WO2006075596A1 - Method for producing 2-allylcarboxylic acid compound - Google Patents

Method for producing 2-allylcarboxylic acid compound Download PDF

Info

Publication number
WO2006075596A1
WO2006075596A1 PCT/JP2006/300183 JP2006300183W WO2006075596A1 WO 2006075596 A1 WO2006075596 A1 WO 2006075596A1 JP 2006300183 W JP2006300183 W JP 2006300183W WO 2006075596 A1 WO2006075596 A1 WO 2006075596A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
bond
chemical
group
Prior art date
Application number
PCT/JP2006/300183
Other languages
French (fr)
Japanese (ja)
Inventor
Hideki Matsuda
Makoto Nakazawa
Koichi Kanehira
Original Assignee
Kuraray Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kuraray Co., Ltd. filed Critical Kuraray Co., Ltd.
Priority to JP2006552923A priority Critical patent/JPWO2006075596A1/en
Publication of WO2006075596A1 publication Critical patent/WO2006075596A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/21—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation

Definitions

  • the present invention relates to a method for producing a 2-arylcarboxylic acid compound.
  • a 2-arylcarboxylic acid compound obtained by the present invention such as 2-aryloctanoic acid, is an (R) -2-propyloctanoic acid useful as a therapeutic or preventive agent for neurodegenerative diseases caused by abnormal function of astrocytes. It is useful as a synthetic intermediate (see WO99Z058513 pamphlet).
  • a method for producing a 2-arylcarboxylic acid compound for example, 2-aryloctanoic acid
  • (1) a method of reacting octanoic acid and allylpromide in the presence of a basic substance see Non-Patent Document 1)
  • (2) a method in which malonic acid diester and allylpromide are reacted in the presence of a base, and further hexylpromide is reacted, followed by hydrolysis and decarboxylation see Non-Patent Document 2.
  • Non-Patent Document 1 Journal of the Chemical Society, Perkin Transactions 1 (1998), p. 1373- 1382
  • Non-Patent Document 2 Chemical & Pharmaceutical Bulletin, 1976, No. 24, No. 3, p. 538-540 Disclosure of the Invention
  • an object of the present invention is to solve the above problems and to use 2-arylcarboxylic acid compound.
  • the object is to provide a method which can be produced industrially advantageously in a yield, and a novel synthetic intermediate therefor.
  • a bond having a solid line and a dotted line force represents a single bond or a double bond
  • X is a formyl group
  • a bond consisting of a solid line and a dotted line represents a single bond or a double bond
  • X is a formyl group or the above dialkoxymethyl group
  • Y represents a hydrogen atom
  • X is the above trialkoxymethyl group.
  • ⁇ represents an alkoxy group represented by the formula (wherein represents an alkyl group or an aryl group having a carbon number to)
  • —arylcarbonyl compound (hereinafter referred to as “)” is represented by the following formula: [0011]
  • a 2-arylcarbonyl compound [hereinafter referred to as 2-arylcarbonyl compound (II-1)] is obtained. Then, the 2-arylcarbonyl compound (II 1) is oxidized, The method for producing a 2-arylcarboxylic acid compound (III) according to 1);
  • the 2-arylcarboxylic acid compound can be produced industrially advantageously in good yield.
  • Powerful 2-arylcarboxylic acid compounds such as 2-aryloctanoic acid are useful as therapeutic or preventive agents for neurodegenerative diseases caused by astrocyte dysfunction (R ) —Useful as an intermediate for the synthesis of 2-propyloctanoic acid.
  • X in the compound (I) is a formyl group, a dialkoxymethyl group represented by the formula CH (OR 1 ), or
  • X is a formyl group or di
  • Y of the arylcarbonyl compound ( ⁇ ) is a hydrogen atom, and the conversion to the arylcarbonyl compound ( ⁇ ) force to the arylcarboxylic acid compound (III) is performed by an oxidation reaction.
  • X is a trialkoxymethyl group
  • Y is an alkoxy group represented by the formula —OR 2 , and the conversion to the arylcarbonyl compound ( ⁇ ) force to the arylcarboxylic acid compound (III) is carried out by a hydrolysis reaction. .
  • Examples of the alkyl group having 16 carbon atoms represented by R 1 and R 2 include, for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, n Examples include pentyl group, isopentyl group, neopentyl group, n-xyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
  • compound (I) is compound (1-1)
  • Y of 2-arylcarbonyl compound ( ⁇ ) is a hydrogen atom
  • 2-arylcarbonyl compound ( ⁇ ) is 2 —Arylcarbonyl compound ( ⁇ —1).
  • reaction step 1 a step in which compound (1-1) is reacted in the presence of an acid catalyst and allylic alcohol to obtain 2-arylcarbonyl compound ( ⁇ -1).
  • Reaction step 1 includes a reaction (hereinafter referred to as “reaction A”) in which a compound (1-1) and a allylic alcohol are also obtained in the presence of an acid catalyst (hereinafter referred to as “reaction A”), a dialylacetal compound Via a reaction (hereinafter referred to as “Reaction B”) in which (IV) is dearylated alcohol, followed by Claisen rearrangement to give 2-arylcarbonyl compound (II 1) It is a process. First, reaction A will be described.
  • the acid catalyst used in Reaction A for example, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; strong acids such as acetic acid, succinic acid, maleic acid, benzoic acid, terephthalic acid, and trifluoroacetic acid; rubonic acid; methane Examples thereof include sulfonic acids such as sulfonic acid, toluenesulfonic acid, and trifluoromethanesulfonic acid; acidic salts such as pyridine and toluenesulfonic acid; acidic ion-exchange resin.
  • inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid
  • strong acids such as acetic acid, succinic acid, maleic acid, benzoic acid, terephthalic acid, and trifluoroacetic acid
  • rubonic acid methane Examples thereof include sulfonic acids such as sulfonic acid, toluenesulfonic acid, and tri
  • Carbonic acid is preferably used, and maleic acid is particularly preferably used.
  • the amount of the acid catalyst to be used is not particularly limited, but is usually from 0.000001 to 1 mol based on 1 mol of the compound (1-1), from an economical viewpoint, it is preferably 0.001.
  • the range of -0.5 mol is more preferred.
  • the range of 0.001-0. 1 mol is more preferred.
  • the amount of allylic alcohol used in reaction A is preferably in the range of 0.1 to 50 mol per mol of compound (I 1), and is preferably in the range of 0.2 to 20 mol. Is more preferably in the range of 0.5 to 10 moles.
  • Reaction A can be carried out in the presence or absence of a solvent.
  • Solvents that can be used are not particularly limited as long as they do not adversely affect the reaction.For example, aromatic hydrocarbons such as toluene, xylene, and mesitylene; aliphatic hydrocarbons such as hexane, heptane, and octane; dichloroethane, black benzene And halogenated hydrocarbons such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme, triglyme and the like.
  • the amount used is not particularly limited, but it is usually preferable that the amount is in the range of 0.1 to 10 times the mass of the compound (I 1), and easy post-treatment. From this viewpoint, the range of 0.2 to 5 times the mass is more preferable.
  • the reaction temperature of the reaction A is usually in the range of 20 to 120 ° C, and from the viewpoint of the reaction rate, the selectivity of the reaction and the stability of the diallyl acetal compound (IV), 80 to 120 ° C. A range of C is preferred.
  • the reaction pressure is not particularly limited, but is usually in the range of 0.1 to 500 kPa, preferably in the range of 1 to 200 kPa.
  • the reaction time varies depending on the type and amount of the acid catalyst used, the reaction temperature, the reaction pressure, etc., but is usually in the range of 30 minutes to 40 hours.
  • the method for carrying out reaction A is not particularly limited.
  • compound (I 1), aryl alcohol, an acid catalyst and, if necessary, a solvent are mixed and reacted at a predetermined temperature and a predetermined pressure. It can be implemented from Sako.
  • the reaction may be carried out while removing powerful water.
  • the method for removing water is not particularly limited.
  • a dehydrating agent that does not adversely affect the reaction such as molecular sieves is added to the reaction system, or the reaction with the solvent in the reaction system is carried out.
  • the method of distilling by boiling and the like can be mentioned.
  • the thus obtained diallyl acetal compound (IV) can also be separated and purified by the reaction mixture force by a method generally used in the separation and purification method of organic compounds. For example, it can be purified by adding water to the reaction mixture, removing the acid catalyst to the aqueous layer, separating and obtaining the organic layer, and distilling the organic layer.
  • the reaction mixture obtained in the above reaction A can be used as it is in the following reaction B described later without separation and purification, and in obtaining a 2-arylcarbonyl compound ( ⁇ -1). This is a more preferable and simple method.
  • 1,1-Diaryloxy-7-otaten is a novel compound.
  • the acid catalyst used in the reaction B is not particularly limited, and examples thereof include the same acid catalysts used in the reaction A described above. Among these, carboxylic acid is preferably used from the viewpoints of easy availability and influence on the reaction apparatus, and maleic acid is particularly preferable.
  • the amount of the acid catalyst used is not particularly limited, but is usually in the range of 0.0001 to 1 mol per mol of diallyl acetal compound (IV). The range of 0001 to 0.5 mol is more preferable. The range of 0.0005-0. 1 mol is more preferable.
  • the diallyl acetal compound (IV) obtained in Reaction A is separated from the reaction mixture and purified. Without being added to the reaction B (preferred embodiment for carrying out the present invention), since the acid catalyst is already present in the reaction system, there is no particular need to add it. There is no problem.
  • Reaction B can be carried out in the presence or absence of a solvent.
  • the powerful solvent include the same solvents as those that can be used in Reaction A, as long as they do not adversely affect the reaction.
  • the amount used is not particularly limited, but usually it is preferably in the range of 0.1 to 10 times the mass with respect to the diarylacetal compound (IV).
  • the diallyl acetal compound (IV) obtained in the reaction A is subjected to the reaction B without being separated and purified from the reaction mixture (preferred embodiment for carrying out the present invention).
  • the solvent may already be present in the reaction mixture, it is not particularly necessary to add it further, but it may be added if necessary.
  • the reaction pressure in the reaction B is preferably in the range of 0.1 to 500 kPa, more preferably in the range of 1 to 50 kPa, from the viewpoint of allowing the reaction to proceed smoothly.
  • the reaction temperature is preferably in the range of 120 to 180 ° C, more preferably in the range of 130 to 170 ° C.
  • the reaction time varies depending on the type of acid catalyst, amount used, reaction temperature, reaction pressure, and the like. Usually, the reaction time is in the range of 30 minutes to 48 hours.
  • the method for carrying out reaction B is not particularly limited.
  • the diaryl acetal compound (IV) when the diaryl acetal compound (IV) is separated and purified, the diaryl acetal compound (IV), an acid catalyst and It can be carried out by mixing the solvent as necessary and reacting at a predetermined temperature and pressure.
  • reaction condition If the reaction temperature and reaction pressure are set to the predetermined values in reaction B, the reaction A can be transferred to the reaction B.
  • Reaction B from the viewpoint of yield, it is preferable to carry out the reaction while removing the by-produced aryl alcohol as the reaction proceeds, and the resulting 2-arylcarbonyl compound is also produced.
  • the separation and purification of the 2-arylcarbolyl compound ( ⁇ -1) from the reaction mixture thus obtained can be carried out by a method generally used in the separation and purification of organic compounds. For example, after adding a solvent and water to the obtained reaction mixture, the aqueous layer is removed, the solvent is appropriately distilled off from the organic layer, and the residue can be further distilled. Further, the residue can be directly subjected to the oxidation reaction described later without purification.
  • reaction step 2 a step of oxidizing the 2-arylcarbonyl-compound ( ⁇ -1) obtained by the above method to obtain a 2-arylcarboxylic acid compound (III) (hereinafter referred to as "reaction step 2"). Will be described).
  • an oxidizing agent generally used for converting aldehydes to carboxylic acids can be used.
  • strong oxidizing agents include oxygen; peroxyhydrogen; organic peracid compounds such as formic acid, peracetic acid, m-peroxybenzoic acid; sodium chlorite, sodium bromate
  • Metal halide salts such as potassium chlorite and potassium bromite
  • metal hypohalite salts such as sodium hypochlorite, sodium hypobromite, potassium hypochlorite and potassium hypobromite
  • Halogenate metal salts such as sodium chlorate, sodium bromate, potassium chlorate and potassium bromate
  • permanganate metal salts such as sodium permanganate and potassium permanganate
  • acid chrome silver oxide
  • silver oxide examples thereof include metal oxides such as ruthenium oxide.
  • reaction step 2 As an example of the reaction step 2, a case where a metal halous acid salt is used as an oxidizing agent will be described.
  • the metal halous acid salt is from the viewpoint of availability.
  • Sodium chlorite is preferably used.
  • the amount of metal phosphite or metal salt of rogenic acid it is usually preferred to be in the range of 0.1 to 20 moles per mole of 2-arylcarbonyl compound ( ⁇ -1). More preferably, it is in the range of 0.5 to 10 mol, and more preferably in the range of 0.8 to 5 mol.
  • a halogen scavenger When the reaction step 2 is performed using a metal halous acid salt, it is preferable to add a halogen scavenger to the reaction system in order to suppress a halogenation reaction as a side reaction.
  • the halogen scavenger include resorcinol, 2-methyl 2-butene, dimethyl sulfoxide and the like.
  • the amount used is not particularly limited, but it is usually in the range of 0.1 to 50 mol with respect to 1 mol of the diarylcarbol compound (11-1). A preferred range is 0.5 to 20 moles, and a more preferred range is 0.8 to 10 moles.
  • Reaction step 2 is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction, for example, aromatic hydrocarbons such as toluene, xylene, mesitylene, etc .; aliphatic hydrocarbons such as hexane, heptane, octane; dichloroethane, black benzene, etc.
  • alcohols such as methanol, ethanol, isopropanol, and t-butanol
  • ethers such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether) and triglyme (triethylene glycol dimethyl
  • the amount of solvent used it is usually preferred that the amount is in the range of 0.1 to 100 times the mass of 2-arylcarbonyl compound (II-1). From the viewpoint of simplicity, the range of 0.2 to 50 times mass is more preferable, and the range of 0.5 to 30 times mass is more preferable.
  • Reaction step 2 is preferably carried out under acidic conditions, more preferably in the range of pH 2-6.
  • an acidic compound such as phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate into the reaction system.
  • an acidic compound such as phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate
  • 2-aryl carbo-louis compound (11-1) 1 It is preferably in the range of 0.1 to 20 mol, more preferably in the range of 0.5 to 10 mol, and even more preferably in the range of 0.8 to 5 mol. preferable.
  • the reaction temperature is preferably in the range of 0 to 100 ° C, in view of the reaction rate, the selectivity of the reaction, and the stability of the target product, in the range of 10 to 70 ° C. Is more preferable.
  • the reaction pressure is preferably in the range of 0.1 to 500 kPa, more preferably in the range of 1 to 200 kPa.
  • the reaction time varies depending on the type and amount of metal halite (oxidizer), halogen scavenger, acidic compound, type and amount of solvent, reaction temperature, reaction pressure, etc. ⁇ 24 hours range.
  • the method for carrying out the reaction step 2 is not particularly limited.
  • a 2-arylcarbonyl compound (II 1), an oxidizing agent, a solvent, and optionally a halogen scavenger and Z or an acidic compound are mixed,
  • the reaction can be carried out at a temperature and under a predetermined pressure.
  • the separation and purification of the diarylcarboxylic acid compound ( ⁇ ) from the reaction mixture thus obtained can be carried out by a method generally used in the separation and purification of organic compounds.
  • a basic compound such as sodium hydroxide and potassium hydroxide is added to the reaction mixture to make it basic, and then concentrated, and water and an organic solvent such as hexane, toluene, diisopropyl ether are added.
  • the organic layer and the aqueous layer are separated, and the aqueous layer is acidified with dilute hydrochloric acid or the like and then extracted with the organic solvent described above.
  • the extract is concentrated and further distilled to obtain a high purity 2-
  • a arylcarboxylic acid compound ( ⁇ ) can be obtained.
  • 2-aryl-7-otatenic acid is a novel compound.
  • compound (I) is compound (I 2)
  • Y of 2-arylcarbonyl compound ( ⁇ ⁇ ) is a hydrogen atom
  • 2-arylcarbonyl compound ( ⁇ ) is 2 —Arylcarbonyl compound (II-1).
  • reaction step ⁇ 2-arylcarbonyl compound ( ⁇ -1)
  • the acid catalyst used in the reaction step ⁇ there are no particular restrictions on the acid catalyst used in the reaction step ⁇ , and the same catalysts as those used in the reaction A in the above-mentioned reaction step 1 can be mentioned. Among them, viewpoints such as availability and influence on the reaction apparatus It is preferable to use carboxylic acid, and it is particularly preferable to use maleic acid.
  • the amount of the acid catalyst to be used is not particularly limited, but it is usually from an economical viewpoint that it is preferably in the range of 0.0001-0. 5 mol with respect to 1 mol of the compound (1-2). A force in the range of 0.001 to 0.1 mol is preferred, and a range of 0.0005 to 0.05 mol is more preferred.
  • the amount of allylic alcohol used in the reaction step ⁇ is preferably in the range of 0.1 to 20 moles relative to 1 mole of compound (I 2), in the range of 0.2 to 10 moles. More preferably, it is more preferably in the range of 0.5 to 5 moles.
  • the reaction step ⁇ can be performed in the presence or absence of a solvent.
  • solvents are not particularly limited as long as they do not adversely affect the reaction, for example, aromatic hydrocarbons such as toluene, xylene and mesitylene; aliphatic hydrocarbons such as hexane, heptane and octane; dichloroethane and black benzene And halogenated hydrocarbons such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), and ethers such as triglyme (triethylene glycol dimethyl ether).
  • the amount used is not particularly limited. Generally, it is preferable that the amount is in the range of 0.1 to 10 times the mass of the compound (I 2). From the viewpoint, it is more preferably in the range of 0.2 to 5 times mass.
  • the reaction pressure in the reaction step ⁇ is preferably in the range of 0.1 to 500 kPa, more preferably in the range of 1 to 200 kPa, from the viewpoint of allowing the reaction to proceed smoothly.
  • the reaction temperature is preferably in the range of 120 to 200 ° C, more preferably in the range of 130 to 180 ° C. preferable.
  • the reaction time varies depending on the type of acid catalyst, amount used, reaction temperature, reaction pressure, etc. Usually, it is in the range of 30 minutes to 48 hours.
  • the method for carrying out the reaction step ⁇ is not particularly limited.
  • the compound (I 2), an acid catalyst and a solvent as necessary are mixed, and aryl alcohol is added dropwise at a predetermined temperature and a predetermined pressure. It can be carried out by reacting.
  • the reaction step 1 from the viewpoint of the yield of the 2-arylcarbonyl compound ( ⁇ -1), the formula I ⁇ OH generated as a by-product as the reaction proceeds (wherein R 1 is as defined above)
  • the reaction may be carried out while distilling off the alcohol indicated by It is also possible to carry out the reaction while distilling the produced 2-arylcarbonyl compound ( ⁇ -1).
  • Separation and purification of the 2-arylcarbonyl compound (II-1) from the reaction mixture containing the 2-arylcarbonyl compound ( ⁇ -1) thus obtained is generally performed in the separation and purification of organic compounds. It can be implemented by the method used. For example, after adding a solvent and water to the obtained reaction mixture, the aqueous layer is removed, and the residue obtained by appropriately distilling off the solvent from the obtained organic layer can be purified by further distillation. In addition, the organic layer can be directly subjected to an acid-acid reaction described later.
  • a step of obtaining a 2-arylcarboxylic acid compound ( ⁇ ) by acidifying the 2-arylcarboxyl compound (II-1) obtained by the above method (hereinafter referred to as reaction step 2, and 1) is the same as Reaction Step 2 in the case where X is a formyl group.
  • the production method of the compound (I 2) which is a raw material of the present invention, is not particularly limited. And trimethyl orthoacetate are reacted and then neutralized, and the low boiling point compound is distilled off.
  • the compound (I2) with higher purity can be obtained by appropriately applying a usual method for separating and purifying organic compounds such as distillation.
  • the compound (I) is the compound (1-3)
  • Y of the 2- arylcarbonyl compound ( ⁇ ) is represented by the formula —OR 2 (wherein R 2 is as defined above)
  • the 2-arylcarbonyl compound (II) is an arylcarbonyl compound (II 2).
  • reaction step 1 ⁇ the step of obtaining the 2-arylcarbonyl compound (II 2) by reacting the compound (1-3) in the presence of an acid catalyst and allylic alcohol (hereinafter referred to as reaction step 1 ⁇ ) will be described. To do.
  • the acid catalyst used in reaction step 1 there are no particular restrictions on the acid catalyst used in reaction step 1 to, and examples thereof include the same ones used in reaction A in reaction step 1 described above. Of these, viewpoints such as availability, influence on the reaction apparatus, etc. It is preferable to use carboxylic acid, and maleic acid is particularly preferable.
  • the amount of the acid catalyst to be used is not particularly limited, but is usually in the range of 0.00001-0. 5 mol with respect to 1 mol of the compound (1-3). A force in the range of 0001 to 0.1 mol is preferred, and a range of 0.0005 to 0.05 mol is more preferred.
  • the amount of allylic alcohol used in the reaction step ⁇ is preferably in the range of 0.1 to 20 mol per mol of compound (I 3), and in the range of 0.2 to 10 mol. More preferably, it is more preferably in the range of 0.5 to 5 moles.
  • the reaction step ⁇ can be carried out in the presence or absence of a solvent.
  • solvents are not particularly limited as long as they do not adversely affect the reaction, for example, aromatic hydrocarbons such as toluene, xylene and mesitylene; aliphatic hydrocarbons such as hexane, heptane and octane; dichloroethane and black benzene And halogenated hydrocarbons such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), and ethers such as triglyme (triethylene glycol dimethyl ether).
  • the amount used is not particularly limited. Generally, it is preferable that the amount is in the range of 0.1 to 10 times the mass of the compound (I 3). From the viewpoint, it is more preferably in the range of 0.2 to 5 times mass.
  • the reaction pressure at ⁇ is preferably in the range of 0.1 to 50 OkPa, more preferably in the range of 1 to 200 kPa, from the viewpoint of allowing the reaction to proceed smoothly.
  • the reaction temperature is preferably in the range of 120 to 200 ° C, more preferably in the range of 130 to 180 ° C.
  • the reaction time varies depending on the type and amount of acid catalyst used, reaction temperature, reaction pressure, etc., but is usually in the range of 30 minutes to 48 hours.
  • the method for carrying out the reaction steps 1 to is not particularly limited. For example, the compound (I 3), an acid catalyst and a solvent as necessary are mixed, and allylic alcohol is added dropwise at a predetermined temperature and a predetermined pressure. It can be carried out by reacting.
  • reaction step 1 ⁇ from the viewpoint of the yield of 2-aryl carbo-louis compound ( ⁇ -2), by-product as the reaction proceeds, the formula I ⁇ OH (wherein R 1 is as defined above).
  • the reaction may be carried out while removing the alcohol represented by). It is also possible to carry out the reaction while distilling the generated 2-aryl carbo-louis compound ( ⁇ -2).
  • Separation and purification of the biarylcarbo-Louis compound ( ⁇ -2) from the reaction mixture thus obtained can be carried out by a method generally used in separation and purification of organic compounds. For example, after adding a solvent and water to the obtained reaction mixture, the aqueous layer is removed, and the residue obtained by distilling off the solvent as appropriate from the obtained organic layer can be further purified. In addition, the organic layer or the reaction mixture is not purified, but can be directly subjected to the hydrolysis reaction described later.
  • reaction step 2 the 2-arylcarbonyl compound ( ⁇ -2) obtained by the above method is hydrolyzed to obtain 2-arylcarboxylic acid compound (III) (hereinafter referred to as reaction step 2 "). ) Will be explained.
  • Examples of basic compounds include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate And hydrogen carbonates.
  • the amount of the basic compound used is usually in the range of 0.1 to 20 mol with respect to 1 mol of 2-arylcarbol compound ( ⁇ -2). More preferably, it is in the range of 0.5 to 10 mol, more preferably in the range of 0.8 to 5 mol.
  • the amount of water used is usually 0. 1 mol of 2-arylcarbonyl compound ( ⁇ -2).
  • the range of 1 to 50 mol is preferred.
  • Reaction steps 2 to are preferably performed in the presence of a solvent.
  • Solvents that can be used are not particularly limited as long as they do not adversely affect the reaction.For example, aromatic hydrocarbons such as toluene, xylene, and mesitylene; aliphatic hydrocarbons such as hexane, heptane, and octane; dichloroethane, black benzene, etc.
  • Halogenated hydrocarbons such as methanol, ethanol, isopropanol, and t-butanol; ethers such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme, and triglyme; -tolyl compounds such as acetonitrile, benzo-tolyl, and the like; Examples include amido compounds such as formamide and dimethylacetamide. Among these, it is preferable to use alcohol. Although there is no particular limitation on the amount of solvent used, it is usually preferred that the 2-allylcarbonyl compound (II-2) is in the range of 0.1 to LOO times mass. From the viewpoint of simplicity, the range of 0.2 to 20 times mass is more preferable, and the range of 0.5 to 10 times mass is more preferable.
  • the reaction temperature in the reaction steps 2 to is preferably in the range of 0 to 150 ° C.
  • the reaction pressure is in the range of 0.1 to 500 kPa, and more preferably in the range of 1 to 200 kPa.
  • the reaction time varies depending on the type and amount of the basic compound used, the amount of water used, the reaction temperature, the reaction pressure, etc., but is usually in the range of 10 minutes to 24 hours.
  • the method for carrying out reaction steps 2 to is not particularly limited, for example, 2-arylcarbonyl compound (II 2) or 2-arylcarbonyl compound (II-) obtained by post-treatment of reaction step ⁇ '. It can be carried out by mixing an organic layer containing 2), a basic compound, water and preferably a solvent and reacting them under a predetermined temperature and a predetermined pressure.
  • the separation and purification of the diarylcarboxylic acid compound ( ⁇ ) from the reaction mixture thus obtained can be carried out by a method generally used in the separation and purification of organic compounds. For example, after concentrating the reaction mixture, water and an organic solvent are added and mixed, and then the aqueous layer is taken out. The aqueous layer is acidified with dilute hydrochloric acid and then with an organic solvent such as hexane, toluene, and diisopropyl ether. By extracting and distilling a powerful extract, A highly pure 2-arylcarboxylic acid compound ( ⁇ ) can be obtained.
  • the production method of the compound (I 3) which is a raw material of the present invention is not particularly limited.
  • octane-tolyl or otaten-tolyl is added in the presence of a solvent such as diisopropyl ether and a salt of hydrogen and a compound.
  • Reaction with an alcohol represented by I ⁇ OH (wherein R 1 is as defined above) at 5-20 ° C for 5-24 hours the precipitated solid is filtered, and the resulting solid is filtered.
  • it can be produced by reacting with an alcohol represented by the formula I ⁇ OH (R 1 is as defined above) in the presence of a solvent such as diisopropyl ether at 20-30 ° C for 5-24 hours. .
  • the organic layer was washed with 100 ml of 5% by mass aqueous sodium hydrogen carbonate solution and then with 100 ml of saturated brine, and then concentrated to obtain 106.8 g of a crude product.
  • the obtained crude product was subjected to gas chromatography [analytical instrument: GC-9A, manufactured by Shimadzu Corporation, column used: G-230 (1. D .: 1.2 mm, Column length: 20 m, membrane thickness: 1.0 m), analysis condition: injection temp. 280 ° C, temperature rise condition: 80 ° C ⁇ (temperature rise in 10 ° CZ minutes) ⁇ 250 ° C (20 minutes) As a result, it was found to contain 1,1-diallyloxyoctane 84. Og (yield 74% based on otatanal).
  • the organic layer was washed with 100 ml of 5% by mass aqueous sodium hydrogen carbonate solution and then with 100 ml of saturated brine, and then concentrated to obtain 105.8 g of a crude product.
  • the obtained crude product was distilled under reduced pressure (116 ° CZ0.7 kPa) to obtain 88.2 g (purity 98.1%, yield 77%) of 1,1 diallyloxy-7-octene having the following physical properties. It was.
  • the solution was dropped into the flask over a period of minutes. After completion of the dropwise addition, the mixture was stirred at 25 ° C for 2 hours.
  • the obtained reaction mixture was adjusted to pHIO or higher by adding 20 mass% aqueous sodium hydroxide solution, concentrated, added with 100 ml of water, washed twice with 100 ml of toluene, and the organic layer was separated. Concentrated hydrochloric acid was added to the aqueous layer, the pH of the aqueous layer was adjusted to 3 or less, and then extracted twice with 50 ml of toluene. The resulting extract was concentrated to obtain 18.9 g of a crude product. The obtained crude product was distilled under reduced pressure (142 ° C / 0.5 kPa) to obtain 15.1 g (purity 99.5%, yield 91%) of 2-aryl 7-otatenic acid having the following physical properties. It was.
  • the pH of the reaction mixture was adjusted to 10 or more by adding 20 mass% aqueous sodium hydroxide solution.
  • the obtained reaction mixture was concentrated, 30 ml of water was added, and the mixture was washed twice with 30 ml of toluene to separate and remove the organic layer.
  • Hydrochloric acid was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 3 or less, followed by extraction twice with 15 ml of toluene, and the resulting extract was concentrated to obtain 6.6 g of a crude product.
  • the obtained crude product was distilled under reduced pressure (138 ° CZ0.5 kPa) to obtain 5.5 g of 2-aryloctanoic acid (purity 99.1%, yield 91%).
  • the precipitated solid was filtered, washed with diisopropyl ether, and then dried under reduced pressure to obtain 21. lg of white solid.
  • 21. lg of the white solid obtained in the above operation 21. lg of the white solid obtained in the above operation, 20.9 g of methanol and 97 ml of diisopropyl ether were placed and stirred at 25 ° C. for 20 hours.
  • the precipitated salt ammonium was filtered off, and the filtrate was concentrated under reduced pressure to obtain 23. lg of a crude product. This crude product was distilled under reduced pressure (86 ° CZ 0.3 kPa) to obtain 19.7 g of trimethyl orthooctanoate (purity 99.9%, yield 51% based on octane-tolyl).
  • Concentrated hydrochloric acid is added to the remaining aqueous layer to adjust the pH of the aqueous layer to 3 or less, followed by extraction twice with 20 ml of toluene. The obtained extract and the previous organic layer are combined and concentrated under reduced pressure. 8.5 g of crude product was obtained. This crude product was distilled under reduced pressure (138 ° CZ0.5 kPa) to obtain 6.8 g of 2-aryloctanoic acid (purity 99.0%, yield 97%).

Abstract

Disclosed is a method for commercially advantageously producing a 2-allylcarboxylic acid with high yield. Specifically disclosed is a method for producing a 2-allylcarboxylic acid compound which is characterized by the process wherein a compound represented by the formula (I) below is reacted in the presence of an acid catalyst and an allyl alcohol, thereby obtaining a 2-allylcarbonyl compound represented by the formula (II) below, and then the thus-obtained 2-allylcarbonyl compound is converted into a 2-allylcarboxylic acid represented by the formula (III) below. [Chemical formula 1] (I) [Chemical formula 2] (II) [Chemical formula 3] (III) (In the above formulae, bonds shown by solid and dotted lines represent a single bond or a double bond; X represents a formyl group, a dialkoxymethyl group or a trialkoxymethyl group; and Y represents a hydrogen atom or an alkoxy group.)

Description

2 -ァリルカルボン酸化合物の製造方法  Method for producing 2-arylcarboxylic acid compound
技術分野  Technical field
[0001] 本発明は 2—ァリルカルボン酸ィ匕合物の製造方法に関する。本発明により得られる 2—ァリルカルボン酸ィ匕合物、例えば 2—ァリルオクタン酸は、ァストロサイトの機能異 常による神経変性疾患の治療または予防剤として有用な (R)— 2—プロピルオクタン 酸の合成中間体として有用である（国際公開第 99Z058513号パンフレット参照)。 背景技術  [0001] The present invention relates to a method for producing a 2-arylcarboxylic acid compound. A 2-arylcarboxylic acid compound obtained by the present invention, such as 2-aryloctanoic acid, is an (R) -2-propyloctanoic acid useful as a therapeutic or preventive agent for neurodegenerative diseases caused by abnormal function of astrocytes. It is useful as a synthetic intermediate (see WO99Z058513 pamphlet). Background art
[0002] 従来、 2—ァリルカルボン酸ィ匕合物、例えば 2—ァリルオクタン酸の製造方法として は、（1)オクタン酸とァリルプロミドとを塩基性物質の存在下に反応させる方法 (非特 許文献 1参照）、（2)マロン酸ジエステルとァリルプロミドとを塩基存在下に反応させ、 さらにへキシルプロミドを反応させた後、加水分解 ·脱炭酸させる方法 (非特許文献 2 参照）などが知られている。  Conventionally, as a method for producing a 2-arylcarboxylic acid compound, for example, 2-aryloctanoic acid, (1) a method of reacting octanoic acid and allylpromide in the presence of a basic substance (see Non-Patent Document 1) ), (2) a method in which malonic acid diester and allylpromide are reacted in the presence of a base, and further hexylpromide is reacted, followed by hydrolysis and decarboxylation (see Non-Patent Document 2).
[0003] 非特許文献 1 :ジャーナル ォブ ザ ケミカル ソサエティ一、パーキン トランスァク ンヨンズ 1 (Journal oi tne Chemical Society, Perkm Transactions 1) , 1998年， p. 1373- 1382  [0003] Non-Patent Document 1: Journal of the Chemical Society, Perkin Transactions 1 (1998), p. 1373- 1382
非特許文献 2 :ケミカル アンド ファーマシューティカル ブレティン（Chemical & Pharmaceutical Bulletin) , 1976年，第 24卷，第 3号， p. 538— 540 発明の開示  Non-Patent Document 2: Chemical & Pharmaceutical Bulletin, 1976, No. 24, No. 3, p. 538-540 Disclosure of the Invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] 前記（1)に記載の方法は、塩基性物質として使用するリチウムジイソプロピルアミド の取り扱!/、が困難であると!/、う問題や、生成物と当量の無機塩 (臭化リチウム)が副生 するため廃棄物が多いという問題を有する。また、前記 (2)に記載の方法も、無機塩 (臭化物塩）が大量に副生するため廃棄物が多ぐそれらの処理が煩雑であるという 問題を有する。したがって、これらの方法は、いずれも 2—ァリルオクタン酸の工業的 に有利な製造方法とは言い難ぐさらなる改善の余地がある。  [0004] In the method described in (1), it is difficult to handle lithium diisopropylamide used as a basic substance! / Lithium) is a by-product, so there is a problem of a lot of waste. In addition, the method described in (2) also has a problem in that a large amount of inorganic salt (bromide salt) is produced as a by-product, so that the treatment with a large amount of waste is complicated. Therefore, both of these methods have room for further improvement, which cannot be said to be industrially advantageous production methods for 2-aryloctanoic acid.
[0005] しかして、本発明の目的は、上記問題を解決し、 2—ァリルカルボン酸ィ匕合物を、好 収率で、工業的に有利に製造し得る方法、およびそのための新規な合成中間体を提 供することにある。 [0005] Therefore, an object of the present invention is to solve the above problems and to use 2-arylcarboxylic acid compound. The object is to provide a method which can be produced industrially advantageously in a yield, and a novel synthetic intermediate therefor.
課題を解決するための手段 Means for solving the problem
本発明によれば、上記の目的は、  According to the present invention, the above object is
下記式  Following formula
[化
Figure imgf000005_0001
[Chemical
Figure imgf000005_0001
[式中、実線および点線力もなる結合は、単結合または二重結合を表し、 Xはホルミ ル基、式 (式中、 1は炭素数 〜 のアルキル基を表す）で表されるジ [In the formula, a bond having a solid line and a dotted line force represents a single bond or a double bond, X is a formyl group, and a formula (wherein 1 represents an alkyl group having 1 to 3 carbon atoms).
2  2
アルコキシメチル基、または式 (式中、 は前記定義の通りである）で表 An alkoxymethyl group or a formula (wherein is as defined above)
3  Three
されるトリアルコキシメチル基を示す] Represents a trialkoxymethyl group
で示される化合物 [以下化合物 と称する]を酸触媒およびァリルアルコールの存 在下に反応させることにより、下記式 Is reacted in the presence of an acid catalyst and allylic alcohol to produce a compound represented by the following formula:
[化 [Chemical
Figure imgf000005_0002
Figure imgf000005_0002
[式中、実線および点線力 なる結合は単結合または二重結合を表し、 Xがホルミル 基もしくは上記ジアルコキシメチル基であるときは Yは水素原子を表し、 Xが上記トリ アルコキシメチル基であるときは γは式 (式中、 は炭素数 〜 のアルキル基 またはァリル基を表す)で示されるアルコキシ基を表す] [In the formula, a bond consisting of a solid line and a dotted line represents a single bond or a double bond, and when X is a formyl group or the above dialkoxymethyl group, Y represents a hydrogen atom, and X is the above trialkoxymethyl group. When γ represents an alkoxy group represented by the formula (wherein represents an alkyl group or an aryl group having a carbon number to)
で示される —ァリルカルボニル化合物 [以下 —ァリルカルボニル化合物（ と称す る]を得、次 、で —ァリルカルボニル化合物 を下記式 [0011] The —arylcarbonyl compound [hereinafter referred to as —arylcarbonyl compound (hereinafter referred to as “)” is represented by the following formula: [0011]
Figure imgf000006_0001
Figure imgf000006_0001
[0012] (式中、実線および点線力 なる結合は、単結合または二重結合を表す） [0012] (In the formula, a bond consisting of a solid line and a dotted line represents a single bond or a double bond)
で示される 2—ァリルカルボン酸ィ匕合物 [以下 2—ァリルカルボン酸ィ匕合物 (III)と称 する]に変換することを特徴とする 2—ァリルカルボン酸ィ匕合物 (III)の製造方法； A method for producing a 2-arylcarboxylic acid compound (III), which is converted to a 2-arylcarboxylic acid compound (hereinafter referred to as 2-arylcarboxylic acid compound (III)) ;
[0013] 2)化合物 (I)を、酸触媒およびァリルアルコールの存在下に反応させることによる、 2 ーァリルカルボニル化合物 (II)の製造方法； [0013] 2) A process for producing 2-arylcarbonyl compound (II) by reacting compound (I) in the presence of an acid catalyst and allylic alcohol;
[0014] 3)下記式 (I 1)  [0014] 3) The following formula (I 1)
[0015] [化 4]  [0015] [Chemical 4]
Figure imgf000006_0002
Figure imgf000006_0002
[0016] (式中実線および点線力 なる結合は、単結合または二重結合を表す)で示される化 合物 [以下化合物 (1—1)と称する]を酸触媒およびァリルアルコールの存在下、 20 〜120°Cで反応させることにより、下記式 (IV) [0016] A compound represented by the following formula (wherein the bond represented by solid and dotted lines represents a single bond or a double bond) [hereinafter referred to as compound (1-1)] in the presence of an acid catalyst and aryl alcohol By reacting at 20 to 120 ° C, the following formula (IV)
[0017] [化 5]  [0017] [Chemical 5]
Figure imgf000006_0003
Figure imgf000006_0003
[0018] (式中実線および点線力もなる結合は、単結合または二重結合を表す)で示されるジ ァリルァセタール化合物 [以下ジァリルァセタールイ匕合物（IV)と称する]を含む反応 混合物を得、得られた反応混合物を 120〜180°Cに昇温して、反応混合物からァリ ルアルコールおよび水を留出させながら更に反応させることにより、下記式 (π ; L)[0018] (In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond) A reaction mixture containing an arylacetal compound [hereinafter referred to as diallyl acetal compound (IV)] is obtained, and the resulting reaction mixture is heated to 120 to 180 ° C. And further reacting while distilling water, the following formula (π; L)
[0019] [化 6] [0019] [Chemical 6]
Figure imgf000007_0001
Figure imgf000007_0001
[0020] (式中実線および点線力 なる結合は、単結合または二重結合を表す)で示される 2 ーァリルカルボニル化合物 [以下 2—ァリルカルボニル化合物（II— 1)と称する]を得 、次いで 2—ァリルカルボニル化合物 (II 1)を酸化することを特徴とする 1)記載の 2 ーァリルカルボン酸ィ匕合物 (III)の製造方法； [0020] (wherein the bond consisting of a solid line and a dotted line represents a single bond or a double bond) A 2-arylcarbonyl compound [hereinafter referred to as 2-arylcarbonyl compound (II-1)] is obtained. Then, the 2-arylcarbonyl compound (II 1) is oxidized, The method for producing a 2-arylcarboxylic acid compound (III) according to 1);
[0021] 4)化合物（1—1)を酸触媒およびァリルアルコールの存在下、 20〜120°Cで反応さ せることにより、ジァリルァセタールイ匕合物 (IV)を含む反応混合物を得、得られた反 応混合物を 120〜 180°Cに昇温して、反応混合物からァリルアルコールおよび水を 留出させながら更に反応させることを特徴とする 2)記載の 2—ァリルカルボ二ルイ匕合 物 (Π— 1)の製造方法；  [0021] 4) A reaction mixture containing the diallyl acetal compound (IV) by reacting the compound (1-1) in the presence of an acid catalyst and allylic alcohol at 20 to 120 ° C. The reaction mixture obtained is heated to 120 to 180 ° C., and further reacted while distilling off the allylic alcohol and water from the reaction mixture. Method for producing Louis compound (Π-1);
[0022] 5)下記式 (I 2)  [0022] 5) The following formula (I 2)
[0023] [化 7] [0023] [Chemical 7]
Figure imgf000007_0002
Figure imgf000007_0002
(式中実線および点線力 なる結合は、単結合または二重結合を表し、 R1は炭素数 1〜6のアルキル基を表す)で示される化合物 [以下化合物 (I 2)と称する]を酸触 媒およびァリルアルコールの存在下反応させることにより、 2—ァリルカルボ-ル化合 物 (II— 1)を得、次いで 2—ァリルカルボ-ルイ匕合物 (II— 1)を酸ィ匕することを特徴と する 1)記載の 2—ァリルカルボン酸ィヒ合物 (ΠΙ)の製造方法； (Wherein the bond represented by solid and dotted lines represents a single bond or a double bond, and R 1 represents an alkyl group having 1 to 6 carbon atoms) [hereinafter referred to as compound (I 2)] Touch By reacting in the presence of solvent and allylic alcohol, 2-aryl carbonyl compound (II-1) is obtained, and then 2-aryl carbonyl-compound (II-1) is acidified. And 1) the method for producing a 2-arylcarboxylic acid compound (ΠΙ) according to 1);
[0025] 6)化合物 (1— 2)を酸触媒およびァリルアルコールの存在下反応させることを特徴と する 2)記載の 2—ァリルカルボニル化合物 (Π— 1)の製造方法； [0025] 6) The method for producing a 2-arylcarbonyl compound (Π-1) according to 2), wherein the compound (1-2) is reacted in the presence of an acid catalyst and allylic alcohol;
[0026] 7)下記式 (I 3) [0026] 7) Formula (I 3)
[0027] [化 8] [0027] [Chemical 8]
Figure imgf000008_0001
Figure imgf000008_0001
[0028] (式中実線および点線力 なる結合は、単結合または二重結合を表し、 R1は炭素数 1〜6のアルキル基を表す)で示される化合物 [以下化合物 (I 3)と称する]を酸触 媒およびァリルアルコールの存在下反応させることにより、下記式 (Π— 2) [0028] (In the formula, a bond consisting of a solid line and a dotted line represents a single bond or a double bond, and R 1 represents an alkyl group having 1 to 6 carbon atoms) [hereinafter referred to as Compound (I 3) ] In the presence of an acid catalyst and allylic alcohol to give the following formula (Π-2)
[0029] [化 9]  [0029] [Chemical 9]
Figure imgf000008_0002
Figure imgf000008_0002
[0030] (式中実線および点線力もなる結合は、単結合または二重結合を表し、 R2は炭素数 1〜6のアルキル基またはァリル基を表す）で示される 2 ァリルカルボニル化合物 [ 以下 2—ァリルカルボニル化合物（Π— 2)と称する]を得、次いで 2—ァリルカルボ- ルイ匕合物を加水分解することを特徴とする 1)記載の 2—ァリルカルボン酸ィ匕合物 (III )の製造方法； [0030] (wherein the bond having solid and dotted line forces represents a single bond or a double bond, and R 2 represents an alkyl group having 1 to 6 carbon atoms or an aryl group) 2) -allylcarbonyl compound (III)), and then 2-hydrolylcarbonyl compound is hydrolyzed. Manufacturing method of
[0031] 8)化合物 (1— 3)を酸触媒およびァリルアルコールの存在下反応させることを特徴と する 2)記載の 2—ァリルカルボ二ルイ匕合物 (Π— 2)の製造方法； [0031] 8) It is characterized by reacting compound (1-3) in the presence of an acid catalyst and allylic alcohol. 2) Method for producing 2-aryl carbonate compound (Π-2) as described above;
[0032] 9)下記式 (Π Γ)  [0032] 9) The following formula (Π Γ)
[0033] [化 10] [0033] [Chemical 10]
Figure imgf000009_0001
Figure imgf000009_0001
[0034] で示される 2 ァリル 7 オタテナ  [0034] 2 Aryl 7 Otatena
[0035] 10)下記式 (ΠΙ— 1) [0035] 10) The following formula (ΠΙ— 1)
[0036] [化 11] [0036] [Chemical 11]
Figure imgf000009_0002
Figure imgf000009_0002
[0037] で示される 2 ァリル 7 ォクテン酸；および  [0037] 2-aryl-7-octenoic acid;
[0038] 11)下記式 (IV— 1) [0038] 11) The following formula (IV— 1)
[0039] [化 12] [0039] [Chemical 12]
Figure imgf000009_0003
Figure imgf000009_0003
[0040] で示される 1， 1 ジァリルォキシ 7 オタテンを提供することにより達成される。 [0040] This is accomplished by providing 1,1 diallyloxy 7 otatene.
発明の効果  The invention's effect
[0041] 本発明によれば、 2—ァリルカルボン酸化合物を、好収率で、工業的に有利に製造 することができる。力かる 2—ァリルカルボン酸ィ匕合物、例えば 2—ァリルオクタン酸は 、ァストロサイトの機能異常による神経変性疾患の治療または予防剤として有用な (R )— 2—プロピルオクタン酸の合成中間体として有用である。 [0041] According to the present invention, the 2-arylcarboxylic acid compound can be produced industrially advantageously in good yield. Powerful 2-arylcarboxylic acid compounds such as 2-aryloctanoic acid are useful as therapeutic or preventive agents for neurodegenerative diseases caused by astrocyte dysfunction (R ) —Useful as an intermediate for the synthesis of 2-propyloctanoic acid.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0042] 化合物（I)の Xはホルミル基、式 CH (OR1) で表されるジアルコキシメチル基、ま [0042] X in the compound (I) is a formyl group, a dialkoxymethyl group represented by the formula CH (OR 1 ), or
2  2
たは式— C (OR1) で表されるトリアルコキシメチル基である。 Xがホルミル基またはジ Or a trialkoxymethyl group represented by the formula —C (OR 1 ). X is a formyl group or di
3  Three
アルコキシメチル基である場合、ァリルカルボニル化合物（Π)の Yは水素原子であり 、ァリルカルボニル化合物（Π)力 ァリルカルボン酸化合物（III)への変換は酸化反 応により行う。 Xがトリアルコキシメチル基である場合、 Yは式— OR2で表されるアルコ キシ基であり、ァリルカルボニル化合物（Π)力 ァリルカルボン酸化合物（III)への変 換は加水分解反応により行う。 In the case of an alkoxymethyl group, Y of the arylcarbonyl compound (Π) is a hydrogen atom, and the conversion to the arylcarbonyl compound (Π) force to the arylcarboxylic acid compound (III) is performed by an oxidation reaction. When X is a trialkoxymethyl group, Y is an alkoxy group represented by the formula —OR 2 , and the conversion to the arylcarbonyl compound (Π) force to the arylcarboxylic acid compound (III) is carried out by a hydrolysis reaction. .
[0043] R1および R2が表す炭素数 1 6のアルキル基としては、例えばメチル基、ェチル基 、プロピル基、イソプロピル基、 n ブチル基、イソブチル基、 s ブチル基、 tーブチ ル基、 n ペンチル基、イソペンチル基、ネオペンチル基、 n キシル基、シクロプ 口ピル基、シクロブチル基、シクロペンチル基、シクロへキシル基が挙げられる。 [0043] Examples of the alkyl group having 16 carbon atoms represented by R 1 and R 2 include, for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, tert-butyl group, n Examples include pentyl group, isopentyl group, neopentyl group, n-xyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
[0044] 以下、化合物（I)の が  [0044] In the following, the compound (I)
1.ホルミル基である場合、  1. If it is a formyl group,
2.ジアルコキシメチル基である場合、  2.If it is a dialkoxymethyl group,
3. トリアルコシキメチル基である場合  3. When it is a trialkoxymethyl group
につ 、てそれぞれ順に説明する。  Each will be described in turn.
[0045] 1. Xがホルミル基である場合  [0045] 1. When X is a formyl group
Xがホルミル基である場合、化合物（I)は化合物（1—1)であり、 2—ァリルカルボ-ル 化合物（Π)の Yは水素原子であり、 2—ァリルカルボニル化合物（Π)は 2—ァリルカル ボニル化合物（Π— 1)である。  When X is a formyl group, compound (I) is compound (1-1), Y of 2-arylcarbonyl compound (Π) is a hydrogen atom, and 2-arylcarbonyl compound (Π) is 2 —Arylcarbonyl compound (Π—1).
[0046] まず、化合物（1—1)を酸触媒およびァリルアルコールの存在下に反応させて 2 ァ リルカルボニル化合物 (Π— 1)を得る工程 (以下、「反応工程 1」と称する）について説 明する。反応工程 1は、酸触媒の存在下、化合物 (1—1)とァリルアルコール力もジァ リルァセタールイ匕合物 (IV)を得る反応（以下、「反応 A」と称する）と、ジァリルァセタ ール化合物 (IV)を脱ァリルアルコールさせ、続いてクライゼン転位させることにより 2 ーァリルカルボニル化合物 (II 1)を得る反応（以下、「反応 B」と称する）を経由する 工程である。まず、反応 Aについて説明する。 First, a step (hereinafter referred to as “reaction step 1”) in which compound (1-1) is reacted in the presence of an acid catalyst and allylic alcohol to obtain 2-arylcarbonyl compound (Π-1). explain. Reaction step 1 includes a reaction (hereinafter referred to as “reaction A”) in which a compound (1-1) and a allylic alcohol are also obtained in the presence of an acid catalyst (hereinafter referred to as “reaction A”), a dialylacetal compound Via a reaction (hereinafter referred to as “Reaction B”) in which (IV) is dearylated alcohol, followed by Claisen rearrangement to give 2-arylcarbonyl compound (II 1) It is a process. First, reaction A will be described.
[0047] 反応 Aで使用する酸触媒に特に制限はなぐ例えば塩酸、硫酸、リン酸などの無機 酸；酢酸、コハク酸、マレイン酸、安息香酸、テレフタル酸、トリフルォロ酢酸などの力 ルボン酸；メタンスルホン酸、トルエンスルホン酸、トリフルォロメタンスルホン酸などの スルホン酸；ピリジン ·トルエンスルホン酸などの酸性塩；酸性イオン交換榭脂などが 挙げられる。これらの中でも、入手の容易性、反応装置への影響などの観点力 カル ボン酸が好適に使用され、マレイン酸を使用するのが特に好ましい。酸触媒の使用 量に特に制限はないが、通常、化合物（1—1) 1モルに対して 0. 00001〜1モルの 範囲であるのが好ましぐ経済的な観点からは、 0. 0001-0. 5モルの範囲であるの がより好ましぐ 0. 001-0. 1モルの範囲であるのがさらに好ましい。  [0047] There are no particular restrictions on the acid catalyst used in Reaction A, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; strong acids such as acetic acid, succinic acid, maleic acid, benzoic acid, terephthalic acid, and trifluoroacetic acid; rubonic acid; methane Examples thereof include sulfonic acids such as sulfonic acid, toluenesulfonic acid, and trifluoromethanesulfonic acid; acidic salts such as pyridine and toluenesulfonic acid; acidic ion-exchange resin. Among these, viewpoints such as availability and influence on the reaction apparatus Carbonic acid is preferably used, and maleic acid is particularly preferably used. The amount of the acid catalyst to be used is not particularly limited, but is usually from 0.000001 to 1 mol based on 1 mol of the compound (1-1), from an economical viewpoint, it is preferably 0.001. The range of -0.5 mol is more preferred. The range of 0.001-0. 1 mol is more preferred.
[0048] 反応 Aにおけるァリルアルコールの使用量は、化合物（I 1) 1モルに対して 0. 1〜 50モルの範囲であるのが好ましぐ 0. 2〜20モルの範囲であるのがより好ましぐ 0. 5〜10モルの範囲であるのがさらに好ましい。  [0048] The amount of allylic alcohol used in reaction A is preferably in the range of 0.1 to 50 mol per mol of compound (I 1), and is preferably in the range of 0.2 to 20 mol. Is more preferably in the range of 0.5 to 10 moles.
[0049] また、反応 Aは溶媒の存在下または不存在下に実施できる。力かる溶媒としては、 反応に悪影響を及ぼさない限り特に制限はなぐ例えばトルエン、キシレン、メシチレ ンなどの芳香族炭化水素;へキサン、ヘプタン、オクタンなどの脂肪族炭化水素;ジク ロロエタン、クロ口ベンゼンなどのハロゲン化炭化水素；ジイソプロピルエーテル、ジブ チルエーテル、テトラヒドロフラン、ジォキサン、ジグライム、トリグライムなどのエーテ ルなどが挙げられる。溶媒を使用する場合、その使用量に特に制限はないが、通常 、化合物 (I 1)に対して 0. 1〜10倍質量の範囲であるのが好ましぐ経済性、後処 理の簡便さの観点からは、 0. 2〜5倍質量の範囲であるのがより好ましい。  [0049] Reaction A can be carried out in the presence or absence of a solvent. Solvents that can be used are not particularly limited as long as they do not adversely affect the reaction.For example, aromatic hydrocarbons such as toluene, xylene, and mesitylene; aliphatic hydrocarbons such as hexane, heptane, and octane; dichloroethane, black benzene And halogenated hydrocarbons such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme, triglyme and the like. When a solvent is used, the amount used is not particularly limited, but it is usually preferable that the amount is in the range of 0.1 to 10 times the mass of the compound (I 1), and easy post-treatment. From this viewpoint, the range of 0.2 to 5 times the mass is more preferable.
[0050] 反応 Aの反応温度は、通常、 20〜120°Cの範囲であり、反応速度、反応の選択性 およびジァリルァセタール化合物（IV)の安定性の観点から、 80〜120°Cの範囲で あるのが好ましい。反応圧力に特に制限はないが、通常、 0. l〜500kPaの範囲で あり、 l〜200kPaの範囲であるのが好ましい。反応時間は、酸触媒の種類や使用量 、反応温度、反応圧力などにより異なるが、通常、 30分〜 40時間の範囲である。  [0050] The reaction temperature of the reaction A is usually in the range of 20 to 120 ° C, and from the viewpoint of the reaction rate, the selectivity of the reaction and the stability of the diallyl acetal compound (IV), 80 to 120 ° C. A range of C is preferred. The reaction pressure is not particularly limited, but is usually in the range of 0.1 to 500 kPa, preferably in the range of 1 to 200 kPa. The reaction time varies depending on the type and amount of the acid catalyst used, the reaction temperature, the reaction pressure, etc., but is usually in the range of 30 minutes to 40 hours.
[0051] 反応 Aを実施する方法に特に制限はなぐ例えば、化合物 (I 1)、ァリルアルコー ル、酸触媒および必要に応じて溶媒を混合し、所定温度および所定圧力下に反応さ せること〖こより実施できる。 [0051] The method for carrying out reaction A is not particularly limited. For example, compound (I 1), aryl alcohol, an acid catalyst and, if necessary, a solvent are mixed and reacted at a predetermined temperature and a predetermined pressure. It can be implemented from Sako.
[0052] また反応の進行に伴い水が副生するので、力かる水を除去しながら反応を行なつ てもよい。水を除去する方法に特に制限はないが、例えば、反応系内にモレキュラー シーブスなどの反応に悪影響を与えない脱水剤を添加する方法、また、反応を行な いながら反応系中の溶媒と共沸蒸留させて留去する方法などが挙げられる。  [0052] Since water is by-produced as the reaction proceeds, the reaction may be carried out while removing powerful water. The method for removing water is not particularly limited. For example, a dehydrating agent that does not adversely affect the reaction such as molecular sieves is added to the reaction system, or the reaction with the solvent in the reaction system is carried out. The method of distilling by boiling and the like can be mentioned.
[0053] こうして得られたジァリルァセタールイ匕合物 (IV)は、有機化合物の分離'精製方法 において一般的に用いられる方法により反応混合物力 分離 ·精製することもできる 。例えば、反応混合物に水を加え、酸触媒を水層へ除去し、有機層を分離取得して 、カゝかる有機層を蒸留することによって精製できる。また、上記反応 Aで得られた反応 混合物を、分離 '精製せずにそのまま後述する次の反応 Bに供することが可能であり 、 2—ァリルカルボ二ルイ匕合物 (Π— 1)を得るに際して、より好適かつ簡便な方法であ る。  [0053] The thus obtained diallyl acetal compound (IV) can also be separated and purified by the reaction mixture force by a method generally used in the separation and purification method of organic compounds. For example, it can be purified by adding water to the reaction mixture, removing the acid catalyst to the aqueous layer, separating and obtaining the organic layer, and distilling the organic layer. In addition, the reaction mixture obtained in the above reaction A can be used as it is in the following reaction B described later without separation and purification, and in obtaining a 2-arylcarbonyl compound (Π-1). This is a more preferable and simple method.
[0054] なお、上記方法により得られるジァリルァセタールイ匕合物（IV)の 1つである下記式（ [0054] It should be noted that one of the diallyl acetal compounds (IV) obtained by the above method is represented by the following formula (
IV- 1) IV- 1)
[0055] [化 13] [0055] [Chemical 13]
Figure imgf000012_0001
Figure imgf000012_0001
[0056] で示される 1, 1—ジァリルォキシ—7—オタテンは新規ィ匕合物である。 [0056] 1,1-Diaryloxy-7-otaten is a novel compound.
[0057] 次に、反応 Bについて説明する。 [0057] Next, reaction B will be described.
[0058] 反応 Bで使用する酸触媒に特に制限はなぐ上記した反応 Aで使用する酸触媒と 同様のものが挙げられる。その中でも、入手の容易性、反応装置への影響などの観 点からカルボン酸が好適に使用され、マレイン酸を使用するのが特に好ましい。酸触 媒の使用量に特に制限はないが、通常、ジァリルァセタールイ匕合物 (IV) 1モルに対 して 0. 00001〜1モルの範囲であるの力 子ましぐ 0. 0001〜0. 5モルの範囲であ るのがより好ましぐ 0. 0005-0. 1モルの範囲であるのがさらに好ましい。なお、反 応 Aにて得られたジァリルァセタール化合物 (IV)を、反応混合物から分離'精製せ ずに反応 Bに供する場合 (本発明を実施する上での好適態様)、酸触媒が既に反応 系に存在しているため、さらに添加する必要性は特にないが、必要に応じ、添加して も差し支えない。 [0058] The acid catalyst used in the reaction B is not particularly limited, and examples thereof include the same acid catalysts used in the reaction A described above. Among these, carboxylic acid is preferably used from the viewpoints of easy availability and influence on the reaction apparatus, and maleic acid is particularly preferable. The amount of the acid catalyst used is not particularly limited, but is usually in the range of 0.0001 to 1 mol per mol of diallyl acetal compound (IV). The range of 0001 to 0.5 mol is more preferable. The range of 0.0005-0. 1 mol is more preferable. The diallyl acetal compound (IV) obtained in Reaction A is separated from the reaction mixture and purified. Without being added to the reaction B (preferred embodiment for carrying out the present invention), since the acid catalyst is already present in the reaction system, there is no particular need to add it. There is no problem.
[0059] 反応 Bは、溶媒の存在下または不存在下に実施できる。力かる溶媒としては、反応 に悪影響を及ぼさない限り特に制限はなぐ反応 Aで使用できる溶媒と同様の溶媒 が挙げられる。溶媒を使用する場合、その使用量に特に制限はないが、通常、ジァリ ルァセタール化合物（IV)に対して 0. 1〜10倍質量の範囲であるのが好ましい。な お、反応 Aにて得られたジァリルァセタールイ匕合物 (IV)を、反応混合物から分離'精 製せずに反応 Bに供する場合 (本発明を実施する上での好適態様)、溶媒が既に反 応混合物に存在している場合もあるため、さらに添加する必要は特にないが、必要に 応じ、添加しても差し支えない。  [0059] Reaction B can be carried out in the presence or absence of a solvent. Examples of the powerful solvent include the same solvents as those that can be used in Reaction A, as long as they do not adversely affect the reaction. When a solvent is used, the amount used is not particularly limited, but usually it is preferably in the range of 0.1 to 10 times the mass with respect to the diarylacetal compound (IV). In the case where the diallyl acetal compound (IV) obtained in the reaction A is subjected to the reaction B without being separated and purified from the reaction mixture (preferred embodiment for carrying out the present invention). ) Since the solvent may already be present in the reaction mixture, it is not particularly necessary to add it further, but it may be added if necessary.
[0060] 反応 Bにおける反応圧力は、反応を円滑に進行させる観点から、 0. l〜500kPaの 範囲であるのが好ましぐ l〜50kPaの範囲であるのがより好ましい。反応温度は、 1 20〜180°Cの範囲であるのが好ましぐ 130〜170°Cの範囲であるのがより好ましい 。また、反応時間は、酸触媒の種類、使用量、反応温度、反応圧力などにより異なる 力 通常、 30分〜 48時間の範囲である。  [0060] The reaction pressure in the reaction B is preferably in the range of 0.1 to 500 kPa, more preferably in the range of 1 to 50 kPa, from the viewpoint of allowing the reaction to proceed smoothly. The reaction temperature is preferably in the range of 120 to 180 ° C, more preferably in the range of 130 to 170 ° C. The reaction time varies depending on the type of acid catalyst, amount used, reaction temperature, reaction pressure, and the like. Usually, the reaction time is in the range of 30 minutes to 48 hours.
[0061] 反応 Bを実施する方法に特に制限はなぐ例えば、ジァリルァセタール化合物 (IV) を分離'精製した場合には、ジァリルァセタールイ匕合物 (IV)、酸触媒および必要に 応じて溶媒を混合し、所定温度および所定圧力下に反応させることにより実施できる [0061] The method for carrying out reaction B is not particularly limited. For example, when the diaryl acetal compound (IV) is separated and purified, the diaryl acetal compound (IV), an acid catalyst and It can be carried out by mixing the solvent as necessary and reacting at a predetermined temperature and pressure.
。なお、反応 Aにおいてジァリルァセタールイ匕合物 (IV)を含む反応混合物力もジァリ ルァセタールイ匕合物 (IV)を分離 '精製せずに、そのまま反応 Bを実施する場合、反 応条件 (反応温度、反応圧力）を反応 Bにおける所定値に設定すれば、反応 Aから 反応 Bに移行することができる。 . In addition, if the reaction mixture containing diallyl acetal compound (IV) in reaction A is separated and purified without reaction, reaction condition ( If the reaction temperature and reaction pressure are set to the predetermined values in reaction B, the reaction A can be transferred to the reaction B.
[0062] 反応 Bでは、収率の観点から、反応の進行に伴!、副生するァリルアルコールを除去 しながら反応を行なうのが好ましぐまた、生成する 2—ァリルカルボ二ルイ匕合物 (II—[0062] In Reaction B, from the viewpoint of yield, it is preferable to carry out the reaction while removing the by-produced aryl alcohol as the reaction proceeds, and the resulting 2-arylcarbonyl compound is also produced. (II—
1)を留出させながら反応を行なうことも可能である。 It is also possible to carry out the reaction while distilling 1).
[0063] こうして得られた反応混合物からの 2—ァリルカルボ-ルイ匕合物 (Π— 1)の分離'精 製は、有機化合物の分離 '精製において一般的に用いられる方法により実施できる。 例えば、得られた反応混合物に溶媒および水を加えた後、水層を除去し、有機層か ら適宜溶媒を留去して、残留物をさらに蒸留することにより精製できる。また、前記残 留物を精製せず、そのまま後述する酸化反応に供することもできる。 [0063] The separation and purification of the 2-arylcarbolyl compound (匕 -1) from the reaction mixture thus obtained can be carried out by a method generally used in the separation and purification of organic compounds. For example, after adding a solvent and water to the obtained reaction mixture, the aqueous layer is removed, the solvent is appropriately distilled off from the organic layer, and the residue can be further distilled. Further, the residue can be directly subjected to the oxidation reaction described later without purification.
[0064] なお、上記方法により得られる 2—ァリルカルボ-ルイ匕合物（Π— 1)の 1つである下 記式 (Π— Γ)  [0064] It should be noted that the following formula (Π-Γ), which is one of the 2-aryl carbo-Louis compound (物 -1) obtained by the above method.
[0065] [化 14] [0065] [Chemical 14]
Figure imgf000014_0001
Figure imgf000014_0001
[0066] で示される 2—ァリル— 7—オタテナールは新規ィ匕合物である。  [0066] 2-Aryl-7-Otatenal is a novel compound.
[0067] 続いて、上記の方法により得られる 2—ァリルカルボ-ルイ匕合物 (Π— 1)を酸化して 2—ァリルカルボン酸ィ匕合物 (III)を得る工程 (以下、「反応工程 2」と称する）につい て説明する。 [0067] Subsequently, a step of oxidizing the 2-arylcarbonyl-compound (Π-1) obtained by the above method to obtain a 2-arylcarboxylic acid compound (III) (hereinafter referred to as "reaction step 2"). Will be described).
[0068] 反応工程 2における 2—ァリルカルボ二ルイ匕合物（Π)の酸ィ匕方法としては、アルデヒ ド類をカルボン酸類に変換する際に一般的に用いられる酸化剤が使用可能である。 力かる酸化剤としては、例えば酸素;過酸ィ匕水素;過ギ酸、過酢酸、 m—クロ口過安 息香酸などの有機過酸ィ匕合物；亜塩素酸ナトリウム、亜臭素酸ナトリウム、亜塩素酸 カリウム、亜臭素酸カリウムなどの亜ハロゲン酸金属塩;次亜塩素酸ナトリウム、次亜 臭素酸ナトリウム、次亜塩素酸カリウム、次亜臭素酸カリウムなどの次亜ハロゲン酸金 属塩;塩素酸ナトリウム、臭素酸ナトリウム、塩素酸カリウム、臭素酸カリウムなどのハロ ゲン酸金属塩;過マンガン酸ナトリウム、過マンガン酸カリウムなどの過マンガン酸金 属塩;酸ィ匕クロム、酸化銀、酸化ルテニウムなどの金属酸ィ匕物などが挙げられる。こ れらの中でも、亜ハロゲン酸金属塩を用いるのが好ましい。  [0068] As the acid method for the 2-arylcarbonyl compound (Π) in the reaction step 2, an oxidizing agent generally used for converting aldehydes to carboxylic acids can be used. Examples of strong oxidizing agents include oxygen; peroxyhydrogen; organic peracid compounds such as formic acid, peracetic acid, m-peroxybenzoic acid; sodium chlorite, sodium bromate Metal halide salts such as potassium chlorite and potassium bromite; metal hypohalite salts such as sodium hypochlorite, sodium hypobromite, potassium hypochlorite and potassium hypobromite Halogenate metal salts such as sodium chlorate, sodium bromate, potassium chlorate and potassium bromate; permanganate metal salts such as sodium permanganate and potassium permanganate; acid chrome, silver oxide, Examples thereof include metal oxides such as ruthenium oxide. Among these, it is preferable to use a metal halous acid salt.
[0069] 以下、反応工程 2の一例として、亜ハロゲン酸金属塩を酸化剤として用いた場合に ついて説明する。  [0069] Hereinafter, as an example of the reaction step 2, a case where a metal halous acid salt is used as an oxidizing agent will be described.
[0070] 亜ハロゲン酸金属塩としては、上記した化合物の中でも、入手の容易性の観点から 、亜塩素酸ナトリウムを使用するのが好ましい。亜ノ、ロゲン酸金属塩の使用量に特に 制限はないが、通常、 2—ァリルカルボ-ル化合物（Π— 1) 1モルに対して 0. 1〜20 モルの範囲であるのが好ましぐ 0. 5〜10モルの範囲であるのがより好ましぐ 0. 8 〜5モルの範囲であるのがさらに好ましい。 [0070] Among the above-mentioned compounds, the metal halous acid salt is from the viewpoint of availability. Sodium chlorite is preferably used. There are no particular restrictions on the amount of metal phosphite or metal salt of rogenic acid, but it is usually preferred to be in the range of 0.1 to 20 moles per mole of 2-arylcarbonyl compound (Π-1). More preferably, it is in the range of 0.5 to 10 mol, and more preferably in the range of 0.8 to 5 mol.
[0071] 亜ハロゲン酸金属塩を用いて反応工程 2を行なう際、副反応であるハロゲン化反応 を抑制するために、ハロゲン捕捉剤を反応系に添加するのが好ましい。ハロゲン捕捉 剤としては、例えばレゾルシノール、 2—メチル 2—ブテン、ジメチルスルホキシドな どが挙げられる。ハロゲン捕捉剤をさらに添加する場合、その使用量に特に制限はな いが、通常、 2 ァリルカルボ-ル化合物（11—1) 1モルに対して 0. 1〜50モルの範 囲であるのが好ましぐ 0. 5〜20モルの範囲であるのがより好ましぐ 0. 8〜10モル の範囲であるのがさらに好ましい。  [0071] When the reaction step 2 is performed using a metal halous acid salt, it is preferable to add a halogen scavenger to the reaction system in order to suppress a halogenation reaction as a side reaction. Examples of the halogen scavenger include resorcinol, 2-methyl 2-butene, dimethyl sulfoxide and the like. When the halogen scavenger is further added, the amount used is not particularly limited, but it is usually in the range of 0.1 to 50 mol with respect to 1 mol of the diarylcarbol compound (11-1). A preferred range is 0.5 to 20 moles, and a more preferred range is 0.8 to 10 moles.
[0072] 反応工程 2は、溶媒の存在下に行なうのが好ましい。力かる溶媒としては、反応に 悪影響を及ぼさない限り特に制限はなぐ例えばトルエン、キシレン、メシチレンなど の芳香族炭化水素;へキサン、ヘプタン、オクタンなどの脂肪族炭化水素;ジクロロェ タン、クロ口ベンゼンなどのハロゲン化炭化水素；メタノール、エタノール、イソプロパノ ール、 tーブタノールなどのアルコール；ジイソプロピルエーテル、ジブチルエーテル 、テトラヒドロフラン、ジォキサン、ジグライム（ジエチレングリコールジメチルエーテル） 、トリグライム（トリエチレングリコールジメチルエーテル）などのエーテル；酢酸ェチル 、酢酸ブチルなどのエステル；ァセトニトリル、ベンゾ-トリルなどの-トリル；ジメチル ホルムアミド、ジメチルァセトアミドなどのアミド；水；またはこれらの混合溶媒が挙げら れる。溶媒の使用量に特に制限はないが、通常、 2—ァリルカルボニル化合物 (II— 1)に対して、 0. 1〜100倍質量の範囲であるのが好ましぐ経済性、後処理の簡便さ の観点からは、 0. 2〜50倍質量の範囲であるのがより好ましぐ 0. 5〜30倍質量の 範囲であるのがさらに好ましい。  [0072] Reaction step 2 is preferably performed in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, for example, aromatic hydrocarbons such as toluene, xylene, mesitylene, etc .; aliphatic hydrocarbons such as hexane, heptane, octane; dichloroethane, black benzene, etc. Halogenated hydrocarbons of: alcohols such as methanol, ethanol, isopropanol, and t-butanol; ethers such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether) and triglyme (triethylene glycol dimethyl ether); Esters such as butyl acetate; -tolyl such as acetonitrile and benzo-tolyl; amides such as dimethylformamide and dimethylacetamide; water; or a mixed solvent thereof Et al are. Although there is no particular limitation on the amount of solvent used, it is usually preferred that the amount is in the range of 0.1 to 100 times the mass of 2-arylcarbonyl compound (II-1). From the viewpoint of simplicity, the range of 0.2 to 50 times mass is more preferable, and the range of 0.5 to 30 times mass is more preferable.
[0073] 反応工程 2は酸性条件下で行なうのが好ましぐ pH2〜6の範囲で行なうのがより好 ましい。反応系を pH2〜6の範囲にするため、リン酸、リン酸二水素ナトリウム、リン酸 二水素カリウムなどの酸性ィ匕合物を反応系内に添加するのが好ましい。かかる酸性 化合物の添加量に特に制限はないが、通常、 2—ァリルカルボ-ルイ匕合物 (11—1) 1 モルに対して、 0. 1〜20モルの範囲であるのが好ましぐ 0. 5〜10モルの範囲であ るのがより好ましぐ 0. 8〜5モルの範囲であるのがさらに好ましい。 [0073] Reaction step 2 is preferably carried out under acidic conditions, more preferably in the range of pH 2-6. In order to bring the reaction system into a pH range of 2 to 6, it is preferable to add an acidic compound such as phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate into the reaction system. There are no particular restrictions on the amount of such acidic compound added, but usually 2-aryl carbo-louis compound (11-1) 1 It is preferably in the range of 0.1 to 20 mol, more preferably in the range of 0.5 to 10 mol, and even more preferably in the range of 0.8 to 5 mol. preferable.
[0074] 反応温度は、 0〜100°Cの範囲であるのが好ましぐ反応速度、反応の選択性およ び目的物の安定性の観点から、 10〜70°Cの範囲であるのがより好ましい。反応圧力 は、 0. l〜500kPaの範囲であるのが好ましぐ l〜200kPaの範囲であるのがより好 ましい。また、反応時間は、亜ハロゲン酸金属塩 (酸化剤）の種類や使用量、ハロゲ ン捕捉剤、酸性化合物、溶媒の種類や使用量、反応温度、反応圧力などにより異な る力 通常、 30分〜 24時間の範囲である。  [0074] The reaction temperature is preferably in the range of 0 to 100 ° C, in view of the reaction rate, the selectivity of the reaction, and the stability of the target product, in the range of 10 to 70 ° C. Is more preferable. The reaction pressure is preferably in the range of 0.1 to 500 kPa, more preferably in the range of 1 to 200 kPa. The reaction time varies depending on the type and amount of metal halite (oxidizer), halogen scavenger, acidic compound, type and amount of solvent, reaction temperature, reaction pressure, etc. ~ 24 hours range.
[0075] 反応工程 2を実施する方法に特に制限はなぐ例えば、 2 ァリルカルボニル化合 物 (II 1)、酸化剤、溶媒および必要に応じてハロゲン捕捉剤および Zまたは酸性 化合物を混合し、所定温度および所定圧力下に反応させることにより実施できる。  [0075] The method for carrying out the reaction step 2 is not particularly limited. For example, a 2-arylcarbonyl compound (II 1), an oxidizing agent, a solvent, and optionally a halogen scavenger and Z or an acidic compound are mixed, The reaction can be carried out at a temperature and under a predetermined pressure.
[0076] こうして得られた反応混合物からの 2 ァリルカルボン酸ィ匕合物 (ΠΙ)の分離'精製 は、有機化合物の分離'精製において一般的に用いられる方法により行なうことがで きる。例えば、反応混合物に水酸化ナトリウム、水酸ィ匕カリウムなどの塩基性ィ匕合物を 加えて塩基性にした後、濃縮し、水およびへキサン、トルエン、ジイソプロピルエーテ ルなどの有機溶媒を加えてから有機層と水層を分離し、該水層を希塩酸などにより 酸性にした後、前記した有機溶媒により抽出し、かかる抽出液を濃縮後、さらに蒸留 することにより、純度の高 、2—ァリルカルボン酸ィ匕合物 (ΠΙ)を得ることができる。  [0076] The separation and purification of the diarylcarboxylic acid compound (ΠΙ) from the reaction mixture thus obtained can be carried out by a method generally used in the separation and purification of organic compounds. For example, a basic compound such as sodium hydroxide and potassium hydroxide is added to the reaction mixture to make it basic, and then concentrated, and water and an organic solvent such as hexane, toluene, diisopropyl ether are added. Then, the organic layer and the aqueous layer are separated, and the aqueous layer is acidified with dilute hydrochloric acid or the like and then extracted with the organic solvent described above. The extract is concentrated and further distilled to obtain a high purity 2- A arylcarboxylic acid compound (匕) can be obtained.
[0077] なお、上記方法により得られる 2 ァリルカルボン酸ィ匕合物（ΠΙ)の 1つである下記 式（III 1)  [0077] In addition, the following formula (III 1), which is one of the two arylcarboxylic acid compounds (物) obtained by the above method
[0078] [化 15]  [0078] [Chemical 15]
(Π )
Figure imgf000016_0001
(Π)
Figure imgf000016_0001
[0079] で示される 2 ァリル— 7 オタテン酸は新規ィ匕合物である。  [0079] 2-aryl-7-otatenic acid is a novel compound.
[0080] 2. Xがジアルコキシメチル基である場合 Xがジアルコキシメチル基である場合、化合物（I)は化合物（I 2)であり、 2—ァリル カルボニル化合物（Π)の Yは水素原子であり、 2—ァリルカルボニル化合物（Π)は 2 —ァリルカルボ-ル化合物（II— 1)である。 [0080] 2. When X is a dialkoxymethyl group When X is a dialkoxymethyl group, compound (I) is compound (I 2), Y of 2-arylcarbonyl compound (リ ル) is a hydrogen atom, and 2-arylcarbonyl compound (Π) is 2 —Arylcarbonyl compound (II-1).
[0081] まず、化合物（1— 2)を酸触媒およびァリルアルコールの存在下に反応させて 2 ァ リルカルボニル化合物 (Π— 1)を得る工程 (以下、反応工程 Γと称する）について説 明する。 [0081] First, the step of reacting compound (1-2) in the presence of an acid catalyst and allylic alcohol to obtain 2-arylcarbonyl compound (Π-1) (hereinafter referred to as reaction step Γ) will be described. To do.
[0082] 反応工程 Γで使用する酸触媒に特に制限はなぐ上記した反応工程 1における反 応 Aで用いるものと同様のものが挙げられる。中でも、入手の容易性、反応装置への 影響などの観点力 カルボン酸を使用するのが好ましく、マレイン酸を使用するのが 特に好ましい。酸触媒の使用量に特に制限はないが、通常、化合物 (1— 2) 1モルに 対して 0. 00001-0. 5モルの範囲であるのが好ましぐ経済的な観点からは、 0. 0 001〜0. 1モルの範囲であるの力 り好ましく、 0. 0005〜0. 05モルの範囲である のがさらに好ましい。  [0082] There are no particular restrictions on the acid catalyst used in the reaction step Γ, and the same catalysts as those used in the reaction A in the above-mentioned reaction step 1 can be mentioned. Among them, viewpoints such as availability and influence on the reaction apparatus It is preferable to use carboxylic acid, and it is particularly preferable to use maleic acid. The amount of the acid catalyst to be used is not particularly limited, but it is usually from an economical viewpoint that it is preferably in the range of 0.0001-0. 5 mol with respect to 1 mol of the compound (1-2). A force in the range of 0.001 to 0.1 mol is preferred, and a range of 0.0005 to 0.05 mol is more preferred.
[0083] 反応工程 Γにおけるァリルアルコールの使用量は、化合物（I 2) 1モルに対して、 0. 1〜20モルの範囲であるのが好ましぐ 0. 2〜10モルの範囲であるのがより好ま しぐ 0. 5〜5モルの範囲であるのがさらに好ましい。  [0083] The amount of allylic alcohol used in the reaction step Γ is preferably in the range of 0.1 to 20 moles relative to 1 mole of compound (I 2), in the range of 0.2 to 10 moles. More preferably, it is more preferably in the range of 0.5 to 5 moles.
[0084] また、反応工程 Γは溶媒の存在下または不存在下に実施できる。かかる溶媒とし ては、反応に悪影響を及ぼさない限り特に制限はなぐ例えばトルエン、キシレン、メ シチレンなどの芳香族炭化水素;へキサン、ヘプタン、オクタンなどの脂肪族炭化水 素；ジクロロェタン、クロ口ベンゼンなどのハロゲン化炭化水素；ジイソプロピルエーテ ル、ジブチルエーテル、テトラヒドロフラン、ジォキサン、ジグライム（ジエチレングリコ ールジメチルエーテル）、トリグライム（トリエチレングリコールジメチルエーテル）など のエーテルなどが挙げられる。溶媒を使用する場合、その使用量に特に制限はない 力 通常、化合物 (I 2)に対して 0. 1〜10倍質量の範囲であるのが好ましぐ経済 性、後処理の簡便さの観点からは、 0. 2〜5倍質量の範囲であるのがより好ましい。  [0084] The reaction step Γ can be performed in the presence or absence of a solvent. Such solvents are not particularly limited as long as they do not adversely affect the reaction, for example, aromatic hydrocarbons such as toluene, xylene and mesitylene; aliphatic hydrocarbons such as hexane, heptane and octane; dichloroethane and black benzene And halogenated hydrocarbons such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), and ethers such as triglyme (triethylene glycol dimethyl ether). When a solvent is used, the amount used is not particularly limited. Generally, it is preferable that the amount is in the range of 0.1 to 10 times the mass of the compound (I 2). From the viewpoint, it is more preferably in the range of 0.2 to 5 times mass.
[0085] 反応工程 Γにおける反応圧力は、反応を円滑に進行させる観点から、 0. 1〜500 kPaの範囲であるのが好ましぐ l〜200kPaの範囲であるのがより好ましい。反応温 度は、 120〜200°Cの範囲であるのが好ましぐ 130〜180°Cの範囲であるのがより 好ましい。また、反応時間は、酸触媒の種類、使用量、反応温度、反応圧力などによ り異なる力 通常、 30分〜 48時間の範囲である。 [0085] The reaction pressure in the reaction step Γ is preferably in the range of 0.1 to 500 kPa, more preferably in the range of 1 to 200 kPa, from the viewpoint of allowing the reaction to proceed smoothly. The reaction temperature is preferably in the range of 120 to 200 ° C, more preferably in the range of 130 to 180 ° C. preferable. The reaction time varies depending on the type of acid catalyst, amount used, reaction temperature, reaction pressure, etc. Usually, it is in the range of 30 minutes to 48 hours.
[0086] 反応工程 Γを実施する方法に特に制限はなぐ例えば、化合物 (I 2)、酸触媒お よび必要に応じて溶媒を混合し、所定温度および所定圧力下にァリルアルコールを 滴下して反応させることにより実施できる。反応工程 1では、 2—ァリルカルボ二ルイ匕 合物（Π—1)の収率の観点から、反応の進行に伴い副生する式 I^OH (式中、 R1は 前記定義の通りである）で示されるアルコールを留去させながら反応を行なってもよ い。また、生成する 2—ァリルカルボ二ルイ匕合物 (Π—1)を留出させながら反応を行な うことも可能である。 [0086] The method for carrying out the reaction step Γ is not particularly limited. For example, the compound (I 2), an acid catalyst and a solvent as necessary are mixed, and aryl alcohol is added dropwise at a predetermined temperature and a predetermined pressure. It can be carried out by reacting. In the reaction step 1, from the viewpoint of the yield of the 2-arylcarbonyl compound (Π-1), the formula I ^ OH generated as a by-product as the reaction proceeds (wherein R 1 is as defined above) The reaction may be carried out while distilling off the alcohol indicated by It is also possible to carry out the reaction while distilling the produced 2-arylcarbonyl compound (Π-1).
[0087] こうして得られた 2 ァリルカルボ-ル化合物（Π— 1)を含む反応混合物からの 2— ァリルカルボニル化合物 (II— 1)の分離 ·精製は、有機化合物の分離'精製において 一般的に用いられる方法により実施できる。例えば、得られた反応混合物に溶媒およ び水を加えた後、水層を除去し、取得した有機層から適宜溶媒を留去して得られた 残留物をさらに蒸留することにより精製できる。また、上記有機層を、そのまま後述す る酸ィ匕反応に供することもできる。  [0087] Separation and purification of the 2-arylcarbonyl compound (II-1) from the reaction mixture containing the 2-arylcarbonyl compound (Π-1) thus obtained is generally performed in the separation and purification of organic compounds. It can be implemented by the method used. For example, after adding a solvent and water to the obtained reaction mixture, the aqueous layer is removed, and the residue obtained by appropriately distilling off the solvent from the obtained organic layer can be purified by further distillation. In addition, the organic layer can be directly subjected to an acid-acid reaction described later.
[0088] 上記の方法により得られる 2 ァリルカルボ-ルイ匕合物（II— 1)を酸ィ匕して 2 ァリ ルカルボン酸ィ匕合物 (ΠΙ)を得る工程 (以下、反応工程 2,と称する）は 1)Xがホルミル 基の場合の反応工程 2と同じである。  [0088] A step of obtaining a 2-arylcarboxylic acid compound (ΠΙ) by acidifying the 2-arylcarboxyl compound (II-1) obtained by the above method (hereinafter referred to as reaction step 2, and 1) is the same as Reaction Step 2 in the case where X is a formyl group.
[0089] なお、本発明の原料である化合物 (I 2)の製造方法に特に制限はなぐ例えば、 硫酸、塩酸、リン酸、 p トルエンスルホン酸などの酸触媒存在下に n オタタナール または 7—オタテナールとオルト酢酸トリメチルを反応させた後、中和し、低沸点化合 物を留去することにより、容易に製造できる。また、適宜、蒸留などの通常の有機化 合物の分離 ·精製方法を適用することで、より純度の高い化合物 (I 2)を得ることが できる。  [0089] The production method of the compound (I 2), which is a raw material of the present invention, is not particularly limited. And trimethyl orthoacetate are reacted and then neutralized, and the low boiling point compound is distilled off. In addition, the compound (I2) with higher purity can be obtained by appropriately applying a usual method for separating and purifying organic compounds such as distillation.
[0090] 3. Xがトリアルコキシメチル基である場合  [0090] 3. When X is a trialkoxymethyl group
Xがトリアルコキシメチル基である場合、化合物 (I)は化合物 (1— 3)であり、 2 ァリ ルカルボニル化合物（Π)の Yは式—OR2 (式中 R2は前記の通り）で示されるアルコキ シ基であり、 2ーァリルカルボニル化合物（II)はァリルカルボニル化合物（II 2)であ る。 When X is a trialkoxymethyl group, the compound (I) is the compound (1-3), Y of the 2- arylcarbonyl compound (Π) is represented by the formula —OR 2 (wherein R 2 is as defined above) The 2-arylcarbonyl compound (II) is an arylcarbonyl compound (II 2). The
[0091] まず、化合物（1— 3)を酸触媒およびァリルアルコールの存在下に反応させて 2 ァ リルカルボニル化合物 (II 2)を得る工程 (以下、反応工程 1~と称する）について説 明する。  [0091] First, the step of obtaining the 2-arylcarbonyl compound (II 2) by reacting the compound (1-3) in the presence of an acid catalyst and allylic alcohol (hereinafter referred to as reaction step 1 ~) will be described. To do.
[0092] 反応工程 1~で使用する酸触媒に特に制限はなぐ上記した反応工程 1における 反応 Aで用いるものと同様のものが挙げられる。中でも、入手の容易性、反応装置へ の影響などの観点力 カルボン酸を使用するのが好ましぐ特にマレイン酸を使用す るのが好ましい。酸触媒の使用量に特に制限はないが、通常、化合物 (1— 3) 1モル に対して 0. 00001-0. 5モルの範囲であるのが好ましぐ経済的な観点からは、 0. 0001〜0. 1モルの範囲であるの力 り好ましく、 0. 0005〜0. 05モルの範囲である のがさらに好ましい。  [0092] There are no particular restrictions on the acid catalyst used in reaction step 1 to, and examples thereof include the same ones used in reaction A in reaction step 1 described above. Of these, viewpoints such as availability, influence on the reaction apparatus, etc. It is preferable to use carboxylic acid, and maleic acid is particularly preferable. The amount of the acid catalyst to be used is not particularly limited, but is usually in the range of 0.00001-0. 5 mol with respect to 1 mol of the compound (1-3). A force in the range of 0001 to 0.1 mol is preferred, and a range of 0.0005 to 0.05 mol is more preferred.
[0093] 反応工程 ΓΊこおけるァリルアルコールの使用量は、化合物（I 3) 1モルに対して 0. 1〜20モルの範囲であるのが好ましぐ 0. 2〜10モルの範囲であるのがより好ま しぐ 0. 5〜5モルの範囲であるのがさらに好ましい。  [0093] The amount of allylic alcohol used in the reaction step Γ is preferably in the range of 0.1 to 20 mol per mol of compound (I 3), and in the range of 0.2 to 10 mol. More preferably, it is more preferably in the range of 0.5 to 5 moles.
[0094] また、反応工程 ΓΊま溶媒の存在下または不存在下に実施できる。かかる溶媒とし ては、反応に悪影響を及ぼさない限り特に制限はなぐ例えばトルエン、キシレン、メ シチレンなどの芳香族炭化水素;へキサン、ヘプタン、オクタンなどの脂肪族炭化水 素；ジクロロェタン、クロ口ベンゼンなどのハロゲン化炭化水素；ジイソプロピルエーテ ル、ジブチルエーテル、テトラヒドロフラン、ジォキサン、ジグライム（ジエチレングリコ ールジメチルエーテル）、トリグライム（トリエチレングリコールジメチルエーテル）など のエーテルなどが挙げられる。溶媒を使用する場合、その使用量に特に制限はない 力 通常、化合物 (I 3)に対して 0. 1〜10倍質量の範囲であるのが好ましぐ経済 性、後処理の簡便さの観点からは、 0. 2〜5倍質量の範囲であるのがより好ましい。  [0094] The reaction step Γ can be carried out in the presence or absence of a solvent. Such solvents are not particularly limited as long as they do not adversely affect the reaction, for example, aromatic hydrocarbons such as toluene, xylene and mesitylene; aliphatic hydrocarbons such as hexane, heptane and octane; dichloroethane and black benzene And halogenated hydrocarbons such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), and ethers such as triglyme (triethylene glycol dimethyl ether). When a solvent is used, the amount used is not particularly limited. Generally, it is preferable that the amount is in the range of 0.1 to 10 times the mass of the compound (I 3). From the viewpoint, it is more preferably in the range of 0.2 to 5 times mass.
[0095] 反応工程 ΓΊこおける反応圧力は、反応を円滑に進行させる観点から、 0. 1〜50 OkPaの範囲であるのが好ましぐ l〜200kPaの範囲であるのがより好ましい。反応 温度は、 120〜200°Cの範囲であるのが好ましぐ 130〜180°Cの範囲であるのがよ り好ましい。また、反応時間は、酸触媒の種類や使用量、反応温度、反応圧力などに より異なるが、通常、 30分〜 48時間の範囲である。 [0096] 反応工程 1~を実施する方法に特に制限はなぐ例えば、化合物 (I 3)、酸触媒 および必要に応じて溶媒を混合し、所定温度および所定圧力下にァリルアルコール を滴下して反応させることにより実施できる。反応工程 1~では、 2—ァリルカルボ- ルイ匕合物（Π— 2)の収率の観点から、反応の進行に伴い副生する、式 I^OH (式中 R 1は前記定義の通りである。 )で示されるアルコールを除去しながら反応を行なっても よい。また、生成する 2—ァリルカルボ-ルイ匕合物 (Π— 2)を留出させながら反応を行 なうことも可能である。 [0095] The reaction pressure at ΓΊ is preferably in the range of 0.1 to 50 OkPa, more preferably in the range of 1 to 200 kPa, from the viewpoint of allowing the reaction to proceed smoothly. The reaction temperature is preferably in the range of 120 to 200 ° C, more preferably in the range of 130 to 180 ° C. The reaction time varies depending on the type and amount of acid catalyst used, reaction temperature, reaction pressure, etc., but is usually in the range of 30 minutes to 48 hours. [0096] The method for carrying out the reaction steps 1 to is not particularly limited. For example, the compound (I 3), an acid catalyst and a solvent as necessary are mixed, and allylic alcohol is added dropwise at a predetermined temperature and a predetermined pressure. It can be carried out by reacting. In the reaction step 1 ~, from the viewpoint of the yield of 2-aryl carbo-louis compound (Π-2), by-product as the reaction proceeds, the formula I ^ OH (wherein R 1 is as defined above). The reaction may be carried out while removing the alcohol represented by). It is also possible to carry out the reaction while distilling the generated 2-aryl carbo-louis compound (Π-2).
[0097] こうして得られた反応混合物からの 2 ァリルカルボ-ルイ匕合物 (Π— 2)の分離'精 製は、有機化合物の分離 '精製において一般的に用いられる方法により実施できる。 例えば、得られた反応混合物に溶媒および水を加えた後、水層を除去し、取得した 有機層から適宜溶媒を留去して得られた残留物をさらに蒸留することにより精製でき る。また、上記有機層または反応混合物を精製せず、そのまま後述する加水分解反 応〖こ供することちでさる。  [0097] Separation and purification of the biarylcarbo-Louis compound (Π-2) from the reaction mixture thus obtained can be carried out by a method generally used in separation and purification of organic compounds. For example, after adding a solvent and water to the obtained reaction mixture, the aqueous layer is removed, and the residue obtained by distilling off the solvent as appropriate from the obtained organic layer can be further purified. In addition, the organic layer or the reaction mixture is not purified, but can be directly subjected to the hydrolysis reaction described later.
[0098] 続いて上記の方法により得られる 2 ァリルカルボ二ルイ匕合物（Π— 2)を加水分解 して 2—ァリルカルボン酸ィ匕合物 (III)を得る工程 (以下、反応工程 2 "と称する。 )に ついて説明する。  [0098] Subsequently, the 2-arylcarbonyl compound (Π-2) obtained by the above method is hydrolyzed to obtain 2-arylcarboxylic acid compound (III) (hereinafter referred to as reaction step 2 "). ) Will be explained.
[0099] 反応工程 2, 'における 2 ァリルカルボニル化合物（II 2)の加水分解方法として は、エステルをカルボン酸に変換する際に一般的に用いられる方法が使用可能であ る。  [0099] As the hydrolysis method of the 2-arylcarbonyl compound (II 2) in the reaction step 2, ', a method generally used for converting an ester into a carboxylic acid can be used.
反応工程 2~の一例として、以下、塩基性化合物の存在下に加水分解する方法に ついて説明する。  As an example of the reaction steps 2 to 2, a method for hydrolysis in the presence of a basic compound will be described below.
塩基性ィ匕合物としては、例えば水酸ィ匕ナトリウム、水酸ィ匕カリウムなどのアルカリ金 属水酸ィ匕物;炭酸ナトリウム、炭酸カリウムなどの炭酸塩;炭酸水素ナトリウム、炭酸水 素カリウムなどの炭酸水素塩などが挙げられる。塩基性化合物の使用量としては、 2 ーァリルカルボ-ル化合物（Π— 2) 1モルに対して、通常、 0. 1〜20モルの範囲であ るのが好ましぐ経済的な観点からは、 0. 5〜10モルの範囲であるのがより好ましぐ 0. 8〜5モルの範囲であるのがさらに好ましい。  Examples of basic compounds include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate And hydrogen carbonates. The amount of the basic compound used is usually in the range of 0.1 to 20 mol with respect to 1 mol of 2-arylcarbol compound (Π-2). More preferably, it is in the range of 0.5 to 10 mol, more preferably in the range of 0.8 to 5 mol.
[0100] また、水の使用量は、通常、 2—ァリルカルボ-ル化合物（Π— 2) 1モルに対して 0. 1〜50モルの範囲であるのが好ましい。 [0100] In addition, the amount of water used is usually 0. 1 mol of 2-arylcarbonyl compound (ァ -2). The range of 1 to 50 mol is preferred.
[0101] 反応工程 2~は、溶媒の存在下に行なうのが好ましい。力かる溶媒としては、反応 に悪影響を及ぼさない限り特に制限はなぐ例えばトルエン、キシレン、メシチレンな どの芳香族炭化水素;へキサン、ヘプタン、オクタンなどの脂肪族炭化水素;ジクロロ ェタン、クロ口ベンゼンなどのハロゲン化炭化水素；メタノール、エタノール、イソプロ パノール、 tーブタノールなどのアルコール；ジイソプロピルエーテル、ジブチルエー テル、テトラヒドロフラン、ジォキサン、ジグライム、トリグライムなどのエーテル；ァセト 二トリル、ベンゾ-トリルなどの-トリル化合物；ジメチルホルムアミド、ジメチルァセトァ ミドなどのアミドィ匕合物などが挙げられる。これらの中でも、アルコールを使用するの が好ましい。溶媒の使用量に特に制限はないが、 2—ァリルカルボニル化合物 (II— 2)に対して、通常、 0. 1〜： LOO倍質量の範囲であるのが好ましぐ経済性、後処理の 簡便さの観点からは、 0. 2〜20倍質量の範囲であるのがより好ましぐ 0. 5〜10倍 質量の範囲であるのがさらに好ましい。  [0101] Reaction steps 2 to are preferably performed in the presence of a solvent. Solvents that can be used are not particularly limited as long as they do not adversely affect the reaction.For example, aromatic hydrocarbons such as toluene, xylene, and mesitylene; aliphatic hydrocarbons such as hexane, heptane, and octane; dichloroethane, black benzene, etc. Halogenated hydrocarbons; alcohols such as methanol, ethanol, isopropanol, and t-butanol; ethers such as diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, diglyme, and triglyme; -tolyl compounds such as acetonitrile, benzo-tolyl, and the like; Examples include amido compounds such as formamide and dimethylacetamide. Among these, it is preferable to use alcohol. Although there is no particular limitation on the amount of solvent used, it is usually preferred that the 2-allylcarbonyl compound (II-2) is in the range of 0.1 to LOO times mass. From the viewpoint of simplicity, the range of 0.2 to 20 times mass is more preferable, and the range of 0.5 to 10 times mass is more preferable.
[0102] 反応工程 2~における反応温度は、 0〜150°Cの範囲であるのが好ましぐ反応速 度、反応の選択性および 2—ァリルカルボン酸ィ匕合物 (III)の安定性の観点から、 20 〜100°Cの範囲であるのがより好ましい。反応圧力は、 0. l〜500kPaの範囲であり 、 l〜200kPaの範囲であるのがより好ましい。また、反応時間は、塩基性化合物の 種類や使用量、水の使用量、反応温度、反応圧力などにより異なるが、通常、 10分 〜24時間の範囲である。  [0102] The reaction temperature in the reaction steps 2 to is preferably in the range of 0 to 150 ° C. The reaction speed, the selectivity of the reaction, and the stability of the 2-arylcarboxylic acid compound (III) From the viewpoint, it is more preferably in the range of 20 to 100 ° C. The reaction pressure is in the range of 0.1 to 500 kPa, and more preferably in the range of 1 to 200 kPa. The reaction time varies depending on the type and amount of the basic compound used, the amount of water used, the reaction temperature, the reaction pressure, etc., but is usually in the range of 10 minutes to 24 hours.
[0103] 反応工程 2~を実施する方法に特に制限はなぐ例えば、 2 ァリルカルボ二ルイ匕 合物 (II 2)もしくは反応工程 Γ 'の後処理で得られた 2—ァリルカルボニル化合物（ II— 2)を含有する有機層、塩基性化合物、水および好ましくは溶媒を混合し、所定 温度および所定圧力下に反応させることにより実施できる。  [0103] The method for carrying out reaction steps 2 to is not particularly limited, for example, 2-arylcarbonyl compound (II 2) or 2-arylcarbonyl compound (II-) obtained by post-treatment of reaction step Γ '. It can be carried out by mixing an organic layer containing 2), a basic compound, water and preferably a solvent and reacting them under a predetermined temperature and a predetermined pressure.
[0104] こうして得られた反応混合物からの 2 ァリルカルボン酸ィ匕合物 (ΠΙ)の分離'精製 は、有機化合物の分離'精製において一般的に用いられる方法により行なうことがで きる。例えば、反応混合物を濃縮した後、水および有機溶媒を加えて混合してから水 層を取り出し、該水層を希塩酸などにより酸性にした後、へキサン、トルエン、ジイソ プロピルエーテルなどの有機溶媒により抽出し、力かる抽出液を蒸留することにより、 純度の高い 2—ァリルカルボン酸ィ匕合物（ΠΙ)を得ることができる。 [0104] The separation and purification of the diarylcarboxylic acid compound (ΠΙ) from the reaction mixture thus obtained can be carried out by a method generally used in the separation and purification of organic compounds. For example, after concentrating the reaction mixture, water and an organic solvent are added and mixed, and then the aqueous layer is taken out. The aqueous layer is acidified with dilute hydrochloric acid and then with an organic solvent such as hexane, toluene, and diisopropyl ether. By extracting and distilling a powerful extract, A highly pure 2-arylcarboxylic acid compound (ΠΙ) can be obtained.
[0105] なお、本発明の原料である化合物 (I 3)の製造方法に特に制限はなぐ例えば、 オクタン-トリルまたはオタテン-トリルを、ジイソプロピルエーテルなどの溶媒の存在 下、塩ィ匕水素および式 I^OH (式中 R1は前記定義の通りである。）で示されるアルコ ールと 5〜20°Cで 5時間〜 24時間反応させ、析出する固体をろ過し、得られた固体 を、さらにジイソプロピルエーテルなどの溶媒の存在下に式 I^OH (R1は前記定義の 通りである。）で示されるアルコールと 20〜30°Cで 5時間〜 24時間反応させることに より製造できる。 [0105] The production method of the compound (I 3) which is a raw material of the present invention is not particularly limited. For example, octane-tolyl or otaten-tolyl is added in the presence of a solvent such as diisopropyl ether and a salt of hydrogen and a compound. Reaction with an alcohol represented by I ^ OH (wherein R 1 is as defined above) at 5-20 ° C for 5-24 hours, the precipitated solid is filtered, and the resulting solid is filtered. Furthermore, it can be produced by reacting with an alcohol represented by the formula I ^ OH (R 1 is as defined above) in the presence of a solvent such as diisopropyl ether at 20-30 ° C for 5-24 hours. .
実施例  Example
[0106] 以下、実施例により本発明をさらに詳細に説明するが、本発明は以下の実施例に よって何ら限定されない。  [0106] Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.
[0107] <実施例 1 > 反応工程 1 :反応 A  <Example 1> Reaction step 1: Reaction A
温度計、ディーンスターク型水分定量受器、冷却管および磁気回転子を備えた内 容積 500mlの三つ口フラスコに、オタタナール 64. lg (0. 50mol)、ァリルアルコー ル 145. 0g (2. 50mol)、マレイン酸 1. 7g (15. Ommol)、およびトルエン 128. 2g を入れ、副生する水をトルエンとの共沸蒸留により除去しながら 98°Cで 20時間加熱 した。得られた反応混合物を 20°Cまで冷却し、水 lOOmlを添加して力も水層を分離 した。有機層を 5質量％炭酸水素ナトリウム水溶液 100ml、次いで飽和食塩水 100 mlで洗浄した後、濃縮することにより、 106. 8gの粗生成物を得た。得られた粗生成 物をガスクロマトグラフィー [分析機器：株式会社島津製作所製 GC - 9A、使用カラ ム：（財)ィ匕学物質評価研究機構 G— 230 (1. D. : 1. 2mm、カラムの長さ：20m、膜 厚： 1. 0 m)、分析条件： injection temp. 280°C、昇温条件： 80°C→(10°CZ分 で昇温)→250°C (20分保持) ]で分析した結果、 1, 1—ジァリルォキシオクタン 84. Og (オタタナール基準で収率 74%)を含有して!/ヽた。  In a 500 ml three-necked flask equipped with a thermometer, a Dean-Stark moisture meter, a condenser and a magnetic rotor, Ottatanal 64. lg (0.50 mol), araryl alcohol 145.0 g (2. 50 mol) Then, 1.7 g (15. Ommol) of maleic acid and 128.2 g of toluene were added, and the mixture was heated at 98 ° C. for 20 hours while removing by-product water by azeotropic distillation with toluene. The resulting reaction mixture was cooled to 20 ° C., and lOOml of water was added to separate the aqueous layer. The organic layer was washed with 100 ml of 5% by mass aqueous sodium hydrogen carbonate solution and then with 100 ml of saturated brine, and then concentrated to obtain 106.8 g of a crude product. The obtained crude product was subjected to gas chromatography [analytical instrument: GC-9A, manufactured by Shimadzu Corporation, column used: G-230 (1. D .: 1.2 mm, Column length: 20 m, membrane thickness: 1.0 m), analysis condition: injection temp. 280 ° C, temperature rise condition: 80 ° C → (temperature rise in 10 ° CZ minutes) → 250 ° C (20 minutes) As a result, it was found to contain 1,1-diallyloxyoctane 84. Og (yield 74% based on otatanal).
[0108] <実施例 2> 反応工程 1 :反応 B  <Example 2> Reaction step 1: Reaction B
温度計、蒸留装置および磁気回転子を備えた内容積 100mlの三つ口フラスコに、 上記実施例 1で得られた粗 1 , 1 -ジァリルォキシオクタン 50. Og [ 1 , 1 ジァリルォ キシオクタンとして 39. 3g (173. 9mmol)相当]、およびマレイン酸 0. 6g (5. 2mmo 1)を入れ、減圧下（8. 0〜8. 7kPa)、 140〜155°Cで反応生成物を留出させながら 10時間加熱した。得られた留出液 31. 6gにトルエン 100mlを添カ卩した後、 5質量％ 炭酸水素ナトリウム水溶液 100ml、次いで飽和食塩水 100mlで洗浄し、有機層を濃 縮して 30. 9gの粗生成物を得た。得られた粗生成物 30. 9gをガスクロマトグラフィー (分析条件は実施例 1と同じ)で分析した結果、 2—ァリルオタタナール 22. 2g (l, 1 ージァリルォキシオクタン基準で収率 76%)を含有して!/ヽた。 In a three-necked flask with an internal volume of 100 ml equipped with a thermometer, a distillation apparatus and a magnetic rotor, the crude 1,1-diallyloxyoctane obtained in Example 1 above was added 50. Og [1,1 diallyloxyoctane. As equivalent to 39.3 g (173.9 mmol)], and 0.6 g maleic acid (5.2 mmo 1) was added, and the mixture was heated for 10 hours under reduced pressure (8.0 to 8.7 kPa) at 140 to 155 ° C while distilling the reaction product. To 31.6 g of the resulting distillate, 100 ml of toluene was added, and then washed with 100 ml of 5% by weight aqueous sodium hydrogen carbonate solution and then with 100 ml of saturated brine, and the organic layer was concentrated to give 30.9 g of crude product. I got a thing. As a result of analyzing 30.9 g of the obtained crude product by gas chromatography (analysis conditions are the same as in Example 1), it was found that 2-allylotatanal 22.2 g (based on l, 1-diallyloxyoctane) Yield of 76%).
[0109] <実施例 3 > 反応工程 1 :反応 A+B <Example 3> Reaction step 1: Reaction A + B
温度計、蒸留装置および磁気回転子を備えた内容積 200mlの三つ口フラスコに、 オタタナール 32. lg (0. 25mol)、ァリルアルコール 72. 5g (l. 25mol)、およびマ レイン酸 0. 9g (7. 5mmol)を入れ、 94°Cで 4時間加熱した。引き続いて反応混合物 を 145°Cに昇温し、反応系カもァリルアルコールおよび水を留出させながら 8時間加 熱した後、さらに減圧下（20kPa)、 145〜150°Cで 4時間加熱して反応させた。得ら れた反応混合物をガスクロマトグラフィー (分析条件は実施例 1と同じ)で分析した結 果、 2—ァリルオタタナール 25. 7g (オタタナール基準で収率 61%)が生成していた  In a three-necked flask with an internal volume of 200 ml equipped with a thermometer, distillation apparatus and magnetic rotor, Ottatanal 32.lg (0.25 mol), aryl alcohol 72.5 g (l.25 mol), and maleic acid 0. 9 g (7.5 mmol) was added and heated at 94 ° C. for 4 hours. Subsequently, the temperature of the reaction mixture was raised to 145 ° C, and the reaction system was heated for 8 hours while distilling the allylic alcohol and water, and further heated at 145 to 150 ° C for 4 hours under reduced pressure (20 kPa). And reacted. As a result of analyzing the obtained reaction mixture by gas chromatography (analysis conditions are the same as in Example 1), 25.7 g of 2-aryl otatanal (yield 61% based on otatanal) was produced.
[0110] <実施例 4> 反応工程 2 <Example 4> Reaction step 2
温度計、滴下ロートおよび磁気回転子を備えた内容積 500mlの三つ口フラスコに、 上記実施例 2の方法で得られた粗生成物 25. 6g[2—ァリルオタタナールとして 18. 4g (109. 5mmol)相当]、 2—メチル—2—ブテン 38. 3g (547. 5mmol)、および t —ブタノール 250mlを入れた。次いで水 150g、リン酸二水素カリウム 14. 0g (102. 9mmol)および亜塩素酸ナトリウム 12. 4g (136. 9mmol)を滴下ロートに入れ、フラ スコ内の温度を 40°C以下に保ちながら 30分かけてフラスコ内へ滴下した。滴下終了 後、 25°Cで 2時間攪拌した。得られた反応混合物に 20%質量水酸化ナトリウム水溶 液をカ卩えて pHIO以上に調整した後、濃縮し、水 100mlを加えてから、トルエン 100 mlで 2回洗浄し、有機層を分離した。水層に濃塩酸を加え、水層の pHを 3以下に調 整した後、トルエン 50mlで 2回抽出し、得られた抽出液を濃縮することにより、粗生成 物 22. Ogを得、さらに減圧蒸留（138°CZ0. 5kPa)することにより、 2—ァリルォクタ ン酸 18. 4g (純度 99. 1%、収率 91%)を得た。 [0111] <実施例 5 > 反応工程 1 :反応 A In a three-necked flask with an internal volume of 500 ml equipped with a thermometer, a dropping funnel and a magnetic rotor, 25.6 g of crude product obtained by the method of Example 2 above [18.4 g as 2-aryl otatanal] (Corresponding to 109.5 mmol)], 38.3 g (547.5 mmol) of 2-methyl-2-butene, and 250 ml of t-butanol were added. Next, 150 g of water, 14.0 g (102.9 mmol) of potassium dihydrogen phosphate and 12.4 g (136.9 mmol) of sodium chlorite were placed in the dropping funnel, and the temperature in the flask was kept at 40 ° C or lower. The solution was dropped into the flask over a period of minutes. After completion of dropping, the mixture was stirred at 25 ° C for 2 hours. A 20% mass aqueous sodium hydroxide solution was added to the resulting reaction mixture, adjusted to pHIO or higher, concentrated, added with 100 ml of water, washed twice with 100 ml of toluene, and the organic layer was separated. Concentrated hydrochloric acid was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 3 or less, followed by extraction twice with 50 ml of toluene, and the resulting extract was concentrated to obtain a crude product 22. Og. Distillation under reduced pressure (138 ° CZ0.5 kPa) gave 18.4 g of 2-aryloctanoic acid (purity 99.1%, yield 91%). <Example 5> Reaction step 1: Reaction A
温度計、ディーンスターク型水分定量受器、冷却管および磁気回転子を備えた内 容積 500mlの三つ口フラスコに、 7—オタテナール 63. Og (0. 50mol)、ァリルアル コール 145. 0g (2. 50mol)、マレイン酸 1. 7g (15. Ommol)、およびトルエン 63. 0 gを入れ、副生する水をトルエンとの共沸蒸留により除去しながら 98°Cで 8時間加熱 した。得られた反応混合物を 20°Cまで冷却し、水 100mlを添加して力も水層を分離 した。有機層を 5質量％炭酸水素ナトリウム水溶液 100ml、次いで飽和食塩水 100 mlで洗浄した後、濃縮することにより、 105. 8gの粗生成物を得た。得られた粗生成 物を減圧蒸留（116°CZ0. 7kPa)することにより、下記の物性を有する 1, 1 ジァリ ルォキシ 7—オタテン 88. 2g (純度 98. 1%、収率 77%)を得た。  In a 500 ml three-necked flask equipped with a thermometer, a Dean-Stark moisture meter, a condenser and a magnetic rotor, 7-Otatenal 63. Og (0.50 mol), Araryl alcohol 145.0 g (2. 50 mol), 1.7 g (15. Ommol) of maleic acid, and 63.0 g of toluene, were heated at 98 ° C. for 8 hours while removing by-product water by azeotropic distillation with toluene. The resulting reaction mixture was cooled to 20 ° C., and 100 ml of water was added to separate the aqueous layer. The organic layer was washed with 100 ml of 5% by mass aqueous sodium hydrogen carbonate solution and then with 100 ml of saturated brine, and then concentrated to obtain 105.8 g of a crude product. The obtained crude product was distilled under reduced pressure (116 ° CZ0.7 kPa) to obtain 88.2 g (purity 98.1%, yield 77%) of 1,1 diallyloxy-7-octene having the following physical properties. It was.
[0112] iH—NMR ^ベクトル（270MHzゝ CDC1、 TMS) δ : 1. 34 (6Η, m)、 1. 62 (2H  [0112] iH—NMR ^ vector (270 MHz ゝ CDC1, TMS) δ: 1. 34 (6 Η, m), 1.62 (2H
3  Three
, q, J = 5. 4Hz)、2. 04 (2H, dddt, J = 5. 4Hz, 2. 7Hz, 1. 6Hz, 1. lHz)、4. 05 (4H, ddd, J = 5. 4Hz, 3. 2Hz, 2. 7Hz)、4. 59 (1H, t, J = 5. 4Hz) , 4. 93 (1H, ddt, J= 10. 5Hz, 2. 2Hz, 1. lHz)、4. 98 (1H, ddt, J= 18. 4Hz, 2. 7 Hz, 1. 1Hz) , 5. 17 (2H, ddt, J= 10. 5Hz, 2. 7Hz, 1. 6Hz) , 5. 29 (2H, ddt , J= 17. 3Hz, 3. 2Hz, 1. 6Hz)、5. 80 (1H, ddt, J= 18. 4Hz, 10. 5Hz, 5. 4 Hz) , 5. 92 (2H, ddt, J= 17. 3Hz, 10. 5Hz, 5. 4Hz)  , q, J = 5.4 Hz), 2.04 (2H, dddt, J = 5.4 Hz, 2. 7 Hz, 1. 6 Hz, 1. lHz), 4.05 (4H, ddd, J = 5.4 Hz) , 3.2 Hz, 2.7 Hz), 4.59 (1H, t, J = 5.4 Hz), 4.93 (1H, ddt, J = 10.5 Hz, 2.2 Hz, 1. lHz), 4. 98 (1H, ddt, J = 18.4 Hz, 2.7 Hz, 1.1 Hz), 5.17 (2H, ddt, J = 10.5 Hz, 2.7 Hz, 1.6 Hz), 5.29 (2H , ddt, J = 17.3 Hz, 3.2 Hz, 1.6 Hz), 5.80 (1H, ddt, J = 18.4 Hz, 10.5 Hz, 5.4 Hz), 5.92 (2H, ddt, (J = 17.3Hz, 10.5Hz, 5.4Hz)
[0113] <実施例 6 > 反応工程 1 :反応 B [0113] <Example 6> Reaction step 1: Reaction B
温度計、蒸留装置および磁気回転子を備えた内容積 200mlの三つ口フラスコに、 上記実施例 5で得られた蒸留後の 1, 1—ジァリルォキシ—7—オタテン 75. 3g[l, 1 —ジァリルォキシ 7—オタテンとして 73. 9g (330. Ommol)相当]、およびマレイン 酸 1. 2g (9. 9mmol)を入れ、副生するァリルアルコールを留去しながら 155〜160 °Cで 4時間加熱し反応させた。さらに減圧下（20. OkPa)、 155〜160°Cで 11時間 加熱した。得られた反応混合物を 20°Cまで冷却し、トルエン 100mlを添加した後、 5 質量％炭酸水素ナトリウム水溶液 100ml、次いで飽和食塩水 100mlで洗浄し、有機 層を濃縮して 56. 2gの粗生成物を得た。得られた粗生成物を減圧蒸留（102°CZl . lkPa)することにより、下記の物性を有する 2 ァリル 7—オタテナール 30. 8g ( 純度 95. 7%、収率 54%)を得た。 [0114] H— NMR ^ベクトル（270MHz、 CDC1 、 TMS) δ : 1. 35 (6H, m)、 1. 64 (2H To a three-necked flask with an internal volume of 200 ml equipped with a thermometer, a distillation apparatus and a magnetic rotator, 1, 1-diarloxy-7-otaten after distillation obtained in Example 5 above 75.3 g [l, 1 — Diallyloxy 7-Otaten, equivalent to 73.9 g (330. Ommol)], and 1.2 g (9.9 mmol) of maleic acid, heated at 155-160 ° C for 4 hours while distilling off the by-produced allylic alcohol And reacted. Further, the mixture was heated at 155 to 160 ° C for 11 hours under reduced pressure (20. OkPa). The obtained reaction mixture was cooled to 20 ° C, 100 ml of toluene was added, washed with 100 ml of 5 mass% aqueous sodium hydrogen carbonate solution and then with 100 ml of saturated brine, and the organic layer was concentrated to 56.2 g of crude product. I got a thing. The obtained crude product was distilled under reduced pressure (102 ° C Zl.lkPa) to obtain 30.8 g of 2-aryl 7-otatenal having the following physical properties (purity 95.7%, yield 54%). [0114] H—NMR ^ vector (270MHz, CDC1, TMS) δ: 1.35 (6H, m), 1.64 (2H
3  Three
, t, J = 5. 4Hz) , 2. 05 (2H, dddd, J = 5. 4Hz, 2. 2Hz, 1. 4Hz, 1. 4Hz) , 2. 25 (1H, dq, J = 5. 4Hz, 2. 4Hz) , 2. 36 (2H, dddt, J = 5. 4Hz, 2. 2Hz, 1. 4 Hz, 1. 4Hz)、4. 94 (2H, ddt, J= 10. 3Hz, 2. 2Hz, 1. 4Hz) , 5. 08 (2H, ddt , J= 17. 3Hz, 2. 2Hz, 1. 4Hz)、5. 75 (2H, ddt, J= 17. 3Hz, 10. 3Hz, 6. 5 Hz)、 9. 60 (1H, d, J = 2. 4Hz)  , t, J = 5.4 Hz), 2. 05 (2H, dddd, J = 5.4 Hz, 2.2 Hz, 1.4 Hz, 1.4 Hz), 2.25 (1H, dq, J = 5.4 Hz , 2.4 Hz), 2.36 (2H, dddt, J = 5.4Hz, 2. 2Hz, 1.4 Hz, 1.4 Hz), 4.94 (2H, ddt, J = 10.3Hz, 2. 2Hz, 1.4Hz), 5.08 (2H, ddt, J = 17.3Hz, 2.2Hz, 1.4Hz), 5.75 (2H, ddt, J = 17.3Hz, 10.3Hz, 6. 5 Hz), 9.60 (1H, d, J = 2.4 Hz)
[0115] <実施例 7> 反応工程 2  <Example 15> Reaction step 2
温度計、滴下ロートおよび磁気回転子を備えた内容積 500mlの三つ口フラスコに、 上記実施例 6で得られた蒸留後の 2 ァリル 7 オタテナール 15. 7g [ 2 ァリル —7—才クテナーノレとして 15. Og (90. 4mmol)ネ目当]、 2—メチノレ一 2 ブテン 31. 6g (452. Ommol)、および t—ブタノール 200mlを入れた。次いで水 124g、リン酸 二水素カリウム 11. 6g (85. Ommol)および亜塩素酸ナトリウム 10. 2g (113. Omm ol)を滴下ロートに入れ、フラスコ内の温度を 40°C以下に保ちながら 30分かけてフラ スコ内へ滴下した。滴下終了後、 25°Cで 2時間攪拌した。得られた反応混合物に 20 質量％水酸ィ匕ナトリウム水溶液を加えて pHIO以上に調整した後、濃縮し、水 100ml を加えてから、トルエン 100mlで 2回洗浄し、有機層を分離した。水層に濃塩酸をカロ え、水層の pHを 3以下に調整した後、トルエン 50mlで 2回抽出し、得られた抽出液 を濃縮することにより、粗生成物 18. 9gを得た。得られた粗生成物を減圧蒸留（142 °C/0. 5kPa)することにより、下記の物性を有する 2 ァリル 7 オタテン酸 15. 1 g (純度 99. 5%、収率 91%)を得た。  Into a 500 ml three-necked flask equipped with a thermometer, a dropping funnel and a magnetic rotator, 2 allyl 7 otatenal after distillation obtained in Example 6 above 15.7 g [2 arly — 7-year-old Kutenanore 15 Og (90.4 mmol)), 2-methylol-2-butene 31.6 g (452. Ommol), and t-butanol 200 ml. Next, 124 g of water, 11.6 g of potassium dihydrogen phosphate (85. Ommol) and 10.2 g of sodium chlorite (113. Ommol) were placed in a dropping funnel, and the temperature in the flask was kept at 40 ° C or lower. The solution was dropped into the flask over a period of minutes. After completion of the dropwise addition, the mixture was stirred at 25 ° C for 2 hours. The obtained reaction mixture was adjusted to pHIO or higher by adding 20 mass% aqueous sodium hydroxide solution, concentrated, added with 100 ml of water, washed twice with 100 ml of toluene, and the organic layer was separated. Concentrated hydrochloric acid was added to the aqueous layer, the pH of the aqueous layer was adjusted to 3 or less, and then extracted twice with 50 ml of toluene. The resulting extract was concentrated to obtain 18.9 g of a crude product. The obtained crude product was distilled under reduced pressure (142 ° C / 0.5 kPa) to obtain 15.1 g (purity 99.5%, yield 91%) of 2-aryl 7-otatenic acid having the following physical properties. It was.
[0116] — NMR ^ベクトル（270MHz、 CDC1 、 TMS) δ : 1. 37—1. 64 (8Η, m)、 2  [0116] — NMR ^ vector (270MHz, CDC1, TMS) δ: 1. 37—1.64 (8Η, m), 2
3  Three
. 05 (2H, dddd, J = 6. 5Hz, 2. 4Hz, 1. 1Hz, 1. lHz)、2. 27 (1H, q, J = 6. 5 Hz) , 2. 39 (2H, dddt, J = 6. 5Hz, 2. 4Hz, 1. 1Hz, 1. lHz)、4. 99 (2H, ddt , J= 10. 5Hz, 2. 4Hz, 1. 1Hz) , 5. 04 (2H, ddt, J= 17. OHz, 2. 4Hz, 1. 1H z) , 5. 78 (2H, ddt, J= 17. OHz, 10. 5Hz, 6. 5Hz)  05 (2H, dddd, J = 6.5 Hz, 2.4 Hz, 1.1 Hz, 1. lHz), 2.27 (1H, q, J = 6.5 Hz), 2.39 (2H, dddt, J = 6.5 Hz, 2.4 Hz, 1.1 Hz, 1. lHz), 4.99 (2H, ddt, J = 10.5Hz, 2.4 Hz, 1.1Hz), 5. 04 (2H, ddt, J = 17. OHz, 2.4 Hz, 1.1 Hz), 5.78 (2H, ddt, J = 17. OHz, 10.5Hz, 6.5 Hz)
[0117] <実施例 8 > 反応工程 Γ <Example 8> Reaction process Γ
温度計、蒸留装置および攪拌装置を備えた内容積 50mlの三つ口フラスコに、オタ タナールジメチルァセタール 10. 4g (60. Ommol)およびマレイン酸 0. 2g (l. 8mm ol)を入れ、 165°Cに昇温した。続いて同温度でァリルアルコール 3. 5g (60. Ommo 1)を 4時間かけて滴下し、さらに同温度で 2時間反応させた。得られた反応混合物 10 . Ogにトルエン 50mlをカ卩えた後、 5質量％炭酸水素ナトリウム水溶液 50ml、次いで 5 質量％食塩水 50mlで洗浄し、有機層を濃縮して粗生成物 9. Ogを得た。得られた粗 生成物をガスクロマトグラフィー (分析条件は実施例 1と同じ)で分析した結果、 2—ァ リルオタタナール 5. 5g (オタタナールジメチルァセタール基準で収率 55%)が生成し ていた。 A 50-ml three-necked flask equipped with a thermometer, distillation apparatus and stirrer was charged with 10.4 g (60. Ommol) otatanal dimethyl acetal and 0.2 g (l. 8 mm) maleic acid. ol) was added and the temperature was raised to 165 ° C. Subsequently, 3.5 g (60. Ommo 1) of allylic alcohol was added dropwise at the same temperature over 4 hours, and further reacted at the same temperature for 2 hours. The obtained reaction mixture 10. Og was charged with 50 ml of toluene, washed with 50 ml of 5% by weight aqueous sodium hydrogen carbonate solution and then with 50 ml of 5% by weight brine, and the organic layer was concentrated to give crude product 9. Og. Obtained. The obtained crude product was analyzed by gas chromatography (analysis conditions were the same as in Example 1). As a result, 5.5 g of 2-aryl otatanal (yield 55% based on otatanal dimethyl acetal) was produced. It was.
[0118] <実施例 9 > 反応工程 2,  <Example 9> Reaction step 2,
温度計、滴下ロートおよび攪拌装置を備えた内容積 500mlの三つ口フラスコに、実 施例 1で得られた粗生成物 9. 0g[2—ァリルオタタナール 5. 5g (33. Ommol)相当] 、 2—メチル—2—ブテン 11. 5g (163. 7mmol)、および t—ブタノール 75mlを入れ た。次いで水 45g、亜塩素酸ナトリウム 3. 7g (40. 9mmol)およびリン酸二水素力リウ ム 4. 2g (30. 8mmol)を、フラスコ内の温度を 40°C以下に保ちながら 30分かけて滴 下した。滴下終了後の反応混合物の pHは 4〜5の範囲になっていた。 25°Cでさらに 2時間反応させてから、 20質量％水酸化ナトリウム水溶液を加えて反応混合物の pH を 10以上に調整した。得られた反応混合物を濃縮し、水 30mlを加えた後、トルエン 30mlで 2回洗浄し、有機層を分離除去した。水層に塩酸を加え、水層の pHを 3以下 に調整した後、トルエン 15mlで 2回抽出し、得られた抽出液を濃縮することにより、粗 生成物 6. 6gを得た。得られた粗生成物を減圧蒸留（138°CZ0. 5kPa)することによ り、 2—ァリルオクタン酸 5. 5g (純度 99. 1%、収率 91%)を得た。  In a three-necked flask with an internal volume of 500 ml equipped with a thermometer, a dropping funnel and a stirrer, 9.0 g [2-aryl otatanal 5.5 g (33. Ommol) obtained in Example 1 was added. 2) -methyl-2-butene (11.5 g, 163.7 mmol) and t-butanol (75 ml) were added. Next, 45 g of water, 3.7 g (40.9 mmol) of sodium chlorite and 4.2 g (30.8 mmol) of dihydrogen phosphate were added over 30 minutes while keeping the temperature in the flask at 40 ° C or lower. Drip. The pH of the reaction mixture after completion of the dropwise addition was in the range of 4-5. After further reaction at 25 ° C for 2 hours, the pH of the reaction mixture was adjusted to 10 or more by adding 20 mass% aqueous sodium hydroxide solution. The obtained reaction mixture was concentrated, 30 ml of water was added, and the mixture was washed twice with 30 ml of toluene to separate and remove the organic layer. Hydrochloric acid was added to the aqueous layer, and the pH of the aqueous layer was adjusted to 3 or less, followed by extraction twice with 15 ml of toluene, and the resulting extract was concentrated to obtain 6.6 g of a crude product. The obtained crude product was distilled under reduced pressure (138 ° CZ0.5 kPa) to obtain 5.5 g of 2-aryloctanoic acid (purity 99.1%, yield 91%).
[0119] <参考例 1 >  [0119] <Reference Example 1>
温度計、導入管および攪拌装置を備えた内容積 300mlの三つ口フラスコに、オタ タン-トリル 23. 7g (189. Ommol)、メタノール 7. 6g (237. 3mmol)およびジィソプ 口ピルエーテル 57mlを入れ、 5°Cに冷却した。次いで、内温を 15°C以下に保持しな がら、導入管から塩ィ匕水素ガス 11. 5g (315. lmmol)をパブリングした。さらに同温 度で 5時間攪拌した後、ジイソプロピルエーテル 38mlを添加し、同温度を保持したま ま 24時間静置した。析出した固体をろ過し、ジイソプロピルエーテルで洗浄した後、 減圧乾燥させて白色固体 21. lgを得た。 温度計、攪拌装置を備えた内容積 200mlの三つ口フラスコに、上記操作で得られ た白色固体 21. lg、メタノール 20. 9gおよびジイソプロピルエーテル 97mlを入れ、 25°Cで 20時間攪拌した。析出した塩ィ匕アンモ-ゥムをろ別した後、ろ液を減圧下に 濃縮することにより、粗生成物 23. lgを得た。この粗生成物を減圧蒸留（86°CZ0. 3kPa)し、オルトオクタン酸トリメチル 19. 7g (純度 99. 9%、オクタン-トリル基準で 収率 51%)を得た。 Into a 300-ml three-necked flask equipped with a thermometer, inlet tube, and stirrer, add 23.7 g (189. Ommol) of otatan-tolyl, 7.6 g (237.3 mmol) of methanol, and 57 ml of dioptric pill ether And cooled to 5 ° C. Next, 11.5 g (315. lmmol) of sodium chloride hydrogen gas was published from the introduction tube while maintaining the internal temperature at 15 ° C. or lower. After further stirring at the same temperature for 5 hours, 38 ml of diisopropyl ether was added, and the mixture was allowed to stand for 24 hours while maintaining the same temperature. The precipitated solid was filtered, washed with diisopropyl ether, and then dried under reduced pressure to obtain 21. lg of white solid. In a 200-ml three-necked flask equipped with a thermometer and a stirrer, 21. lg of the white solid obtained in the above operation, 20.9 g of methanol and 97 ml of diisopropyl ether were placed and stirred at 25 ° C. for 20 hours. The precipitated salt ammonium was filtered off, and the filtrate was concentrated under reduced pressure to obtain 23. lg of a crude product. This crude product was distilled under reduced pressure (86 ° CZ 0.3 kPa) to obtain 19.7 g of trimethyl orthooctanoate (purity 99.9%, yield 51% based on octane-tolyl).
[0120] <実施例 10 > 反応工程 1~ <Example 20> Reaction step 1 to
温度計、蒸留装置および攪拌装置を備えた内容積 50mlの三つ口フラスコに、参 考例 1の方法で得られたオルトオクタン酸トリメチル 10. 2g (50. Ommol)およびマレ イン酸 0. 2g (l. 5mmol)を入れ、 155°Cにカロ熱した。続いて同温度でァリルアルコ ール 7. 3g (125. Ommol)を 4時間かけて滴下し、さらに同温度で 8時間反応させた 。得られた反応混合物 10. lgをガスクロマトグラフィー (分析条件は実施例 1と同じ） で分析した結果、 2—ァリルオクタン酸メチル 7. 3g (オルトオクタン酸トリメチル基準で 収率 74%)および 2—ァリルオクタン酸ァリル 0. 6g (オルトオクタン酸トリメチル基準 で収率 5%)が生成して ヽた。  In a three-necked flask with an internal volume of 50 ml equipped with a thermometer, a distillation apparatus and a stirrer, 10.2 g (50. Ommol) of trimethyl orthooctanoate and 0.2 g of maleic acid obtained by the method of Reference Example 1 were added. (l. 5 mmol) was added and heated to 155 ° C. Subsequently, allylic alcohol (7.3 g, 125. Ommol) was added dropwise at the same temperature over 4 hours, and the reaction was further continued at the same temperature for 8 hours. The resulting reaction mixture (10 lg) was analyzed by gas chromatography (analysis conditions were the same as in Example 1). As a result, 7.3 g of methyl 2-aryloctanoate (74% yield based on trimethyl orthooctanoate) and 2— 0.6 g of allyl octanoate (yield 5% based on trimethyl orthooctanoate) was produced.
[0121] く実施例 11 > 反応工程 2~ [0121] Example 11> Reaction Step 2 ~
温度計、ジムロート冷却器および攪拌装置を備えた内容積 100mlの三つ口フラス コに、実施例 1で得られた反応混合物 9. 6g[2—ァリルオクタン酸メチル 6. 9g (35. Ommol)および 2—ァリルオクタン酸ァリル 0. 5g (2. 4mmol)相当]、水酸化ナトリウ ム 2. 5g (62. 7mmol)、水 10gおよびメタノール 12. 5gを入れ、還流温度（内温 75 〜78°C)で 1時間攪拌した。得られた反応混合物を減圧下に濃縮し、水 20mlを加え てから、トルエン 20mlで 2回洗浄し、有機層を分離した。残った水層に濃塩酸を加え 、水層の pHを 3以下に調整した後、トルエン 20mlで 2回抽出し、得られた抽出液と 先の有機層を合わせて減圧下に濃縮することにより、粗生成物 8. 5gを得た。この粗 生成物を減圧蒸留（138°CZ0. 5kPa)し、 2—ァリルオクタン酸 6. 8g (純度 99. 0% 、収率 97%)を得た。  To a 100-ml three-necked flask equipped with a thermometer, a Dimroth condenser, and a stirrer, 9.6 g of the reaction mixture obtained in Example 1 [6.9 g (35. Ommol) of methyl 2-aryloctanoate and 2-aryl octanoate equivalent to 0.5 g (2.4 mmol)], sodium hydroxide 2.5 g (62.7 mmol), 10 g of water and 12.5 g of methanol, and reflux temperature (internal temperature 75 to 78 ° C) For 1 hour. The obtained reaction mixture was concentrated under reduced pressure, 20 ml of water was added, and the mixture was washed twice with 20 ml of toluene to separate the organic layer. Concentrated hydrochloric acid is added to the remaining aqueous layer to adjust the pH of the aqueous layer to 3 or less, followed by extraction twice with 20 ml of toluene. The obtained extract and the previous organic layer are combined and concentrated under reduced pressure. 8.5 g of crude product was obtained. This crude product was distilled under reduced pressure (138 ° CZ0.5 kPa) to obtain 6.8 g of 2-aryloctanoic acid (purity 99.0%, yield 97%).

Claims

請求の範囲 下記式 (I) Claims The following formula (I)
[化 1]
Figure imgf000028_0001
[Chemical 1]
Figure imgf000028_0001
[式中、実線および点線力もなる結合は、単結合または二重結合を表し、 Xはホルミ ル基、式 ) (式中、 1は炭素数 〜 のアルキル基を表す）で表されるジ [In the formula, a bond that also has a solid line and a dotted line force represents a single bond or a double bond, X is a formyl group, a formula) (wherein 1 represents an alkyl group having a carbon number of ˜).
2  2
アルコキシメチル基、または式 (式中、 は前記定義の通りである）で表 An alkoxymethyl group or a formula (wherein is as defined above)
3  Three
されるトリアルコキシメチル基を示す] Represents a trialkoxymethyl group
で示される化合物を酸触媒およびァリルアルコールの存在下に反応させることによりIs reacted in the presence of an acid catalyst and allylic alcohol.
、下記式 (II) The following formula (II)
[化 2] [Chemical 2]
Figure imgf000028_0002
Figure imgf000028_0002
[式中、実線および点線力 なる結合は単結合または二重結合を表し、 Xがホルミル 基もしくは上記ジアルコキシメチル基であるときは Yは水素原子を表し、 Xが上記トリ アルコキシメチル基であるときは γは式 (式中、 は炭素数 〜 のアルキル基 またはァリル基を表す)で示されるアルコキシ基を表す] [In the formula, a bond consisting of a solid line and a dotted line represents a single bond or a double bond, and when X is a formyl group or the above dialkoxymethyl group, Y represents a hydrogen atom, and X is the above trialkoxymethyl group. When γ represents an alkoxy group represented by the formula (wherein represents an alkyl group or an aryl group having a carbon number to)
で示される 2ーァリルカルボニル化合物を得、次!、で該 2—ァリルカルボニル化合物 を下記式 (III) Then, the 2-arylcarbonyl compound is converted into the following formula (III):
[化 3] OH [Chemical 3] OH
(式中、実線および点線力 なる結合は、単結合または二重結合を表す） で示される 2ーァリルカルボン酸化合物に変換することを特徴とする 2—ァリルカルボ ン酸化合物の製造方法。 (Wherein the bond represented by a solid line and a dotted line represents a single bond or a double bond) is converted to a 2-arylcarboxylic acid compound represented by the formula:
下記式 (I)  Formula (I)
[化 4]
Figure imgf000029_0001
[Chemical 4]
Figure imgf000029_0001
[式中、実線および点線力もなる結合は、単結合または二重結合を表し、 Xはホルミ ル基、式 CH OR1) (式中、 R1は炭素数 1〜6のアルキル基を表す）で表されるジ [In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond, X is a formyl group, and a formula CHOR 1 ) (wherein R 1 represents an alkyl group having 1 to 6 carbon atoms) Represented by
2  2
アルコキシメチル基、または式— CH (OR1) (式中、 R1は前記の通りである）で表され An alkoxymethyl group or a formula —CH 2 (OR 1 ) (wherein R 1 is as defined above)
3  Three
るトリアルコキシメチル基を示す] Represents a trialkoxymethyl group]
で示される化合物を、酸触媒およびァリルアルコールの存在下に反応させることによ る、下記式 (II) By reacting the compound represented by formula (II) in the presence of an acid catalyst and allylic alcohol.
[化 5] [Chemical 5]
Figure imgf000029_0002
Figure imgf000029_0002
[式中、実線および点線力もなる結合は、単結合または二重結合を表し、 Xがホルミ ル基もしくは上記ジアルコキシメチル基であるときは Yは水素原子を表し、 Xが上記ト リアルコキシメチル基であるときは Υは式 OR2 (式中、 R2は炭素数 1〜 6のアルキル 基またはァリル基を表す)で示されるアルコキシ基を表す] [In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond, and X is Y represents a hydrogen atom, and when X is the above-mentioned trialkoxymethyl group, Υ is the formula OR 2 (wherein R 2 is an alkyl having 1 to 6 carbon atoms) Represents an alkoxy group represented by a group or an aryl group]
で示される 2ーァリルカルボニル化合物の製造方法。  The manufacturing method of 2-aryl carbonyl compound shown by these.
[3] 下記式 (I 1)  [3] The following formula (I 1)
[化 6]  [Chemical 6]
Figure imgf000030_0001
Figure imgf000030_0001
(式中実線および点線力 なる結合は、単結合または二重結合を表す)で示される化 合物を酸触媒およびァリルアルコールの存在下、 20〜120°Cで反応させることにより 、下記式 (IV) (The bond represented by the solid and dotted lines in the formula represents a single bond or a double bond) By reacting a compound represented by the following formula at 20 to 120 ° C in the presence of an acid catalyst and allylic alcohol, (IV)
[化 7]  [Chemical 7]
Figure imgf000030_0002
で示される 2—ァリルァセタールイ匕合物を含む反応混合物を得、得られた反応混合 物を 120〜 180°Cに昇温して、反応混合物からァリルアルコールおよび水を留出さ せながら更に反応させることにより、下記式 (Π— 1)
Figure imgf000030_0002
To obtain a reaction mixture containing a 2-arlylacetal compound represented by the formula (1), and the temperature of the obtained reaction mixture is raised to 120 to 180 ° C. to distill allylic alcohol and water from the reaction mixture. By further reaction, the following formula (Π— 1)
[化 8]  [Chemical 8]
(Π-1)
Figure imgf000030_0003
(式中実線および点線力 なる結合は、単結合または二重結合を表す)で示される 2 ーァリルカルボニル化合物を得、次 、で 2—ァリルカルボ-ル化合物を酸化すること を特徴とする請求項 1記載の 2—ァリルカルボン酸化合物の製造方法。 (Π-1)
Figure imgf000030_0003
(Wherein the bond represented by the solid and dotted lines represents a single bond or a double bond), the 2-arylcarbonyl compound is obtained, and then the 2-arylcarbonyl compound is oxidized with Item 2. A method for producing a 2-arylcarboxylic acid compound according to Item 1.
[4] 下記式 (I 1)  [4] Formula (I 1)
[化 9]  [Chemical 9]
Figure imgf000031_0001
Figure imgf000031_0001
(式中実線および点線力 なる結合は、単結合または二重結合を表す)で示される化 合物を酸触媒およびァリルアルコールの存在下、 20〜120°Cで反応させることにより 、下記式 (IV) (The bond represented by the solid and dotted lines in the formula represents a single bond or a double bond) By reacting a compound represented by the following formula at 20 to 120 ° C in the presence of an acid catalyst and allylic alcohol, (IV)
[化 10]  [Chemical 10]
Figure imgf000031_0002
Figure imgf000031_0002
で示される 2—ァリルァセタールイ匕合物を含む反応混合物を得、得られた反応混合 物を 120〜 180°Cに昇温して、反応混合物からァリルアルコールおよび水を留出さ せながら更に反応させることを特徴とする請求項 2記載の 2—ァリルカルボ-ルイ匕合 物の製造方法。  To obtain a reaction mixture containing a 2-arlylacetal compound represented by the formula (1), and the temperature of the obtained reaction mixture is raised to 120 to 180 ° C. to distill allylic alcohol and water from the reaction mixture. 3. The method for producing a 2-aryl carbo-louie compound according to claim 2, wherein the reaction is further performed.
[5] 下記式 (I 2)  [5] The following formula (I 2)
[化 11]  [Chemical 11]
OR 1OR 1
Figure imgf000031_0003
(式中実線および点線力 なる結合は、単結合または二重結合を表し、 R1は炭素数 1〜6のアルキル基を表す）で示される化合物を酸触媒およびァリルアルコールの存 在下反応させることにより、下記式 (Π— 1)
Figure imgf000031_0003
(In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond, and R 1 represents an alkyl group having 1 to 6 carbon atoms.) A compound represented by the above is reacted in the presence of an acid catalyst and allylic alcohol. Therefore, the following formula (Π— 1)
[化 12] [Chemical 12]
Figure imgf000032_0001
Figure imgf000032_0001
(式中実線および点線力 なる結合は、単結合または二重結合を表す)で示される 2 ーァリルカルボニル化合物を得、次 、で 2—ァリルカルボ-ル化合物を酸化すること を特徴とする請求項 1記載の 2—ァリルカルボン酸化合物の製造方法。 (Wherein the bond represented by the solid and dotted lines represents a single bond or a double bond), the 2-arylcarbonyl compound is obtained, and then the 2-arylcarbonyl compound is oxidized with Item 2. A method for producing a 2-arylcarboxylic acid compound according to Item 1.
下記式 (I 2)  The following formula (I 2)
[化 13] [Chemical 13]
Figure imgf000032_0002
Figure imgf000032_0002
(式中実線および点線力 なる結合は、単結合または二重結合を表し、 R1は炭素数 1〜6のアルキル基を表す）で示される化合物を酸触媒およびァリルアルコールの存 在下反応させることを特徴とする請求項 2記載の 2—ァリルカルボ二ルイ匕合物の製造 方法。 (In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond, and R 1 represents an alkyl group having 1 to 6 carbon atoms.) A compound represented by the above is reacted in the presence of an acid catalyst and allylic alcohol. The method for producing a 2-aryl carbonate compound according to claim 2, wherein:
下記式 (I 3)  The following formula (I 3)
[化 14]
Figure imgf000033_0001
[Chemical 14]
Figure imgf000033_0001
(式中実線および点線力 なる結合は、単結合または二重結合を表し、 R1は炭素数 1〜6のアルキル基を表す）で示される化合物を酸触媒およびァリルアルコールの存 在下反応させることにより、下記式 (Π— 2) (In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond, and R 1 represents an alkyl group having 1 to 6 carbon atoms.) A compound represented by the above is reacted in the presence of an acid catalyst and allylic alcohol. Therefore, the following formula (Π— 2)
[化 15] [Chemical 15]
Figure imgf000033_0002
Figure imgf000033_0002
(式中実線および点線力もなる結合は、単結合または二重結合を表し、 R2は炭素数 1〜6のアルキル基またはァリル基を表す）で示される 2 ァリルカルボ-ル化合物を 得、次 、で 2—ァリルカルボ二ルイ匕合物を加水分解することを特徴とする請求項 1記 載の 2—ァリルカルボン酸化合物の製造方法。 (In the formula, a bond having a solid line and a dotted line force represents a single bond or a double bond, and R 2 represents an alkyl group or an aryl group having 1 to 6 carbon atoms). 2. The method for producing a 2-arylcarboxylic acid compound according to claim 1, wherein the 2-arylcarbonyl compound is hydrolyzed.
下記式 (I 3)  The following formula (I 3)
[化 16] [Chemical 16]
Figure imgf000033_0003
Figure imgf000033_0003
(式中実線および点線力 なる結合は、単結合または二重結合を表し、 R1は炭素数 1〜6のアルキル基を表す）で示される化合物を酸触媒およびァリルアルコールの存 在下反応させることを特徴とする請求項 2記載の 2—ァリルカルボ二ルイ匕合物の製造 方法。 (In the formula, a bond having a solid line and a dotted line represents a single bond or a double bond, and R 1 represents an alkyl group having 1 to 6 carbon atoms.) A compound represented by the above is reacted in the presence of an acid catalyst and allylic alcohol. 3. The production of a 2-aryl carbonate compound according to claim 2 Method.
下記式 (π  The following formula (π
[化 17]  [Chemical 17]
Figure imgf000034_0001
Figure imgf000034_0001
で示される 2 ァリル 7 オタテナ  2 Aryl 7 Otatena
[10] 下記式 (III 1)  [10] The following formula (III 1)
[化 18]  [Chemical 18]
Figure imgf000034_0002
Figure imgf000034_0002
で示される 2 ァリル 7 オタテン酸, 下記式 (IV— 1)  2-aryl-7 otatenic acid represented by the formula (IV— 1)
[化 19]  [Chemical 19]
Figure imgf000034_0003
で示される 1, 1ージァリルォキシ 7—オタテン,
Figure imgf000034_0003
1, 1-Dialyloxy 7-Otaten represented by
PCT/JP2006/300183 2005-01-13 2006-01-11 Method for producing 2-allylcarboxylic acid compound WO2006075596A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006552923A JPWO2006075596A1 (en) 2005-01-13 2006-01-11 Method for producing 2-allylcarboxylic acid compound

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP2005006705 2005-01-13
JP2005-006705 2005-01-13
JP2005-115025 2005-04-12
JP2005115025 2005-04-12
JP2005244028 2005-08-25
JP2005-244028 2005-08-25
JP2005295492 2005-10-07
JP2005-295492 2005-10-07

Publications (1)

Publication Number Publication Date
WO2006075596A1 true WO2006075596A1 (en) 2006-07-20

Family

ID=36677621

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/300183 WO2006075596A1 (en) 2005-01-13 2006-01-11 Method for producing 2-allylcarboxylic acid compound

Country Status (2)

Country Link
JP (1) JPWO2006075596A1 (en)
WO (1) WO2006075596A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675166A (en) * 2012-05-11 2012-09-19 山东齐都药业有限公司 New intermediate for preparing 2-propylheptylic acid and preparation method thereof, and preparation method of 2-propylheptylic acid
WO2012169475A1 (en) * 2011-06-08 2012-12-13 第一三共株式会社 Method for producing bicyclic compound via claisen rearrangement
JP2014208698A (en) * 2007-04-11 2014-11-06 第一三共株式会社 Method for producing neuraminic acid derivative

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3907718A (en) * 1974-07-22 1975-09-23 Int Flavors & Fragrances Inc 2-Methyl-4-pentenoic acid ester fragrance
US3976801A (en) * 1972-07-22 1976-08-24 International Flavors & Fragrances Inc. Flavoring compositions containing alkyl esters of 2-methyl-4-pentenoic acid
US4307252A (en) * 1978-10-13 1981-12-22 Ruhrchemie Aktiengesellschaft 2-Propyl-pent-4-en-1-al
JPH07316092A (en) * 1993-06-01 1995-12-05 Ono Pharmaceut Co Ltd Pentaenoic acid derivative, its production and medicine containing the same
WO1999058513A1 (en) * 1998-05-12 1999-11-18 Ono Pharmaceutical Co., Ltd. Novel intermediates and processes for the preparation of optically active octanoic acid derivatives
WO2000048982A1 (en) * 1999-02-18 2000-08-24 Ono Pharmaceutical Co., Ltd. Process for the preparation of (2r)-2-propyloctanoic acid

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976801A (en) * 1972-07-22 1976-08-24 International Flavors & Fragrances Inc. Flavoring compositions containing alkyl esters of 2-methyl-4-pentenoic acid
US3907718A (en) * 1974-07-22 1975-09-23 Int Flavors & Fragrances Inc 2-Methyl-4-pentenoic acid ester fragrance
US4307252A (en) * 1978-10-13 1981-12-22 Ruhrchemie Aktiengesellschaft 2-Propyl-pent-4-en-1-al
JPH07316092A (en) * 1993-06-01 1995-12-05 Ono Pharmaceut Co Ltd Pentaenoic acid derivative, its production and medicine containing the same
WO1999058513A1 (en) * 1998-05-12 1999-11-18 Ono Pharmaceutical Co., Ltd. Novel intermediates and processes for the preparation of optically active octanoic acid derivatives
WO2000048982A1 (en) * 1999-02-18 2000-08-24 Ono Pharmaceutical Co., Ltd. Process for the preparation of (2r)-2-propyloctanoic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KABUSHIKI KAISHA TOKYO KAGAKU DOJIN: "McMurry Yuki Kagaku (Chu),", KABUSHIKI KAISHA TOKYO KAGAKU DOJIN, XX, XX, no. ED. 4, 1 January 1998 (1998-01-01), XX, pages 747 - 749, XP002999580 *
TAMAO K. ET AL.: "Synthetic Applications of Functionalized Silyl Anions: Aminosilyl Anions as Hydroxy Anion Equivalent", TETRAHEDRON, vol. 52, no. 16, 1996, pages 5765 - 5772, XP004104143 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014208698A (en) * 2007-04-11 2014-11-06 第一三共株式会社 Method for producing neuraminic acid derivative
WO2012169475A1 (en) * 2011-06-08 2012-12-13 第一三共株式会社 Method for producing bicyclic compound via claisen rearrangement
EP2719677A4 (en) * 2011-06-08 2014-12-03 Daiichi Sankyo Co Ltd Method for producing bicyclic compound via claisen rearrangement
JPWO2012169475A1 (en) * 2011-06-08 2015-02-23 第一三共株式会社 Method for producing bicyclic compound by Claisen rearrangement reaction
US9162971B2 (en) 2011-06-08 2015-10-20 Daiichi Sankyo Company, Limited Methods for producing bicyclic compounds via claisen rearrangements
CN102675166A (en) * 2012-05-11 2012-09-19 山东齐都药业有限公司 New intermediate for preparing 2-propylheptylic acid and preparation method thereof, and preparation method of 2-propylheptylic acid
CN102675166B (en) * 2012-05-11 2014-03-26 山东齐都药业有限公司 New intermediate for preparing 2-propylheptylic acid and preparation method thereof, and preparation method of 2-propylheptylic acid

Also Published As

Publication number Publication date
JPWO2006075596A1 (en) 2008-06-12

Similar Documents

Publication Publication Date Title
US20100267988A1 (en) Processes for preparing intermediate compounds useful for the preparation of cinacalcet
WO2006075596A1 (en) Method for producing 2-allylcarboxylic acid compound
JP5211876B2 (en) Method for producing high purity 2&#39;-trifluoromethylpropiophenone
JP2011121951A (en) Process for producing tetrahydropyran-4-one and pyran-4-one
US8609886B2 (en) Method for producing high purity terminal olefin compound
EP1720851B1 (en) Process for synthesising heliotropine and its derivatives
JP3795970B2 (en) Method for producing α, β-unsaturated aldehyde
JP3229408B2 (en) Process for producing novel 4-amino-5-hexenoic acid
JP5115762B2 (en) Process for producing 4-formylpiperidine acetal derivative
JP4800933B2 (en) Process for producing cyclopropane monoacetal derivative and its intermediate
JP3477915B2 (en) Method for producing 1,6-dioxyiminohexane
JP2009155232A (en) Method for producing mixture of 2-(1-hydroxyalkyl)cycloalkanone and dehydrated material of the same
JP3357147B2 (en) Method for producing 5-phenylpentanoic acid
RU2612956C1 (en) Method for producing 1-adamantyl acetaldehyde
JP2000063373A (en) Production of 4-hydroxymethyl-gamma-butyro-lactone, intermediate useful for the production and production of the intermediate
JP2752489B2 (en) Novel macrocyclic compound and method for producing the same
JP2003113189A (en) Method for producing cyclopentabenzofuran derivative and novel compound to be raw material of the same
JPH0819045B2 (en) Process for producing 3-formyl-crotonic acid-alkyl ester
JP2002308815A (en) Method for manufacturing lavandulal
JPH11189566A (en) Production of fluoroalkylcarboxylic acid
JPH08333295A (en) Production of 6-methylheptan-2-one
JPH093025A (en) Production of 1,6-dioxyiminohexane
JP2002138087A (en) Sesamol formate and method for producing the same
JP2008150301A (en) Method for producing 4-hydroxymethyltetrahydropyran compound
JPH11152280A (en) Preparation of 3-methyl-4-hydroxy-2-butenolide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006552923

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06711532

Country of ref document: EP

Kind code of ref document: A1

WWW Wipo information: withdrawn in national office

Ref document number: 6711532

Country of ref document: EP