノールから選ばれる少なくとも１種である上記１．又は上記２．に記載のマロン酸エステル誘導体又はケト酸エステル誘導体の製造方法。
４．下記一般式（４）で表される中間体を製造する工程を備える上記１．乃至３．のいずれかに記載のマロン酸エステル誘導体又はケト酸エステル誘導体の製造方法。

〔一般式（４）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕
５．下記一般式（１）で表される溶媒中で、下記一般式（２）で表される化合物から下記一般式（３）で表されるマロン酸エステル誘導体又はケト酸エステル誘導体を製造する製造方法であって、２価の金属ヨウ化物及びヨウ素から選ばれる少なくとも１種の触媒と、酸素との存在下で、光照射により、下記一般式（２）で表される化合物から下記一般式（４）で表される中間体を製造する第１工程と、１価の金属ヨウ化物、２価の金属ヨウ化物、１価の金属水酸化物及び２価の金属水酸化物から選ばれる少なくとも１種の触媒の存在下で、下記一般式（４）で表される中間体から下記一般式（３）で表されるマロン酸エステル誘導体又はケト酸エステル誘導体を製造する第２工程と、を、順次、備えることを特徴とするマロン酸エステル誘導体又はケト酸エステル誘導体の製造方法。
ＲＯＨ （１）
〔一般式（１）において、Ｒは炭素数１〜５のアルキル基を示す。〕

〔一般式（２）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕

〔一般式（３）において、Ｒは炭素数１〜５のアルキル基を示し、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^３は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕

〔一般式（４）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕
６．下記一般式（４）で表されることを特徴とする化合物。

〔一般式（４）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕 The present invention is as follows.
1. In the solvent represented by the following general formula (1), light is present in the presence of a catalyst composed of a divalent metal iodide and / or a catalyst composed of a divalent metal hydroxide and iodine and oxygen. A malonic acid ester derivative or keto acid ester characterized by producing a malonic acid ester derivative or keto acid ester derivative represented by the following general formula (3) by irradiation with a compound represented by the following general formula (2) A method for producing a derivative.
ROH (1)
[In General formula (1), R shows a C1-C5 alkyl group. ]

[In General Formula (2), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, and an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

In [Formula (3), R represents an alkyl group having 1 to 5 carbon atoms, ^{R 1} represents an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, 7 carbon atoms 12 represents an alkoxyphenyl group having 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, and R ³ represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. Show. ]
2. The catalyst is used in an amount of 0.15 to 0.4 mol per mol of the compound represented by the general formula (2). A method for producing a malonic ester derivative or a keto ester derivative described in 1.
3. The above 1. wherein the solvent is at least one selected from methanol, ethanol and propanol. Or 2. A method for producing a malonic ester derivative or a keto ester derivative described in 1.
4). The said 1. provided with the process of manufacturing the intermediate body represented by following General formula (4). To 3. A method for producing a malonic ester derivative or a keto ester derivative according to any one of the above.

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]
5). The manufacturing method which manufactures the malonic acid ester derivative or keto acid ester derivative represented by the following general formula (3) from the compound represented by the following general formula (2) in the solvent represented by the following general formula (1) In the presence of at least one catalyst selected from divalent metal iodides and iodine and oxygen, the compound represented by the following general formula (2) is irradiated with light in the presence of the following general formula (4). And at least one selected from a monovalent metal iodide, a divalent metal iodide, a monovalent metal hydroxide, and a divalent metal hydroxide. In the presence of the catalyst, the second step of producing the malonic ester derivative or keto ester derivative represented by the following general formula (3) from the intermediate represented by the following general formula (4), sequentially, A malonic acid ester derivative characterized by comprising Method for producing a keto acid ester derivative.
ROH (1)
[In General formula (1), R shows a C1-C5 alkyl group. ]

[In General Formula (2), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, and an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

In [Formula (3), R represents an alkyl group having 1 to 5 carbon atoms, ^{R 1} represents an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, 7 carbon atoms 12 represents an alkoxyphenyl group having 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, and R ³ represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. Show. ]

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]
6). The compound represented by following General formula (4).

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

According to the production method of the present invention, a catalyst comprising a divalent metal iodide and / or a catalyst comprising a divalent metal hydroxide and iodine in the solvent represented by the general formula (1) The malonic acid ester derivative or keto acid ester derivative represented by the general formula (3) can be produced from the compound represented by the general formula (2) by light irradiation in the presence of oxygen. Therefore, the malonic acid ester derivative or keto acid ester derivative can be produced efficiently and reliably by a simple operation.
Moreover, when the said catalyst is 0.15-0.4 mol with respect to 1 mol of said dicarbonyl compounds, a malonic acid ester derivative or a keto acid ester derivative can be manufactured still more efficiently.
Furthermore, when the solvent is at least one selected from methanol, ethanol and propanol, the malonic acid ester derivative or keto acid ester derivative can be produced particularly efficiently.
Moreover, since it can be set as a manufacturing process provided with the process of manufacturing the intermediate body represented by General formula (4), it is useful at the point which can utilize this intermediate body.
Further, from the compound represented by the above general formula (2) by light irradiation in the presence of at least one catalyst selected from divalent metal iodides and iodine and oxygen, the following general formula (4) A first step of producing an intermediate represented by the formula: at least one selected from a monovalent metal iodide, a divalent metal iodide, a monovalent metal hydroxide, and a divalent metal hydroxide. In the presence of a catalyst, the second step of producing the malonic acid ester derivative or keto acid ester derivative represented by the general formula (3) from the intermediate represented by the general formula (4) is sequentially performed. In the case of the method for producing a malonic ester derivative or keto ester derivative provided, a catalyst with higher yield can be selected in each step, and in the second step, oxygen and light irradiation are required. More efficient and reliable It can be produced malonic acid ester derivative or keto acid ester derivative.
Moreover, since the compound represented by the general formula (4) is chemically stable, it can be used as a raw material for various malonic acid derivatives.

〔一般式（２）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕

〔一般式（３）において、Ｒは炭素数１〜５のアルキル基を示し、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^３は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕 The present invention will be described in detail below.
[1] Method for producing malonic ester derivative or keto ester derivative The method for producing the malonic ester derivative or keto ester derivative of the present invention is a divalent metal in a solvent represented by the following general formula (1). From the compound represented by the above general formula (2) by light irradiation in the presence of a catalyst composed of iodide and / or a catalyst composed of a divalent metal hydroxide and iodine and oxygen, the following general formula It is characterized by producing a malonic ester derivative or a keto ester derivative represented by (3).
In the present specification, a compound represented by the following general formula (3) is referred to as “malonic ester derivative or keto ester derivative”.
Yeah.
ROH (1)
[In General formula (1), R shows a C1-C5 alkyl group. ]

[In General Formula (2), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, and an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

In [Formula (3), R represents an alkyl group having 1 to 5 carbon atoms, ^{R 1} represents an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, 7 carbon atoms 12 represents an alkoxyphenyl group having 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, and R ³ represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. Show. ]

The above “solvent represented by the general formula (1)” means a lower alcohol having 1 to 5 carbon atoms.
Since alcohol can be used as a solvent, it is not necessary to use a halogen-based solvent, and the reaction is environmentally friendly and fulfills the concept of so-called green chemistry.
R in the general formula (1) represents an alkyl group having 1 to 5 carbon atoms, and may be linear or branched. Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, and pentyl group. Can be mentioned.
With these solvents, malonic acid derivatives can be produced efficiently. On the other hand, when R in the general formula (1) has 6 or more carbon atoms, the boiling point becomes high and it becomes difficult to remove (evaporate) from the reaction mixture. There is a risk of decreasing the solubility of the reagent.

  The solvent is preferably at least one selected from methanol, ethanol and propanol. If it is reaction with these solvents, the solubility with respect to a reaction reagent is high, and since the molecule | numerator is small, reaction rate is also quick. Furthermore, since it has a low boiling point, it can be easily removed (evaporated) from the reaction mixture, so that the malonic acid derivative can be produced more efficiently.

The “catalyst” is a catalyst composed of a divalent metal iodide and / or a catalyst composed of a divalent metal hydroxide and iodine. Only a catalyst composed of a divalent metal iodide, only a catalyst composed of a combination of a divalent metal hydroxide and iodine, may be used, or they may be used in combination.
The "divalent metal iodide", if a divalent metal iodide compound formed from a divalent metal is not particularly limited, for _example, MgI _{2, CaI} 2, SrI _2, BaI 2, ZnI ₂ , NiI ₂ , CoI ₂ , SmI ₂ , MnI ₂ , TiI ₂ . Among _these, preferred are _{MgI 2, CaI 2, SrI 2} , BaI 2, ZnI 2, NiI 2, CoI 2, SmI 2, MgI 2, CaI 2, SrI 2, ZnI 2, NiI 2, CoI 2 more preferably , CaI ₂ , NiI ₂ , and CoI ₂ are particularly preferable. If _{CaI 2, NiI 2, CoI 2} , can be produced very efficiently malonic acid derivatives.

Instead of “divalent metal iodide” or “divalent metal iodide”, “divalent metal hydroxide and iodine” may be used. In addition, since the catalyst which consists of a bivalent metal hydroxide and iodine is "and", both a bivalent metal hydroxide and iodine are required.
The “divalent metal hydroxide” is not particularly limited as long as it is a divalent metal hydroxide compound formed from a divalent metal. For example, Mg (OH) ₂ , Ca (OH) ₂ , Ba (OH) ₂ , Ni (OH) ₂ , Co (OH) ₂ , and Cu (OH) ₂ may be mentioned. Among these, Ca (OH) ₂ , Ni (OH) ₂ , and Co (OH) ₂ are preferable, and Ca (OH) ₂ is particularly preferable.
Iodine means simple iodine. The mixing ratio (molar ratio) of the divalent metal hydroxide and iodine is preferably divalent metal hydroxide: iodine = (1:20) to (20: 1), (1: 2) More preferably, it is-(2: 1).

  The amount of the catalyst is preferably 0.15 to 0.4 mol relative to 1 mol of the compound represented by the general formula (2) (hereinafter also simply referred to as “compound”), and 0.2 More preferably, it is -0.4 mol. If it is less than 0.15 mol, the effect as a catalyst may be reduced, and if it exceeds 0.4 mol, it may hinder the transmission of light when irradiated with light and may cause a reduction in reaction efficiency.

The above “oxygen” means simple molecular oxygen. This is because molecular oxygen has very high atomic efficiency and plays a role as an oxidizing agent.
“In the presence of oxygen” means that oxygen is present in the reaction system at normal temperature and normal pressure, which means a so-called oxygen atmosphere. For example, a gas other than oxygen, such as air, may be contained, and oxygen may be 100%, or may contain oxygen and an inert gas such as nitrogen, helium, or argon.
The oxygen gas concentration is preferably 70% by volume or more, and more preferably 80% by volume or more. A high concentration of oxygen is preferably present, and the reaction efficiency can be increased by the high concentration of oxygen.
Specifically, oxygen can be present by blowing oxygen into a closed reaction vessel with an oxygen balloon.
The amount of oxygen in the reaction may be equal to or more than the equivalent of the compound, but a large excess of 5 times equivalent or more is preferable with respect to the compound represented by the general formula (2), more preferably 10 times equivalent or more. A double equivalent or more is more preferable.
Further, the pressure condition may be any of reduced pressure, increased pressure or normal pressure, but the pressure is preferably 0.09 to 5 MPa, more preferably 0.09 to 1.2 MPa, and further preferably 0.1 to 1.1 MPa. preferable. Although the reaction can be promoted by increasing the pressure, normal pressure in the range of 0.09 to 0.11 MPa or near normal pressure is preferable in that the production conditions can be simplified.
This reaction may be a batch reaction or a continuous reaction.

The reaction temperature is appropriately selected depending on the reaction conditions such as the type of compound, the solvent used and the reaction time. Although the reaction can be promoted by heating, the heating temperature is preferably not higher than the boiling point of the solvent used. In addition, reaction temperature is 0-200 degreeC, for example, Preferably it is 10-150 degreeC, More preferably, it is 10-100 degreeC, More preferably, it is 10-60 degreeC.
Moreover, it can also be set as the reaction temperature of the normal temperature vicinity which does not heat 20-25 degreeC.

The “light irradiation” refers to irradiating the reaction system with light. By irradiating with light, a photo-oxygen oxidation reaction can be performed in the presence of the oxygen.
The light is preferably visible light or ultraviolet light, and more preferably visible light. Specifically, artificial light and sunlight can be used. For example, general-purpose fluorescent lamps as artificial lamps that emit visible light can be arranged and irradiated on the reaction vessel. A general-purpose fluorescent lamp is simple and low-cost.
The reaction time, which is the irradiation time, is not particularly limited, but is preferably 1 hour to 72 hours, more preferably 5 hours to 48 hours, and particularly preferably 8 hours to 24 hours. When the reaction time is within the above range, the malonic ester derivative or keto ester derivative is efficiently produced.

In the compound represented by the general formula (2), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or a carbon number. 7 to 12 aralkyl groups, halogenated phenyl groups, nitrophenyl groups or pyridyl groups are shown.
The alkyl group having 1 to 8 carbon atoms may be linear or branched, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n -Butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-hexyl group, n-octyl group and the like can be mentioned. Of these, a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group are preferable.

  Examples of the alkylphenyl group having 7 to 12 carbon atoms include 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, ethylphenyl group, 4-tert-butylphenyl group, 4-butylphenyl group. And dimethylphenyl group

  Examples of the alkoxyphenyl group having 7 to 12 carbon atoms include a methoxyphenyl group, an ethoxyphenyl group, an n-propoxyphenyl group, an isopropoxyphenyl group, an n-butoxyphenyl group, an isobutoxyphenyl group, and a tert-butoxyphenyl group. , Sec-butoxyphenyl group, n-pentoxyphenyl group, neopentoxyphenyl group and the like. Of these, a methoxyphenyl group is preferable.

  Examples of the aralkyl group having 7 to 12 carbon atoms include a benzyl group and a phenethyl group.

  Examples of the halogenated phenyl group include a fluorophenyl group, a chlorophenyl group, and a bromophenyl group.

R ² in the general formula (2) represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms.
Incidentally, R ² in the general formula (2) is, in the case of alkyl group having 1 to 5 carbon atoms, a compound represented by the general formula (2) means a diketone compound, in the formula (2) When R ² is an alkoxy group having 1 to 5 carbon atoms, the compound represented by the general formula (2) means a dicarbonyl compound.

The alkyl group of 1 to 5 carbon atoms for R ² in formula (2) is the same as the alkyl group for R in the above general formula (1). Examples of the alkoxy group having 1 to 5 carbon atoms include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, and n-pentoxy group. And neopentoxy group. Of these, a methoxy group, an ethoxy group, and an isopropoxy group are preferable.

The malonic acid ester derivative or keto acid ester derivative (hereinafter also referred to as “derivative”) represented by the general formula (3) is a solvent represented by the general formula (1) (hereinafter also referred to as “solvent”). It is produced by reacting with the compound represented by the general formula (2).
That is, R ¹ in the compound is replaced with R in the solvent. Further, hydrogen contained in the methylene group in the compound is substituted with R ¹ and the hydroxyl group in the compound.
Here, R ² in the above compound usually remains R ² after the reaction, and therefore R ³ in the general formula (3) means R ² derived from the compound. However, an alkoxy group R ² is a 1 to 5 carbon atoms in the compound, the number of carbon atoms in the alkyl group in R of the solvent, is less than the number of carbon atoms of the alkoxy group in R ² of the compound, R ² of the compound solvent May be replaced by OR. For example, if R of the solvent is a methyl group and R ^{2 of} the compound is an ethoxy group, R ² of the compound may be substituted with OR of the solvent. Therefore, in this case, R ³ in the general formula (3) means OR derived from a solvent.

R ³ in the general formula (3) represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. The alkyl group having 1 to 5 carbon atoms is the same as the alkyl group represented by R in the general formula (1). As for the alkoxy group having 1 to 5 carbon atoms which is the same as the alkoxy group of R ² in the above general formula (2).
When R ³ in the general formula (3) is an alkyl group having 1 to 5 carbon atoms, the compound represented by the general formula (3) means a keto ester derivative, and the general formula (3 If R ³ is an alkoxy group having 1 to 5 carbon atoms in), the compound represented by the general formula (3) means malonic acid ester derivative.
That is, when the compound represented by the general formula (2) is a dicarbonyl compound, the product represented by the general formula (3) is a malonic ester derivative, and the general formula (2) When the represented compound is a diketone compound, the product represented by the general formula (3) is a keto acid ester derivative.

〔一般式（４）において、Ｒ^１は炭素数１〜８のアルキル基、フェニル基、炭素数７〜１２のアルキルフェニル基、炭素数７〜１２のアルコキシフェニル基、炭素数７〜１２のアラルキル基、ハロゲン化フェニル基、ニトロフェニル基又はピリジル基を示し、Ｒ^２は炭素数１〜５のアルキル基又は炭素数１〜５のアルコキシ基を示す。〕
上記一般式（４）におけるＲ^１は、前述の一般式（２）におけるＲ^１と同様であり、上記一般式（４）におけるＲ^２は、前述の一般式（２）におけるＲ^２と同様である。 Moreover, the manufacturing method of the malonic acid ester derivative or keto acid ester derivative in this invention can be equipped with the process of manufacturing the intermediate body represented by following General formula (4).
The compound represented by the following general formula (4) (hereinafter also referred to as “intermediate”) reacts with the solvent represented by the above general formula (1) and the compound represented by the above general formula (2). In the process of producing the derivative represented by the above general formula (3).

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]
^{R 1} in the general formula (4) is the same as ^{R 1} in the above general formula (2), ^{R 2} in the general formula (4) is the same as ^{R 2} in the above general formula (2) is there.

For example, as shown in the following formula (5), the derivative (C) can be produced from the compound (A) by irradiation with light in the presence of oxygen in a methanol solvent using calcium iodide as a catalyst. However, intermediate (B) is produced in this production process.

  Moreover, the manufacturing method of the malonic ester derivative or keto ester derivative in the present invention according to claim 5 is the compound represented by the general formula (2) in the solvent represented by the general formula (1). A production method for producing a malonic acid ester derivative or keto acid ester derivative represented by the above general formula (3) from at least one catalyst selected from divalent metal iodide and iodine, and oxygen A first step of producing an intermediate represented by the above general formula (4) from a compound represented by the above general formula (2) by light irradiation in the presence; a monovalent metal iodide; In the presence of at least one catalyst selected from metal iodides, monovalent metal hydroxides and divalent metal hydroxides, the intermediate represented by the above general formula (4) is converted into the above general formula (3). ) Or a malonic ester derivative represented by A second step of producing a preparative acid ester derivative, a sequentially a method of manufacturing a malonic acid ester derivative or a keto ester derivatives, characterized in that it comprises.

  The said 1st process is a process of manufacturing the intermediate body represented by the said General formula (4) from the compound represented by the said General formula (2). In the first step, the intermediate is produced in the presence of oxygen and at least one catalyst selected from divalent metal iodide and iodine by light irradiation. The “divalent metal iodide” and “iodine” are the same as the above-mentioned “divalent metal iodide” and “iodine”. Further, “in the presence of oxygen” and “light irradiation” are the same as the above-mentioned “in the presence of oxygen” and “light irradiation”.

  The reaction time in the first step is not particularly limited, but is preferably 1 hour to 36 hours, more preferably 2 hours to 24 hours, and particularly preferably 3 hours to 12 hours. When the reaction time is within the above range, the intermediate is efficiently produced.

  The second step is a step of producing a malonic ester derivative or a keto ester derivative represented by the general formula (3) from the intermediate represented by the general formula (4). In this second step, oxygen and light irradiation are unnecessary, and at least one selected from monovalent metal iodide, divalent metal iodide, monovalent metal hydroxide and divalent metal hydroxide. In the presence of the catalyst, a malonic acid ester derivative or a keto acid ester derivative represented by the general formula (3) is produced. The catalyst used in the second step is not limited to a divalent metal iodide and a divalent metal hydroxide, but may be a monovalent metal iodide and a monovalent metal hydroxide.

Examples of the monovalent metal iodide include LiI, NaI, KI, RbI, and CsI.
Examples of the monovalent metal hydroxide include LiOH, NaOH, KOH, RbOH, and CsOH. Among these, NaOH and KOH which are excellent in reaction efficiency are preferable.
The “divalent metal iodide” and the “divalent metal hydroxide” are the same as the “divalent metal iodide” and the “divalent metal hydroxide” described above.

  The reaction time in the second step is not particularly limited, but is preferably 1 hour to 36 hours, more preferably 2 hours to 24 hours, and particularly preferably 3 hours to 12 hours. When the reaction time is within the above range, the malonic ester derivative or keto ester derivative is efficiently produced.

The pressure conditions in the first step and the second step may be any of reduced pressure, increased pressure or normal pressure, but the pressure is preferably 0.09 to 5 MPa, more preferably 0.09 to 1.2 MPa. 0.1 to 1.1 MPa is more preferable. Although the reaction can be promoted by increasing the pressure, normal pressure in the range of 0.09 to 0.11 MPa or near normal pressure is preferable in that the production conditions can be simplified.
This reaction may be a batch reaction or a continuous reaction.

The reaction temperature in the first step and the second step is appropriately selected depending on the reaction conditions such as the reaction time, the solvent used, and the catalyst. Although the reaction can be promoted by heating, the heating temperature is preferably not higher than the boiling point of the solvent used. In addition, reaction temperature is 0-200 degreeC, for example, Preferably it is 10-150 degreeC, More preferably, it is 10-100 degreeC, More preferably, it is 10-60 degreeC.
Moreover, it can also be set as the reaction temperature of the normal temperature vicinity which does not heat 20-25 degreeC.

The reaction mechanism in the production method of the present invention is presumed as in the following schemes (1) to (4).

The above (1) is a scheme in which iodine anions are dissociated from divalent metal iodide. It is believed that dissociation is particularly promoted by light irradiation.
The above (2) represents the production of simple iodine from iodine anion. In this reaction, simple iodine is essential because the reaction progresses even in the presence of a divalent metal hydroxide and simple iodine, as the reaction progresses to a pale yellow color derived from simple iodine. . Therefore, when a divalent metal iodide is used, it is considered that iodine anion is oxidized by photooxygen oxidation to generate simple iodine.
The above (3) shows the mechanism of the rearrangement reaction from a dicarbonyl compound to a β-ketoester derivative (including a malonic acid derivative). First, simple iodine reacts with metal enolate 4 to generate iodide 5 and radical species 6 by light irradiation. This 6 traps molecular oxygen and produces intermediate 3 via peroxy radical species 7 and hydroperoxide 8. 3 forms enolate 9 with a divalent metal ion, and reaches a β-ketoester derivative through a rearrangement reaction starting from nucleophilic attack of alcohols.
The above (4) shows the regeneration of elemental iodine. Since the divalent metal iodide and the divalent metal hydroxide proceed in a catalytic amount, it is necessary to regenerate simple iodine in the reaction system. It is considered that iodine radicals (I.) and hydrogen iodide (HI) generated in the process of (3) above undergo photooxygen oxidation under the reaction conditions to regenerate simple iodine.
Incidentally, ^{R 1} and ^{R 2} in Scheme above (3) is the same as ^{R 1} and ^{R 2} in the above general formula (2).

The catalyst leading to the formation of the intermediate requires divalent metal iodide or iodine.
However, the catalyst from the intermediate to the final product derivative is only monovalent metal iodide, divalent metal iodide, monovalent metal hydroxide, or divalent metal hydroxide. It's okay. That is, a derivative which is a final product can be obtained from an intermediate only in the presence of a monovalent or divalent metal ion. On the other hand, iodine alone does not lead to derivatives from intermediates.

Moreover, the said intermediate is a novel substance and exists stably. For example, it exists stably for about 30 days at a temperature of 10 ° C to 30 ° C.
Therefore, it is possible to produce various malonic acid derivatives using this substance as a raw material.

  Hereinafter, the present invention will be described specifically by way of examples. Examples are Experimental Examples 1 to 10, Experimental Examples 19 to 23, Experimental Examples 27 to 32, Experimental Examples 37 to 48, and Experimental Examples 50 to 59. Comparative examples are Experimental Examples 11 to 18, Experimental Examples 24 to 26, Experimental Examples 33 to 36, and Experimental Example 60. In addition, the yield in an experiment example is a value calculated from the ratio of the number of moles of the obtained product with respect to the number of moles of the used raw material, and all indicate the isolated yield after purification.

In this example, the infrared spectrum was measured with a “Perkin-Elmer Spectrum One FT-IR spectrometer”. ¹ H-NMR spectrum was measured by “JEOL JMN-EX-400 spectrometer”. Chemical shifts were recorded in ppm using tetramethylsilane as an internal standard (CDCl ₃ ). ^{The 13} C-NMR spectrum was measured with “JEOL JMN-AL-400 spectrometer” by complete proton decoupling. Chemical shifts were recorded in ppm using TMS (tetramethylsilane) (0 ppm) as an internal standard. Mass was measured by “JMS-SX 102A”. For elemental analysis, “YANACO MT-5” was used. TLC used “Kieselgel F-254”.

  Data are chemical shift, integral value, multiplicity (s = single line, d = double line, t = triple line, q = quadruple line, quin = quintet line, brs = wide single line), And the coupling constant (Hz).

パイレックス（登録商標）試験管中でメチル３−オキソヘプタノエート０．３ｍｍｏｌと、表１に示す実験例１〜１８の触媒のうちのいずれか０．０６ｍｍｏｌ（０．２当量）をメタノール（溶媒）５ｍｌに溶解し、酸素雰囲気下（酸素風船）、攪拌しながら蛍光灯（２２ワット、松下電器産業株式会社製パルックボール；品番：ＥＦＲ２５ＥＤ／２２）４個で光照射した。蛍光灯は、原料等を入れた試験管より７ｃｍ離し、その試験管を四方から囲む形で設置した。
そして、反応後、得られた反応混合液を減圧下で溶媒留去し、残渣を酢酸エチルに溶解し分液ロートに移した。その後、チオ硫酸ナトリウムで有機層を洗浄した後、抽出を行った。その抽出した粗生成物をＰＴＬＣにて精製することにより、目的のジメチルブチルヒドロキシマロネートを得た。また、得られた生成物は、^１Ｈ−ＮＭＲ、^１３Ｃ−ＮＭＲ、ＩＲ及びＭａｓｓの測定結果から確認した。
尚、得られた生成物（Ｃ）（ジメチル２−ブチル−２−ヒドロキシマロネート）における^１Ｈ−ＮＭＲの測定結果を図１、^１３Ｃ−ＮＭＲの測定結果を図２、ＩＲの測定結果を図３に示す。
実験例１〜１８での用いた触媒及び反応時間を表１に示す。また、反応開始後１０時間、反応開始後２４時間、反応開始後４８時間及び反応開始後７２時間の反応経過時間毎の収率を表１に併記する。 [1] Production experiment based on the type of catalyst (Experimental Examples 1 to 18)
(1) Production of Malonic Acid Ester Derivative As shown in the following formula (7), a malonic acid ester derivative as a product was produced from methyl 3-oxoheptanoate as a dicarbonyl compound as a raw material.

In a Pyrex (registered trademark) test tube, 0.3 mmol of methyl 3-oxoheptanoate and 0.06 mmol (0.2 equivalent) of any of the catalysts of Experimental Examples 1 to 18 shown in Table 1 were added to methanol (solvent). The sample was dissolved in 5 ml, and irradiated with four fluorescent lamps (22 Watts, Matsushita Electric Industrial Co., Ltd. Palook Ball; product number: EFR25ED / 22) under stirring in an oxygen atmosphere (oxygen balloon). The fluorescent lamp was placed 7 cm away from the test tube containing the raw materials, and the test tube was installed so as to surround it from all sides.
After the reaction, the resulting reaction mixture was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and transferred to a separatory funnel. Thereafter, the organic layer was washed with sodium thiosulfate and then extracted. The extracted crude product was purified by PTLC to obtain the desired dimethylbutylhydroxymalonate. Moreover, the obtained product was confirmed from the measurement result of < ¹ > H-NMR, < ¹³ > C-NMR, IR, and Mass.
In addition, the measurement result of ¹ H-NMR in the obtained product (C) (dimethyl 2-butyl-2-hydroxymalonate) is shown in FIG. 1, the measurement result of ¹³ C-NMR is shown in FIG. 2, and the measurement result of IR is shown. As shown in FIG.
The catalysts and reaction times used in Experimental Examples 1 to 18 are shown in Table 1. Table 1 also shows the yields for each elapsed time of 10 hours after the start of the reaction, 24 hours after the start of the reaction, 48 hours after the start of the reaction, and 72 hours after the start of the reaction.

Dimethyl 2-butyl-2-hydroxymalonate <Dimethyl 2-butyl-2-hydroxymalonate>;
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 3.76 (s, 6H), 1.97 (t, J = 8.1 Hz, 2H), 1.29-1.20 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 171.0, 79.0, 53.2, 34.6, 25.2, 22.5, 13.8 ppm;
[3] IR (neat): 3495, 2960, 1745, 1438, 1233, 1159 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₉ H ₁₇ O ₅ [M ⁺ +1]: 205.1060, found 205.1816.

(2) Type of catalyst and yield of target product As shown in Table 1, in the case of the divalent metal iodides of Experimental Examples 1 to 10, the target product could be obtained in all cases. Among them, in the case of Experimental Examples 1 to 8, a yield of 24% or more could be obtained in 10 hours. _{Particularly,} in the case of _{CaI 2, NiI 2, CoI 2} , it was high yields of about 80%. Among them, in particular, CaI ₂ had a high yield of 85%.
Here, the yield of CaI _{2 of} Experimental Example 2 was 85% in 10 hours, and the yield after 24 hours was as high as 92% as shown in Table 1. About Experimental example 1 and Experimental examples 3-8, although the yield of only 10-hour progress is investigated, it is estimated that a yield increases by passing further time.
On the other hand, for the monovalent metal iodides of Experimental Examples 11 to 14, the tetravalent metal iodide of Experimental Example 15, the chloride of Experimental Example 16, the bromide of Experimental Example 17, and the simple iodine of Experimental Example 18, No product was obtained.
Here, in the yields of Table 1, “-” indicates no data, “nr” indicates that no reaction occurred and the raw material was recovered, and “trace” indicates a very small amount of the target product. "0" indicates that the target product was not produced, but the intermediates described later were produced (the same applies to the yields in Tables 2 to 5). In the case where the yield is trace, it is considered that the yield increases if the reaction time is further extended.

[2] Production experiment of catalyst amount, light irradiation, and influence of oxygen (Experimental Examples 19 to 26)
(1) Production of malonic ester derivative In Experimental Examples 19 to 26, calcium iodide was used as a catalyst, and methyl 3-oxoheptanoate was used as a dicarbonyl compound as a raw material. In Experimental Examples 19 to 22, the reaction time was 10 hours, and the amount of catalyst was changed to 0.1 to 0.4 equivalents relative to the dicarbonyl compound to produce the target product.
0.1 equivalent means adding 0.1 mol with respect to 1 mol of raw materials. That is, 0.03 mmol is 0.1 equivalent with respect to 0.3 mmol of methyl 3-oxoheptanoate (hereinafter, the meaning of “equivalent” is the same).
Other conditions were the same as in the production experiment of [1] above. Moreover, the obtained product was confirmed from the measurement results of ¹ H-NMR, ¹³ C-NMR, IR and Mass in the same manner as in the production experiment of [1] above.
In Experimental Example 23, the reaction time was 5 hours. Other conditions were the same as in Experimental Example 20.
In Experimental Example 24, no catalyst was used. Other conditions were the same as in Experimental Examples 19-22.
In Experimental Example 25, the test tube used in the production experiment was completely wrapped with aluminum foil and shielded from light, and was not irradiated with light. Other conditions were the same as in Experimental Example 20.
In Experimental Example 26, the test was performed in an argon atmosphere instead of an oxygen atmosphere. Other conditions were the same as in Experimental Example 20.
In addition, Table 2 shows the catalysts, catalyst amounts, presence / absence of light irradiation, presence / absence of oxygen, reaction time and yield used in Experimental Examples 19 to 26.

(2) Experimental results In Experimental Examples 19 to 22, the best yield was obtained when 0.2 equivalent was added to the raw material. The reason why the yield is lowered even if 0.3 equivalent or more is added is considered to be that the light transmittance is reduced by the catalyst and the reaction efficiency is lowered.
In Experimental Examples 24-26, it was found that the target product could not be obtained at all if any of the catalyst, light irradiation, and oxygen was missing.

[3] Production experiment by type of metal hydroxide (Experimental examples 27 to 36)
(1) Production of malonic ester derivative In Experimental Examples 27 to 36, tests were performed using iodine and metal hydroxides shown in Table 3 instead of divalent metal iodides as catalysts. The reaction time was 10 hours, and other conditions were the same as in the production experiment of [1] above.
In Experimental Examples 27 to 32, 0.2 equivalent of iodine and 0.2 equivalent of divalent metal hydroxide were used. In Experimental Examples 33 to 35, 0.1 equivalent of iodine and 0.2 equivalent of monovalent metal hydroxide were used, and in Experimental Example 36, 0.3 equivalent of iodine and 0.2 equivalent of trivalent metal hydroxide were used. .
Table 3 shows the catalyst, catalyst amount, reaction time, and yield used in Experimental Examples 27 to 36.
Moreover, the obtained product was confirmed from the measurement results of ¹ H-NMR, ¹³ C-NMR, IR and Mass in the same manner as in the production experiment of [1] above.

(2) Experimental results From the results of Experimental Examples 27 to 36, it was found that the target product could be obtained even when iodine or metal hydroxide was used as the catalyst instead of divalent metal iodide. A combination of iodine, calcium hydroxide, nickel hydroxide, and cobalt hydroxide yielded a yield of 60% or more. In particular, the combination of iodine and calcium hydroxide yielded a high yield of 85%.
On the other hand, in Experimental Examples 33 to 36, the target product was not obtained at all.

[4] Production experiment of malonic ester derivatives and keto ester derivatives from various dicarbonyl compounds and diketone compounds (Experimental Examples 37 to 48)
(1) Production of Malonic Acid Derivatives Various dicarbonyl compounds and diketone compounds shown in Table 4 were used as raw materials and converted into malonic acid ester derivatives and keto acid ester derivatives.
Various solvents shown in Table 4 were used. As the catalyst, calcium iodide was used. The catalyst amount was 0.5 equivalent for Experimental Examples 39 and 44, and 0.2 equivalent for the other Experimental Examples 37, 38, 40 to 43, and 45 to 48. The reaction time was 24 hours for Experimental Examples 43 and 46, and 10 hours for the other Experimental Examples 37 to 42, 44, 45, 47 and 48. Other conditions were the same as in the production experiment of [1] above.
In addition, Table 4 shows raw materials, solvents, products and yields used in Experimental Examples 37 to 48.
Moreover, the obtained product was confirmed from measurement results such as ¹ H-NMR, ¹³ C-NMR, and IR.

Product of Experimental Example 37 [Ethyl methyl 2-butyl-2-hydroxymalonate] <Ethyl methyl 2-butyl-2-hydroxymalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 4.29-4.24 (m, 2H), 3.80 (s, 3H), 3.77 (s, 1H), 2.03 (T, J = 8.1 Hz, 2H), 1.35-1.28 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7. 0 Hz, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 171.1, 170.6, 79.0, 62.5, 53.1, 34.4, 25.2, 22.5, 14. 0, 13.8 ppm;
[3] IR (neat): 3500, 2961, 1739, 1440, 1369, 1216, 1158 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₁₀ H ₁₉ O ₅ [M ⁺ +1]: 219.1325, found 219.12411.

Product of Experimental Example 38 [Isopropyl methyl 2-butyl-2-hydroxymalonate] <Isopropyl methyl 2-butyl-2-hydroxymalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 5.08-5.05 (m, 1H), 3.76 (s, 3H), 3.70 (s, 1H), 1.98 (T, J = 8.0 Hz, 2H), 1.36-1.24 (m, 4H), 1.24 (q, J = 3.9 Hz, 6H), 0.87 (t, J = 7. 2Hz, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 171.0, 170.3, 79.0, 70.5, 53.0, 34.2, 25.1, 22.6, 21. 5, 21.4, 13.8 ppm;
[3] IR (neat): 3500, 2960, 1739, 1455, 1377, 1232, 1160, 1105 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₁₁ H ₂₁ O ₅ [M ⁺ +1]: 233.113890, found 233.113825.

Product of Experimental Example 39 [Dimethyl 2-butyl-2-hydroxymalonate] <Dimethyl 2-butyl-2-hydroxymalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 3.76 (s, 6H), 1.97 (t, J = 8.1 Hz, 2H), 1.29-1.20 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 171.0, 79.0, 53.2, 34.6, 25.2, 22.5, 13.8 ppm;
[3] IR (neat): 3495, 2960, 1745, 1438, 1233, 1159 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₉ H ₁₇ O ₅ [M ⁺ +1]: 205.1060, found 205.1816.

Product of Experimental Example 40 [Diethyl 2-butyl-2-hydroxymalonate] <Diethyl 2-butyl-2-hydroxymalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 4.21 (q, J = 7.1 Hz, 4H), 3.73 (br, 1H), 1.97 (t, J = 8. 1 Hz, 2H), 1.35-1.20 (m, 4H), 1.24 (t, J = 7.2 Hz, 6H), 0.85 (t, J = 7.1 Hz, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 170.6, 78.9, 62.3, 34.2, 25.1, 22.5, 13.9, 13.8 ppm;
[3] IR (neat): 3500, 2962, 1739, 1467, 1368, 1212 and 1158 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₁₁ H ₂₁ O ₅ [M ⁺ +1]: 233.113890, found 233.113796.

Product of Experimental Example 41 [Ethyl isopropyl 2-butyl-2-hydroxymalonate] <Ethyl isopropyl 2-butyl-2-hydroxymalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 5.13-5.07 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.75 (s, 1H), 2.01 (t, J = 8.0 Hz, 2H), 1.34-1.26 (m, 13H), 0.90 (t, J = 7.1 Hz, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 170.6, 170.3, 78.9, 70.2, 62.1, 34.1, 25.1, 22.6, 21. 5, 21.4, 14.0, 13.8 ppm;
[3] IR (neat): 3500, 2962, 1733, 1468, 1376, 1215, 1105 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd forC ₁₂ H ₂₃ O ₅ [M ⁺ +1]: 247.15455, found 247.15538.

Product of Experimental Example 42 [Dimethyl 2-hydroxy-2-isopropylmalonate] <Dimethyl 2-hydroxy-2-isopropylmalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 3.82 (s, 6H), 3.68 (s, 1H), 2.66-2.63 (m, 1H), 0. 92 (d, J = 6.1 Hz, 6H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 170.9, 82.3, 53.3, 33.4, 16.5 ppm;
[3] IR (KBr): 3501, 1753, 1433, 1389, 1369, 1296, 1231, 1185, 1164, 1046 cm ⁻¹ ;
[4] _{Anal: Calcd for C 8 H 14} O 5: C, 50.52; H, 7.42,
found C, 50.29; H, 7.37.

Product of Experimental Example 43 [Dimethyl 2-tert-butyl-2-hydroxymalonate] <Dimethyl 2-tert-butyl-2-hydroxymalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 3.83 (s, 1H), 3.77 (s, 6H), 1.07 (s, 9H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 170.6, 83.5, 52.9, 38.0, 25.5 ppm;
[3] IR (neat): 3494, 2959, 1738, 1436, 1369, 1213, 1108, 1060 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₉ H ₁₇ O ₅ [M ⁺ +1]: 205.1060, found 205.10751.

Product of Experimental Example 44 [Dimethyl 2-hydroxy-2-phenylmalonate] <Dimethyl 2-hydroxy-2-phenylmalonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.63 (d, J = 6.3 Hz, 2H), 7.38-7.36 (m, 3H), 4.39 (s , 1H), 3.83 (s, 6H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 170.3, 135.7, 128.7, 128.1, 126.5, 80.0, 53.7 ppm;
[3] IR (KBr): 3432, 1731, 1441, 1291, 1118, 734, 693 cm ⁻¹ ;
[4] _{Anal: Calcd for C 11 H 12} O 5: C, 58.93; H, 5.39, found C, 58.95; H, 5.21.

Product of Experimental Example 45 [Dimethyl 2-hydroxy-2- (4-methoxyphenyl) malonate] <Dimethyl 2-hydroxy-2- (4-methoxyphenyl) malonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.53 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.27 (S, 1H), 3.82 (s, 6H), 3.79 (s, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 170.5, 159.8, 127.8, 127.7, 113.5, 79.7, 55.2, 53.7 ppm;
[3] IR (KBr): 3450, 1731, 1515, 1432, 1295, 1260, 1178, 1098, 835 cm ⁻¹ ;
[4] _{Anal: Calcd for C 12 H 14} O 6: C, 56.69; H, 5.55, found C, 56.56; H, 5.54.

Product of Experimental Example 46 [Dimethyl 2-hydroxy-2- (4-nitrophenyl) malonate] <Dimethyl 2-hydroxy-2- (4-nitrophenyl) malonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 8.24 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 4.51 (S, 1H), 3.88 (s, 6H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 169.2, 148.1, 142.1, 128.0, 123.1, 79.6, 54.2 ppm;
[3] IR (KBr): 3445, 1737, 1519, 1356, 1291 cm ⁻¹ ;
[4] HRMS (FAB ⁺ ): m / z calcd for C ₁₁ H ₁₂ NO ₇ [M ⁺ +1]: 270.06137, found 270.06224.

Product of Experimental Example 47 [Dimethyl 2-hydroxy-2- (pyridin-3-yl) malonate] <Dimethyl 2-hydroxy-2- (pyridine-3-yl) malonate>:
[1] ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 8.83 (s, 1H), 8.51 (d, J = 3.7 Hz, 1H), 7.95 (d, J = 8. 3 Hz, 1 H), 7.25 (dd, J = 4.3 Hz, 1 H), 3.77 (s, 6 H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 169.6, 149.3, 148.1, 134.8, 132.0, 122.9, 78.8, 53.8 ppm;
[3] IR (KBr): 3091, 1744, 1595, 1487, 1436, 1272 cm ⁻¹ ;
[4] _{Anal: Calcd for C 10 H 11} NO 5: C, 53.33; H, 4.92; N, 6.22, found C, 53.07; H, 4.77; N, 6.13 .

(2) Experimental results Experimental Examples 37 and 38 are the same raw materials as in Experimental Example 2, except for the solvent. In each of Experimental Examples 2, 37, and 38, the n-butyl group in the starting dicarbonyl compound was substituted with the alkoxy group of the solvent, and the hydrogen of the methylene group in the dicarbonyl compound was substituted with the n-butyl group and the hydroxyl group. The smaller the number of carbon atoms in the alkoxy group of the solvent, the higher the yield. In addition, the yield was slightly reduced with an isopropyl group having a branched structure.

The dicarbonyl compound used in Experimental Examples 39 to 41 is a dicarbonyl compound in which the methoxy group in the starting dicarbonyl compound used in Experimental Examples 2, 37, and 38 is replaced with an ethoxy group. In Experimental Examples 40 and 41, as in Experimental Examples 2, 37 and 38, the n-butyl group in the dicarbonyl compound was replaced with the alkoxy group of the solvent, and the hydrogen in the methylene group in the dicarbonyl compound was replaced with the n-butyl group and the hydroxyl group. Was replaced.
However, in Experimental Example 39, the ethoxy group in the starting dicarbonyl compound is replaced with a methoxy group in the product. This is considered that when the number of carbon atoms of the alkoxy group of the solvent is small, the alkoxy group in the dicarbonyl compound is substituted with the alkoxy group of the solvent.
However, in this Experimental Example 39, 0.5 equivalent of the catalyst was used with respect to the raw material. In addition, in Example 39, when 0.2 equivalent of catalyst was used, 56% of the product was substituted with a methoxy group, and 29% was not substituted with a methoxy group but remained an ethoxy group. Obtained.

The dicarbonyl compounds used in Experimental Examples 42 and 43 were dicarbonyls in which the n-butyl groups in the starting dicarbonyl compounds used in Experimental Examples 2, 37, and 38 were replaced with i-propyl groups and t-butyl groups, respectively. A compound. Also in this case, the i-propyl group and the t-butyl group were substituted with the alkoxy group in the solvent, and the hydrogen of the methylene group in the dicarbonyl compound was substituted with the i-propyl group and the t-butyl group.
However, in Experimental Example 43, the yield is after 24 hours.

In Experimental Examples 44 to 48, a dicarbonyl compound having a group containing an aromatic ring is used as a raw material. As shown in Table 4, in all of Experimental Examples 44 to 47, the same substitution reaction as in the above Experimental Example occurred.
In Experimental Example 44, as in Experimental Example 39, the ethoxy group in the dicarbonyl compound is replaced with the methoxy group of the solvent. In Experimental Example 44, 0.5 equivalent of the catalyst was used.
The high yield of Experimental Example 45 is considered to be due to the fact that the raw material methoxyphenyl group is an electron donating group.
The yield in Experimental Example 46 is that after 24 hours. Furthermore, in Experimental Example 46, methyl 4-nitrobenzoate was obtained in a yield of 12% in addition to the products shown in Table 4.
In Experimental Example 46, the yield was slightly low at 57%, which is considered to be due to the fact that the nitrophenyl group is an electron withdrawing group.

  Experimental Example 48 uses a diketone compound different from the above ester compound as a raw material. As for the obtained product, a product in which both phenyl group and methyl group were substituted was obtained in the same yield. In addition to the products shown in Table 4, dimethyl 2-hydroxy-2-phenylmalonate was also obtained in a yield of 12%.

[5] Production experiment from dicarbonyl compound to malonic acid derivative via intermediate (Experimental Example 49)
(1) Confirmation of Intermediate Example 49 is a reaction for producing a malonic acid derivative from an intermediate from a raw dicarbonyl compound.
Specifically, 0.3 mmol of methyl 3-oxoheptanoate and 0.06 mmol (0.2 equivalent) of calcium iodide (CaI ₂ ) were dissolved in 5 ml of methanol (solvent) in a Pyrex (registered trademark) test tube. Then, under an oxygen atmosphere (oxygen balloon), light was irradiated with four fluorescent lamps (22 Watts, Matsushita Electric Industrial Co., Ltd. Palook Ball; product number: EFR25ED / 22) while stirring. The fluorescent lamp was placed 7 cm away from the test tube containing the raw materials, and the test tube was installed so as to surround it from all sides.
Then, as shown in the following formula (8), an intermediate (B) is produced from the compound (A) by irradiation with light in the presence of oxygen in a methanol solvent using calcium iodide as a catalyst. (C) was produced. Moreover, the compound (A), the obtained intermediate body (B), and the derivative (C) were confirmed from the measurement results of ¹ H-NMR, ¹³ C-NMR, Mass, IR, and elemental analysis.
In addition, the measurement result of ¹ H-NMR in the following intermediate (B) is shown in FIG. 4, the measurement result of ¹³ C-NMR is shown in FIG. 5, and the measurement result of IR is shown in FIG.

Intermediate (B) <Methyl 2-hydroxyperoxy-3-hydroxyhept-2-enoate>:
[1] ¹ H-NMR (400 MHz, CDCl 3): δ = 4.94 (br, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 2.79 (t, J = 7.2 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 1.64-1.59 (m, 2H), 1.36-1.27 (m, 2H), 00-0.86 (m, 3H) ppm;
[2] ¹³ C-NMR (400 MHz, CDCl ₃ ): δ = 203.2, 197.9, 182.0, 169.5, 162.3, 92.3, 53.6, 53.0, 36. 5,35.3, 25.2, 24.5, 21.9, 13.5 ppm;
[3] IR (neat): 3441, 2960, 1733, 1263, 1128 cm ⁻¹ ;
[4] _{Anal: Calcd for C 8 H 14} O 5: C, 50.52; H, 7.42, found C, 50.56; H, 7.34.

  About the above compound (A), the above intermediate (B) and the above derivative (C), before reaction start, 2 hours after reaction start, 4 hours after reaction start, 6 hours after reaction start, 8 hours after reaction start and reaction start The isolated yields of the above (A), (B) and (C) in each reaction time after 10 hours were confirmed. The change in the ratio is shown in FIG.

(2) Experimental results As shown in FIG. 1, only the compound (A) is initially present at 100% by mass, and after 2 hours, the intermediate (B) is produced by 40% by mass or more and the compound (A ) Is reduced to 2% by mass or less. Thereafter, the intermediate (B) gradually decreased and disappeared after 10 hours, and the derivative (C) was obtained in a yield of 92% by mass.
From the above results, it was confirmed that the reaction of compound (A) → intermediate (B) → derivative (C) was proceeding.

[6] Production experiment from intermediate to malonic acid derivative (Experimental Examples 50 to 60)
(1) Production of malonic acid derivative Experimental examples 50 to 60 are reactions for producing a malonic acid derivative from an intermediate.
As shown in the following formula (9), a malonic ester derivative as the target product (C) was produced from the intermediate (B).

Specifically, in the Pyrex (registered trademark) test tube, about 0.3 mmol of the intermediate (B) and the catalysts of Experimental Examples 50 to 60 shown in Table 5, the catalyst amount shown in Table 5 (equivalent to the intermediate) ) Was dissolved in 5 ml of methanol (solvent), and irradiated with four fluorescent lamps (22 Watts, Matsushita Electric Industrial Co., Ltd. Palookball; product number: EFR25ED / 22) under stirring in an oxygen atmosphere (oxygen balloon). The fluorescent lamp was placed 7 cm away from the test tube, and was surrounded by the test tube from all sides. The reaction time was 10 hours. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and transferred to a separatory funnel, and the organic layer was washed with sodium thiosulfate and extracted. The extracted crude product was purified by PTLC to obtain the target product, dimethyl 2-butyl-2-hydroxymalonate.
In Experimental Example 51, the test tube used in the production experiment was completely covered with aluminum foil and shielded from light, and was not irradiated with light. Moreover, it was performed not in an oxygen atmosphere but in an argon atmosphere. Other conditions were the same as described above.
Table 5 shows the catalyst, catalyst amount, solvent, presence / absence of light irradiation, presence / absence of oxygen, and yield used in Experimental Examples 50-60.
Moreover, the obtained product was confirmed from the measurement result of < ¹ > H-NMR, Mass, IR, and elemental analysis.

(2) Experimental results Table 5 also shows the results of determining the yield of the target product after 10 hours from the start of the reaction. According to Experimental Example 50, when calcium iodide was used as a catalyst, the target product could be obtained from the intermediate in a high yield of 90%.
In Experimental Example 51, even when calcium hydroxide was used as the catalyst, the target product could be obtained from the intermediate with a high yield of 80%.
In Experimental Example 52, the target product was obtained in a high yield of 79% even without light irradiation and oxygen. This shows that light irradiation and oxygen are not necessary in producing a malonic ester derivative or the like from an intermediate.
In Experimental Examples 52 to 55 using calcium hydroxide as a catalyst, the catalyst amount was changed to 0.2 to 0.01 equivalent. A yield of 80% was obtained with 0.2 equivalent, a yield of 87% with 0.1 equivalent, and a yield of 80% with 0.05 equivalent. Only a trace amount was obtained under the reaction conditions.
Further, when magnesium hydroxide was used as a catalyst, the target product was obtained in a yield of 10%.
In Experimental Example 57 using lithium hydroxide, which is a monovalent metal hydroxide, as a catalyst, the yield was 76%. In Experimental Example 58 using sodium hydroxide, the yield was 80%. In Example 59, the yield was 92%, and the target product was obtained in high yield even with monovalent metal hydroxide.
On the other hand, in Experimental Example 60, when only molecular iodine was used as the catalyst, the target product could not be obtained at all.
That is, in order to obtain the target product from the intermediate, it is sufficient that monovalent metal ions or divalent metal ions are present, and iodine is unnecessary.

  INDUSTRIAL APPLICABILITY The present invention is useful in a malonic acid derivative, a method for producing a malonic acid ester derivative and a keto acid ester derivative, and further in the field of products such as pharmaceuticals and agricultural chemicals produced from the malonic acid derivative.

It is a measurement result of ¹ H-NMR of dimethyl 2-butyl-2-hydroxymalonate. It is a measurement result of ¹³ C-NMR of dimethyl 2-butyl-2-hydroxymalonate. It is a measurement result of IR of dimethyl 2-butyl-2-hydroxymalonate. It is a measurement result of ¹ H-NMR of an intermediate produced from methyl 3-oxoheptanoate. It is a ¹³ C-NMR measurement result of an intermediate produced from methyl 3-oxoheptanoate. It is an IR measurement result of an intermediate produced from methyl 3-oxoheptanoate. It is a graph which shows the process in which the malonic acid derivative based on this invention is manufactured.

Claims (6)

In a solvent represented by the following general formula (1),
A catalyst comprising a divalent metal iodide and / or a catalyst comprising a divalent metal hydroxide and iodine;
In the presence of oxygen,
A malonic ester derivative or keto acid, characterized by producing a malonic ester derivative or keto ester derivative represented by the following general formula (3) from a compound represented by the following general formula (2) by light irradiation A method for producing an ester derivative.
ROH (1)
[In General formula (1), R shows a C1-C5 alkyl group. ]

[In General Formula (2), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, and an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

In [Formula (3), R represents an alkyl group having 1 to 5 carbon atoms, ^{R 1} represents an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, 7 carbon atoms 12 represents an alkoxyphenyl group having 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, and R ³ represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. Show. ]   The method for producing a malonic ester derivative or keto ester derivative according to claim 1, wherein the catalyst is used in an amount of 0.15 to 0.4 mol with respect to 1 mol of the compound represented by the general formula (2).   The method for producing a malonic ester derivative or keto ester derivative according to claim 1 or 2, wherein the solvent is at least one selected from methanol, ethanol, and propanol. The manufacturing method of the malonic acid ester derivative or keto acid ester derivative in any one of Claims 1 thru | or 3 provided with the process of manufacturing the intermediate body represented by following General formula (4).

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ] The manufacturing method which manufactures the malonic acid ester derivative or keto acid ester derivative represented by the following general formula (3) from the compound represented by the following general formula (2) in the solvent represented by the following general formula (1) Because
In the presence of at least one catalyst selected from divalent metal iodide and iodine and oxygen, the compound represented by the following general formula (4) is represented by the following general formula (4) by light irradiation. A first step of producing an intermediate to be produced;
In the presence of at least one catalyst selected from a monovalent metal iodide, a divalent metal iodide, a monovalent metal hydroxide, and a divalent metal hydroxide, it is represented by the following general formula (4). A second step of producing a malonic acid ester derivative or keto acid ester derivative represented by the following general formula (3) from the intermediate produced:
In order, The manufacturing method of the malonic acid ester derivative or keto acid ester derivative characterized by the above-mentioned.
ROH (1)
[In General formula (1), R shows a C1-C5 alkyl group. ]

[In General Formula (2), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, and an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

In [Formula (3), R represents an alkyl group having 1 to 5 carbon atoms, ^{R 1} represents an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, 7 carbon atoms 12 represents an alkoxyphenyl group having 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, and R ³ represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. Show. ]

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ] The compound represented by following General formula (4).

[In General Formula (4), R ¹ is an alkyl group having 1 to 8 carbon atoms, a phenyl group, an alkylphenyl group having 7 to 12 carbon atoms, an alkoxyphenyl group having 7 to 12 carbon atoms, or an aralkyl having 7 to 12 carbon atoms. Group, a halogenated phenyl group, a nitrophenyl group or a pyridyl group, R ² represents an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms. ]

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