WO2015008629A1 - ケトマロン酸化合物の製造方法 - Google Patents
ケトマロン酸化合物の製造方法 Download PDFInfo
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- WO2015008629A1 WO2015008629A1 PCT/JP2014/067728 JP2014067728W WO2015008629A1 WO 2015008629 A1 WO2015008629 A1 WO 2015008629A1 JP 2014067728 W JP2014067728 W JP 2014067728W WO 2015008629 A1 WO2015008629 A1 WO 2015008629A1
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- acid compound
- chlorine dioxide
- hydrate
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- reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
Definitions
- the present invention relates to a method for producing a ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof by reacting a malonic acid compound such as a malonic acid diester with chlorine dioxide.
- Ketomalonic acid diester or its hydrate is a compound useful as a raw material in the production of pyrazin-2-one-3-carboxylic acid ester derivatives by reaction with diamines (Patent Documents 1-4 and Non-Patent Documents 1- 2). This reaction is used in the production of pharmaceuticals, agricultural chemicals, etc., particularly as a method for producing a quinoxalinone derivative from an aromatic diamine.
- a method in which a compound in which the active methylene portion of the malonic acid diester is substituted with bromine is reacted with silver nitrate (see, for example, Non-Patent Document 7), and a compound in which the active methylene portion of the malonic acid diester is substituted with an azo group A method of reacting with oxirane (for example, see Non-Patent Document 8), a method of reacting a compound in which the active methylene moiety of malonic acid diester is substituted with a methylene group with ozone (for example, see Non-Patent Documents 5 and 9), malonic acid A method of producing a ketomalonic acid diester such as a method of reacting a compound in which the active methylene portion of the diester is substituted with a hydroxyl group in the presence of a noble metal catalyst (see, for example, Patent Document 5) is also known.
- Patent Document 6 Furthermore, a method of reacting malonic diester with sodium chlorite has been reported (see Patent Document 6). The method described in Patent Document 6 is superior to the prior art known before Patent Document 6, but there is still room for improvement in consideration of economic and environmental aspects as described later.
- An object of the present invention is to provide a method for producing an industrially useful ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof in a more preferable method from the viewpoints of economy and environment and safety. There is.
- Another object of the present invention is to provide a very safe method for producing a ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof, which can avoid the risk of explosion and can also suppress reaction runaway. .
- Still another object of the present invention is to provide a method for producing a ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof, which can solve one or more disadvantages or problems in the prior art described above. .
- a ketomalonic acid compound such as a ketomalonic acid diester or a hydrated body thereof.
- a ketomalonic acid compound represented by the following general formula (2) or a hydrate thereof was produced, and the present invention was completed based on this finding.
- the ketomalonic acid compound such as ketomalonic acid diester or the like can be safely and efficiently introduced. They found that a hydrated body could be produced. That is, the present invention provides the following general formula (1)
- Rs may be the same or different and have a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
- the following general formula (2) is obtained by reacting a malonic acid compound represented by formula (2) with chlorine dioxide.
- the manufacturing method of the ketomalonic acid compound represented by these, or its hydrate is characterized in that the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 4 to pH 11, preferably pH 5 to pH 10. About.
- the method of the present invention provides a novel industrial method for producing a ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof.
- the present invention is characterized in that a malonic acid compound (raw material compound) represented by the general formula (1) is reacted with chlorine dioxide as an oxidizing agent.
- chlorine dioxide has the ability to specifically oxidize the methylene moiety of a malonic acid compound such as malonic acid diester.
- chlorite such as sodium chlorite is used as an oxidizing agent.
- a method for producing a chlorite such as sodium chlorite used as an oxidizing agent for example, a method for producing chlorine dioxide by reacting with a base such as sodium hydroxide and a reducing agent such as hydrogen peroxide. It has been known.
- chlorite such as sodium chlorite using chlorine dioxide as a raw material as an oxidizing agent is produced and used as an oxidizing agent. That is, in this method, a chlorite such as sodium chlorite had to be produced.
- chlorine dioxide can be used directly, and the purpose is simpler in that it is no longer necessary to produce chlorite such as sodium chlorite. Things came to be obtained.
- the method of the present invention is characterized in that chlorine dioxide gas is used as an oxidizing agent in the oxidation reaction of a malonic acid compound such as malonic acid diester.
- a more preferred embodiment of the method of the present invention is a method in which the pH of the reaction is controlled in the range of pH 4 to pH 11, preferably pH 5 to pH 10. It was found for the first time that the desired reaction efficiently proceeds with chlorine dioxide when the pH of the reaction is controlled, as shown in the Examples described later.
- the production method described in Patent Document 6 suggests that the pH of the reaction is preferably in the acidic region.
- a desired reaction proceeds not only in a weakly acidic region (for example, pH 5 to 6) but also in a neutral region (for example, pH 6 to 8) to a basic region (for example, pH 8 to 10). It was considered. Therefore, in the method for producing ketomalonic acid compounds such as ketomalonic acid diesters, the method of the present invention provides a new option related to the pH of the reaction. For example, in the chemical industry, neutral conditions are often preferred over acidic conditions, and the method of the present invention is considered to be a more industrially preferred method.
- the stability of the ester residue of the malonic acid compound (raw material compound) represented by the general formula (1) may vary depending on the pH. In such cases, the process of the present invention may be able to provide a choice of new or preferred reaction conditions.
- the ester residue of the malonic acid compound represented by the general formula (1) is R in the general formula (1).
- the present inventors have found a method for safely and efficiently handling chlorine dioxide gas in the oxidation reaction of a malonic acid compound such as malonic acid diester.
- the chlorine dioxide used in the method of the present invention is a substance that can be safely used as a bleaching agent for pulp, fiber or food, or as a disinfectant for water disinfection when the concentration is low. Furthermore, chlorine dioxide is inexpensive and industrially preferable. However, on the other hand, chlorine dioxide is also a substance that is known to be dangerous such as an explosion at high concentrations. However, according to the method of the present invention, the reaction can be performed by blowing a required amount of chlorine dioxide gas at a low concentration, and the danger of explosion can be avoided without excessive chlorine dioxide filling the system, And again, the runaway reaction can be suppressed. In addition, in the organic synthesis reaction, due to heat generation and induction period, there are cases where appropriate measures or cautions such as cooling and divided charging or dropping are required, but according to the method of the present invention, Such a measure or attention becomes easy.
- a ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof can be suppressed from a malonic acid compound such as a malonic acid diester, or the risk of explosion and reaction runaway can be suppressed, and can be generated extremely safely. Can do.
- a ketomalonic acid compound such as a ketomalonic acid diester or a hydrate thereof can be efficiently and industrially produced with high yield and high purity.
- a carboxylic acid compound such as acetic acid is used.
- the used carboxylic acid compound such as acetic acid is likely to become waste, and its reuse is not easy and causes environmental pollution.
- a target ketomalonic acid compound such as a ketomalonic acid diester can be produced without using a carboxylic acid compound such as acetic acid. Not using a carboxylic acid compound such as acetic acid helps to reduce cost and environmental burden.
- the method of the present invention solves problems such as serious toxicity or difficulty of handling of reagents that are expected in industrialization, does not require special reagents, does not require expensive reagents, and does not require precious metals.
- a ketomalonic acid compound such as a ketomalonic acid diester can be produced without requiring a transition metal. Further, in the method of the present invention, since no harmful waste derived from the catalyst or the transition metal is produced, the waste treatment is easy, the environment is friendly, and the industrial utility value is high.
- a malonic acid compound such as a malonic acid diester represented by the general formula (1) which is easily available as a raw material.
- the malonic acid compound such as malonic acid diester as a raw material in the method of the present invention is a compound widely used in organic synthesis, and is safe and easily available.
- water can be used as a solvent. Water is highly safe, inexpensive and easy to handle.
- the method of the present invention can select mild reaction conditions without requiring high temperature and high pressure, and can produce a ketomalonic acid compound such as a ketomalonic acid diester under simple conditions suitable for industrialization. As described above, the method of the present invention is extremely useful as an industrial production method.
- Rs may be the same or different and have a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
- the pH is controlled using an inorganic base as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 5 to pH 8, any one of [1], [11] or [12] A method for producing a ketomalonic acid compound or a hydrate thereof according to item 1.
- the pH is controlled using an inorganic base as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 6 to pH 8, [1], [11], [12], or [ [13]
- the pH is controlled using an alkali metal hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 5 to pH 8, [1], [15], or [16 ]
- the pH is controlled using an alkali metal hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 6 to pH 8. [1], [15], [16] Or the method for producing a ketomalonic acid compound or a hydrate thereof according to any one of [17].
- the pH is controlled using sodium hydroxide or potassium hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is performed in the range of pH 5 to pH 10, [1] or [19] A method for producing a ketomalonic acid compound or a hydrate thereof.
- the pH is controlled using sodium hydroxide or potassium hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is performed in the range of pH 5 to pH 8, [1], [19], or [20]
- the pH is controlled using sodium hydroxide or potassium hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 6 to pH 8, [1], [19], [ 20] or the method for producing a ketomalonic acid compound or a hydrate thereof according to any one of [21].
- the pH is controlled using sodium hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 5 to pH 8, [1], [23] or [24] The manufacturing method of the ketomalonic acid compound of any one, or its hydrate.
- the pH is controlled using sodium hydroxide as a pH adjuster, and the reaction between the malonic acid compound and chlorine dioxide is carried out in the range of pH 6 to pH 8, [1], [23], [24], or [25]
- R in the general formula (1) may be the same or different, and (a) a C 1 -C 6 alkyl group which may have a substituent; (B) an optionally substituted C 3 -C 6 cycloalkyl group; (C) an aromatic hydrocarbon group having 6 to 12 carbon atoms which may have a substituent; (D) an optionally substituted 5- to 10-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; or (E) two R's may be bonded to each other to form a ring with adjacent oxygen atoms;
- the method for producing a ketomalonic acid compound or a hydrate thereof according to any one of [1] to [26], which is a group selected from any of the above.
- the substituent in R of the general formula (1) is a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 haloalkyl group, a hydroxyl group, or a C 1 -C
- the gas used for diluting the chlorine dioxide gas is one or more inert gases selected from the group consisting of air, nitrogen, argon, helium, and carbon dioxide, [38] to [41 ] The manufacturing method of the ketomalonic acid compound or its hydrate of any one of.
- Chlorine dioxide is chlorine dioxide gas in which the concentration of chlorine dioxide gas is in the range of 2 (vol%) to 10 (vol%), and the purity of chlorine dioxide gas is 70% to 100%.
- Chlorine dioxide is chlorine dioxide gas in which the concentration of chlorine dioxide gas is in the range of 2 (vol%) to 10 (vol%), and the purity of chlorine dioxide gas is 90% to 100%.
- Chlorine dioxide is chlorine dioxide gas in which the concentration of chlorine dioxide gas is in the range of 5 (vol%) to 10 (vol%), and the purity of chlorine dioxide gas is 70% to 100%.
- Chlorine dioxide is chlorine dioxide gas in which the concentration of chlorine dioxide gas is in the range of 5 (vol%) to 10 (vol%), and the purity of chlorine dioxide gas is 90% to 100%.
- Chlorine dioxide gas is one of the following methods: (A) a method of generating from a chlorite aqueous solution and a strong inorganic acid; (B) a method of generating from an aqueous chlorate solution, a strong inorganic acid and hydrogen peroxide; or (C) a method of generating from a chlorate aqueous solution and a strong inorganic acid; The method for producing a ketomalonic acid compound or a hydrate thereof according to any one of [38] to [51], wherein the chlorine dioxide gas generated in step 1 is diluted.
- C a -C b means that the number of carbon atoms is ab.
- C 1 -C 4 means having 1 to 4 carbon atoms.
- alkyl group examples include a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
- the C 1 -C 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
- the C 1 -C 4 alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms.
- alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, more preferably methyl, ethyl, propyl, isopropyl, and still more preferably methyl, ethyl.
- Examples of the cycloalkyl group include a C 3 to C 6 cycloalkyl group.
- the C 3 -C 6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms.
- Specific examples of the C 3 -C 6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- aromatic hydrocarbon group examples include aromatic hydrocarbon groups having 6 to 12 carbon atoms. Specific examples of the aromatic hydrocarbon group include phenyl, 1-naphthyl, 2-naphthyl, biphenyl and the like. The aromatic hydrocarbon group is preferably phenyl.
- aromatic heterocyclic group examples include, for example, a 5- to 10-membered aromatic heterocyclic group having a hetero atom selected from one or more (for example, 1 to 4) nitrogen atom, oxygen atom and sulfur atom in addition to the carbon atom.
- a cyclic group etc. are mentioned.
- Specific examples of the aromatic heterocyclic group include a furyl group, a thienyl group, a pyrazolyl group, a pyridyl group, and a quinolinyl group. More specific examples of the aromatic heterocyclic group include 2- or 3-furyl, 2- or 3-thienyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl. , 2- or 8-quinolyl and the like.
- Preferable examples of the aromatic heterocyclic group include 2- or 4-pyridyl, more preferably 2-pyridyl.
- the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- haloalkyl group examples include a C 1 -C 4 haloalkyl group.
- the C 1 -C 4 haloalkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms substituted by the same or different 1 to 9 halogen atoms (wherein the halogen atom Has the same meaning as above.)
- Examples of the C 1 -C 4 haloalkyl group include fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2 , 2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 2,2,
- alkoxy group examples include C 1 -C 4 alkoxy groups.
- a C 1 -C 4 alkoxy group means a (C 1 -C 4 alkyl) -O— group (where C 1 -C 4 alkyl has the same meaning as described above).
- a C 1 -C 4 alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, or tert-butoxy.
- Examples of the substituent that may have a substituent include a halogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, an aromatic hydrocarbon group, and an aromatic heterocyclic group. .
- substituent “which may have a substituent” include a hydroxyl group and the like.
- “Two Rs may be bonded to each other to form a ring” means that two R groups are linked to form a divalent group and form a ring with an adjacent oxygen atom.
- Examples of the divalent group formed by linking two R groups include an optionally substituted alkylene group having 1 to 6 carbon atoms such as a methylene group and an ethylene group.
- the alkylene group may have a substituent as described above, for example, a halogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, an aromatic hydrocarbon group and the like.
- R in the general formula (1) may be the same or different, and represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
- An aromatic hydrocarbon group that may have or an aromatic heterocyclic group that may have a substituent, and two Rs may be bonded to each other to form a ring.
- R in the general formula (1) include a C 1 to C 4 alkyl group, more preferably methyl, ethyl, propyl, isopropyl, and still more preferably methyl and ethyl.
- malonic acid compound represented by the general formula (1) include, for example, malonic acid, dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, diisobutyl malonate, and malon.
- Preferred malonic acid compounds include dialkyl malonates (eg, dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, diisobutyl malonate, di-sec-butyl malonate, di-tert malonate).
- dialkyl malonates eg, dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, diisobutyl malonate, di-sec-butyl malonate, di-tert malonate.
- the malonic acid compound (raw material compound) represented by the general formula (1) is a known compound or can be produced from a known compound by a known method (for example, esterification of malonic acid by a conventional method). .
- malonic acid compound (raw material compound) represented by the general formula (1) can be used alone or as a mixture in an arbitrary ratio.
- ketomalonic acid compound represented by the general formula (2), which is an object produced by the method of the present invention, will be described.
- R in the general formula (2) may be the same or different, and represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
- An aromatic hydrocarbon group that may have or an aromatic heterocyclic group that may have a substituent, and two Rs may be bonded to each other to form a ring.
- R in the general formula (2) include C 1 -C 4 alkyl groups, more preferably methyl, ethyl, propyl, isopropyl, and still more preferably methyl and ethyl.
- ketomalonic acid compound represented by the general formula (2) include, for example, ketomalonic acid, dimethyl ketomalonate, diethyl ketomalonate, dipropyl ketomalonate, diisopropyl ketomalonate, dibutyl ketomalonate, diisobutyl ketomalonate, ketomalon Di-sec-butyl acid, di-tert-butyl ketomalonate, dipentyl ketomalonate, dihexyl ketomalonate, dicyclopropyl ketomalonate, dicyclopentyl ketomalonate, dicyclohexyl ketomalonate, diphenyl ketomalonate, di (4-pyridyl) ketomalonate , Ketomalonate di (2-pyridyl), methyl ethyl ketomalonate, methylpropyl ketomalonate, methyl-tert-butyl ketomalonate, ethylpropyl ketomalonate, ethyl ketomalonate
- ketomalonic acid compounds include dialkyl ketomalonate (eg, dimethyl ketomalonate, diethyl ketomalonate, dipropyl ketomalonate, diisopropyl ketomalonate, dibutyl ketomalonate, diisobutyl ketomalonate, di-sec-butyl ketomalonate, di-tert ketomalonic acid).
- dialkyl ketomalonate eg, dimethyl ketomalonate, diethyl ketomalonate, dipropyl ketomalonate, diisopropyl ketomalonate, dibutyl ketomalonate, diisobutyl ketomalonate, di-sec-butyl ketomalonate, di-tert ketomalonic acid.
- ketomalonate dihexyl ketomalonate methyl ethyl, ketomalonate methylpropyl, ketomalonate methyl-tert-butyl, ketomalonate ethylpropyl, ketomalonate ethyl tert-butyl, etc.
- ketomalonic acid Dimethyl, diethyl ketomalonate, dipropyl ketomalonate, diisopropyl ketomalonate, dibutyl ketomalonate, diisobutyl ketomalonate, di-se ketomalonate -Butyl, di-tert-butyl ketomalonate, methyl-tert-butyl ketomalonate, ethyl-tert-butyl ketomalonate, more preferably dimethyl ketomalonate, diethyl ketomalonate, dipropyl ketomalonate, diisopropyl ketomalonate, dibutyl
- the malonic acid compound represented by the general formula (2) produced by the method of the present invention may be a single compound or a mixture at any ratio.
- the ketomalonic acid compound represented by the general formula (2) produced by the method of the present invention is a compound having a keto group between two ester groups or the like, in other words, electron withdrawing at a position adjacent to the keto group.
- a compound having a group. Therefore, the ketomalonic acid compound represented by the general formula (2) has the following general formula (3) in the presence of water.
- R represents the same meaning as described above
- This hydrate can be converted into a ketomalonic acid compound represented by the general formula (2) of keto type by performing dehydration treatment such as heat treatment, if necessary.
- dehydration treatment such as heat treatment
- Such a reversible reaction is similar to the general properties of hydrated bodies such as chloral hydrate.
- the reaction of the present invention when the reaction of the present invention is carried out in the presence of water, the product is obtained in the form of a hydrate of a ketomalonic acid compound represented by the general formula (3).
- the reaction of the present invention is carried out under anhydrous conditions, the product is obtained in the form of a ketomalonic acid compound represented by the general formula (2).
- the reaction of the present invention is carried out in the presence of water and the product is to be isolated in the form of the ketomalonic acid compound represented by the general formula (2)
- the post-treatment after the reaction Specifically, for example, by performing a dehydration treatment such as azeotropic dehydration with toluene, the product can be easily obtained in the form of a ketomalonic acid compound represented by the general formula (2).
- the form of the product to be isolated is changed to that of the ketomalonic acid compound represented by the general formula (2).
- Either the shape or the form of a hydrate of the ketomalonic acid compound represented by the general formula (3) can be used.
- chlorine dioxide used in the method of the present invention.
- a method for producing chlorine dioxide there are a method in which hydrochloric acid is added dropwise to a sodium chlorite aqueous solution and a method in which hydrochloric acid and hydrogen peroxide are dropped into a sodium chlorate aqueous solution.
- a method using a sodium chlorate aqueous solution hydrochloric acid and hydrogen peroxide
- a method using sulfuric acid instead of hydrochloric acid is also known.
- a method is also known in which chlorine dioxide and chlorine are generated from an aqueous sodium chlorate solution and hydrochloric acid without using hydrogen peroxide, and then the chlorine is removed by washing with water. As long as the desired reaction proceeds sufficiently, any of these methods may be used, and the present invention is not limited thereto.
- the form of chlorine dioxide used in the method of the present invention is preferably a form in which the desired reaction proceeds sufficiently and safely.
- Gas or liquid is known as a form of chlorine dioxide.
- gas is preferable.
- the form of chlorine dioxide may be diluted with a gas or liquid other than chlorine dioxide.
- Examples of the gas used for diluting chlorine dioxide include air, nitrogen, and inert gases such as argon, helium, and carbon dioxide. From the viewpoints of availability, ease of handling, safety, price, etc., preferred examples of the gas used for dilution of chlorine dioxide include air or nitrogen, more preferably nitrogen, but are not limited thereto. It is not a thing. In addition, the gas used for dilution of chlorine dioxide can be used individually or in mixture in arbitrary ratios.
- the liquid used for diluting chlorine dioxide is preferably water from the viewpoints of availability, ease of handling, price, stability of chlorine dioxide in the solution, and the like.
- the form of chlorine dioxide may be a solution, in which case it is preferably an aqueous solution.
- a solvent other than water which will be described later, is not excluded as a liquid used for diluting chlorine dioxide. Accordingly, a solution of a solvent other than water is also included in the scope of the present invention as the form of chlorine dioxide.
- the form of chlorine dioxide used in the method of the present invention is particularly preferably a diluted gas from the viewpoints of availability, ease of handling, safety, price, and the like.
- the method of using chlorine dioxide used in the method of the present invention is not limited, it is particularly preferable to introduce it into the reaction system as diluted chlorine dioxide gas.
- the method of introducing the diluted chlorine dioxide gas may be either blowing into the gas phase of the reaction system or blowing into the reaction solution (for example, bubbling).
- the gas concentration of the introduced chlorine dioxide gas is preferably in the range of 2 (vol%) to 10 (vol%), more preferably 5 (vol%) to 10 (vol%). Since chlorine dioxide has the property of having explosive properties at a high concentration, it is preferably handled at 10 (vol%) or less. However, considering the method of the present invention, it was presumed that the reaction progresses slowly because the concentration is less than 2 (vol%) because it is too dilute.
- the gas purity of the introduced chlorine dioxide gas is preferably in the range of 70% to 100%.
- chlorine dioxide gas containing substantially no chlorine gas is preferable in order to avoid side reactions due to chlorine gas contained as impurities.
- Chlorine gas contained in chlorine dioxide gas can be removed by washing with water.
- the gas purity of chlorine dioxide gas is 70% or more, preferably 90% or more, that is, more preferably 90% to 100%.
- the gas purity of chlorine dioxide gas indicates a value excluding the gas used for generation and dilution of chlorine dioxide gas.
- the amount of chlorine dioxide used in the method of the present invention may be within a range in which the reaction sufficiently proceeds.
- the range is 1 mol to 10 mol, more preferably 1 mol to 7 mol, still more preferably 1 mol to 3 mol, still more preferably 1 mol to 2 mol.
- the reaction of the present invention is preferably carried out in an appropriate pH range.
- the pH at which the reaction of the present invention is carried out is, for example, from pH 4 to pH 11, preferably from pH 5 to pH 10, more preferably from pH 5 to pH 8, and even more preferably from pH 6 to pH 8, from the viewpoints of reactivity, suppression of by-products and safety. Range.
- the pH in the method of the present invention for example, before introducing chlorine dioxide, the pH ranges from 7 to 11, preferably from 8 to 11, more preferably from 9 to 11, even more preferably from 9 to 10, and in the reaction by introducing chlorine dioxide gas, a range of pH 4 to pH 11, preferably pH 5 to pH 10, more preferably pH 5 to pH 8, and further preferably pH 6 to pH 8 is also exemplified, but not limited thereto. .
- the pH in the method of the present invention was estimated as follows.
- the pH is too low (for example, in the acidic range where the pH is less than 5)
- pH was high (for example, when it reacted in the alkaline region where pH exceeds 9), it was considered that the by-product by a side reaction becomes easy to produce and a yield may fall.
- any pH adjuster may be used as long as the desired reaction proceeds sufficiently, but an alkaline reagent exhibiting alkalinity (that is, an inorganic base) is suitable.
- Examples of the inorganic base as the pH adjuster include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, and the like.
- alkali metal hydroxide examples include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
- alkaline earth metal hydroxide examples include calcium hydroxide, magnesium hydroxide, barium hydroxide and the like.
- alkali metal carbonate examples include sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate and the like.
- alkaline earth metal carbonate examples include calcium carbonate, magnesium carbonate, barium carbonate, calcium hydrogen carbonate, magnesium hydrogen carbonate, barium hydrogen carbonate and the like.
- the pH adjuster is preferably an alkali metal hydroxide, specifically sodium hydroxide or potassium hydroxide is more preferable, and sodium hydroxide is further included. preferable.
- the form of the pH adjuster used in the method of the present invention may be any form as long as the desired reaction proceeds sufficiently.
- the pH adjuster used in the method of the present invention is usually preferably used as an aqueous solution.
- the concentration when the pH adjuster is used as an aqueous solution is, for example, 0.1% to 60%, preferably 0.1% to 50%, more preferably 0.1% to 30%, and further preferably 1% to The range is 30%, particularly preferably 1% to 10%. That is, it is usually preferable to use the pH adjuster as an aqueous solution of about several percent.
- a pH adjuster can be used individually or in mixture in arbitrary ratios.
- the amount of the pH adjusting agent used in the method of the present invention may be in a range where the reaction proceeds sufficiently. For example, it is usually 1 equivalent or more, preferably 1 equivalent, per 1 mol of chlorine dioxide used. A range of ⁇ 5 equivalents, more preferably 1 equivalents to 2 equivalents, still more preferably 1.2 equivalents to 1.5 equivalents.
- the reaction of the present invention may be performed, for example, by simultaneously adding a pH adjuster while blowing chlorine dioxide into an aqueous suspension of a malonic acid compound such as malonic acid diester.
- a ketomalonic acid compound such as a ketomalonic acid diester can be obtained by simultaneously adding a malonic acid compound such as a malonic acid diester and a pH adjuster while blowing chlorine dioxide into an aqueous solvent or the like.
- a pH adjusting agent such as alkali metal hydroxide (eg, sodium hydroxide) is charged in advance to make the reaction system alkaline for a long time. More preferably, it should be avoided.
- the method of the present invention can be carried out in the presence of a solvent.
- a solvent for example, from the viewpoint of smooth progress of the reaction, the method of the present invention can be carried out in the presence of a solvent.
- it does not exclude practice in the absence of solvent.
- the solvent that can be used in the method of the present invention is preferably water from the viewpoints of availability, ease of handling, cost, stability of chlorine dioxide in the solution, and the like.
- a solvent other than water described later is not excluded. Therefore, implementation in the presence of a solvent other than water is also included in the scope of the present invention.
- solvents other than water examples include nitriles, alcohols, carboxylic acid esters, carbonates, amides, alkylureas, phosphoric acid amides, sulfoxides, sulfones, ethers, and ketones.
- nitriles include acetonitrile, propionitrile, and preferably acetonitrile.
- alcohols examples include methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, ethylene glycol, and preferably methanol.
- carboxylic acid esters examples include acetic acid esters and the like, specifically, methyl acetate, ethyl acetate, butyl acetate and the like, preferably ethyl acetate.
- carbonate esters examples include ethylene carbonate and propylene carbonate.
- amides include N, N-dimethylformamide (DMF), N, N-diethylformamide, N, N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), and preferably N, N -Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, more preferably N, N-dimethylformamide.
- alkylureas examples include tetramethylurea, N, N′-dimethylimidazolidinone (DMI), and the like.
- phosphoric acid amides examples include hexamethylphosphoric triamide (HMPA).
- sulfoxides include dimethyl sulfoxide.
- sulfones examples include sulfolane and dimethyl sulfone.
- ethers examples include tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, di-tert-butyl ether, diphenyl ether, cyclopentyl methyl ether ( CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme and the like, preferably tetrahydrofuran.
- THF tetrahydrofuran
- 2-methyltetrahydrofuran 1,4-dioxane
- diethyl ether diethyl ether
- dipropyl ether diisopropyl ether
- dibutyl ether di-tert-butyl ether
- diphenyl ether diphenyl ether
- CPME cyclopentyl methyl ether
- ketones include acetone, ethyl methyl ketone, isopropyl methyl ketone, isobutyl methyl ketone (MIBK), cyclohexanone and the like, preferably acetone and isobutyl methyl ketone.
- carboxylic acids examples include formic acid, acetic acid, propionic acid, and preferably acetic acid.
- aromatic hydrocarbons examples include benzene, toluene, xylene, ethylbenzene, cumene, trimethylbenzene, and preferably toluene and xylene.
- halogenated aromatic hydrocarbons examples include chlorobenzene, dichlorobenzene, and trichlorobenzene. Preferably, chlorobenzene is used.
- Examples of the aliphatic hydrocarbons include pentane, hexane, octane, decane, dodecane, isododecane, hexadecane, isohexadecane, cyclohexane, ethylcyclohexane, methyldecalin, dimethyldecalin, and the like.
- halogenated aliphatic hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and preferably dichloromethane.
- a solvent other than water is allowed as long as the desired reaction proceeds.
- a polar solvent is preferable from the viewpoint of affinity, solubility, reactivity, and the like, but is not limited thereto.
- the polar solvent is a solvent having a relative dielectric constant of 5 or more.
- the relative dielectric constant is the value described in the Chemical Society of Japan, “Chemical Handbook” (Basics), Rev. 5, I-770-777, Maruzen, 2004.
- the relative dielectric constant of the solvent used in the method of the present invention is usually 5 or more, preferably 7 or more, more preferably 17 or more, and still more preferably 20 or more.
- the solvent used in the method of the present invention is most preferable from the viewpoint of safety because water is simple and inexpensive.
- the form of the product to be isolated can be represented by the general formula (2) by selecting appropriate post-treatment conditions as described above.
- the form of the ketomalonic acid compound to be produced or the form of the hydrated body of the ketomalonic acid compound represented by the general formula (3) can also be selected. Therefore, it is preferable to carry out the method of the present invention in the presence of an aqueous solvent.
- the solvents can be used alone or mixed at an arbitrary ratio.
- a water-miscible organic solvent for example, a water-miscible organic solvent such as THF, methanol, DMF, etc.
- a reaction in a two-layer system such as a system composed of a water solvent and a water immiscible solvent is not excluded.
- reaction system may be a suspension, emulsion, homogeneous solution or any other form.
- the amount of the solvent in the method of the present invention may be an amount that can sufficiently stir the reaction system. For example, it is usually 0 to 20 L (liter) with respect to 1 mol of the raw material compound represented by the general formula (1).
- the range is preferably 0.01 L to 10 L, more preferably 0.05 L to 5 L, still more preferably 0.1 L to 3 L, and particularly preferably 0.2 L to 2 L, but is not limited thereto.
- reaction temperature Next, the reaction temperature in the method of the present invention will be described.
- the reaction temperature in the method of the present invention is, for example, from ⁇ 10 ° C. (minus 10 ° C.) to 80 ° C., preferably from 0 ° C. to 40 ° C., more preferably from 5 ° C. to 35 ° C., from the viewpoint of suppressing byproducts or safety. ° C, more preferably 5 ° C to 25 ° C, more preferably 10 ° C to 25 ° C.
- the reaction pressure in the method of the present invention may be any of reduced pressure, increased pressure, and normal pressure, but is preferably performed at normal pressure.
- reaction time Next, the reaction time in the method of the present invention will be described.
- the reaction time in the method of the present invention is, for example, usually 0.5 hours to 100 hours, preferably 1 hour to 48 hours, more preferably 2 hours to 48 hours, and still more preferably from the viewpoint of suppression of byproducts or safety. Is in the range of 3 hours to 48 hours, more preferably 4 hours to 48 hours, particularly preferably 4 hours to 12 hours.
- Example 1 (Production of diethyl ketomalonate) (Reaction at pH 5-8) (1) 30 g (0.187 mol) of diethyl malonate was suspended in 100 g of water, the pH was adjusted to 10 with several drops of 5% aqueous sodium hydroxide solution, and the liquid temperature was adjusted to 10 ° C.
- Example 2 (Production of diethyl ketomalonate) (Reaction near pH 10) 30 g (0.187 mol) of diethyl malonate was suspended in 100 g of water, the pH was adjusted to 10 with a few drops of 5% aqueous sodium hydroxide solution, the liquid temperature was adjusted to 10 ° C., and the same procedure as in Example 1 was performed. Then, blowing of 8 vol% chlorine dioxide gas was started, and chlorine dioxide gas was blown for 5 hours at 13 ° C. to 18 ° C. while maintaining the pH at around 10 by appropriately dropping a 5% sodium hydroxide aqueous solution. .
- the 5% sodium hydroxide aqueous solution used was 180 g.
- Comparative Example 1 (Examination of production of diethyl ketomalonate) (Method not controlling pH) After 30 g (0.187 mol) of diethyl malonate was suspended in 100 g of water and the liquid temperature was 10 ° C., the blowing of 8 vol% chlorine dioxide gas was started in the same manner as in Example 1, Chlorine dioxide gas was blown in at 5 ° C. for 5 hours.
- the reaction mixture after completion of blowing was separated into two layers, an oil layer and an aqueous layer, and the pH of the aqueous layer was 2.
- the target product, diethyl ketomalonate (diethyl mesoxalate) was 1.8%, and the raw material, diethyl malonate, remained 96.0%.
- GC-MS Gas chromatography mass spectrometry
- the pH was measured with a glass electrode type hydrogen ion concentration indicator.
- a glass electrode type hydrogen ion concentration indicator specifically, for example, a model: personal pH / ORP meter PH72 (manufactured by Yokogawa Electric Co., Ltd.) or a model: HM-20P (manufactured by Toa DKK Corporation) can be used. .
- iodine titration of chlorine dioxide gas can be carried out by the following procedure; chlorine dioxide gas is absorbed in a 5 to 10% potassium iodide aqueous solution adjusted to pH 7 or pH 8 with a phosphate buffer. Using starch as an indicator, the released iodine is titrated with a 10N aqueous sodium thiosulfate solution. Thereafter, the titrated solution is acidified with 2N sulfuric acid or the like. The liberated iodine is titrated in the same way.
- the method of the present invention can be used as a raw material when producing a pyrazin-2-one-3-carboxylic acid ester derivative by reacting with a diamine, and as a raw material compound when producing a quinoxalinone derivative from an aromatic diamine.
- a novel industrial production method of a ketomalonic acid compound such as a ketomalonic acid diester or its hydrate used in the production of food and agricultural chemicals.
- the method of the present invention is suitable for producing a ketomalonic acid compound represented by the general formula (2) or a hydrate thereof safely and efficiently by an industrial method, and includes organic chemistry including pharmaceuticals and agricultural chemicals. Useful in industry.
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Abstract
Description
即ち、本発明は、次の一般式(1)
で表されるマロン酸化合物を二酸化塩素と反応させることによる、次の一般式(2)
で表されるケトマロン酸化合物又はその抱水体の製造方法に関する。特に、マロン酸化合物と二酸化塩素との反応がpH4~pH11、好ましくはpH5~pH10の範囲で行われることを特徴とする一般式(2)で表されるケトマロン酸化合物又はその抱水体の製造方法に関する。
本発明は、一般式(1)で表されるマロン酸化合物(原料化合物)を酸化剤としての二酸化塩素と反応させること特徴とする。本発明者らは、二酸化塩素がマロン酸ジエステル等のマロン酸化合物のメチレン部分を特異的に酸化する能力を有していることを、初めて見出したのである。
以上のように、本発明の方法は工業的な製造方法として極めて有用である。
〔1〕一般式(1)
で表されるマロン酸化合物を二酸化塩素と反応させることによる、一般式(2)
で表されるケトマロン酸化合物又はその抱水体の製造方法。
(a)置換基を有していてもよいC1~C6アルキル基;
(b)置換基を有していてもよいC3~C6シクロアルキル基;
(c)置換基を有していてもよい炭素原子数6~12個の芳香族炭化水素基;
(d)置換基を有していてもよい窒素原子、酸素原子及び硫黄原子から選ばれる1~4個のヘテロ原子を有する5~10員環の芳香族複素環基;又は、
(e)2つのRは互いに結合して隣接する酸素原子と共に環を形成してもよい;
のいずれかから選ばれる基である、〔1〕から〔26〕のいずれか1項に記載のケトマロン酸化合物又はその抱水体の製造方法。
(a)亜塩素酸塩水溶液と無機強酸から発生させる方法;
(b)塩素酸塩水溶液、無機強酸及び過酸化水素から発生させる方法;又は、
(c)塩素酸塩水溶液と無機強酸から発生させる方法;
で発生させた二酸化塩素ガスを希釈したものである、〔38〕から〔51〕のいずれか1項に記載のケトマロン酸化合物又はその抱水体の製造方法。
次に、本発明の方法の原料として用いる、上記した一般式(1)で表されるマロン酸化合物(以下、「原料化合物」と記載することがある。)について説明する。
次に、本発明の方法により製造される目的物である一般式(2)で表されるケトマロン酸化合物について説明する。
次に、本発明の方法により製造される目的物である一般式(2)で表されるケトマロン酸化合物の抱水体について説明する。
次に、本発明の方法に用いる二酸化塩素について説明する。
本発明の方法に用いる二酸化塩素の使用量は、反応が充分に進行する範囲であればよいが、例えば、一般式(1)で表される原料化合物1モルに対して、通常1モル~20モル、好ましくは1モル~10モル、より好ましくは1モル~7モル、さらに好ましくは1モル~3モル、さらに好ましくは1モル~2モルの範囲である。
次に、本発明の方法におけるpHについて説明する。
次に、本発明の方法に用いるpH調整剤について説明する。
本発明の方法に用いるpH調整剤の使用量としては、反応が充分に進行する範囲であればよいが、例えば、使用される二酸化塩素1モルに対して、通常1当量以上、好ましくは1当量~5当量、より好ましくは1当量~2当量、さらに好ましくは1.2当量~1.5当量の範囲が挙げられる。
次に、本発明の方法における溶媒について説明する。
本発明の方法における溶媒量は、反応系の撹拌が充分にできる量であればよいが、例えば、一般式(1)で表される原料化合物1モルに対して、通常0~20L(リットル)、好ましくは0.01L~10L、より好ましくは0.05L~5L、さらに好ましくは0.1L~3L、特に好ましくは0.2L~2Lの範囲であるが、これらに限定されるものではない。
次に、本発明の方法における反応温度について説明する。
本発明の方法における反応圧力としては、減圧、加圧、常圧のいずれでもよいが、常圧で行うのが好ましい。
次に、本発明の方法における反応時間について説明する。
次に、実施例を挙げて本発明を具体的に説明するが、本発明はこれら実施例によって何ら限定されるものではない。
(ケトマロン酸ジエチルの製造)
(pH5~8における反応)
(1) マロン酸ジエチル30g(0.187mol)を水100gに懸濁させ、数滴の5%水酸化ナトリウム水溶液でpHを10に調整し、液温を10℃にした。
1H NMR(300MHz,CDCl3) δ ppm:
4.39 (q, J = 6.0 Hz, 2H), 1.36 (t, J = 6.0 Hz, 3H).
13C NMR(300MHz,CDCl3) δ ppm:
178.2, 160.2, 63.5, 13.9.
GC-MS(EI)m/z:
174 [M]+.
(ケトマロン酸ジエチルの製造)
(pH10付近における反応)
マロン酸ジエチル30g(0.187mol)を水100gに懸濁させ、数滴の5%水酸化ナトリウム水溶液でpHを10に調整し、液温を10℃にした後に、実施例1と同様にして、8vol%の二酸化塩素ガスの吹き込みを開始し、5%水酸化ナトリウム水溶液を適宜滴下することによりpHを10付近に維持しながら、13℃~18℃で5時間かけて二酸化塩素ガスを吹き込んだ。使用した5%水酸化ナトリウム水溶液は180gであった。
1H NMR(300MHz,CDCl3)δ ppm:
4.39 (q, J = 6.0 Hz, 2H), 1.36 (t, J = 6.0 Hz, 3H).
13C NMR(300MHz,CDCl3)δ ppm:
178.2, 160.2, 63.5, 13.9.
1H NMR(300MHz,CDCl3)δ ppm:
4.36 (q, J = 6.0 Hz, 2H), 1.33 (t, J = 6.0 Hz, 3H).
13C NMR(300MHz,CDCl3)δ ppm:
163.0, 100.5, 64.5, 13.6.
(ケトマロン酸ジエチルの製造の検討)
(pHをコントロールしない方法)
マロン酸ジエチル30g(0.187mol)を水100gに懸濁させ、液温を10℃にした後に、実施例1と同様にして、8vol%の二酸化塩素ガスの吹き込みを開始し、13℃~18℃で5時間かけて二酸化塩素ガスを吹き込んだ。
1H核磁気共鳴スペクトル分析(1H-NMR)は、機種:JNM-LA300 FT NMR SYSTEM(日本電子株式会社製)、内部基準物質:テトラメチルシラン又はクロロホルムを用いて実施された。
GC分析は、機種:6890N Network GC System(Agilent Technologies製)を用いて実施された。GC分析方法に関しては、必要に応じて、以下の文献を参照することができる。
(a):(社)日本化学会編、「新実験化学講座9 分析化学 II」、第60~86頁(1977年)、発行者 飯泉新吾、丸善株式会社(例えば、カラムに使用可能な固定相液体に関しては、第66頁を参照できる。)
(b):(社)日本化学会編、「実験化学講座20-1 分析化学」第5版、第121~129頁(2007年)、発行者 村田誠四郎、丸善株式会社(例えば、中空キャピラリー分離カラムの具体的な使用方法に関しては、第124~125頁を参照できる。)
GC-MS分析は、分析装置に機種:6890N Network GC System(Agilent Technologies製)、質量検出器に機種:5973N MSD(Agilent Technologies製)を用いて実施された。
pHはガラス電極式水素イオン濃度指示計により測定した。ガラス電極式水素イオン濃度指示計としては、具体的には、例えば、形式:パーソナルpH/ORPメータPH72(横川電気株式会社製)又は形式:HM-20P(東亜ディーケーケー株式会社製)などが使用できる。
二酸化塩素ガスのガス濃度及びガス純度に関して、二酸化塩素ガスの定量分析は、当業者に知られたヨウ素滴定により行われた。例えば、二酸化塩素ガスのヨウ素滴定は、次のような手順で行うことができる;リン酸緩衝液でpH7又はpH8に調整した5~10%ヨウ化カリウム水溶液に、二酸化塩素ガスを吸収させる。澱粉を指示薬として、遊離したヨウ素を10規定チオ硫酸ナトリウム水溶液で滴定する。その後、滴定後の溶液を2規定硫酸などで酸性にする。遊離したヨウ素を、同様にして滴定する。
Claims (13)
- マロン酸化合物と二酸化塩素との反応がpH5~pH10の範囲で行われる、請求項1に記載のケトマロン酸化合物又はその抱水体の製造方法。
- マロン酸化合物と二酸化塩素との反応がpH5~pH8の範囲で行われる、請求項1又は2に記載のケトマロン酸化合物又はその抱水体の製造方法。
- マロン酸化合物と二酸化塩素との反応がpH6~pH8の範囲で行われる、請求項1から3のいずれか1項に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤を用いてpHをコントロールする、請求項1から4のいずれか1項に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤として無機塩基を用いる、請求項5に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤としてアルカリ金属水酸化物を用いる、請求項5に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤として水酸化ナトリウムを用いる、請求項5に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤として水酸化ナトリウムを用いてpHをコントロールし、マロン酸化合物と二酸化塩素との反応がpH5~pH10の範囲で行われる、請求項1に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤として水酸化ナトリウムを用いてpHをコントロールし、マロン酸化合物と二酸化塩素との反応がpH5~pH8の範囲で行われる、請求項1に記載のケトマロン酸化合物又はその抱水体の製造方法。
- pH調整剤として水酸化ナトリウムを用いてpHをコントロールし、マロン酸化合物と二酸化塩素との反応がpH6~pH8の範囲で行われる、請求項1に記載のケトマロン酸化合物又はその抱水体の製造方法。
- 一般式(1)のRがC1~C4アルキル基である、請求項1から11のいずれか1項に記載のケトマロン酸化合物又はその抱水体の製造方法。
- 一般式(1)のRがメチル又はエチルである、請求項1から11のいずれか1項に記載のケトマロン酸化合物又はその抱水体の製造方法。
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Cited By (3)
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WO2015122361A1 (ja) * | 2014-02-17 | 2015-08-20 | イハラケミカル工業株式会社 | 流通反応器を用いたケトマロン酸化合物の連続製造方法 |
JP6017710B2 (ja) * | 2014-02-17 | 2016-11-02 | イハラケミカル工業株式会社 | 流通反応器を用いたケトマロン酸化合物の連続製造方法 |
US10035753B2 (en) | 2014-02-17 | 2018-07-31 | Kumiai Chemical Industry Co., Ltd. | Method for continuously producing ketomalonic acid compound using flow reactor |
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AU2014291365A1 (en) | 2016-02-18 |
ES2713376T3 (es) | 2019-05-21 |
EP3023411B1 (en) | 2018-12-05 |
TW201536737A (zh) | 2015-10-01 |
AU2014291365B2 (en) | 2018-02-22 |
KR102034610B1 (ko) | 2019-10-21 |
US9499469B2 (en) | 2016-11-22 |
KR20160033120A (ko) | 2016-03-25 |
EP3023411A4 (en) | 2017-03-15 |
EP3023411A1 (en) | 2016-05-25 |
JP2015020975A (ja) | 2015-02-02 |
JP5921500B2 (ja) | 2016-05-24 |
US20160194268A1 (en) | 2016-07-07 |
CN105377803B (zh) | 2018-10-26 |
IL243644A (en) | 2017-04-30 |
TWI639581B (zh) | 2018-11-01 |
CN105377803A (zh) | 2016-03-02 |
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