JPH07126217A - Method for producing 5-hydroxy-3-ketoester derivative - Google Patents

Abstract

(57) [Abstract] [Objective] Presence of a metal compound consisting of titanium or aluminum having a group represented by -OR ^2a (R ^2a represents a hydrocarbon group which may be substituted) of aldehydes and diketene. Provided is a method by which a 5-hydroxy-3-ketoester derivative can be easily obtained in a high yield by performing a reaction under the following conditions. [Structure] By reacting an aldehyde and a diketene in the presence of a metal compound consisting of titanium or aluminum having a group represented by -OR ^2a (R ^2a represents a hydrocarbon group which may be substituted), It relates to a method for producing a 5-hydroxy-3-ketoester derivative.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION Industrial field: 5-hydroxy-3
-A keto ester derivative, for example, a novel process for producing (E) -7- (2,4-dichlorophenyl) -5-hydroxy-3-oxo-6-heptenoic acid methyl ester. The above-mentioned 5-hydroxy-3-ketoester derivative is, for example, a drug, especially a blood cholesterol lowering agent [4-hydroxy-3-methylglutar (HMG) Co-A reductase inhibitor] [eg trans- 6- [2- (2,4-dichlorophenyl) ethyl] 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran
-2-one] is useful as an intermediate when synthesizing.

[0002]

2. Description of the Related Art Conventionally, as a method of reacting an aldehyde with a diketene to obtain a corresponding 5-hydroxy-3-ketoester derivative, there is the following method. Chemistry Letters, 1975
Pp. 161-164), there is a method for producing methyl 5-phenyl-5-hydroxy-3-oxopentanoate by reacting benzaldide and hydrdiketene as aldehydes with alcohol in the presence of titanium chloride. It is disclosed. This method is not industrially satisfactory in that it requires a low temperature of -78 ° C. Chemistry Express (Chemistry Express,
1991 (Vol. 6, No. 3, pages 193-196), benzaldide and diketene as aldehydes were reacted with methanol in the presence of trivalent samarium iodide to give 5-phenyl-5- A method of making methyl hydroxy-3-oxopentanoate is disclosed. This method is not industrially satisfactory in that it requires a low temperature of -45 ° C.

Therefore, all of the known manufacturing methods are 5-
The method for obtaining the hydroxy-3-ketoester derivative has been unsatisfactory.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made earnest studies to improve the above-mentioned problems in the known production method, and as a result, when aldehydes, diketene and a metal compound were reacted, The present invention has been completed by finding that a 5-hydroxy-3-ketoester derivative can be obtained without requiring a very low temperature.

Therefore, an object of the present invention is to provide a method for producing a 5-hydroxy-3-ketoester derivative by reacting an aldehyde, a diketene and a metal compound without requiring a low temperature of -45 ° C. And

[0006]

The present invention provides a compound represented by the general formula (I): R ¹ CHO (I) (wherein R ¹ is an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group). A group or a heterocyclic group), and the formula:

[0007]

[Chemical 3]

The diketene represented by the formula: is at least one group represented by the general formula (II): --OR ² (II) (wherein R ² represents an optionally substituted hydrocarbon group). By reacting in the presence of a metal compound composed of titanium or aluminum having the general formula (III):

[0009]

[Chemical 4]

(In the formula, R ¹ has the same meaning as described above, and R ^1
3 represents a hydrocarbon group which may be substituted) and a method for producing a 5-hydroxy-3-ketoester derivative.

R in the aldehydes represented by the general formula (I) used in the production method of the present invention and the 5-hydroxy-3-ketoester derivative represented by the general formula (III) which is the object compound of the production method of the present invention. ¹ is carbon number 1
To 12 alkyl groups, substituted alkyl groups having 1 to 12 carbon atoms, alkenyl groups having 2 to 12 carbon atoms, and substituted alkenyl groups having 2 to 12 carbon atoms, preferably 1 to 12 carbon atoms. 12 alkyl group, C1-C12 alkyl group substituted with an aromatic group, C2-C12
2 to 2 carbon atoms substituted with alkenyl groups and aromatic groups of
A alkenyl group having 12 carbon atoms is more preferable, and an alkenyl group having 2 to 12 carbon atoms substituted with a heterocyclic group (which may be condensed) is most preferable.

In the 5-hydroxy-3-ketoester derivative represented by the general formula (III), which is the target compound of the production method of the present invention, R ³ is an alkyl group having 1 to 12 carbon atoms or an ant having 6 to 15 carbon atoms. An aralkyl group having 7 to 20 carbon atoms or an aralkyl group having 6 to 15 carbon atoms having at least one substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms. It is preferably an aryl group or an aralkyl group having 7 to 20 carbon atoms.

In the metal compound having at least one group represented by the general formula (II) used in the production method of the present invention, R ² is an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 15 carbon atoms. Group, aralkyl group having 7 to 20 carbon atoms or halogen atom, cyano group, nitro group and 1 carbon atom
It is preferably an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms and having at least one substituent selected from the group consisting of alkyl groups having 6 to 6 carbon atoms.

The metal compound having at least one group represented by the general formula (II) used in the production method of the present invention is represented by the titanium compound represented by the general formula (IV) or the general formula (V). Aluminum compounds such as Ti (OR ^2a ) ₄ , Ti (OR ^2a ) ₃ A, Ti
(OR ^2a ) ₂ A ₂ , Al (OR ^2a ) ₃ , Al (OR ^2a )
Is preferably a metal compound represented by ₂ A, the metal compound is _{^{Ti (OR 2a) 4, Ti}} (OR 2a) 3 A,
The metal compound represented by Al (OR ^2a ) ₃ or Al (OR ^2a ) ₂ A is more preferable, and the metal compound is T
Most preferably, it is a metal compound represented by i (OR ^2a ) ₄ or Al (OR ^2a ) ₃ .

Ti (OR) having at least one group represented by the general formula (II) used in the production method of the present invention.
² ) R ² in the titanium compound represented by ₄ is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 15 carbon atoms,
C6 having at least one substituent selected from the group consisting of an aralkyl group having 7 to 20 carbon atoms or a halogen atom, a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms.
It is preferably an aryl group having from 15 to 15 or an aralkyl group having from 7 to 20 carbon atoms.

R ³ in the 5-hydroxy-3-ketoester derivative represented by the general formula (III), which is the target compound of the production method of the present invention, is the titanium compound represented by the general formula (IV) and the general formula (V It is preferable that R ^{2 s} in the aluminum compound represented by) are the same.

In the production method of the present invention, the reaction is carried out in the range of -30 to 3
It is preferably carried out in the temperature range of 0 ° C.

The production method of the present invention is, for example, a reaction formula (I) shown below.

[0019]

[Chemical 5]

It can be represented by

R ¹ in the aldehydes represented by the general formula (I) [hereinafter also referred to as compound (I)] used in the production method of the present invention is an optionally substituted alkyl group or an optionally substituted alkyl group. An alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, and an optionally substituted heterocyclic group (which may be condensed) are shown. Optionally substituted aryl group and optionally substituted heterocyclic group (which may be condensed)
Are sometimes together referred to as an aromatic group.

The optionally substituted aryl group represented by R ¹ in the compound (I) is an optionally substituted phenyl group or an optionally substituted naphthyl group. The optionally substituted phenyl group is an unsubstituted phenyl group or a substituted phenyl group.
Examples of the substituent of the substituted phenyl group include a halogen atom, an alkyl group having 1 to 10 carbon atoms, and 1 carbon atom.
Examples thereof include an alkoxy group having 10 to 10 alkyl groups, a nitro group, a cyano group, a phenyl group and the like, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,
Methyl group, ethyl group, propyl group (including each isomer),
A butyl group (including each isomer), a methoxy group, an ethoxy group, a propoxy group (including each isomer), a butoxy group (including each isomer), a nitro group, a cyano group, and a phenyl group. The number of substituents and the bonding position are arbitrary.

The optionally substituted naphthyl group represented by R ¹ in the compound (I) is an unsubstituted naphthyl group or a substituted naphthyl group. Examples of the substituent of the substituted naphthyl group include a halogen atom, an alkyl group having 1 to 10 carbon atoms and 1 to 10 carbon atoms.
Alkoxy groups, nitro groups, cyano groups, phenyl groups, etc., each having an alkyl group moiety are preferred, and fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, propyl group (each isomer Body), butyl group (including each isomer), pentyl group (including each isomer), methoxy group, ethoxy group, propoxy group (including each isomer), butoxy group (including each isomer) , A nitro group, a cyano group, and a phenyl group. The number of substituents and the bonding position are arbitrary.

An optionally substituted heterocyclic group represented by R ¹ in compound (I) (which may be condensed)
Is a heterocyclic group which is not substituted (which may be condensed) and a heterocyclic group which is substituted (which may be condensed). Examples of the unsubstituted heterocyclic group (which may be condensed) include furyl group (furyl group, benzofuryl group), thienyl group, pyrrolyl group, pyridyl group (pyridyl group, quinolyl group), pyrimidyl group, piperidyl group. , A morphonyl group, a thiazolyl group (thiazolyl group, benzothiazolyl group), an imidazolyl group, a heterocyclic group such as a triazolyl group (which may be condensed), and the like, and preferably a furyl group (which may be condensed) ), A thienyl group, a pyrrolyl group, a pyridyl group (which may be condensed), a pyrimidyl group, and a triazolyl group. The substituent of the optionally substituted heterocyclic group,
For example, a halogen atom, an alkyl group having 1 to 10 carbon atoms,
Examples thereof include an alkoxy group having a C 1-10 alkyl group moiety, a nitro group, a cyano group, and the like, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a propyl group ( (Including each isomer), butyl group (including each isomer), methoxy group, ethoxy group,
A propoxy group (including each isomer), a butoxy group (including each isomer), a nitro group, a cyano group, and a phenyl group.
The heterocyclic group of the optionally substituted heterocyclic group is the same as the above-mentioned "unsubstituted heterocyclic group (which may be substituted)". The number of substituents and the bonding position are arbitrary.

In R ¹ in the compound (I), the optionally substituted alkyl group is a cycloalkyl group,
It is a substituted alkyl group or an unsubstituted alkyl group. In R ¹ , an optionally substituted alkenyl group (in the present invention, the alkenyl group means an atomic group remaining after removing one hydrogen atom from the alkene group represented by C _n H _2n ) means It is an alkenyl group which is not substituted or an alkenyl group which is substituted. In R ¹ , an optionally substituted alkynyl group [in the present invention, an alkynyl group means an atomic group remaining after removing one hydrogen atom from the alkyne group represented by C _n H _2n-2 ]. , An unsubstituted alkynyl group and a substituted alkynyl group.

In R ¹ , the cycloalkyl group may be, for example, a cycloalkyl group having 3 to 10 carbon atoms, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, which is an unsubstituted alkyl group. Examples of the group include an alkyl group having 1 to 12 carbon atoms, preferably a methyl group, an ethyl group, a propyl group (including each isomer), and a butyl group (including each isomer), which are substituted. Not an alkenyl group,
Examples thereof include an alkenyl group having 2 to 12 carbon atoms, preferably a vinyl group, a propenyl group (including each isomer), a butenyl group (including each isomer), and an unsubstituted alkynyl group is Examples thereof include an alkynyl group having 2 to 12 carbon atoms, preferably an ethynyl group,
A propynyl group (including each isomer) and a butynyl group (including each isomer).

Examples of the substituent of the substituted alkyl group include an optionally substituted aromatic group and heterocyclic compound, and more specifically, the following can be shown.

Examples of the substituent of the substituted alkyl group include a phenyl group, 4-tolyl group, 4-chlorophenyl group, 4-methoxyphenyl group, 2,4-dichlorophenyl group and 3,5-dichloro-6 ( "Substituted phenyl group" such as 4-fluorophenyl) phenyl group and 2,4-dimethyl-6- (4-fluoro-3-methylphenyl) phenyl group,

Pyrrolyl group (non-fused pyrrolyl group) and 4- (4-fluorophenyl) -2-isopropyl
"Substituted pyrrolyl group (non-fused pyrrolyl group)" such as -1-phenyl-pyrrol-3-yl group,
Indolyl group (condensed pyrrolyl group) and 3-
(4-Fluorophenyl) -1-isopropylindole-2
-"Substituted indolyl group (condensed pyrrolyl group)" such as yl group, pyridyl group (non-fused pyridyl group) and 2-methyl-4-phenylpyridine
-3-yl group, 4- (4-fluorophenyl) -2-isopropyl-6-phenylpyridin-3-yl group, 2,5-diisopropyl-4- (4-fluorophenyl) pyridin-3-yl group, Five-
Benzyloxymethyl-2,6-diisopropyl-4- (4-fluorophenyl) pyridin-3-yl group, 2,6-diisopropyl-5-ethoxycarbonyl-4- (4-fluorophenyl) pyridin-3-yl group "Substituted pyridyl group (non-fused pyridyl group)", quinolyl group (fused pyridyl group) and 1- (4-fluorophenyl) -3-isopropyl-4-oxoquinoline-2 -Ile group,
2-cyclopropyl-4- (4-fluorophenyl) quinoline-3
-"Substituted quinolyl group (condensed pyridyl group)" such as yl group, pyrimidyl group and 4- (4-fluorophenyl) -6-isopropyl-2-phenylpyrimidin-5-yl group, 4 -(4-Fluorophenyl) -6-methyl
-2-Phenylpyrimidin-5-yl group, 2,4-dimethyl-6-
(4-Fluorophenyl) pyrimidin-5-yl group, 2- (N-
“Substituted pyrimidyl group” such as methyl-N-methanesulfonyl) amino-6- (4-fluorophenyl) -4-isopropylpyrimidin-5-yl group,

"Substituted pyrazolyl group" such as pyrazolyl group and 5- (4-fluorophenyl) -3-isopropyl-1-phenylpyrazol-4-yl group, pyridazyl group and 3,4-bis ( "Substituted pyridazyl group" such as 4-fluorophenyl) -6-isopropylpyridazin-5-yl group, imidazolyl group and 1- (4-fluorophenyl) -4-isopropyl-2-phenyl-1H-imidazo “Substituted imidazolyl group” such as -l-5-yl group, imidazolin-2-one group and 4- (4-fluorophenyl) -1-methyl-3-phenylimidazoline-2-
“Substituted imidazolines such as on-5-yl groups
-2-one group ”, furyl group, thiophene group and the like.

The substituents of the substituted alkenyl group and alkynyl group are not limited to these, and in addition to the above-mentioned substituents, for example, vinyl group and 1-phenylethenyl group, 2,2-diphenyl group. Ethenyl group, 1-isopropyl-2,2-bis (4-fluorophenyl) ethenyl group, 1-
(1-Methyl-1H-tetrazol-5-yl) -2,2-bis (4-fluorophenyl) ethenyl group such as "substituted vinyl group", ethynyl group and phenylethynyl group, 4- Examples thereof include "substituted ethynyl group" such as chlorophenylethynyl group and 4-methoxyphenylethynyl group. The alkyl group of the substituted alkyl group, the alkenyl group of the substituted alkenyl group, and the alkynyl group of the substituted alkynyl group are the same as above. The number of substituents and the bonding position are arbitrary.

The above-mentioned substituted alkyl group, substituted alkenyl group and substituted alkynyl group are preferably the following groups. Such groups include "alkyl groups having a phenyl group as a substituent" such as benzyl group, phenethyl group, 3-phenylpropyl group and 4-phenylbutyl group, "phenyl group such as styryl group and cinnamyl group". Alkenyl group having a substituent ”, 2- (4-tolyl) ethenyl group, 2- (2,4-dichlorophenyl) ethenyl group, 2- (4-chlorophenyl) ethenyl group, 2- (4-methoxyphenyl) ethenyl group , 2- [3,5-dichloro-6- (4-fluorophenyl) phenyl] ethenyl group, 2- [2,4-dimethyl-6- (4-fluoro-3-methylphenyl) phenyl] ethenyl group "Alkenyl group having a substituted phenyl group as a substituent", phenylethynyl group, 3-phenyl-2-propynyl group, 4-phenyl-3
-"Alkynyl group having a phenyl group as a substituent" such as butyn-1-yl group,

2- (indole-2-yl) ethenyl group and
"Alkenyl group having" substituted indolyl group (condensed pyrrolyl group) as a substituent "such as 2- [3- (4-fluorophenyl) -1-isopropylindol-2-yl] ethenyl group ], 2- (pyridin-3-yl) ethenyl group and 2- [2-methyl-4-phenylpyridin-3-yl]
Ethenyl group, 2- [4- (4-fluorophenyl) -2-isopropyl-6-phenylpyridin-3-yl] ethenyl group, 2-
[2,5-diisopropyl-4- (4-fluorophenyl) pyridin-3-yl] ethenyl group, 2- [5-benzyloxymethyl
-2,6-Diisopropyl-4- (4-fluorophenyl) pyridin-3-yl] ethenyl group, 2- [2,6-diisopropyl-5-
Ethoxycarbonyl-4- (4-fluorophenyl) pyridine
-3-yl] ethenyl group "alkenyl group having a substituted pyridyl group (non-fused pyridyl group) as a substituent", 2- (quinolin-3-yl) ethenyl group, 2- (quinoline -2-yl) ethenyl group and 2- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] ethenyl group, 2- [3-cyclopropyl-1- (4-fluorophenyl)- "Alkoxy group having a substituted quinolyl group (condensed pyridyl group) as a substituent" such as 4-oxoquinolin-2-yl] ethenyl group, 2- (pyrimidin-5-yl) ethenyl group and 2- [4- (4-fluorophenyl) -6-isopropyl-2-phenylpyrimidine-5-
Il] ethenyl group, 2- [4- (4-fluorophenyl) -6-
Methyl-2-phenylpyrimidin-5-yl] ethenyl group, 2- [2,4-dimethyl-6- (4-fluorophenyl) pyrimidin-5-yl] ethenyl group, 2- [2- (N-methyl- N-
Methanesulfonyl) amino-6- (4-fluorophenyl) -4
-Isopropylpyrimidin-5-yl] ethenyl group such as "alkenyl group having a substituted pyrimidyl group as a substituent",

"Substituted pyridazyl, such as 2- (pyridazin-5-yl) ethenyl and 2- [3,4-bis (4-fluorophenyl) -6-isopropylpyridazin-5-yl] ethenyl. Having an alkenyl group as a substituent ”, 2- (imidazol-5-yl) ethenyl group and 2-
[Alkenyl group having a substituted imidazolyl group as a substituent] such as [1- (4-fluorophenyl) -4-isopropyl-2-phenyl-1H-imidazol-5-yl] ethenyl group, 2 -(Pyrrol-3-yl) ethenyl group and 2- [4- (4-fluorophenyl) -2-isopropyl-1-
"Alkenyl group having a substituted pyrrolyl group as a substituent" such as phenylpyrrol-3-yl] ethenyl group, 2- (imidazolin-2-on-5-yl) ethenyl group and 2- [4- (4-Fluorophenyl) -1-methyl-3-phenylimidazol-2-one-5-yl] ethenyl group such as "alkenyl group having a substituted imidazolin-2-one group as a substituent" , 2- (furan-2-yl) ethenyl group and 2- (thiophen-2-yl) ethenyl group, 2-
(Pyrazol-4-yl) ethenyl group, 2- [5- (4-fluorophenyl) -3-isopropyl-1-phenylpyrazole
-4-yl] ethenyl group.

Of the above-mentioned substituted alkyl group, substituted alkenyl group and substituted alkynyl group, the following groups are specifically preferred. (A) 3-
"Alkyl group having a substituted phenyl group as a substituent" such as phenylpropyl group, (B) styryl group,
"Alkenyl group having a phenyl group as a substituent" such as cinnamyl group, 2- (4-tolyl) ethenyl group, 2- (4-chlorophenyl) ethenyl group, 2- (4-methoxyphenyl)
Ethenyl group, 2- [3,5-dichloro-6- (4-fluorophenyl) phenyl] ethenyl group, 2- [2,4 dimethyl-6- (4-fluoro-3-methylphenyl) phenyl] ethenyl group Such as "alkenyl group having a substituted phenyl group as a substituent", (C) 2- (pyridin-3-yl) ethenyl group and 2- (2-methyl-4-phenylpyridin-3-yl) ethenyl group Group, 2- [4- (4-fluorophenyl) -2-isopropyl-6-phenylpyridin-3-yl] ethenyl group, 2- [2,4
-Diisopropyl-4- (4-fluorophenyl) pyridine-3-
Il] ethenyl group, 2- [5-benzyloxymethyl-2,6-
Diisopropyl-4- (4-fluorophenyl) pyridine-3-
Ile] ethenyl group, 2- [2,6-diisopropyl-5-ethoxycarbonyl-4- (4-fluorophenyl) pyridine-3-
“Alkyl group having a substituted pyridyl group (non-condensed pyridyl group) as a substituent” such as an yl] ethenyl group, and further (D) 2- (quinolin-3-yl) ethenyl group, 2- ( Quinolin-2-yl) ethenyl group and 2- [2-
Cyclopropyl-4- (4-fluorophenyl) quinoline-3
-Yl] ethenyl group, 2- [3-cyclopropyl-1- (4-fluorophenyl) -4-oxoquinolin-2-yl] ethenyl group such as "substituted quinolyl group (condensed pyridyl Group) as a substituent.

The following aldehydes are suitable as the aldehydes represented by the general formula (I) used in the production method of the present invention. (1) Benzaldehyde, 4-methylbenzaldehyde, 4-
"Aldehyde having an aldehyde group directly bonded to a carbon atom forming an optionally substituted benzene ring" such as methoxybenzaldehyde and 2,4-dichlorobenzaldehyde. (2) "Aldehyde in which an aldehyde group is indirectly bonded via an alkyl group to an atom forming an optionally substituted benzene ring" such as 3-phenylpropanal. (3) (E)-"Aldehyde having an aldehyde group directly bonded to an alkenyl group" such as crotonaldehyde, methacrylaldehyde, and tiglic aldehyde. (4) "Aldehyde having an aldehyde group directly bonded to an alkyl group" such as n-butanal and trimethylacetaldehyde. (5) "Aldehyde having an aldehyde group directly bonded to a heterocycle" such as 2-thiophene aldehyde and 2-furan aldehyde. (6) Cinnamaldehyde, 3- (2,4-dichlorophenyl)
"Aldehyde in which an aldehyde group is indirectly bonded to an atom forming an optionally substituted benzene ring via an alkenylene group" such as prop-2-en-1-aryl. (7) An alkenylene group is used as an atom constituting an “optionally substituted pyridine ring (unfused pyridyl ring)” such as 3- (pyridin-3-yl) prop-2-en-1-al. Aldehyde having an aldehyde group indirectly bound via the ‘ (8) An alkenylene group is used as an atom forming an “optionally substituted quinoline ring (condensed pyridyl ring)” such as 3- (quinolin-3-yl) prop-2-en-1-aryl. Aldehyde having an aldehyde group indirectly bound via the ‘ (9) "Aldehyde in which an aldehyde group is directly bonded to an atom constituting a cycloalkyl ring" such as cyclohexanecarboxaldehyde.

Examples of the aldehydes represented by the general formula (I) used in the production method of the present invention include (E) -3- [2-
Cyclopropyl-4- (4-fluorophenyl) -quinoline-3-
Il] prop-2-en-1-al is disclosed in JP-A-1-2798.
It can be produced according to the method described in Japanese Patent Publication No. 66.

In the production method of the present invention, the metal compound made of titanium or aluminum having at least one —OR ² group represented by the general formula (II) has the general formula (IV) Ti (OR ² ) _m A _4-m. (IV) (however, A and R ² have the same meanings as described above) [hereinafter also referred to as metal compound (IV)] or general formula (V) Al (OR ² ) _n A _3-n (V) A metal compound represented by (where A and R ² have the same meanings as described above) [hereinafter also referred to as a metal compound (V)].

The metal compound represented by the general formula (IV) (I
The optionally substituted hydrocarbon group represented by R ² in V) is at least one selected from the group consisting of an alkyl group, an optionally substituted aryl group and an optionally substituted aralkyl group. Indicates a group

The metal compound represented by the general formula (IV) (I
Examples of the alkyl group represented by R ² in V) include a linear or branched alkyl group having 1 to 12 carbon atoms, preferably a methyl group, an ethyl group, a propyl group (each isomer is Included), a butyl group (including each isomer), and a pentyl group (including each isomer). The optionally substituted aryl group represented by R ² in the metal compound (IV) represented by the general formula (IV) is an unsubstituted aryl group or a substituted aryl group. . Examples of the “unsubstituted aryl group represented by R ² ” in the metal compound (IV) include aryl groups having 6 to 15 carbon atoms, such as a phenyl group and a naphthalene group. Group is preferred, and phenyl group is more preferred. Examples of the aryl group of the “substituted aryl group represented by R ² ” in the metal compound (IV) include the above aryl groups, and the substituted aryl group represented by R ² Examples of the substituent of "ru group" include a halogen atom, a cyano group, a nitro group, and an alkyl group having 1 to 6 carbon atoms.

The metal compound represented by the general formula (IV) (I
The optionally substituted aralkyl group represented by R ² in V) is an unsubstituted aralkyl group or a substituted aralkyl group. The “unsubstituted aralkyl group represented by R ² ” in the metal compound (IV) is, for example, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group or the like having 7 to 2 carbon atoms.
An aralkyl group of 0 can be mentioned, and a benzyl group is preferable. Examples of the aralkyl group of the “substituted aralkyl group represented by R ² ” in the metal compound (IV) include the above aralkyl groups, and the substituent of the “substituted aralkyl group represented by R ² ” is Examples thereof include a halogen atom, a cyano group, a nitro group, and an alkyl group having 1 to 6 carbon atoms.

The metal compound represented by the general formula (IV) (I
A in V) represents a halogen atom. Examples of the halogen atom represented by A in the metal compound (V) include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferable.

Metal compound (I) represented by compound (IV)
N in V) represents an integer of 1, 2, 3 or 4, preferably 2, 3 or 4, more preferably 3 or 4, and most preferably 4.

The metal compound (IV) having R ² and A is titanium tetraethoxide or titanium tetran.
-Propoxide, titanium tetraisopropoxide,
Preference is given to titanium tetraalkoxides such as titanium n-butoxide, titanium tetra n-pentoxide and titanium haloalkoxides such as titanium halotrioxide, and the abovementioned titanium tetraalkoxides are more preferred. Such a metal compound (IV), for example, titanium monochlorotriisopropoxide is prepared according to the method described in Chemische Berichte (Vol. 118, No. 4, 1421-1440, 1985). it can.

Alternatively, R ² and A in the metal compound represented by the general formula (V) [hereinafter also referred to as compound (V)] have the same meanings as described above. N in the compound (V) is 1,
It represents an integer of 2 or 3, preferably 2 or 3, and more preferably 3.

The metal compound (V) having R ² and A is preferably an aluminum haloalkoxide such as aluminum trialkoxide and aluminum monohalodiaalkoxide, and aluminum triisopropoxide and aluminum monologide. Isopropoxide is more preferred.

Such metal compound (V), for example, aluminum monochlorodiisopropoxide can be produced by the following method. In a methylene chloride solution of diethylaluminum chloride in the presence of argon gas,
The cooled isopropanol is added to obtain a mixed solution.
The resulting mixed solution is warmed to room temperature and stirred for 1 hour to produce aluminum monochlorodipropoxide. The reaction solution containing aluminum monochlorodiisopropoxide can be directly used in the production method of the present invention.

The target compound produced by the production method of the present invention, 5-hydroxy-3-, represented by the general formula (III)
In the keto ester derivative, R ¹ has the same meaning as described above. R ³ may represent at least one group selected from the group consisting of an alkyl group having the same meaning as R ² , an optionally substituted aryl group and an optionally substituted aralkyl group, and R ³ And R ² are preferably the same group. Such R ^1, has a R ³ "formulas (I
The “5-hydroxy-3-ketoester derivative represented by II)” may be determined by the aldehydes which are the starting materials and the metal compound (IV) [or metal compound (V)]. In addition, the 5-hydroxy-3-ketoester derivative represented by the general formula (III) includes a keto form and an eno-form.
Although there are tautomeric isomers in the process of the present invention,
The 5-hydroxy-3-ketoester derivative is a keto form, an eno-
It may be any of the two types.

In the present invention, the order of addition of aldehydes, metal compound (IV) [or metal compound (V)] and diketene to the reaction system may be arbitrary. Further, the aldehydes, metal compound (IV) [or metal compound (V)] and diketene may be dissolved in a solvent described below and added to the reaction system.

The amount of diketene used in the present invention is usually 0.5 to 1 mol per mol of aldehydes.
The amount may be 4.0 mol, and is about 0.7 to
The amount of 3.0 mol is preferable, and 0.8 to 2.5.
More preferably, the amount is a molar ratio.

The metal compound (I used in the present invention
V) [or metal compound (V)] may be used in an amount such that the amount used is usually 0.5 to 4.0 mol per 1 mol of aldehydes, and about 0.7 to 3. The amount of 0 mol is preferable, and the amount of 0.8 to 2.5 mol is more preferable.

In the present invention, diketene is a liquid substance, and when an aldehyde or a metal compound (IV) [or compound (V)] is a liquid substance, an organic solvent is particularly required to carry out the reaction. However, the reaction can also be performed using an organic solvent. When the aldehyde or the metal compound (IV) [or the compound (V)] is not a liquid substance, it may be dissolved in a solvent and added to the reaction. The solvent used in the present invention is not particularly limited as long as it does not participate in the reaction, for example, methylene chloride, a halogen-based solvent such as chloroform, an aromatic solvent such as benzene, toluene, xylene, pentane, hexane, heptane, etc. Aliphatic hydrocarbon solvents, diethyl ether, diisopropyl ether, ether type solvents such as tetrahydrofuran,
Examples thereof include nitrile solvents such as acetonitrile and propionitrile.

In the present invention, the organic solvent may be used in an amount of 0.01 to 100% (weight ratio) with respect to 1 mol of aldehydes, and 0.1 to 50% (weight ratio). ) Is preferable, and an amount of 1 to 20% (weight ratio) is more preferable.

In the present invention, the reaction temperature varies depending on the amount and type of solvent used, but may be -50 ° C to 50 ° C, preferably -30 ° C to 30 ° C, and -25 ° C to 25 ° C.
C is even more preferred.

In the production method of the present invention, the method of obtaining the target compound from the reaction mixture containing the 5-hydroxy-3-ketoester derivative thus formed may be carried out by combining ordinary washing operation and separation operation. After adding a dilute acid aqueous solution and stirring, extraction, washing and drying operations are preferably performed to obtain the target compound by a method such as silica gel column chromatography or distillation operation.

In the isolation operation, the acid used is
Examples thereof include inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, and hydrochloric acid is preferable. The concentration of the acid used is not particularly limited, but a concentration of 0.05N to 10N is preferable, a concentration of 0.1N to 10N is preferable, and a concentration of 0.3 to 2.
A concentration of 0N is more preferred. The amount of these acids used (volume ratio) with respect to the reaction mixture varies depending on the concentration and type of the acid. For example, when 1N-hydrochloric acid is used,
The amount of 0.5 times to 20 times (volume ratio) is good and 0.7 times to
The amount is preferably 10 times (volume ratio).

[0057]

According to the present invention, the aldehydes of the general formula (I), the metal compound (V) of the general formula (V) or the metal compound (IV) of the general formula (IV) are reacted with diketene. Thus, the target compound, a 5-hydroxy-3-ketoester derivative, can be easily obtained without requiring a very low temperature of -78 ° C.

[0058]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto.

Example 1 10 ml of methylene chloride and 2.8 ml (9.43 mmol) of titanium tetraisopropoxide were added to a Schlenk tube in which argon gas was passed, and the mixture was cooled to 0 ° C. with stirring and mixing. 0.96 ml (9.42 ml) of benzaldehyde was added to the methylene chloride solution.
mmol), 1.5 ml of diketene (18.8 m
mol) was added and the reaction was carried out by vigorously stirring for 25 hours while maintaining 0 ° C. The obtained reaction mixture was added to a mixed solution of 1N-hydrochloric acid 50 ml + diethyl ether 50 ml and vigorously stirred at room temperature for 24 hours to obtain a separating solution. 50 ml of diethyl ether was added to the obtained separating solution, and the organic layer was separated after stirring (the same operation was repeated 3 times using fresh diethyl ether each time). The obtained organic layer was washed twice with 50 ml of a saturated sodium hydrogen carbonate aqueous solution and further twice with 50 ml of a saturated saline solution to obtain a washed organic layer. Anhydrous sodium sulfate was added to the obtained washed organic layer for drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give isopropyl. 5-hydroxy-3-oxo-5-phenylpentanoate 1.74
g was obtained. (Yield to benzaldehyde: 74%)

Physical property values IR ν _Max (neat): 3508 cm ^-1 , 2984
^{cm -1, 2936cm -1, 1746cm -1} , 1646c
m ^-1 , 1314 cm ^-1 , 1106 cm ^-1 . ¹ H-NMR (CDCl ₃ , 250 MHz) δ: 1.26 (d, J = 6.7 Hz, 6 H), 2.4
(Brs, 1H), 2.94 (d, J = 3.7Hz, 1
H), 2.97 (d, J = 9.2 Hz, 1H), 3.4
6 (s, 2H), 5.0 to 5.1 (m, 1H), 5.2
(Dd, J = 3.7 Hz, 9.2 Hz, 1H), 7.3
~ 7.4 (m, 5H).

Example 2 50 ml of methylene chloride and 25.8 g (0.091 mol) of titanium tetraisopropoxide were added to a Schlenk tube in which argon gas was passed, and the mixture was cooled to 0 ° C. with stirring and mixing. 10 g (0.076 mo) of (E) -cinnamaldehyde in the methylene chloride solution.
1) and 13.2 g (0.152 mol) of diketene were added, and the mixture was reacted by vigorously stirring for 25 hours while maintaining 0 ° C. The obtained reaction mixture was added to a mixed solution of 1N-hydrochloric acid 250 ml + diethyl ether 250 ml and vigorously stirred at room temperature for 15 hours to obtain a separating solution. Diethyl ether 25 was added to the obtained separating solution.
0 ml was added, and the organic layer was separated after stirring (1
The operation was repeated 3 times using fresh diethyl ether each time). The obtained organic layer was washed twice with 50 ml of a saturated sodium hydrogen carbonate aqueous solution and further twice with 50 ml of a saturated saline solution to obtain a washed organic layer. Anhydrous sodium sulfate was added to the obtained washed organic layer for drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give isopropyl. 5-hydroxy
18.5 g of 3-oxo-7-phenylheptenoate was obtained. [Yield based on (E) -cinnamaldehyde: 89
%]

Physical property values IR ν _Max (neat): 3472 cm ^-1 , 2984
^{cm -1, 2936cm -1, 1716cm -1} , 1314c
m ^-1 , 1106 cm ^-1 . ¹ H-NMR (CDCl ₃ , 250 MHz) δ: 1.16 (d, J = 6.1 Hz, 6 H), 2.4
(Brs, 1H), 2.75 (s, 1H), 2.77
(S, 1H), 3.37 (s, 2H), 4.69 (d
d, J = 6.1 Hz, 1.2 Hz, 1H), 4.97
(Sept, J = 6.1 Hz, 1H), 6.1 (dd,
J = 16.5 Hz, 6.1 Hz, 1H), 6.55 (d
d, J = 16.5 Hz, 1.2 Hz, 1 H), 7.1-
7.3 (m, 5H).

Example 3 10 ml of methylene chloride and 4.34 ml of isopropyl alcohol (56.52 mmo) were placed in a Schlenk tube cooled to 0 ° C., which was ventilated with argon gas.
1) and 2.38 ml (9.42 mmol) of aluminum triisobutyl were added, and the mixture was stirred for 1 hour while maintaining 0 ° C. To the methylene chloride solution, 1.92 ml (18.84 mmol) of benzaldehyde and 1.5 ml (18.84 mmol) of diketene were added, and the mixture was vigorously stirred and reacted for 24 hours while maintaining 0 ° C. The obtained reaction mixture was added to a mixed solution of 1 N-hydrochloric acid 50 ml + diethyl ether 50 ml and vigorously stirred for 1 hour while maintaining 0 ° C. to obtain a separating solution. 50 ml of diethyl ether was added to the obtained separating solution, and the organic layer was separated after stirring (the same operation was repeated 3 times using fresh diethyl ether each time). The obtained organic layer was washed 3 times with 50 ml of a saturated saline solution to obtain a washed organic layer. Anhydrous sodium sulfate was added to the obtained washed organic layer for drying, the solvent was distilled off under reduced pressure, and silica gel column chromatography (eluting solvent; hexane: ethyl acetate = 5:
Purification in 1) yielded 1.2 g of isopropyl 5-hydroxy-3-oxo-5-phenylpentanoate. [Yield to benzaldehyde: 55%]

Example 4 10 ml of methylene chloride and 1.92 g (7.5 mmol) of titanium monochlorotriisopropoxide were added to a Schlenk tube in which argon gas was passed.
It cooled to 0 degreeC, stirring and mixing, and the methylene chloride solution was obtained. In the methylene chloride solution, 0.99 g (7.5 mmol) of (E) -cinnamaldehyde and 1.16 of diketene.
Milliliter (15 mmol) was added, and the mixture was vigorously stirred for 21 hours while keeping it at 0 ° C. for reaction. 0.6 ml of isopropanol was added to the obtained reaction mixture,
After stirring vigorously for 1 hour while maintaining at 0 ° C, 1N-
The solution was added to a mixed solution of 50 ml of hydrochloric acid + 50 ml of methylene chloride and vigorously stirred at room temperature for 2 hours to obtain a separating solution. Methylene chloride was added to the obtained separating solution.
After adding milliliter and stirring, a separating operation was performed to separate an organic layer (three times in total using 10 ml of fresh methylene chloride each time). Anhydrous magnesium sulfate was added to the organic layers after the separated organic layers were combined and dried, and then the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 7:
3) Purified with isopropyl E-5-hydroxy-3-
0.64 g of oxo-7-phenyl-6-heptenoate was obtained. [Yield based on (E) -cinnamaldehyde: 31
%]

Reference Example 1 Titanium monochlorotriisopropoxide was obtained by Chemische Berichte (Vol. 118, Vol. 4).
No., 1421-1440, 1985), and was synthesized as follows. 34.5 g (0.12 mol) of titanium tetraisopropoxide was added into a round bottom flask in which argon gas was bubbled, and the mixture was cooled to 0 ° C. While vigorously stirring, 4.4 ml (0.04 mol) of titanium tetrachloride was added dropwise over 5 minutes, and after completion of the addition, the mixture was further stirred at room temperature for 1 hour for reaction. The obtained reaction mixture was purified by vacuum distillation to obtain titanium monochlorotriisopropoxide (40 g, 0.15 mo) as a fraction of 96-97 ° C / 3 mmHg.
l) was obtained.

Example 5 10 ml of methylene chloride and 2.5 ml (5 mmol) of a 2M-titanium dichlorodiisopropoxide solution in methylene chloride were added to a Schlenk tube in which argon gas was passed, and the mixture was stirred and mixed. While -25
Cooling to 0 ° C. gave a methylene chloride solution. 0.656 g of (E) -cinnamaldehyde in the methylene chloride solution
(5 mmol), 0.77 ml of diketene (10
mmol) was added, and the mixture was reacted by vigorously stirring for 69 hours while maintaining -25 ° C. 1.5 ml of isopropanol was added to the obtained reaction mixture, and the mixture was vigorously stirred for another 1 hour while maintaining the temperature at -25 ° C, and then added to a mixed solution of 25 ml of 1N-hydrochloric acid and 25 ml of methylene chloride at room temperature. Vigorous stirring for 2 hours gave a separating solution. 5 ml of methylene chloride was added to the obtained separating solution, and the mixture was stirred and then separated to separate the organic layer (a new methylene chloride of 5 ml was used for each time, a total of 3 times). To the organic layers after the separated organic layers were combined, anhydrous magnesium sulfate was added and dried, and then the solvent was distilled off under reduced pressure, followed by silica gel column chromatography.
Purification with (eluting solvent: hexane: ethyl acetate = 7: 3) gave 0.188 g of isopropyl E-5-hydroxy-3-oxo-7-phenyl-6-heptenoate.
[Yield to (E) -cinnamaldehyde: 14%]

Reference Example 2 Titanium dichlorodiisopropoxide is described in JP-A 2-4.
It was synthesized as follows according to the method described in Japanese Patent No. 0344. Hexane 5 ml and titanium tetraisopropoxide 3 ml (10 mmol) were added to a round bottom flask in which argon gas was aerated, and titanium tetrachloride 1.1 ml (10 mmol) was added with vigorous stirring to react. Let The reaction mixture was vigorously stirred at room temperature for 10 minutes, cooled to 0 ° C. and allowed to stand for 10 minutes to obtain a mixture containing white crystals. The solution was extracted from the obtained mixture with a syringe to obtain crude crystals. 5 ml of fresh hexane was added to the obtained crude crystals, and the mixture was vigorously stirred at room temperature for 10 minutes,
The mixture was cooled to 0 ° C. and allowed to stand for 10 minutes to precipitate white crystals, and the solution was extracted with a syringe to obtain crude crystals. This operation was repeated once more to obtain a purified crystal. The obtained purified crystals were dried under reduced pressure to obtain 3.66 g (15 mmol) of titanium dichlorodiisopropoxide.

Example 6 10 ml of methylene chloride and 5.0 ml (5 mmol) of a 1M-titanium trichloromonoisopropoxide solution in methylene chloride were added to a Schlenk tube in which argon gas was passed, and the mixture was stirred and mixed. While-
Cooling to 30 ° C. gave a methylene chloride solution. 0.677 of (E) -cinnamaldehyde in the methylene chloride solution
g (5.1 mmol) and 0.77 ml (10 mmol) of diketene were added, and the mixture was vigorously stirred for 1 hour while maintaining -30 ° C to react. 1.5 ml of isopropanol was added to the obtained reaction mixture, and the mixture was cooled to -30 ° C.
The mixture was vigorously stirred for 40 minutes while maintaining the above temperature, added to a mixed solution of 25 ml of 1N hydrochloric acid + 25 ml of methylene chloride, and stirred vigorously at room temperature for 2 hours to obtain a separating solution. 5 ml of methylene chloride was added to the obtained separating solution, and the mixture was stirred and then separated to separate the organic layer (a new methylene chloride of 5 ml was used for each time, a total of 3 times). After the separated organic layers were combined, the organic layers were combined with anhydrous magnesium sulfate and dried,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 7: 3) to give isopropyl E-5-hydroxy-3-oxo.
0.31 g of -7-phenyl-6-heptenoate was obtained.
[Yield based on (E) -cinnamaldehyde: 22%]

Reference Example 3 Titanium trichloromonoisopropoxide was synthesized as follows. Hexane 5 ml and titanium tetraisopropoxide 1.5 ml (5 mmol) were added into a round bottom flask in which argon gas was aerated, and titanium tetrachloride 1.
65 ml (15 mmol) was added and reacted. The reaction mixture was vigorously stirred at room temperature for 10 minutes, cooled to 0 ° C. and allowed to stand for 10 minutes to obtain a mixture containing white crystals. The solution was extracted from the obtained mixture with a syringe to obtain crude crystals. To the obtained crude crystals, 5 ml of fresh hexane was added, and the mixture was vigorously stirred at room temperature for 10 minutes, cooled to 0 ° C., and allowed to stand for 10 minutes to precipitate white crystals. Obtained.
This operation was repeated once more to obtain a purified crystal. The obtained purified crystal was dried under reduced pressure to obtain 3.89 g (18 mmol) of titanium trichloromonoisopropoxide. ¹ H
-The results of NMR measurements are based on Organo Metallics (Organo
metallics, Volume 10, Pages 205-2025, 199.
1 year).

Example 7 A solution prepared by dissolving 0.6 g (5 mmol) of diethylaluminum chloride in 5 ml of methylene chloride was added to a Schlenk tube through which argon gas was passed, and isopropanol (0.1%) was cooled to 0 ° C. 77 ml was added to obtain a mixture 1. The resulting mixture 1 was warmed to room temperature, stirred for 1 hour to complete the reaction, and then cooled to 0 ° C., then 1.0 ml (9.8 mmol) of benzaldehyde and 1.52 ml (19.6 mmol) of diketene. ) And were added and reacted at 0 ° C. for 24 hours with stirring. The obtained reaction mixture was added to a solution of 50 ml of 1N hydrochloric acid + 50 ml of ether while maintaining 0 ° C. to obtain a separating solution. 100 ml of dimethyl ether was added to the obtained separating solution, and the mixture was stirred and separated to separate the ether layer (each time, 100 ml of new ether was used for a total of 3 times). . Anhydrous magnesium sulfate was added to the ether layers after the separated ether layers were combined and dried, and then the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 7). :
3) Purified with isopropyl 5-hydroxy-3-oxo
1.1 g of -5-phenylpentanoate was obtained. [Yield to benzaldehyde: 45%]

Comparative Example 1 0.55 ml (5 mmol) of titanium tetrachloride was placed in a Schlenk tube in which argon gas was passed.
And methylene chloride (9 ml) were added, and the mixture was stirred and cooled to 0 ° C. to obtain a methylene chloride solution. (E) -Cinnamaldehyde in the resulting methylene chloride solution 0.6
8 g (5.2 mmol) and 0.77 ml (10 mmol) of diketene were added, and the temperature was kept at 0 ° C. to 30
The reaction was carried out by vigorously stirring for a minute. 2 ml of isopropanol was added to the obtained reaction mixture, and the mixture was vigorously stirred for 30 minutes while maintaining 0 ° C. to obtain an isopropanol solution. The resulting isopropanol solution was added to a mixed solution of 1N-hydrochloric acid 25 ml + methylene chloride 25 ml and vigorously stirred at room temperature for 30 minutes to obtain a separating solution. 5 ml of methylene chloride was added to the obtained separation solution, and the organic layer was separated after stirring (1
Use 5 ml of fresh methylene chloride each time,
The same operation was repeated 3 times. ). After the obtained organic layers were combined, anhydrous magnesium sulfate was added to the organic layers for drying, and then the solvent was distilled off under reduced pressure to obtain a concentrate. The obtained concentrate was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 7: 3), and isopropyl E-5-based on the knowledge obtained in Example 6 was purified.
An elution fraction corresponding to hydroxy-3-oxo-7-phenyl-6-heptenoate was obtained. The obtained elution fraction was measured using ¹ H-NMR,
A peak corresponding to isopropyl E-5-hydroxy-3-oxo-7-phenyl-6-heptenoate could not be confirmed.

The preferred embodiments of the present invention described above are as follows.

(1) R ¹ in the aldehydes represented by the general formula (I) and the 5-hydroxy-3-ketoester derivative represented by the general formula (III) has 1 to 10 carbon atoms.
Carbon number 1 substituted with 12 alkyl groups and aromatic groups
~ 12 alkyl group, C2-12 alkenyl group,
The method for producing a 5-hydroxy-3-ketoester derivative as described above, which represents an alkenyl group having 2 to 12 carbon atoms and which is substituted with an aromatic group.

(2) R ¹ in the aldehydes represented by the general formula (I) and the 5-hydroxy-3-ketoester derivative represented by the general formula (III) is a heterocyclic group (which may be condensed). ) Substituted with 2 to 2 carbon atoms
The method for producing a 5-hydroxy-3-ketoester derivative as described above, which represents 12 alkenyl groups.

(3) 5-represented by the general formula (III)
R ³ in the hydroxy-3-keto ester derivative is
C1-C12 alkyl group, C6-C15 ary-
Group, an aralkyl group having 7 to 20 carbon atoms or an aralkyl group having 6 to 15 carbon atoms having at least one substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms. Group described above, which represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms.
Process for producing ketoester derivative.

(4) R ² in the metal compound is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or a halogen atom,
The above shows an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, which has at least one substituent selected from the group consisting of a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms. A method for producing the described 5-hydroxy-3-ketoester derivative.

(5) The metal compound is aluminum halodialkoxide, aluminum trialkoxide,
The method for producing a 5-hydroxy-3-ketoester derivative as described above, which is titanium tetraalkoxide or titanium halotothialcoxide.

(6) The method for producing a 5-hydroxy-3-ketoester derivative as described above, wherein the metal compound is aluminum trialkoxide or titanium tetraalkoxide.

(7) The method for producing a 5-hydroxy-3-ketoester derivative as described above, wherein the metal compound is titanium tetraalkoxide.

(8) Titanium tetraalkoxide is
The method for producing a 5-hydroxy-3-ketoester derivative as described above, which is titanium tetraethoxide, titanium tetra n-propoxide, titanium tetraisopropoxide, titanium n-butoxide, or titanium tetra n-pentoxide. (9) The method for producing a 5-hydroxy-3-ketoester derivative as described above, wherein R ² in the titanium compound represented by Ti (OR ² ) ₄ has the meaning defined in claim 1.

(10) 5 represented by the general formula (III)
In hydroxy-3-ketoester derivative
³ is R ² in the titanium compound represented by the general formula (IV) and the aluminum compound represented by the general formula (V)
Are the same, and the method for producing a 5-hydroxy-3-ketoester derivative as described above.

(11) The method for producing a 5-hydroxy-3-ketoester derivative as described above, wherein the above reaction is carried out in the temperature range of -30 to 30 ° C.

Claims (3)

[Claims] 1. General formula (I): R ¹ CHO
An aldehyde represented by formula (I) (wherein R ¹ represents an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or heterocyclic group); Titanium having at least one group represented by the general formula (II): —OR ² (II) (wherein R ² represents an optionally substituted hydrocarbon group). Alternatively, by reacting in the presence of a metal compound composed of aluminum, the compound of the general formula (III): (In the formula, R ¹ has the same meaning as described above, and R ³ represents an optionally substituted hydrocarbon group.) A method for producing a 5-hydroxy-3-ketoester derivative. 2. An aldehyde represented by the general formula (I) and 5-hydroxy-3- represented by the general formula (III).
R ¹ in the ketoester derivative is an alkyl group having 1 to 12 carbon atoms, a substituted alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, or a substituted alkenyl group having 2 to 12 carbon atoms. 5 according to claim 1,
-A method for producing a hydroxy-3-ketoester derivative. 3. A metal compound represented by the general formula (IV): Ti (OR ² ) _m A _4-m (IV) (wherein R ² has the same meaning as described above, A represents a halogen atom, and m Is an integer of 1 to 4), or a general formula (V): Al (OR ² ) _n A _3-n (V) (wherein R ² and A are as described above). Has the same meaning, n is 1-3
Is an aluminum compound represented by the formula), and the method for producing a 5-hydroxy-3-ketoester derivative according to claim 1.