JPH08283203A - Production of asymmetric cyclopropanecarboxylic acid compound - Google Patents

Abstract

PURPOSE: To easily obtain the subject compound useful as an intermediate for medicines and agrochemicals through relatively short processes, etc., by reaction between an olefin and a diazoacetic ester in the presence of a stable optically active oxazoline compound. CONSTITUTION: This compound expressed by formula III is obtained by reaction between (A) a compound of formula I [R<5> -R<8> are each H, a (substituted) alkenyl, (substituted) alkyl, (substituted) aralkyl, (substituted) aryl, or, R<5> and R<7> are combined to form a ring] and (B) a compound of the formula N2 CH2 COOR<9> [R<9> is a (substituted) alkyl, (substituted) aralkyl or (substituted) aryl] in the presence of (C) a compound of formula II [R<1> -R<4> are each H, a halogen, a (substituted) alkyl, (substituted) aralkyl, (substituted) aryl(oxy), (substituted) alkenyl or (substituted) alkoxyl, R<3> is not the same as R<4> ; (n) is 2 or 3; *denotes an asymmetric carbon atom], a tertiary amine and a copper salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing asymmetric cyclopropanecarboxylic acids.

[0002]

BACKGROUND OF THE INVENTION Asymmetric cyclopropanecarboxylic acids are useful as intermediates for medicines, agricultural chemicals and the like, and a method for producing them is a method of reacting olefins with diazoacetic acid esters in the presence of an asymmetric ligand. Is known (Tetr
ahedron Letters, Vol.32, No.50, pp.7373-7376, 1991).
However, the optically active methylenebisoxazolines used as an asymmetric ligand in such a method are not only unstable and easily polymerized, but also produced, for example, using malononitrile as a raw material through multiple steps (Helvetica).
Chimica Acta, Vol.74, p.2, 1991), which cannot always be produced industrially advantageously, and the production method of asymmetric cyclopropanecarboxylic acids using such methylenebisoxazolines as an asymmetric ligand is industrial. I could not say that it was advantageous.

[0003]

SUMMARY OF THE INVENTION Accordingly, the present inventors
Develop a method for producing asymmetric cyclopropanecarboxylic acids by reacting olefins with diazoacetic acid esters in the presence of copper salts using a stable asymmetric ligand that can be produced in a relatively short process As a result of intensive studies, the present invention has been accomplished.

[0004]

That is, the present invention is
Formula (2)(In the formula, R^Five, R⁶, R⁷, R⁸Are hydrogen atoms,
Alkenyl group optionally having substituent, having substituent
Optionally substituted alkyl group, optionally substituted alkyl group
Aralkyl group or aryl group which may have a substituent
Indicates R^FiveAnd R ⁷And may combine to form a ring
Yes. However, R^Five, R⁶, R⁷And R⁸Are the same at the same time
Never be. ) And general formula
(3) N₂CHCOOR⁹ (3) (In the formula, R⁹Is an alkyl group which may have a substituent,
An aralkyl group or a substituent which may have a substituent
The aryl group which may be possessed is shown. ) Zia
Zoacetic acid esters are represented by the general formula (4)(In the formula, R¹, R², R³, R^FourAre hydrogen atoms,
Halogen atom, an alkyl group which may have a substituent,
Optionally substituted aralkyl group, having a substituent
Optionally substituted aryl group, optionally substituted aryl group
Lucenyl group, alkoxyl which may have a substituent
Group, an aryloxy group which may have a substituent is shown.
However, n represents 2 or 3, and * represents an asymmetric carbon atom.
However, R²And R^FourAnd are never the same. )
Optically active oxazolines, tertiary amines and copper salts
General formula (1) characterized by reacting in the presence of(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, * Are respectively
It has the same meaning as described above. ) Asymmetric cyclopropa
The present invention provides a method for producing carboxylic acid.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION
In the reffins, the substituent R^Five, R⁶, R ⁷, R⁸To
2-Methyl-1-propenyl as the alkenyl group in
Group, 2-butenyl group, trans-β-styryl group, 3
-Phenyl-1-propenyl group, 1-cyclohexenyl
Groups such as a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, t-butyl
Cyl group, n-amyl group, neopentyl group, n-hexyl
Group, cyclohexyl group, n-octyl group, n-nonyl group
Group, menthyl group, 2,3,4-trimethyl-3-pentyl
Group, 2,4-dimethyl-3-pentyl group, etc.
The alkyl group is a benzyl group, a 2-phenylethyl group,
2-naphthylethyl group, diphenylmethyl group, etc.
Reel groups include phenyl, naphthyl, biphenyl
Group, furyl group, thiophenyl group, etc.
R^FiveAnd R⁷Ring when and are combined to form a ring
Include, for example, a cyclohexenyl ring and the like.
It Each of these substituents and rings is, for example, a chlorine source.
Child, halogen atom such as bromine atom, methyl group, ethyl
Group, n-propyl group, isopropyl group, n-butyl group,
a low t-butyl group, n-amyl group, n-hexyl group, etc.
Grade alkyl group, methoxy group, ethoxy group, n-propoxy group
Si, t-butoxy and other lower alkoxy groups,
Aryloxy group such as noxyl group, n-propylthio
Group, lower alkylthio group such as t-butylthio group, and
Arylthio group such as Nylthio group, Nitro group, Hydroxyl group
It may be substituted with a substituent such as.

As the substituent R ⁹ in the diazoacetic acid ester represented by the general formula (3), the same alkyl group as in the above substituents R ⁵ , R ⁶ , R ⁷ and R ⁸ ,
Examples thereof include an aralkyl group and an aryl group.

Examples of such diazoacetic acid esters include diazoacetic acid methyl ester, ethyl ester, n
-Propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, t-butyl ester, benzyl ester, cyclohexyl ester, 1-
Menthyl ester, n-pentyl ester, neopentyl ester, n-hexyl ester, n-heptyl ester and the like can be mentioned.

Examples of olefins include 2,5-dimethyl-2,4-hexadiene, isobutylene, 2-methyl-2-butene, 3-methyl-1-butene and 3,3-.
Dimethyl-1-butene, 2-pentene, 4-methyl-1
-Pentene, 2-methyl-2-pentene, 1-hexene, 2-hexene, 2-heptene, isoprene, 1-methyl-1-cyclohexene, vinylcyclopentane, styrene, 4-phenyl-1-butene and the like. , The amount used is usually 0.5 with respect to diazoacetic acid esters
It is in the range of up to 30 mol times.

The method of the present invention has the following general formula (2):
The olefins represented by the formula (3) and the diazoacetic acid esters represented by the general formula (3) are reacted in the presence of the optically active oxazolines represented by the general formula (4), a tertiary amine and a copper salt. In the substituents R ¹ , R ² , R ³ and R ⁴ in the optically active oxazolines, the alkyl group, the aralkyl group, the aryl group and the alkenyl group are the same as those described above, but the halogen atom is a chlorine atom. Examples thereof include a bromine atom, an alkoxyl group such as a methoxy group, an ethoxy group, an n-propoxy group and a t-butoxy group, and an aryloxy group such as a phenoxy group. These alkoxyl group and aryloxy group may further have a substituent in the same manner as in the above substituents R ⁵ , R ⁶ , R ⁷ and R ⁸ .

Examples of such optically active oxazolines include 1,2-di- (4-R-phenyloxazolin-2-yl) ethane and 1,2-di- (4-S-t-butyloxazoline-). 2-yl) ethane, 1,2-di-
(4-R-benzyloxazolin-2-yl) ethane,
1,2- (4-R-methyl-5-R-phenyloxazolin-2-yl) ethane, 1,3-di- (4-R-phenyloxazolin-2-yl) propane, 1,3-di-
(4-R-benzyloxazolin-2-yl) propane, 1,3-di- (4-S-t-butyloxazoline-
2-yl) propane, 1,3-di- (4-S-methyl-
5-R-phenyloxazolin-2-yl) propane and the like can be mentioned, and the amount thereof to be used is usually in the range of 0.001 to 0.5 mole times that of diazoacetic acid esters.

All of these optically active oxazolines are known and, for example, optically active 2-aminoethanols and succinonitrile or glutatonitrile are treated with Lewis acid such as zinc chloride in an inert solvent such as chlorobenzene. It can be easily produced in one step by reacting in the presence of an acid.

The tertiary amine includes, for example, triethylamine, tributylamine, diisopropylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine and the like, and the amount thereof is usually 0.01 mol times with respect to the copper salt. The above range is preferably 1 to 2 times by mole.

Examples of the copper salt include organic acid salts of copper (I) such as copper (I) trifluoromethanesulfonate, copper (I) trifluoroacetate and copper (I) acetate, copper (I) bromide, A monovalent copper salt such as a halide of copper (I) such as copper (I) chloride and an organic acid salt of copper (II) in which copper (I) in each of the above compounds corresponds to copper (II), copper (II) ) And divalent copper salts such as halides. These copper salts are used alone or in admixture of two or more, and the amount used is usually 0.01 with respect to the optically active oxazolines.
The range is ˜2 mol times, preferably 0.1 to 1 mol times.

The reaction may be carried out without a solvent depending on the kind of the olefin used, but it is usually carried out in a solvent, and examples of such a solvent include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane. , Hydrocarbon solvents such as hexane, halogenated hydrocarbon solvents such as chloroform and dichloromethane, ester solvents such as ethyl acetate.

In the reaction, for example, olefins, optically active oxazolines, tertiary amines and copper salts may be mixed in a solvent, and then diazoacetic acid esters may be added. The reaction temperature is usually -50 to 200 ° C. Preferably 0
It is in the range of 50 ° C.

After the reaction, the obtained reaction mixture is concentrated as it is, or the reaction mixture is mixed with an ammonium chloride aqueous solution, and an organic solvent insoluble in water such as toluene, ethyl acetate, diethyl ether, dichloromethane is used. By extracting and concentrating the obtained organic layer,
It is possible to obtain the desired asymmetric cyclopropanecarboxylic acid represented by the general formula (1). The asymmetric cyclopropanecarboxylic acid thus obtained may be further purified by a conventional method, for example, column chromatography treatment, distillation operation and the like.

The asymmetric cyclopropanecarboxylic acids thus obtained include, for example, 1- (S) -ethoxycarbonyl-2- (S) -phenylcyclopropane and 1- (S) -ethoxycarbonyl-2- (S) -phenylcyclopropane.
(R) -Ethoxycarbonyl-2,2-dimethylcyclopropane, 1- (R) -ethoxycarbonyl-2-
(R)-(2-Methyl-1-propenyl) cyclopropane, 1- (S) -ethoxycarbonyl-2- (S) -t
-Butylcyclopropane and the like.

[0018]

INDUSTRIAL APPLICABILITY The method of the present invention can easily produce asymmetric cyclopropanecarboxylic acids by using stable optically active oxazolines in a relatively short process.

[0019]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

Reference Example 1 3.2 g (40 mmol) of succinonitrile, (R)-
33 g (240 mmol) of 2-phenylglycinol and 3.3 g (24.2 mmol) of zinc chloride were mixed with 150 g of chlorobenzene and stirred for 8 hours while heating under reflux. Then, saturated sodium hydrogen carbonate aqueous solution 400
g was added and the mixture was stirred for 30 minutes, and then the precipitated solid was filtered off. The filtrate was extracted twice with 300 g of ethyl acetate each,
The organic layers were combined, washed with 100 g of water, dried over anhydrous sodium sulfate, and then concentrated. The obtained residue was subjected to column chromatogram treatment with chloroform-acetone (10: 1) to give 1,2-di- (4-R-phenyloxazolin-2-yl) ethane 8.84 g (27.6 mmo).
1) was obtained (69% yield from succinonitrile).

Reference Example 2 9.45 g (100 mmol) of glutaronitrile,
82 g of (R) -2-phenylglycinol (598 mm
ol) and 8.2 g (60.2 mmol) of zinc chloride were mixed with 300 g of chlorobenzene, and the mixture was stirred for 8 hours while heating under reflux. Then, after adding 800 g of saturated sodium hydrogen carbonate aqueous solution and stirring for 30 minutes, the precipitated solid was separated by filtration. The filtrate was extracted twice with 400 g of ethyl acetate each time, the organic layers were combined, washed with 200 g of water, dried over anhydrous sodium sulfate, and then concentrated. The obtained residue was subjected to column chromatography with chloroform-acetone (10: 1) to give 17.5 g (51%) of 1,3-di- (4- (R) -phenyloxazolin-2-yl) propane.
mmol) was obtained (yield 51 from glutaronitrile).
%).

Example 1 18 mg of copper (II) trifluoromethanesulfonate
(0.05 mmol) and 1,2-di- (4- (R)
-Phenyloxazolin-2-yl) ethane 80.1 m
g (0.25 mmol) was dissolved in 3 g of dichloromethane and stirred at 25 ° C. for 15 minutes, then 17 μl (0.1 mmol) of diisopropylethylamine was added, and the mixture was further stirred at the same temperature for 15 minutes, and then 5 μl of phenylhydrazine (0.05 mmol ) Was added and stirred for 5 minutes.
Then, after adding 1.04 mg (10 mmol) of styrene and stirring for 10 minutes, diazoacetic acid ethyl ester 0.1.
114 g (1 mmol) of dichloromethane solution (1 g)
Was added dropwise, and the mixture was further stirred at the same temperature for 3 hours. Then, the reaction mixture was concentrated, and the obtained residue was subjected to column chromatography with hexane-ethyl acetate (30: 1) to give cis-1- (S) -ethoxycarbonyl-2-.
(R) -Phenylcyclopropane 95.6 mg (0.3
45 mmol, optical purity 94% ee, yield 34.5%)
And trans-1- (S) -ethoxycarbonyl-2-
111 mg of (S) -phenylcyclopropane (0.58
2 mmol, optical purity 59.2% ee, yield 58.2
%) And got.

Example 2 1,2-di- (4- (R) -phenyloxazoline-2
-Yl) ethane instead of 1,2-di- (4- (R) -benzyloxazolin-2-yl) ethane 87.1 mg
Cis-1- (R) -ethoxycarbonyl-2 was operated in the same manner as in Example 1 except that (0.25 mmol) was used.
-(S) -phenylcyclopropane 69.5 mg (0.
366 mmol, optical purity 57.9% ee, yield 36.
6%) and trans-1- (R) -ethoxycarbonyl-
103 mg of 2- (R) -phenylcyclopropane (0.
542 mmol, optical purity 63.6% ee, yield 54.
2%).

Example 3 1,2-di- (4- (R) -phenyloxazoline-2
-Yl) ethane in place of 1,3-di- (4- (R) -phenyloxazolin-2-yl) propane 83.6 mg
Cis-1- (S) -ethoxycarbonyl-2 was operated in the same manner as in Example 1 except that (0.25 mmol) was used.
61 mg of ((R) -phenylcyclopropane (0.32
1 mmol, optical purity 44.8% ee, yield 32.1
%) And trans-1- (S) -ethoxycarbonyl-2
-(S) -Phenylcyclopropane 103.6 mg
(0.545 mmol, optical purity 58.7% ee, yield 54.5%) was obtained.

Example 4 1,2-di- (4- (R) -phenyloxazoline-2
-Yl) ethane in place of 1,3-di- (4- (R) -benzyloxazolin-2-yl) propane 90.6 mg
Cis-1- (R) -ethoxycarbonyl-2 was operated in the same manner as in Example 1 except that (0.25 mmol) was used.
-(S) -Phenylcyclopropane 67.5 mg (0.
355 mmol, optical purity 67.7% ee, yield 35.
5%) and trans-1- (S) -ethoxycarbonyl-
2- (S) -phenylcyclopropane 84.7 mg
(0.446 mmol, optical purity 65.3% ee, yield 44.6%).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 69/74 9546-4H C07C 69/74 A // C07B 61/00 300 C07B 61/00 300 C07D 263/10 C07D 263/10 C07M 7:00

Claims (3)

[Claims] 1. General formula (2)(In the formula, R^Five, R⁶, R⁷, R⁸Are hydrogen atoms,
Alkenyl group optionally having substituent, having substituent
Optionally substituted alkyl group, optionally substituted alkyl group
Aralkyl group or aryl group which may have a substituent
Indicates R^FiveAnd R ⁷And may combine to form a ring
Yes. However, R^Five, R⁶, R⁷And R⁸Are the same at the same time
Never be. ) And general formula
(3) N₂CHCOOR⁹ (3) (In the formula, R⁹Is an alkyl group which may have a substituent,
An aralkyl group or a substituent which may have a substituent
The aryl group which may be possessed is shown. ) Zia
Zoacetic acid esters are represented by the general formula (4)(In the formula, R¹, R², R³, R^FourAre hydrogen atoms,
Halogen atom, an alkyl group which may have a substituent,
Optionally substituted aralkyl group, having a substituent
Optionally substituted aryl group, optionally substituted aryl group
Lucenyl group, alkoxyl which may have a substituent
Group, an aryloxy group which may have a substituent is shown.
However, n represents 2 or 3, and * represents an asymmetric carbon atom.
However, R²And R^FourAnd are never the same. )
Optically active oxazolines, tertiary amines and copper salts
General formula (1) characterized by reacting in the presence of(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, * Are respectively
It has the same meaning as described above. ) Asymmetric cyclopropa
Method for producing carboxylic acid. 2. The method according to claim 1, wherein the copper salt is a divalent copper salt. 3. The production method according to claim 2, wherein the divalent copper salt is an organic acid salt or a halide of copper (II).