JP2001278851A - Method for producing asymmetric copper complex and method for producing optically active cyclopropane compound using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide both a method for producing a more effective asymmetric copper complex by an operation simpler than that of a conventionally known method and a method for producing an optically active cyclopropane compound using the obtained asymmetric copper complex as a catalyst. SOLUTION: This method for producing an asymmetric copper complex is characterized in that an optically active N-salicylidene amino alcohol of general formula (1) and a monovalent or divalent copper compound in an amount of less than an equimolar amount based on the alcohol are subjected to mixing treatment in an inert solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing an asymmetric copper complex using an optically active N-salicylideneamino alcohol and a copper compound, and an optically active cyclopropane compound using the obtained asymmetric copper complex as a catalyst. A method for producing the same.

[0002]

2. Description of the Related Art Optically active cyclopropanecarboxylic acid esters are important compounds as intermediates for pharmaceuticals and agricultural chemicals. For example, (+)-2,2-dimethyl-3-, which is known as primary chrysanthemic acid
(2-Methyl-1-propenyl) cyclopropanecarboxylic acid constitutes an acid component of a synthetic pyrethroid insecticide. It is known that (+)-2,2-dimethylcyclopropanecarboxylic acid is useful as a synthetic intermediate for β-lactam antibiotics. Heretofore, as a method for directly producing an optically active cyclopropanecarboxylic acid derivative by a synthetic method, for example, an optically active bis [2- (4,5-diphenyl-1,3-
Oxazolinyl)] A method of reacting a prochiral olefin with a diazoacetate in the presence of an asymmetric copper complex using methane (Tetrahedron Lett., 32, 7373, 1991)
Etc.) are known. However, this method has problems in that the raw materials used for the synthesis of the ligand are expensive and the method for synthesizing the ligand is complicated, and thus cannot always be said to be an industrially advantageous method. Further, a binuclear copper complex is produced by reacting an equimolar or more cupric salt with an optically active salicylideneamino alcohol which is a Schiff base of an amino alcohol having a tertiary hydroxyl group and a salicylaldehyde derivative. Methods have been reported (JP-B 53-43955)
No.). It has been reported that this copper complex can be used for asymmetric synthesis of cyclopropanecarboxylic acid esters such as chrysanthemic acid esters (Japanese Patent Application Laid-Open Nos. 50-151842 and 54-54).
73758, JP-A-59-225194). However, in the method using an excess of a copper compound with respect to the optically active Schiff base, the yield of the complex per the Schiff base is low, and the excess copper compound is washed / removed with methanol or the like or recrystallized. As a result, purification becomes necessary, and the operation including the treatment of the filtrate and the recovery of the solvent becomes complicated, and furthermore, the reproducibility is poor.

[0003]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, have realized simpler operation and more effective operation than conventional methods. A method for producing an asymmetric copper complex and a method for producing an optically active cyclopropane compound using the obtained asymmetric copper complex as a catalyst have been completed. That is, the present invention relates to general formula (1) (Wherein * represents an asymmetric carbon, R ¹ represents an optionally substituted alkyl, aralkyl, aryl or cycloalkyl, and R ² represents a hydrogen atom, an alkyl group, a cycloalkyl group, An aralkyl group which may be
Represents an optionally substituted phenyl group. The substituent in R ¹ and R ² represents an alkyl, alkoxyl, aralkoxyl, aryloxyl or cycloalkoxyl group. X ¹ and X ² are each a hydrogen atom,
Represents a halogen atom, a nitro group, an alkyl group, an alkoxyl group or a cyano group. The following groups May represent a 2-hydroxy-1-naphthyl group or a 1-hydroxy-2-naphthyl group. Production of an asymmetric copper complex by mixing less than an equimolar amount of a monovalent or divalent copper compound in an inert solvent with respect to the optically active N-salicylideneamino alcohol and the alcohol And a method for producing an optically active cyclopropane compound using the obtained asymmetric copper complex as a catalyst.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The optically active N-salicylideneamino alcohols represented by the general formula (1) correspond to the following general formulas (5), respectively.
And a salicylaldehyde derivative represented by the general formula (6) by dehydration condensation. (In the formula, *, R ¹ , R ² , X ¹ and X ² have the same meaning as described above.)

The above reaction is usually carried out in a solvent at room temperature or below the boiling point of the solvent. Examples of the solvent include aromatic hydrocarbons such as toluene and xylene, and alcohols such as methanol and ethanol. For example, heating and stirring each equimolar in a toluene solvent to near the boiling point of the reaction solution,
The reaction is performed while removing generated water. Since the reaction proceeds almost quantitatively, the product can be used for the next complexation without purification. In some cases, the product may be purified and used by a recrystallization method or the like. Among the optically active N-salicylideneamino alcohols (1) obtained from the optically active amino alcohol represented by the general formula (5) and the salicylaldehyde derivative represented by the general formula (6), the N-3-fluoro compound, -Nitro form, 5-fluoro form, 5-chloro form, 5
When asymmetric cyclopropanation is carried out using a copper complex produced from a bromo compound or the like as a catalyst, more favorable results can be obtained with a smaller amount of catalyst than before.

As the optically active N-salicylideneamino alcohol (1), either the (S) or (R) form can be used, and the following compounds can be exemplified. N-
Salicylidene-2-amino-1,1-diphenyl-1-propanol, N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N-salicylidene-2-amino-1, 1-di (2-isopropoxyphenyl) -1-propanol, N-salicylidene-2-amino-1,1-di (2-butoxy-5-t-butylphenyl) -1-propanol, N-salicylidene-2 -Amino-1,1-diphenyl-3-phenyl-1-propanol, N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) -3-phenyl-1-propanol, N-salicylidene-2 -Amino-1,1-di (2-isopropoxyphenyl) -3-phenyl-1-propanol, N-salicylidene-2
-Amino-1,1-di (2-butoxy-5-t-butylphenyl) -3
-Phenyl-1-propanol, N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) -3-methyl-1-butanol, N- (3-fluorosalicylidene) -2-amino-
1,1-di (2-butoxy-5-t-butylphenyl)
-1-propanol, N- (3-fluorosalicylidene)
-2-amino-1,1-di (2-octyloxy-5-
t-butylphenyl) -1-propanol, N- (3-
(Fluorosalicylidene) -2-amino-1,1-di (2-
(Butoxy-5-t-butylphenyl) -3-phenyl-
1-propanol, N- (3-fluorosalicylidene)-
2-amino-1,1-di (2-methoxyphenyl) -1
-Propanol, N- (3-fluorosalicylidene) -2
-Amino-1,1-diphenyl-1-propanol, N
-(3-Fluorosalicylidene) 2-amino-1,1-di (2-benzyloxy-5-methylphenyl) -3-
(4-isoproxyphenyl) -1-propanol, N
-(3-Fluorosalicylidene) -2-amino-1,1-
Diphenyl-3-phenyl-1-propanol, N-
(3-Fluorosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -3-methyl-1-butanol, N- (5-nitrosalicylidene) -2-amino-
1,1-diphenyl-1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-diphenyl-3-phenyl-1-propanol, N- (5-nitrosalicylidene)- 2-amino-1,1-di (2-butoxy-5-tert-butylphenyl) -1-propanol, N
-(5-nitrosalicylidene) -2-amino-1,1-
Di (2-butoxy-5-t-butylphenyl) -3-phenyl-1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-di (2-benzyloxy-5- Methylphenyl) -3- (4-isoproxyphenyl) -1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N -(5-nitrosalicylidene) -2-amino-1,1-di (2-t-butyl-4-methylphenyl) -3-phenyl-1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-di (4-t
-Butylphenyl) -1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -3-methyl-1-butanol, N-
(5-bromosalicylidene) -2-amino-1,1-diphenyl-1-propanol, N- (5-bromosalicylidene) -2-amino-1,1-di (2-methoxyphenyl)- 1-propanol, N- (3,5-dibromosalicylidene) -2-amino-1,1-diphenyl-1-
Propanol, N- (3,5-dibromosalicylidene)
-2-amino-1,1-di (2-methoxyphenyl)-
1-propanol, N- (3,5-dichlorosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N- (3,5-dichlorosalicylidene)- 2-amino-1,1-diphenyl-1-propanol, N- (3,5-dinitrosalicylidene)-
2-amino-1,1-di (2-methoxyphenyl) -1
-Propanol, N- (3,5-dinitrosalicylidene) -2-amino-1,1-diphenyl-1-propanol, N- (3-methoxy-5-nitrosalicylidene)
-2-amino-1,1-di (2-methoxyphenyl)-
1-propanol, N- (3-methoxy-5-nitrosalicylidene) -2-amino-1,1-diphenyl-1-
Propanol, N- (3-bromo-5-nitrosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N- (3-bromo-5-nitrosalicylidene ) -2-Amino-1,1-diphenyl-
1-propanol, N- (3-nitro-5-bromosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N- (3-nitro-5-
Bromosalicylidene) -2-amino-1,1-diphenyl-1-propanol, and the like.

[0007] Specific examples of the monovalent or divalent copper compound include the following. Copper carboxylate having 2 to 15 carbon atoms such as copper acetate, copper naphthenate, copper octylate, copper chloride, copper bromide, copper nitrate, copper sulfate, copper methanesulfonate, copper trifluoromethanesulfonate, copper cyanide , Copper carbonate, copper oxide and the like.

As a method for producing an asymmetric copper complex, the above-mentioned copper compound is used in an amount less than equimolar to the asymmetric ligand represented by the general formula (1), and is usually 0.4 to 0.99 mole times. . The complexation reaction is usually performed by mixing both in a solvent. Examples of such a solvent include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, halogenated hydrocarbons such as chloroform, dichloroethane and monochlorobutane, methyl acetate, ethyl acetate and ethyl propionate. Or a conjugated diolefin used for asymmetric synthesis, or a mixed solvent thereof, and it is desirable that the formed asymmetric copper complex is soluble to some extent.

The reaction is usually carried out in these solvents in a temperature range from room temperature to the boiling point of the solvent or lower. The generated acids may be used after being removed by washing with water, but may be used as they are. If necessary, the solvent can be removed for isolation and purification. Further, in order to complete the complexation reaction, there is a method in which an alkaline compound is added to accelerate the reaction. As such an alkaline compound, for example, sodium methylate or sodium ethylate is used and may be used as a powder or as a solution of methanol, ethanol or the like. In addition, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like can be mentioned. These are usually used as aqueous solutions. These alkaline compounds are used in an amount of 0.1 to 8 times, preferably 0.5 to 3 times the mole of the copper compound.

[0010] The reaction time is usually from 1 hour to 20 hours. The generated acids (for example, acetic acid when copper acetate is used, naphthenic acid when copper naphthenate is used, or their sodium salts) can be used as they are in the catalytic reaction without removing them, but washing with water as described above is possible. It is preferable to use it after removing it. In this case, usually, it may be used after dehydration, but it can be used as it is.

The asymmetric copper complex thus obtained is usually obtained as a solution and does not require a purification step, but it can be used after removing the solvent and isolated. Since it can be used as a solution as it is, when it is used as a catalyst for a continuous reaction, it is convenient for feeding, and from this point, the present preparation method is far more advantageous than the conventional method.

Although the structure of the obtained asymmetric copper complex is not clear, in the reaction between the prochiral olefin represented by the general formula (2) and the diazoacetate represented by the general formula (3), It shows more excellent effect as a catalyst for asymmetric synthesis of the corresponding cyclopropane compound. That is, in the presence of the asymmetric copper complex catalyst obtained above, the compound represented by the general formula (2) (Wherein, R ³ , R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom; a halogen atom; an alkyl group optionally substituted with a halogen atom or a lower alkoxy group; a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl alkenyl group which may be substituted with a group or halogenated alkoxycarbonyl group;. a halogen atom, a lower alkyl group, optionally substituted lower alkoxy group an aryl group or an aralkyl group also, R ³ and R ⁴ or R ³ and R ⁶ may combine to form a methylene group having 2 to 4 carbon atoms, provided that when R ³ and R ⁶ are the same group,
R ⁴ and R ⁵ represent different groups. ) And a general formula (3) (Wherein, R ⁷ is phenyl optionally substituted with an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group optionally substituted with a lower alkyl group, or a lower alkyl group, a lower alkoxy group, or a phenoxy group. Asymmetric cyclopropanation reaction proceeds very smoothly by reacting with a diazoacetic acid ester represented by the following general formula (4): (Wherein, R ³ , R ⁴ , R ⁵ , R ^{6, and} R ⁷ have the same meanings as described above).

Hereinafter, the above manufacturing method will be described in detail. Examples of the prochiral olefin (2) include monoolefins such as propene, 1-butene, isobutylene, 2-methyl-2-butene, 1,1,1-trichloro-4-methyl-3-pentene, 1,1, 1-tribromo-4-methyl-3-pentene, 2-bromo-2,5-dimethyl-4-hexene, 2-chloro-2,5-dimethyl-4-hexene, 1-methoxy-2-methyl-1- Propene, 1-ethoxy-2-methyl-1-propene, 1-
Propoxy-2-methyl-1-propene, 1-methoxy-3-methyl-2-butene, 1-ethoxy-3-methyl-2-butene, 1-propoxy-3-methyl-2-butene, 1,1- Dimethoxy-3-methyl-2-butene,
Examples thereof include 1,1-diethoxy-3-methyl-2-butene, isopropylidenecyclopropane, isopropylidenecyclobutane, and isopropylidenecyclopentane.

As the conjugated diene, for example, 2,5
-Dimethyl-2,4-hexadiene, 2-chloro-5-
Methyl-2,4-hexadiene, 2-fluoro-5-methyl-2,4-hexadiene, 1,1,1-trifluoro-2,5-dimethyl-2,4-hexadiene, 1,1
-Difluoro-4-methyl-1,3-pentadiene,
1,1-dichloro-4-methyl-1,3-pentadiene, 1,1-dibromo-4-methyl-1,3-pentadiene, 1-chloro-1-fluoro-4-methyl-1,3
-Pentadiene, 1-fluoro-1-bromo-4-methyl-1,3-pentadiene, 2-methoxycarbonyl-
5-methyl-2,4-hexadiene, 2-hexafluoroisopropoxycarbonyl-5-methyl-2,4-hexadiene, 1-lower alkoxy (methyl, ethyl, propyl) -4-methyl-1,3-pentadiene, Examples thereof include 1-fluoro-1-lower alkoxy (methyl, ethyl, propyl) -4-methyl-1,3-pentadiene and the like. Preferably, isobutylene, 2,5-dimethyl-2,4-hexadiene and the like are mentioned.

The amount of the prochiral olefin (2) used is
It is usually at least 1 mole times, preferably about 2 to 50 times, the moles of the diazoacetates (3).

The diazoacetates (3) used in the present invention can be obtained by a known method. For example, the corresponding amino acid esters are subjected to a diazotization reaction, and then chloroform, toluene, hexane, cyclohexane,
It can be obtained by extraction with a solvent such as heptane or a substrate such as prochiral olefin (2). If necessary, it can be isolated by distillation or the like.

In the diazoacetic acid ester represented by the general formula (3), R ⁷ is an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group optionally substituted by a lower alkyl group, or a lower alkyl group or a lower alkosyl group. Or a phenyl group or a benzyl group which may be substituted with a phenoxy group, and specific examples of R ⁷ include, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 1-
Menthyl, d-menthyl, benzyl, cyclohexyl,
Phenyl, m-methylphenyl, m-methoxyphenyl, m-phenoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethoxyphenyl, 4-methyl-2,6
-Di-t-butylphenyl, m-phenoxybenzyl and the like.

Specific examples of the production method for reacting a prochiral olefin (2) with a diazoacetic acid ester (3) using the asymmetric copper complex of the present invention as a catalyst (asymmetric cyclopropanation) include, for example, A method of adding a diazoacetic acid ester (3) dissolved in a solvent to a mixture of the asymmetric copper complex and the prochiral olefin (2) obtained as described above.

As the solvent used, for example, 1,2
-Halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride, and monochlorobutane; aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; aromatic hydrocarbons such as toluene and xylene; methyl acetate, ethyl acetate, and methyl propionate And esters such as ethyl propionate. Prochiral olefin (2) can also be used as a solvent. These can also be used as a mixture. The amount of the solvent to be used is generally about 2 to 50 times by weight, preferably about 3 to 30 times by weight, relative to the diazoacetates (3).

If necessary, an asymmetric copper complex comprising divalent copper may be represented by the general formula (7): (In the formula, R represents an aryl group, an aralkyl group or an alkyl group.) The catalyst can be activated by the action of a monosubstituted hydrazine represented by the formula: Such monosubstituted hydrazines include, for example, phenylhydrazine. The use of the mono-substituted hydrazine is particularly effective in a batch reaction, and the amount is 0.2 to 2 moles, preferably 0.5 to 1 mole, relative to copper of the copper complex catalyst. Activation of such an asymmetric copper complex catalyst has the effect of smoothly starting the reaction when performing an asymmetric cyclopropanation reaction at a relatively low temperature.

The amount of the asymmetric copper complex catalyst used is usually 0.00001 to 0.01 times, preferably about 0.00002 to 0.005 times, based on the diazoacetic acid ester (3).

The asymmetric cyclopropanation reaction is usually carried out in an atmosphere of an inert gas such as nitrogen or argon. The reaction temperature is usually -20 ° C to 160 ° C, preferably about -10 ° C to 130 ° C. The reaction time varies depending on the amount of the catalyst used and the reaction temperature, but is usually about 30 minutes to 20 hours. The reaction method is appropriately selected. For example, a method in which the asymmetric copper complex catalyst, diazoacetic esters, and prochiral olefin are continuously fed to the reaction vessel at the above reaction temperature, and the reaction solution is continuously withdrawn. Is also an effective reaction method for effectively acting the asymmetric copper complex catalyst.

The optically active cyclopropanecarboxylic acid esters obtained by the above reaction can be isolated, if necessary, by a conventional method such as distillation or column chromatography. Specific examples of the optically active cyclopropane compound (4) thus obtained include, for example, 2-methylcyclopropanecarboxylic acid ester, 2,2-dimethylcyclopropanecarboxylic acid ester, 2,2,3-
Trimethylcyclopropanecarboxylic acid ester, 2,2
-Dimethyl-3- (2,2,2-trichloroethyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-
3- (2,2,2-tribromoethyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3- (2-chloro-2-methyl) propylcyclopropanecarboxylic acid ester, 2,2-dimethyl-3 -(2-bromo-2-
Methyl) propylcyclopropanecarboxylate,
2,2-dimethyl-3-methoxycyclopropanecarboxylate, 2,2-dimethyl-3-ethoxycyclopropanecarboxylate, 2,2-dimethyl-3-
Methoxymethylcyclopropanecarboxylate,
2,2-dimethyl-3-ethoxymethylcyclopropanecarboxylate, 2,2-dimethyl-3-propoxycyclopropanecarboxylate, 2,2-dimethyl-3-propoxymethylcyclopropanecarboxylate, 2,2 -Dimethyl-3-dimethoxymethylcyclopropanecarboxylic acid ester, 2,2-dimethyl-3
-Diethoxymethylcyclopropanecarboxylic acid ester, 2,2-dimethyl-3- (1,3-dioxa-2-
Cyclopentyl) cyclopropanecarboxylate,
2,2-dimethyl-3,3-cyclopropylidenecyclopropanecarboxylic acid ester, 2,2-dimethyl-3,
Examples thereof include optically active substances such as 3-cyclobutylidenecyclopropanecarboxylate and 2,2-dimethyl-3,3-cyclopentylidenecyclopropanecarboxylate.

The optically active alkenyl-substituted cyclopropane compounds include, for example, 2,2-dimethyl-3
-(2-methyl-1-propenyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3- (2-chloro-1-propenyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3- (2- Fluoro-1-propenyl) cyclopropanecarboxylic acid ester, 2,2-
Dimethyl-3- (2-chloro-2,2,2-trifluoromethylethenyl) cyclopropanecarboxylate, 2,2-dimethyl-3- (2,2-difluoro-1
-Ethenyl) cyclopropanecarboxylic acid ester, 2,
2-dimethyl-3- (2,2-dichloro-1-ethenyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3- (2,2-dibromo-1-ethenyl) cyclopropanecarboxylic acid ester, 2, 2-dimethyl-3-
(2-fluoro-2-chloro-1-ethenyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3-
(2-fluoro-2-bromo-1-ethenyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3-
(2-methoxycarbonyl-1-propenyl) cyclopropanecarboxylic acid ester, 2,2-dimethyl-3-
(2-hexafluoroisopropoxycarbonyl-1-
Propenyl) cyclopropanecarboxylic acid ester, 2,
2-dimethyl-3- (2-alkoxy-1-ethenyl)
Optically active substances such as cyclopropanecarboxylic acid ester and 2,2-dimethyl-3- (2-fluoro-2-alkoxy-1-ethenyl) cyclopropanecarboxylic acid ester can be given.

The ester residue of the optically active cyclopropane compound (4) is, for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, cyclohexyl, menthyl, 4-methyl- 2,6
-Di-t-butylphenyl, m-phenoxybenzyl and the like.

The thus obtained optically active cyclopropane compound can be subjected to a deesterification reaction by a known method to convert it into an optically active cyclopropanecarboxylic acid having a substituent R ⁷ being a hydrogen atom. At that time, the optically active cyclopropane compound produced by the method of the present invention can be subjected to a deesterification reaction without isolation and purification.

The method of the deesterification reaction is not particularly limited and is carried out according to a known method. For example, a method of hydrolysis with an alkali metal hydroxide or the like, or a method of heating in the presence of an acid catalyst, It can be carried out by a method of decomposing and desorbing.

[0028]

Next, the present invention will be described in more detail with reference to examples, but the present invention is of course not limited thereto. The yield and optical purity were calculated by the following equations. Cyclopropanecarboxylic acid ester yield (%) = B × 100 / A Optical purity: (+)-trans ee% = (C−D) × 100 / (C + D) (+)-cis ise% = ( E−F) × 100 / (E + F) where A = prepared diazoacetate (mol) B = cyclopropanecarboxylate (mol) generated after the reaction C = (+)-trans-form D = (−) -Trans form E = (+)-cis form F = (-)-cis form

Reference Example 1 (R) -2-amino-1,1
-Di (2-butoxy-5-t-butylphenyl) -1-
0.968 g (2.0 mmol) of propanol and 0.244 g (2.0 mmol) of salicylaldehyde were dissolved in 20 ml of ethanol and 20 ml of toluene, and heated under reflux for 1 hour. After evaporating the solvent from the reaction product, it was dried and dried as a yellow solid (R) -N-salicylidene-2-amino-
1,1-di (2-butoxy-5-t-butylphenyl)
1.17 g of 1-propanol was obtained.

(Example 1A) A glass Schlenk tube having an inner volume of 50 ml was replaced with nitrogen, and then the (R) -N-salicylidene-2-amino-1,1-di (2) obtained in Reference Example 1 was obtained.
-Butoxy-5-t-butylphenyl) -1-propanol 58.8 mg (0.1 mmol) and 53.5% copper naphthenate toluene solution 63.5 mg (0.05 mg-at)
om Cu) was dissolved in 25 ml of toluene at room temperature for 1 hour, 19.3 mg of 28% sodium methylate (methanol solution) was added, and the mixture was stirred at room temperature for 1 hour to prepare a complex catalyst solution.

(Example 1B) After a glass Schlenk tube having an inner volume of 100 ml was replaced with nitrogen, 5 ml (0.01 mg-atom of Cu) of the complex catalyst prepared in Example 1A was charged. Next, 2,5-dimethyl-2,4-hexadiene
After adding 30 g (273 mmol), 1.1 mg (0.01 mmol) of phenylhydrazine was added. Then, it heated up to 80 degreeC. 10 ml of a toluene solution of ethyl diazoacetate (containing 20 mmol of diazoacetate) was added over 2 hours. Then, 30 minutes, 80 °
, And then cooled to room temperature. The yield of the chrysanthemic acid ethyl ester of the product and the trans / cis isomer ratio were analyzed by GC, and the optical purity was analyzed by LC. Yield of chrysanthemic acid ethyl ester 90.1% (based on charged diazoacetate), trans / cis = 55/45, optical purity 71% ee (t),
The ee (c) was 60%.

Reference Examples 2 to 19 In the same manner as in Reference Example 1, optically active N-salicylideneamino alcohol (optically active Schiff base) was synthesized from an optically active amino alcohol and a salicylaldehyde derivative. The results are shown in Table 1.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

The properties of the N-salicylideneamino alcohol obtained in Reference Examples are shown below. m. p. Is Metra
Based on an automatic melting point analyzer manufactured by the company. Reference Example 2 (R) -N- (5-nitrosalicylidene) -2-amino-
1,1-di (2-butoxy-5-t-butylphenyl)
-1-propanol ¹ H-NMR (CDCl ₃ , TMS) δ 0.87 to 1.56 (m, 35H),
3.72 to 3.81 (m, 4H), 5.08 (s, 1H), 5.5 (s, 1H) 6.63 to 8.05 (m, 10H) mp 67.9 ° C

Reference Example 3 (R) -N- (3-fluorosalicylidene) -2-amino-
1,1-di (2-butoxy-5-t-butylphenyl)
-1-propanol ¹ H-NMR (CDCl ₃ , TMS) δ 0.86 to 1.57 (m, 35H),
3.66 to 3.77 (m, 4H), 4.95 (s, 1H), 5.34 (s, 1H), 6.4 to 8.01 (m, 10H) mp 51.9 ° C

Reference Example 6 (R) -N- (5-nitrosalicylidene) -2-amino-
1,1-diphenyl- ¹ -propanol ¹ H-NMR (CDCl ₃ , TMS) δ 1.34 to 1.36 (d, 3H), 2.
59 (s, 1H), 4.64 to 4.66 (q, 1H), 6.82 to 6.9
(M, 1H), 7.2 to 7.54 (m, 10H), 8.12 to 8.15
(M, 2H), 8.26 (s, 1H) mp 208.3 ° C

Reference Example 7 (R) -N- (3-fluorosalicylidene) -2-amino-
1,1-diphenyl- ¹ -propanol ¹ H-NMR (CDCl ₃ , TMS) δ 1.27 to 1.29 (d, 3H), 2.
58 (s, 1H), 4.54 to 4.61 (q, 1H), 6.7 to 7.54
(M, 13H), 8.34 (s, 1H) mp 100 ° C

Reference Example 8 (R) -N- (5-bromosalicylidene) -2-amino-
1,1-diphenyl- ¹ -propanol ¹ H-NMR (CDCl ₃ , TMS) δ 1.25 to 1.27 (d, 3H), 2.
56 (s, 1H), 4.55-4.62 (q, 1H), 6.76-6.91
(D, 1H), 7.15 to 7.54 (m, 13H), 8.28 (s, 1
H) mp 173 ℃

Reference Example 9 (R) -N- (3,5-dibromosalicylidene) -2-amino-1,1-diphenyl- ¹ -propanol ¹ H-NMR (CDCl ₃ , TMS) δ 1.28-1.30 (D, 3H), 2.
59 (s, 1H), 4.52 to 4.59 (q, 1H), 7.1 to 7.66
(M, 12H), 8.13 (s, 1H) mp 128.1 ° C

Reference Example 10 (S) -N- (5-nitrosalicylidene) -2-amino-
1,1-di (2-benzyloxy-5-methylphenyl) -3- (4-isoproxyphenyl) -1-propanol ¹ H-NMR (CDCl ₃ , TMS) δ 1.26 to 1.31 (q, 6H), 1.
94 (s, 3H), 2.13 (s, 3H), 2.87 to 2.91 (d, 2
H), 4.42 to 4.50 (m, 1H), 4.82 to 4.95 (m, 4
H), 5.86 (s, 1H), 6.59-8.02 (m, 24H)

Reference Example 11 (S) -N- (3-fluorosalicylidene) 2-amino-
1,1-di (2-benzyloxy-5-methylphenyl) -3- (4-isoproxyphenyl) -1-propanol ¹ H-NMR (CDCl ₃ , TMS) δ 1.27 to 1.31 (t, 6H), 1.
94 (s, 3H), 2.11 (s, 3H), 2.91 to 2.94 (m, 2
H), 4.42 to 4.50 (m, 1H), 4.77 to 4.92 (m, 4
H), 5.67 (s, 1H), 6.31-7.39 (m, 24H) mp 82.7 ° C,

Reference Example 12 (R) -N- (5-nitrosalicylidene) -2-amino-
1,1-di (2-butoxy-5-t-butylphenyl)
-3-phenyl- ¹ -propanol ¹ H-NMR (CDCl ₃ , TMS) δ 0.91 to 1.57 (m, 34H),
3.78 to 3.96 (m, 4H), 5.05 (s, 1H), 5.75 (s, 1H)
H), 6.62 to 8.57 (m, 15H) Oil

Reference Example 13 (R) -N- (3-fluorosalicylidene) -2-amino-
1,1-di (2-butoxy-5-t-butylphenyl)
-3-phenyl- ¹ -propanol ¹ H-NMR (CDCl ₃ , TMS) δ 0.87 to 1.56 (m, 34H),
3.71 to 3.97 (m, 4H), 4.85 (s, 1H), 5.75 (s, 1H)
H), 6.62 to 8.57 (m, 15H) Oil

Reference Example 14 (R) -N- (5-nitrosalicylidene) -2-amino-
1,1-diphenyl-3-phenyl-1-propanol mp 202 ° C.

Reference Example 15 (R) -N- (3-fluorosalicylidene) -2-amino-
1,1-diphenyl-3-phenyl-1-propanol mp 159.8 ° C.

Reference Example 16 (S) -N- (5-nitrosalicylidene) -2-amino-1,1-
Di (2-methoxyphenyl) -3-methyl-1-butanol mp 118.7 ° C

Reference Example 17 (S) -N- (3-Fluorosalicylidene) -2-amino-1,1-
Di (2-methoxyphenyl) -3-methyl-1-butanol mp 79.6 ° C

(Examples 2A to 17A) In the same manner as in Example 1A, a complex catalyst solution was prepared using the optically active Schiff bases shown in Table 1 and copper naphthenate and sodium methylate. Table 2 shows the results.

[Table 5]

[Table 6]

(Examples 2B to 16B) In the same manner as in Example 1B, a reaction was carried out using a complex catalyst shown in Table 2. The results are shown in Table-3.

[Table 7]

[Table 8]

(Examples 18A and 19A) Internal volume 100
0.2 mmol of the asymmetric ligand shown in Table 4 and 35.9 mg of copper acetate monohydrate were placed in a 1 ml glass Schlenk tube.
(0.18 mmol) and 50 ml of toluene,
The mixture was reacted at 80 ° C. for 1 hour with stirring. After cooling to room temperature, 30 ml of a 0.13% aqueous sodium hydroxide solution was added. The whole was transferred to a separating funnel, stirred, and allowed to stand still to separate. 10 ml of water was added and stirred again. The mixture was allowed to stand and separated, and the oil layer was transferred to a Schlenk tube. After a cooling tube with an extraction tube was installed at the top, the reaction solution was heated and azeotropically dehydrated. After cooling to room temperature, toluene was added to make up to 50 ml to prepare an asymmetric copper complex catalyst.

[Table 9]

(Examples 17B and 18B) Internal volume 100
After replacing the inside of the glass Schlenk tube of 1 ml with nitrogen, 1 ml of the above-prepared asymmetric copper complex catalyst solution was added.
Using the same raw materials as in B, a reaction was carried out in the same manner.
The results are shown in Table-5.

[Table 10]

Example 20A A glass Schlenk tube having an inner volume of 50 ml was replaced with nitrogen.
16.4 mg (0.0%) of the Schiff base obtained in Reference Example 2.
259 mmol) and 5% copper naphthenate toluene solution 2
After dissolving 9.9 mg (containing 0.0235 mg-atom Cu) in 13 ml of ethyl acetate, the solution was dissolved at room temperature in 1 ml.
After stirring for an hour, a complex catalyst solution was prepared.

Example 21A A glass Schlenk tube having an inner volume of 50 ml was replaced with nitrogen.
(R) -N- (5-nitrosalicylidene) -2-amino-
11.3-mg (0.0259 mmol) of 1,1-di (2-methoxyphenyl) -1-propanol and 29.9 mg (0.0235 m) of a 5% copper naphthenate toluene solution
g-atom Cu) 13 ml of ethyl acetate
, And stirred at room temperature for 1 hour to prepare a complex catalyst solution.

Example 19B After replacing the inside of a glass Schlenk tube having an inner volume of 100 ml with nitrogen, 4 ml of the asymmetric copper complex catalyst solution prepared in Example 20A was used.
The reaction was carried out in the same manner using the same raw materials as in Example 1B. 89.2 Yield of Chrysanthemic Acid Ethyl Ester
% (Based on charged ethyl diazoacetate), trans / cis = 5
4/46, optical purity 66% ee (t), 46% ee
(C).

Example 20B After replacing the inside of a glass Schlenk tube having an inner volume of 100 ml with nitrogen, 4 ml of the asymmetric copper complex catalyst solution prepared in Example 21A was used.
The reaction was carried out in the same manner using the same raw materials as in Example 1B. 90.9 Yield of chrysanthemic acid ethyl ester
% (Based on charged ethyl diazoacetate), trans / cis = 5
9/41, optical purity 55% ee (t), 47% ee
(C).

(Example 21B) After replacing a stainless steel autoclave having an inner volume of 100 ml with nitrogen, 10 ml of a complex catalyst prepared in Example 1A (0.02 mg-atom of Cu).
Insert Next, 2.2 mg of phenylhydrazine (0.
02 mmol), and 4.5 g of isobutylene were added.
(80.4 mmol) was added. Thereafter, the mixture was heated to 40 ° C., and a 10 ml toluene solution of ethyl diazoacetate was heated.
(Ethyl diazoacetate: 20 mmol) was charged by a pump over 2 hours. After charging, the mixture was maintained at 40 ° C. for 1 hour, cooled to room temperature, and the yield of the product ethyl cyclopropanecarboxylate was analyzed by GC. The optical purity was determined by hydrolyzing cyclopropanecarboxylic acid ethyl ester, derivatizing it into 1-menthol ester, and performing GC analysis. Yield of cyclopropanecarboxylic acid ethyl ester
91% (based on charged ethyl diazoacetate), optical purity 81
% Ee.

(Examples 22B and 23B) Example 21
The reaction was carried out in the same manner as in B, using the complex catalyst shown in Table-2. The results are shown in Table-6.

[Table 11]

Example 22A (R) -N-salicylidene-2-amino-1,1-di (2-butoxy-5-t-butylphenyl) -3- was added to a glass Schlenk tube having an inner volume of 100 ml. Phenyl-1-propanol 0.133
g (0.2 mmol), copper acetate monohydrate 35.9 m
g (0.18 mmol) and 50 ml of toluene were charged and reacted at 80 ° C. for 1 hour with stirring. After cooling to room temperature, 0.13% aqueous sodium hydroxide solution 30
ml was added. After transferring the whole to a separating funnel and stirring,
The mixture was allowed to stand and separated. 10 ml of water was added and the mixture was stirred again. The mixture was allowed to stand and separated, and the oil layer was transferred to a Schlenk tube. After a cooling tube with an extraction tube was installed at the top, the reaction solution was heated and azeotropically dehydrated. After cooling to room temperature, toluene was added to 50 ml to prepare an asymmetric copper complex catalyst.

(Example 24B) 10 ml of the asymmetric copper complex solution prepared in Example 22A (0.036 mg-atom of Cu)
The reaction was carried out in the same manner as in Example 21B except for using m). Yield of cyclopropanecarboxylic acid ethyl ester
91% (based on charged diazoacetate), optical purity 87
% Ee.

(Example 23A) After replacing a glass Schlenk tube having an inner volume of 50 ml with nitrogen, 8.2 mg (0.013 mmol) of the Schiff base obtained in Reference Example 2 and 15 mg of a 5% copper naphthenate toluene solution (0. 0118 mg-
atom Cu) was dissolved in 13 ml of ethyl acetate at room temperature for 1 hour, and then 4.6 mg of 28% sodium methylate (methanol solution) was added. After stirring at room temperature for 1 hour, 1.3 μl of phenylhydrazine was added. A complex catalyst solution was prepared.

(Example 24A) The procedure of Example 23A was repeated, except that 10 mg of the Schiff base obtained in Reference Example 12 was used.

Example 25B 5 ml of the complex catalyst solution prepared in Example 23A (0.0045 mg of Cu-ato
m containing), and reacted in the same manner as in Example 21B. Yield of cyclopropanecarboxylic acid ethyl ester 91% (based on charged diazoacetate), optical purity 86
% Ee.

Example 26B 5 ml of the complex catalyst solution prepared in Example 24A (0.0045 mg Cu-ato
m containing), and reacted in the same manner as in Example 21B. 92% yield of cyclopropanecarboxylic acid ethyl ester (based on charged diazoacetate), optical purity 87
% Ee.

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Claims (3)

[Claims] 1. The general formula (1) (Wherein * represents an asymmetric carbon, R ¹ represents an optionally substituted alkyl, aralkyl, aryl or cycloalkyl, and R ² represents a hydrogen atom, an alkyl group, a cycloalkyl group, An aralkyl group which may be
Represents an optionally substituted phenyl group. The substituent in R ¹ and R ² represents an alkyl, alkoxyl, aralkoxyl, aryloxyl or cycloalkoxyl group. X ¹ and X ² are each a hydrogen atom,
Represents a halogen atom, a nitro group, an alkyl group, an alkoxyl group or a cyano group. The following groups May represent a 2-hydroxy-1-naphthyl group or a 1-hydroxy-2-naphthyl group. Asymmetric copper which is mixed with an optically active N-salicylideneamino alcohol represented by the following formula) and a monovalent or divalent copper compound in less than equimolar amount in an inert solvent. A method for producing a complex. 2. The general formula (2) (Wherein, R ³ , R ⁴ , R ⁵ , and R ⁶ are each a hydrogen atom; a halogen atom; an alkyl group optionally substituted with a halogen atom or a lower alkoxy group; a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl alkenyl group which may be substituted with a group or halogenated alkoxycarbonyl group;. a halogen atom, a lower alkyl group, optionally substituted lower alkoxy group an aryl group or an aralkyl group also, R ³ and R ⁴ or R ³ and R ⁶ may combine to form a methylene group having 2 to 4 carbon atoms, provided that when R ³ and R ⁶ are the same group,
R ⁴ and R ⁵ represent different groups. ) And a general formula (3) (Wherein R ⁷ is an alkyl group having 1 to 8 carbon atoms; a cycloalkyl group optionally substituted with a lower alkyl group; or phenyl optionally substituted with a lower alkyl group, a lower alkoxy group, or a phenoxy group) Or a benzyl group) when reacting with a diazoacetic acid ester represented by the general formula (1).
-A salicylidene amino alcohol and an asymmetric copper complex obtained by mixing in a solvent with less than an equimolar amount of a monovalent or divalent copper compound with respect to the alcohol, and using the compound as a catalyst. Equation (4) (Wherein, R ³ , R ⁴ , R ⁵ , R ^{6, and} R ⁷ have the same meanings as described above). 3. The reaction between a prochiral olefin represented by the general formula (2) and a diazoacetic acid ester represented by the general formula (3), wherein the reaction is carried out in the presence of a mono-substituted hydrazine. 3. The method for producing an optically active cyclopropane compound according to 2.