JPH09194479A - Oxazolines, their production and production of asymmetric cyclopropanecarboxylic acids using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce new oxazolines useful as a catalyst, etc., for producing asymmetric cyclopropanecarboxylic acids which are intermediates for medicines and agrochemicals by reacting an optically active substance or a racemic modification of 2-aminoethanols with a thiopheneacetonitrile. SOLUTION: The new optically active substances or racemic modifications of oxazolines are represented by formula I [R<1> to R<5> are each H, a halogen, a (substituted)alkyl, a (substituted)aralkyl, a (substituted)aryl, a (substituted) alkenyl, a (substituted)alkoxy or a (substituted)aryloxy; * indicates asymmetric carbon atom, with the proviso that R<2> and R<3> are each mutually not same] and are useful as asymmetric ligands of asymmetric cyclopropanecarboxylic acids useful as intermediates for medicines, agrochemicals, etc. The compounds are obtained by reacting an optically active substance or a racemic modification of 2-aminoethanols represented by formula II with thiopheneacetonitriles represented by formula III in the presence of a Lewis acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to oxazolines,
The present invention relates to a method for producing the same and a method for producing asymmetric cyclopropanecarboxylic acids using the method.

[0002]

BACKGROUND OF THE INVENTION Asymmetric cyclopropanecarboxylic acids are useful as intermediates for pharmaceuticals, agricultural chemicals, etc. For example, olefins and diazoacetic acid esters are reacted in the presence of a copper salt and an asymmetric ligand. It is known that these compounds are produced by the method described above, and conventionally, optically active methylenebisoxazolines have been proposed as such an asymmetric ligand (Tetrahedron Le
tters, Vol. 32, No. 50, pp. 7373-7376, 1991). However, optically active methylenebisoxazolines are not only unstable and easily polymerized, but also produced in low yield through multiple steps using malononitrile as a raw material (Helvetica Chimic
a Acta, Vol.74, p.2, 1991), a method for producing asymmetric cyclopropanecarboxylic acids using such methylenebisoxazolines as an asymmetric ligand has not been industrially advantageous. .

[0003]

SUMMARY OF THE INVENTION Accordingly, the present inventors
It can be produced in good yield in one step using thiopheneacetonitrile as a raw material, is stable, and can be used as an asymmetric ligand when reacting an olefin and a diazoacetic acid ester in the presence of a copper salt. As a result of extensive studies to develop a new compound, the present invention has been achieved.

[0004]

That is, the present invention provides a compound represented by the following general formula (1): (In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. An aryl group which may have a group, an alkenyl group which may have a substituent, an alkoxyl group which may have a substituent or an aryloxy group which may have a substituent, * Represents an asymmetric carbon atom, provided that R ² and R ³ are not the same as each other.) And an optically active or racemic oxazoline.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION In the substituents R ¹ , R ² , R ³ , R ⁴ and R ⁵ of the oxazolines of the present invention, a halogen atom is a chlorine atom, a bromine atom or the like, an alkyl group is a methyl group, Ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, n-amyl group, neopentyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-nonyl group, menthyl group, Two
3,4-trimethyl-3-pentyl group, 2,4-dimethyl-3-pentyl group and the like, aralkyl groups such as benzyl group, 2-phenylethyl group, 2-naphthylethyl group and diphenylmethyl group are aryl. Examples of the group include a phenyl group, naphthyl group, biphenyl group, furyl group and thiophenyl group, and examples of the alkenyl group include 2-methyl-
1-propenyl group, 2-butenyl group, trans-β-styryl group, 3-phenyl-1-propenyl group, 1-cyclohexenyl group and the like, as the alkoxyl group, methoxy group, ethoxy group, n-propoxy group, t Examples thereof include a -butoxy group and the like, and examples of the aryloxy group include a phenoxy group. These alkyl group, aralkyl group, aryl group, alkenyl group, alkoxyl group, and aryloxy group may be, for example, the same halogen atom as described above, the same alkoxyl group as described above, the same aryloxy group as described above, or methyl. Group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, n-amyl group, lower alkyl group such as n-hexyl group, lower alkyl group such as n-propylthio group and t-butylthio group It may be substituted with an arylthio group such as an alkylthio group or a phenylthio group, a nitro group or a hydroxyl group.

The oxazolines represented by the general formula (1) have at least two kinds of optically active substances having an asymmetric carbon atom represented by * as an asymmetric center. May be any optically active substance, or may be a racemate thereof.

Both the optically active form and the racemic form of such oxazolines are compounds which have not been described in the literature, and are represented by the general formula (2). (In the formula, R ² , R ³ , R ⁴ , R ⁵ , and * each have the same meaning as described above.) And an optically active form or racemic form of 2-aminoethanols and the general formula (3). By reacting the thiopheneacetonitrile represented by the formula (wherein R ¹ has the same meaning as described above) in the presence of a Lewis acid, the compound can be easily produced in one step in good yield.

Examples of optically active 2-aminoethanols include (R) -t-leucinol and (R).
-Phenylglycinol, L-phenylalaninol,
L-norephedrine, L-valinol and compounds in which (R) or L in each of the above compounds corresponds to (S) or D, etc., and as a racemate, for example, (R) or L in each of the above compounds is (RS) Alternatively, compounds corresponding to DL and the like can be mentioned, respectively.

Examples of thiopheneacetonitriles include 2-thiopheneacetonitrile and 5-methyl-2-
Thiopheneacetonitrile, 4-t-butyl-2-thiopheneacetonitrile, 3-methoxy-2-thiopheneacetonitrile, 5-phenyl-2-thiopheneacetonitrile, 4-phenyloxy-2-thiopheneacetonitrile, 3-chloro-2-thiopheneacetonitrile , 5- (2-methyl-1-propenyl) -2-thiopheneacetonitrile, 4-benzyl-2-thiopheneacetonitrile and the like, and the amount thereof is usually 0.5 to 3 with respect to 2-aminoethanols. Molar range,
The range is preferably 0.5 to 2 mole times.

Examples of the Lewis acid include zinc chloride, iron chloride, tin chloride, aluminum trichloride, boron trifluoride, iron bromide, aluminum triisopropoxide, zinc acetate, etc., which may be used alone or in combination. The above is mixed and used. The amount of such Lewis acid used is usually in the range of 0.01 to 10 mole times, preferably 0.1 to 3 mole times, relative to 2-aminoethanols.

The reaction is usually carried out in a solvent, and as such a solvent, for example, a solvent inert to the reaction using a Lewis acid such as toluene, xylene, hexane, chlorobenzene or the like is used. These solvents are used alone or in combination of two or more, and the amount used is usually in the range of 2 to 200 times by weight with respect to 2-aminoethanol.

In the reaction, for example, an optically active or racemic form of 2-aminoethanol, a thiopheneacetonitrile and a Lewis acid may be mixed in a solvent, and the reaction temperature is usually 50 to 250 ° C., preferably 60.
Is in the range of to 160 ° C.

After the reaction, an aqueous alkali solution such as an aqueous solution of sodium hydrogencarbonate is added to the obtained reaction mixture, and then a water-insoluble organic solvent such as toluene, ethyl acetate, diethyl ether or dichloromethane is added by a conventional method. If the organic layer obtained is concentrated using
An optically active or racemic oxazoline compound corresponding to the 2-aminoethanol used as a raw material can be obtained. Such oxazolines may be further purified by a conventional method such as column chromatographic treatment or distillation.

In the oxazolines represented by the general formula (1) thus obtained, the configuration centered on the asymmetric carbon atom represented by * is the same as in the used 2-aminoethanol represented by the general formula (2). It is similar to the case. Further, when the obtained oxazolines are racemic, they can be easily optically resolved into optically active compounds by a conventional method, for example, an optically active column chromatographic treatment.

The oxazolines thus obtained include (4R) -2- (2-thiophenylmethyl) -4-
Phenyloxazoline, (4R) -2- (2-thiophenylmethyl) -4-isopropyloxazoline, (4
R) -2- (2-thiophenylmethyl) -4-t-butyloxazoline, (4R) -2- (2-thiophenylmethyl) -4-phenylmethyloxazoline, (4R)-
2- (2-thiophenylmethyl) -4- (2,6-di-
t-butyl-p-tolyl) oxazoline and compounds in which (4R) in each of the above compounds corresponds to (4S), and the like, and racemic compounds include compounds in which (4R) in each of the above compounds corresponds to (4RS), etc., respectively. It is illustrated.

All of these oxazolines are stable.
Therefore, the optically active substance can be used as an asymmetric ligand,
For example, the presence of such optically active oxazoline compounds and copper salts
Under the general formula (4)(Where R⁶, R⁷, R⁸, R⁹Is a hydrogen atom,
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
And R⁶And R ⁷And may combine to form a ring
Yes. Where R⁶, R⁷, R⁸, R⁹Are the same at the same time
Never. ) And general formula
(5)(Where R^TenIs 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
By reacting with zoacetic acid esters, the general formula
(6)(Where R⁶, R⁷, R⁸, R⁹, R^Ten, * Are respectively
It has the same meaning as described above. ) Asymmetric cyclopropa
Carboxylic acids can be produced.

Here, the alkenyl group in the substituents R ⁶ , R ⁷ , R ⁸ and R ⁹ is, for example, the substituent R ¹ ,
R ² , R ³ , R ⁴ and R ^{5 are the same} as those described above, and examples of the ring in the case where R ⁶ and R ⁷ are combined to form a ring include a cyclohexenyl ring and the like. And these substituents and rings are as defined above for the substituent R ¹ ,
Similar to the case of R ² , R ³ , R ⁴ and R ⁵ , it may further have a substituent. Further, the substituents R ⁶ , R ⁷ and R
Examples of the alkyl group, aralkyl group and aryl group for ⁸ , R ⁹ and R ¹⁰ include substituents R ¹ , R ² , R ³ , R ⁴ and R
Examples of ^{5 are the same} as those described above.

Examples of such diazoacetic acid esters include methyl diazoacetic acid ester, ethyl ester, and diazoacetic acid ester.
-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 the olefins are 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 amount of oxazolines used is usually in the range of 0.001 to 2 mol times, preferably 0.01 to 1 mol times, relative to the diazoacetic acid esters.

Examples of the copper salt include monovalent monofluorotrifluoromethanesulfonates such as copper (I) triacetate, copper (I) acetate, copper (I) bromide, copper (I) chloride, and copper (I) trifluoroacetate. Copper salt,
A divalent copper salt in which copper (I) in each of the above compounds corresponds to copper (II) and the like can be mentioned, and the amount thereof is usually 0.01 to 2 mol times, preferably 0.
It is in the range of 1 to 1 molar 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 diethyl ether, diethoxymethane, tetrahydrofuran, dimethoxyethane, dioxane and the like. Ether solvents, hydrocarbon solvents such as hexane, chloroform, dichloromethane, 1,
A halogenated hydrocarbon solvent such as 2-dichloroethane,
A solvent inert to the reaction such as an ester solvent such as ethyl acetate can be used. These solvents are used alone or in admixture of two or more, and the amount used is usually in the range of 2 to 200 times by weight with respect to the diazoacetic acid esters.

In the reaction, for example, olefins, oxazolines and copper salts may be mixed in a solvent and then diazoacetic acid esters may be added. The reaction temperature is usually -5.
It is in the range of 0 to 200 ° C, preferably 0 to 50 ° C.

When a divalent copper salt is used as the copper salt, it is possible to accelerate the reaction rate of the olefins and the diazoacetic acid ester by adding a hydrazine compound before adding the diazoacetic acid ester, which is preferable. .
Examples of such a hydrazine compound include phenylhydrazine and the like, and the amount thereof is usually in the range of 0.8 to 1.2 times the molar amount of the copper salt.

After the reaction, the obtained reaction mixture is added with, for example, an aqueous solution of ammonium chloride, and then extracted by a conventional method, for example, using an organic solvent insoluble in water such as toluene, ethyl acetate, diethyl ether and dichloromethane. ,
The desired asymmetric cyclopropanecarboxylic acid can be obtained by concentrating the obtained organic layer.

The asymmetric cyclopropanecarboxylic acids thus obtained are, 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.

[0027]

INDUSTRIAL APPLICABILITY The oxazolines of the present invention can be produced in a good yield in one step using thiopheneacetonitrile as a raw material, are stable, and react olefins with diazoacetic acid esters in the presence of a copper salt. It can be used as an asymmetric ligand when producing asymmetric cyclopropanecarboxylic acids.

[0028]

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.

Example 1 6.64 g (54 mmo) of 2-thiopheneacetonitrile
l), (R) -2-phenylglycinol 22 g (16
0.4 mmol) and 2.2 g of zinc chloride (16.1 m)
(mol) was dissolved in chlorobenzene and stirred with heating under reflux for 8 hours. Then, after cooling, 450 g of a saturated sodium hydrogen carbonate aqueous solution was added, and the mixture was stirred for 30 minutes, and then the precipitated solid was filtered off. The obtained filtrate is chloroform 300 g.
The extraction process using is carried out twice, the organic layers are combined, and water 10
The extract was washed with 0 g, dried over anhydrous sodium sulfate and then concentrated to give (4R) -2- (2-thiophenylmethyl) -4.
-Phenyloxazoline 11.2 g (45.9 mmo
1) was obtained (85% yield from 2-thiopheneacetonitrile). ¹ H-NMR (CDCl ₃ , TMS) δ 3.93 (S,
2H), 4.12 (t, 1H), 4.65 (t, 1)
H), 5.21 (t, 1H), 6.90 to 7.00.
(M, 2H), 7.20 to 7.40 (m, 6H)

Example 2 L- (S) in place of (R) -2-phenylglycinol
-Using the same procedure as in Example 1 except using 16.5 mg (160.4 mmol) of valinol, (4S) -2-
10.2 g (49.1 mmol) of (2-thiophenylmethyl) -4-isopropyloxazoline was obtained (91% yield from 2-thiopheneacetonitrile). ¹ H-NMR (CDCl ₃ , TMS) δ 0.86 (d,
3H), 0.95 (d, 3H), 1.69 to 1.85.
(M, 1H), 3.83 (s, 2H), 3.85-4.
00 (m, 2H), 4.23 (q, 1H), 6.90-
7.05 (m, 2H), 7.15 to 7.20 (m, 1
H)

Example 3 L- (S) in place of (R) -2-phenylglycinol
-Phenylalaninol 24.2 g (160.4 mmo
The same operation as in Example 1 except that (l) was used, and (4
S) -2- (2-thiophenylmethyl) -4-benzyloxazoline 12.1 g (47 mmol) was obtained (2-
Yield 87% from thiopheneacetonitrile). ¹ H-NMR (CDCl ₃ , TMS) δ 2.65 (q,
1H), 3.09 (q, 1H), 3.80 (s, 1
H), 3.91 (s, 1H), 3.99 (t, 1H),
4.20 (t, 1H), 4.35 to 4.49 (m, 1
H), 6.90 to 7.05 (m, 2H), 7.15 to
7.35 (m, 6H)

Example 4 18 mg of copper (II) trifluoromethanesulfonate
(0.05 mmol) and (4R) -2- (2-thiophenylmethyl) -4-phenyloxazoline 60.8
After dissolving mg (0.25 mmol) in 3 g of chloroform and stirring at 25 ° C. for 15 minutes, 5 μl (0.05 mmol) of phenylhydrazine was added and further stirred for 5 minutes. Then, at the same temperature, 2,5-dimethyl-2,4-
Hexadiene (1.102 g, 10 mmol) was added, and 1 was added.
After stirring for 0 minutes, diazoacetic acid ethyl ester 114
2 mg of a solution of mg (1 mmol) in dichloromethane (1 g)
After adding dropwise over a period of time and further stirring at the same temperature for 3 hours, the solvent was distilled off. The obtained residue was treated with silica gel column chromatography (hexane: ethyl acetate = 3).
0: 1) and trans-1- (R) -ethoxycarbonyl-2- (R)-(2-methyl-1-propenyl) cyclopropane 108.4 mg (0.553 mmol, 5
3.3% ee, yield 55.3%) and cis-1- (R)-
Ethoxycarbonyl-2- (S)-(2-methyl-1-
Propenyl) cyclopropane 44.9 mg (0.229
mmol, 38.8% ee, yield 22.9%).

EXAMPLE 5 (4R) -2- (2-thiophenylmethyl) -4-phenyloxazoline was replaced with (4S) -2- (2-thiophenylmethyl) -4-isopropyloxazoline 52.
Trans-1- (S) -ethoxycarbonyl-2- (S)-(2-methyl-1-propenyl) was operated in the same manner as in Example 4 except that 3 mg (0.25 mmol) was used.
Cyclopropane 98.8 mg (0.504 mmol, 3
5.2% ee, yield 50.4%) and cis-1- (S)-
Ethoxycarbonyl-2- (R)-(2-methyl-1-
Propenyl) cyclopropane 44.5 mg (0.227
mmol, 30.3% ee, yield 22.7%).

Example 6 (4S) -2- (2-thiophenylmethyl) -4-benzyloxazoline 64.3 m in place of (4R) -2- (2-thiophenylmethyl) -4-phenyloxazoline
trans-1- (S) -ethoxycarbonyl-2- (S)-(2-methyl-1-propenyl) cyclopropane 114. is operated in the same manner as in Example 4 except that g (0.25 mmol) is used. 9 mg (0.586 mmol, 4
6.3% ee, yield 58.6%) and cis-1- (S)-
Ethoxycarbonyl-2- (R)-(2-methyl-1-
Propenyl) cyclopropane 55.7 mg (0.284
mmol, 23.2% ee, yield 28.4%).

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Claims (5)

[Claims] 1. The general formula (1) (In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. An aryl group which may have a group, an alkenyl group which may have a substituent, an alkoxyl group which may have a substituent or an aryloxy group which may have a substituent, * Represents an asymmetric carbon atom, provided that R ² and R ³ are not the same as each other.) An optically active or racemic oxazoline compound. 2. The general formula (2) (In the formula, R ² , R ³ , R ⁴ , R ⁵ , and * each have the same meaning as described above.) And an optically active form or racemic form of 2-aminoethanols and the general formula (3). The thiopheneacetonitrile represented by the formula (wherein R ¹ has the same meaning as described above) is reacted in the presence of a Lewis acid. Body manufacturing method. 3. A general formula (4)(Where R⁶, R⁷, R⁸, R⁹Is a hydrogen atom,
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
And R⁶And R ⁷And may combine to form a ring
Yes. Where R⁶, R⁷, R⁸, R⁹Are the same at the same time
Never. ) And general formula
(5)(Where R^TenIs 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
The zoacetic acid ester is represented by the oxalate represented by the general formula (1).
The reaction is performed in the presence of an optically active zoline compound and a copper salt.
General formula (6) characterized by(Where R⁶, R⁷, R⁸, R⁹, R^Ten, * Are respectively
It has the same meaning as described above. ) Asymmetric cyclopropa
Method for producing carboxylic acids. 4. The method according to claim 3, wherein the copper salt is a divalent copper salt. 5. The method according to claim 4, wherein the divalent copper salt is copper (II) trifluoromethanesulfonate.