JP2001181235A - Method for producing optically active cyclopropanecarboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active cycloprpanecarboxylic acid in a good optical purity. SOLUTION: This method for producing the optically active cyclopropane- carboxylic acid is provided by reacting a diazoacetic acid ester of general formula I: N2CHCOOR1, with an olefin of general formula II in the presence of a copper catalyst and an optically active bisoxazoline (wherein, R1 is a 1-10C straight chain/branched or cyclic alkyl; R2 is H or methyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active cyclopropanecarboxylic acids.

[0002]

2. Description of the Related Art The following general formula (4) (Wherein, R ¹ represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, R ² represents a hydrogen atom or a methyl group, and Z represents — (CH ₂ ) _n − R ³ or -C
H (OR ⁴ ) ₂ . Here, R ³ is a halogen atom,
Represents an alkoxy group having 1 to 10 carbon atoms or an acyloxy group having 2 to 10 carbon atoms, and n represents an integer of 0 to 10. R ⁴ represents an alkyl group having 1 to 10 carbon atoms, and two R ⁴ 's may form a ring together. * Represents an asymmetric carbon. The optically active cyclopropanecarboxylic acids represented by ()) are useful as intermediates for pharmaceuticals, agricultural chemicals and the like.

As a method for producing such optically active cyclopropanecarboxylic acids, for example, vinyl acetate and ethyl diazoacetate are used in a catalytic amount of copper trifluoromethanesulfonate and (-)-(4R, 5R) -bis (4-isopropyloxazoline). -2-yl) -2,2-dimethyl-1,3
-Optically active ethyl 2-acetyloxycyclopropanecarboxylate by reacting in the presence of dioxane (J. Org. Chem., 62, 2518 (19
97)) and the like, but the resulting optically active 2-
The optical purity of ethyl acetyloxycyclopropanecarboxylate was low and was not always satisfactory.

[0004]

Under these circumstances, the present inventors have further studied a method for producing optically active cyclopropanecarboxylic acids with high optical purity. The present inventors have found that by using an oxazoline-based ligand in combination, an optically active cyclopropanecarboxylic acid can be produced with higher optical purity, and the present invention has been accomplished.

[0005]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein R ¹ represents a linear, molecular chain or cyclic alkyl group having 1 to 10 carbon atoms) and a general formula (2) (Wherein R ² represents a hydrogen atom or a methyl group;
It is - represents a (CH _{2) n} -R ³ or -CH (OR ⁴⁾ _2. Here, R ³ represents a halogen atom, an alkoxy group having 1 to 10 carbon atoms or an acyloxy group having 2 to 10 carbon atoms, and n represents an integer of 0 to 10. R ⁴ has 1 to 1 carbon atoms
Represents 10 alkyl groups, and two R ⁴ 's may form a ring together. Olefins represented by the formula (3): (Wherein, R ⁵ represents an isopropyl group, a tert-butyl group or a phenyl group, R ⁶ represents a hydrogen atom or a linear alkyl group having 1 to 10 carbon atoms. * Represents an asymmetric carbon atom, 2 Asymmetric carbons have the same asymmetric configuration.)
Wherein the reaction is carried out in the presence of an optically active bisoxazoline represented by the general formula (4): (Wherein R ¹ , R ² , Z and * have the same meanings as described above.) The present invention provides a method for producing an optically active cyclopropanecarboxylic acid represented by the formula:

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. General formula (1) In the formula of diazoacetates represented by R ¹ represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec
-Butyl group, tert-butyl group, n-pentyl group, n
-Hexyl group, cyclohexyl group, n-heptyl group, n
-Octyl group, n-decyl group, menthyl group and the like.

The diazoacetates represented by the general formula (1) include, for example, methyl diazoacetate, ethyl diazoacetate, n-propyl diazoacetate, isopropyl diazoacetate, n-butyl diazoacetate, tert-diazoacetate.
-Butyl, cyclohexyl diazoacetate, menthyl diazoacetate and the like. The diazoacetic esters represented by the general formula (1) are prepared, for example, by reacting the corresponding aminoacetic esters with a diazotizing agent such as sodium nitrite.

General formula (2) Wherein R ² represents a hydrogen atom or a methyl group, and Z represents-(CH ₂ ) _n -R ³ or-
CH (OR ⁴ ) ₂ . Here, R ³ is a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or a C ² to C 1
Represents an acyloxy group of 0, and n represents an integer of 0 to 10. R ⁴ represents an alkyl group having 1 to 10 carbon atoms;
And two R ⁴ 's may form a ring together.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples of the alkoxy group having 1 to 10 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-hexoxy, n-
An octoxy group and the like are exemplified, and examples of the acyloxy group having 2 to 10 carbon atoms include an acetyloxy group, a propionyloxy group, and a butyryloxy group.

When Z represents —CH (OR ⁴ ) ₂ , R ⁴
Represents an alkyl group having 1 to 10 carbon atoms, and two R ⁴ 's may form a ring together. Carbon number 1-10
Examples of the alkyl group include a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-
Examples include a hexyl group, an n-octyl group, an isooctyl group, and an n-decyl group.

Examples of the substituent Z include a fluorine atom, chlorine atom, bromine atom, iodine atom, chloromethyl group, 2-chloroethyl group, 4-chlorobutyl group, 8-chlorooctyl group, methoxy group, ethoxy group, n -A propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group,
n-hexoxy group, n-octoxy group, methoxymethyl group, methoxyethyl group, ethoxymethyl group, acetyloxy group, propionyloxy group, butyryloxy group, acetyloxymethyl group, propionyloxymethyl group,
Examples include a dimethoxymethylene group, a diethoxymethylene group, a dipropoxymethylene group, an ethylenedioxymethyl group, a propylenedioxymethyl group, and a butylenedioxymethyl group.

The olefins represented by the general formula (2) include, for example, vinyl chloride, vinyl bromide, allyl chloride, allyl bromide, 4-chloro-1-butene, 6-chloro-1-hexene, 10- Chloro-1-decene, ethyl vinyl ether, propyl vinyl ether, vinyl acetate,
Allyl acetate, vinyl propionate, allyl propionate, 1-chloro-2-methylpropene, 1-chloro-3
-Methyl-2-butene, 1-ethoxy-2-methylpropene, 1-acetoxy-2-methylpropene, 1-acetoxy-3-methyl-2-butene, 3,3-diethoxy-1-propene, 2-vinyl -1,3-dioxolan,
2- (2-methylpropenyl) -1,3-dioxolan and the like.

The amount of the olefin represented by the general formula (2) is usually at least 1 mol, preferably at least 2 mol, based on the diazoacetate represented by the general formula (1). Preferably it is 3 mole times or more. There is no particular upper limit, but too much can be economically disadvantageous,
Practically, it is not more than 10 mole times the diazoacetic acid ester represented by the general formula (1).

According to the present invention, a diazoacetic acid ester represented by the general formula (1) and an olefin represented by the general formula (2) are converted into a copper catalyst and a compound represented by the general formula (3): (In the formula, R ⁵ represents an isopropyl group, a tert-butyl group or a phenyl group, R ⁶ represents a hydrogen atom or a linear alkyl group having 1 to 10 carbon atoms. Asymmetric carbons have the same asymmetric configuration.)
The reaction is carried out in the presence of an optically active bisoxazoline represented by the following formula. Examples of the copper catalyst include copper (I) trifluoromethanesulfonate and copper (II) trifluoromethanesulfonate. The amount of copper catalyst used is
The amount of the diazoacetic acid ester represented by the general formula (1) is usually 0.01 to 5 mol%, preferably 0.05 to 1 mol%.
Mol%.

In the formula of the optically active bisoxazoline represented by the general formula (3), R ⁵ is an isopropyl group,
represents a t-butyl group or a phenyl group;
An rt-butyl group is preferred. R ⁶ represents a hydrogen atom or a linear alkyl group having 1 to 10 carbon atoms,
Examples of the linear alkyl group of 10 include a methyl group,
Examples include an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-octyl group, and an n-decyl group. Among them, a hydrogen atom, a methyl group and an ethyl group are preferred. In the above formula, * represents an asymmetric carbon, and the two asymmetric carbons have the same asymmetric configuration.

The optically active bisoxazolines represented by the general formula (3) include, for example, methylene [bis-
(4S) -4-tert-butyl-2-oxazoline], methylene [bis- (4R) -4-tert-butyl-2-oxazoline], methylene [bis- (4S)-
4-isopropyl-2-oxazoline], methylene [bis- (4R) -4-isopropyl-2-oxazoline], methylene [bis- (4S) -4-phenyl-2-
Oxazoline], methylene [bis- (4R) -4-phenyl-2-oxazoline], isopropylidene [bis-
(4S) -4-tert-butyl-2-oxazoline], isopropylidene [bis- (4R) -4-ter
t-butyl-2-oxazoline], isopropylidene [bis- (4S) -4-isopropyl-2-oxazoline], isopropylidene [bis- (4R) -4-isopropyl-2-oxazoline], isopropylidene [bis- (4S) -4-phenyl-2-oxazoline], isopropylidene [bis- (4R) -4-phenyl-2-oxazoline], and the like. The optically active bisoxazoline represented by the general formula (3) is A commercially available product may be used, or a product manufactured by a known method may be used.

The amount of the optically active bisoxazoline represented by the general formula (3) is usually 1 to 1 with respect to the copper catalyst used.
２2 mole times.

In this reaction, for example, after mixing an olefin represented by the general formula (2), a copper catalyst and a bisoxazoline represented by the general formula (3), a diazoacetic acid ester represented by the general formula (1) is mixed. Is implemented by adding The diazoacetic esters may be added continuously or intermittently. This reaction may be carried out under normal pressure conditions or may be carried out under pressurized conditions. In particular, when a low boiling point olefin is used as the olefin represented by the general formula (2), it is practical to carry out the reaction under pressurized conditions.

The reaction temperature is generally 0-100 ° C, preferably 0-70 ° C.

This reaction may be carried out in the presence of a solvent. Examples of the solvent include aliphatic hydrocarbon solvents such as hexane, heptane and cyclohexane, dichloromethane, and the like.
Halogenated hydrocarbon solvents such as dichloroethane and the like, ester solvents such as ethyl acetate and the like, the amount of use is not particularly limited, but in consideration of economy, volumetric efficiency, and the like,
It is practically 100 times or less the weight of the diazoacetic acid ester represented by the general formula (1).

The above reaction may be carried out in the presence of a dehydrating agent such as molecular sieves and magnesium sulfate. The amount of the dehydrating agent used is not particularly limited, but is usually 0.5 times by weight or less based on the diazoacetic acid ester represented by the general formula (1).

After completion of the reaction, if necessary, insolubles are removed by filtration or the like, and then subjected to a usual post-treatment such as distillation or column chromatography to obtain the desired compound of the general formula (4) (Wherein, R ¹ , R ² , Z and * have the same meanings as described above).

The optically active cyclopropanecarboxylic acid represented by the general formula (4) is usually a mixture of an optically active cis-isomer and an optically active trans-isomer. And an optically active trans form.

The optically active cyclopropanecarboxylic acids represented by the general formula (4) include, for example, optically active 2
-Methyl chlorocyclopropanecarboxylate, optical activity 2
-Ethyl chlorocyclopropanecarboxylate, optical activity 2
Tert-butyl chlorocyclopropanecarboxylate,
Optically active menthyl 2-chlorocyclopropanecarboxylate, optically active methyl 2-bromocyclopropanecarboxylate, optically active ethyl 2-bromocyclopropanecarboxylate, optically active 2-bromocyclopropanecarboxylic acid te
rt-butyl, optically active menthyl 2-bromocyclopropanecarboxylate, optically active methyl 2- (chloromethyl) cyclopropanecarboxylate, optically active ethyl 2- (chloromethyl) cyclopropanecarboxylate, optically active 2-
(Chloromethyl) cyclopropanecarboxylic acid tert-
Butyl, optically active menthyl 2- (chloromethyl) cyclopropanecarboxylate, optically active methyl 2- (bromomethyl) cyclopropanecarboxylate, optically active ethyl 2- (bromomethyl) cyclopropanecarboxylate, optically active 2
-(Bromomethyl) cyclopropanecarboxylic acid tert
-Butyl, optically active menthyl 2- (bromomethyl) cyclopropanecarboxylate,

Optically active methyl 2- (2-chloroethyl) cyclopropanecarboxylate, optically active ethyl 2- (2-chloroethyl) cyclopropanecarboxylate, optically active 2
-(2-chloroethyl) cyclopropanecarboxylic acid te
rt-butyl, optically active menthyl 2- (2-chloroethyl) cyclopropanecarboxylate, optically active methyl 2- (4-chlorobutyl) cyclopropanecarboxylate, optically active ethyl 2- (4-chlorobutyl) cyclopropanecarboxylate, optical Active tert-butyl 2- (4-chlorobutyl) cyclopropanecarboxylate, optically active 2- (4-
(Chlorobutyl) menthyl cyclopropanecarboxylate, optically active methyl 2- (8-chlorooctyl) cyclopropanecarboxylate, ethyl optically active 2- (8-chlorooctyl) cyclopropanecarboxylate, optically active 2- (8-chlorooctyl) Tert-butyl cyclopropanecarboxylate, optically active menthyl 2- (8-chlorooctyl) cyclopropanecarboxylate,

Optically active methyl 2-methoxycyclopropanecarboxylate, optically active ethyl 2-methoxycyclopropanecarboxylate, optically active tert-butyl 2-methoxycyclopropanecarboxylate, optically active menthyl 2-methoxycyclopropanecarboxylate, optical Active methyl 2-ethoxycyclopropanecarboxylate, optically active ethyl 2-ethoxycyclopropanecarboxylate, optically active tert-butyl 2-ethoxycyclopropanecarboxylate, optically active menthyl 2-ethoxycyclopropanecarboxylate, optically active 2-propoxy Methyl cyclopropanecarboxylate, optically active ethyl 2-propoxycyclopropanecarboxylate, optically active tert-butyl 2-propoxycyclopropanecarboxylate, optically active 2-propoxycyclopropanecarbo Menthyl,

Optically active methyl 2-acetyloxycyclopropanecarboxylate, optically active ethyl 2-acetyloxycyclopropanecarboxylate, optically active tert-butyl 2-acetyloxycyclopropanecarboxylate, optically active 2-acetyloxycyclopropanecarboxylate Menthyl acid, optically active methyl 2- (acetyloxymethyl) cyclopropanecarboxylate, optically active ethyl 2- (acetyloxymethyl) cyclopropanecarboxylate, optically active tert-butyl 2- (acetyloxymethyl) cyclopropanecarboxylate, Optically active 2- (acetyloxymethyl) cyclopropanecarboxylate menthyl, optically active 2
-Methyl (propionyloxy) cyclopropanecarboxylate, ethyl optically active 2- (propionyloxy) cyclopropanecarboxylate, tert-butyl optically active 2- (propionyloxy) cyclopropanecarboxylate, optically active 2- (propionyloxy) cyclo Menthyl propanecarboxylate, optically active methyl 2- (propionyloxymethyl) cyclopropanecarboxylate, optically active 2-
Ethyl (propionyloxymethyl) cyclopropanecarboxylate, optically active 2- (propionyloxymethyl)
Tert-butyl cyclopropanecarboxylate, menthyl optically active 2- (propionyloxymethyl) cyclopropanecarboxylate,

Optically active ethyl 3-chloro-2,2-dimethylcyclopropanecarboxylate, optically active 3-chloro-
2,2-dimethylcyclopropanecarboxylic acid tert-
Butyl, optically active menthyl 3-chloro-2,2-dimethylcyclopropanecarboxylate, optically active methyl 3-chloromethyl-2,2-dimethylcyclopropanecarboxylate, optically active 3-chloromethyl-2,2-dimethylcyclo Ethyl propanecarboxylate, optically active 3-chloromethyl-2,2-dimethylcyclopropanecarboxylic acid ter
t-butyl, optically active menthyl 3-chloromethyl-2,2-dimethylcyclopropanecarboxylate, optically active 3-
Methyl ethoxy-2,2-dimethylcyclopropanecarboxylate, optically active ethyl 3-ethoxy-2,2-dimethylcyclopropanecarboxylate, optically active 3-ethoxy-
2,2-dimethylcyclopropanecarboxylic acid tert-
Butyl, optically active menthyl 3-ethoxy-2,2-dimethylcyclopropanecarboxylate,

Optically active methyl 3-acetyloxy-2,2-dimethylcyclopropanecarboxylate, optically active 3-
Ethyl acetyloxy-2,2-dimethylcyclopropanecarboxylate, optically active 3-acetyloxy-2,2-
Tert-butyl dimethylcyclopropanecarboxylate,
Optically active 3-acetyloxy-2,2-dimethylcyclopropanecarboxylate menthyl, optically active 3- (acetyloxymethyl) -2,2-dimethylcyclopropanecarboxylate, optically active 3- (acetyloxymethyl)
Ethyl 2,2-dimethylcyclopropanecarboxylate,
Tert-butyl optically active 3- (acetyloxymethyl) -2,2-dimethylcyclopropanecarboxylate, menthyl optically active 3- (acetyloxymethyl) -2,2-dimethylcyclopropanecarboxylate,

Optically active 2- (1,3-dioxolan-2)
-Yl) methyl cyclopropanecarboxylate, optical activity 2
Ethyl- (1,3-dioxolan-2-yl) cyclopropanecarboxylate, optically active tert-butyl 2- (1,3-dioxolan-2-yl) cyclopropanecarboxylate, optically active 2- (1,3- Dioxolan-2-yl) menthyl cyclopropanecarboxylate, optically active 3-
Methyl (1,3-dioxolan-2-yl) -2,2-dimethylcyclopropanecarboxylate, optically active 3-
Ethyl (1,3-dioxolan-2-yl) -2,2-dimethylcyclopropanecarboxylate, optically active 3-
Tert-Butyl (1,3-dioxolan-2-yl) -2,2-dimethylcyclopropanecarboxylate, optically active 3- (1,3-dioxolan-2-yl) -2,2-
Menthyl dimethylcyclopropanecarboxylate,

Optically active methyl 2- (diethoxymethyl) cyclopropanecarboxylate, optically active ethyl 2- (diethoxymethyl) cyclopropanecarboxylate, optically active 2
-(Diethoxymethyl) cyclopropanecarboxylic acid te
rt-butyl, optically active menthyl 2- (diethoxymethyl) cyclopropanecarboxylate, optically active methyl 3- (diethoxymethyl) -2,2-dimethylcyclopropanecarboxylate, optically active 3- (diethoxymethyl)- 2,
Ethyl 2-dimethylcyclopropanecarboxylate, optically active 3- (diethoxymethyl) -2,2-dimethylcyclopropanecarboxylate tert-butyl, optically active 3-
Menthyl (diethoxymethyl) -2,2-dimethylcyclopropanecarboxylate.

[0032]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. The content and the cis / trans ratio were analyzed by gas chromatography, and the optical purity was analyzed by gas chromatography using an optically active column.

Example 1 A reaction vessel was charged with 25 g of cyclohexane, 72 mg of copper (II) trifluoromethanesulfonate, 65 mg of isopropylidene [bis- (4S) -4-tert-butyl-2-oxazoline] and 43 g of vinyl acetate. .
After adjusting the internal temperature to 10 to 15 ° C, ethyl diazoacetate 1
38 g of a cyclohexane solution containing 1.4 g was added dropwise.
Further, it is kept at an internal temperature of 10 to 15 ° C. for one hour,
104.3 g of a solution containing ethyl acetyloxycyclopropanecarboxylate was obtained. Content: 14.5% by weight, yield: 88%, cis / trans ratio = 29/71. Further, the optical purity of the cis form was 96% ee, and the optical purity of the trans form was 95% ee.

Example 2 The procedure of Example 1 was repeated, except that 36.1 g of ethyl vinyl ether was used in place of 43 g of vinyl acetate, to contain optically active ethyl 2-ethoxycyclopropanecarboxylate. 95 g of solution were obtained. Content: 16.
9% by weight, the yield was almost quantitative, and the cis / trans ratio was 14/86. Further, the optical purity of the cis form is 8
The optical purity of the trans form was 2% ee and 80% ee.

Example 3 The procedure of Example 1 was repeated, except that 31.5 g of allyl acetate was used instead of 43 g of vinyl acetate, to give an optically active 2- (acetyloxymethyl) cyclopropanecarboxylic acid. 99.2 g of a solution containing ethyl acid were obtained. Content: 3.5% by weight, yield: 19%, cis / trans ratio = 26/74. Further, the other optical isomer was not detected in both the cis-form and the trans-form.

Example 4 An optically active ethyl 2-bromomethylcyclopropanecarboxylate was prepared in the same manner as in Example 1, except that 60.5 g of allyl bromide was used instead of 43 g of vinyl acetate. 128 g of a solution containing Content: 3.2% by weight, yield: 20%, cis / trans ratio = 22/78. Further, the other optical isomer was not detected in both the cis-form and the trans-form.

Example 5 An optically active ethyl 2-chloromethylcyclopropanecarboxylate was prepared in the same manner as in Example 1, except that 38.3 g of allyl chloride was used instead of 43 g of vinyl acetate. 108 g of a solution were obtained. Content: 5.1% by weight, yield: 34%, cis / trans ratio = 22/78. Further, the other optical isomer was not detected in both the cis-form and the trans-form.

[0038]

According to the present invention, optically active cyclopropanecarboxylic acids, which are important as intermediates for pharmaceuticals, agricultural chemicals, etc., can be produced with higher optical purity.

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Claims (3)

[Claims] 1. The general formula (1) (Wherein R ¹ represents a linear, molecular chain or cyclic alkyl group having 1 to 10 carbon atoms) and a general formula (2) (Wherein R ² represents a hydrogen atom or a methyl group;
It is - represents a (CH _{2) n} -R ³ or -CH (OR ⁴⁾ _2. Here, R ³ represents a halogen atom, an alkoxy group having 1 to 10 carbon atoms or an acyloxy group having 2 to 10 carbon atoms, and n represents an integer of 0 to 10. R ⁴ has 1 to 1 carbon atoms
Represents 10 alkyl groups, and two R ⁴ 's may form a ring together. Olefins represented by the formula (3): (In the formula, R ⁵ represents an isopropyl group, a tert-butyl group or a phenyl group, R ⁶ represents a hydrogen atom or a linear alkyl group having 1 to 10 carbon atoms. Asymmetric carbons have the same asymmetric configuration.)
Wherein the reaction is carried out in the presence of an optically active bisoxazoline represented by the general formula (4): (Wherein, R ¹ , R ² , Z and * have the same meanings as described above). 2. The process for producing optically active cyclopropanecarboxylic acids according to claim 1, wherein R ^{5 in} the formula (3) is a tert-butyl group. 3. The copper catalyst is copper (I) trifluoromethanesulfonate or copper (I) trifluoromethanesulfonate.
The method for producing an optically active cyclopropanecarboxylic acid according to claim 1, which is I).