JPH08134048A - Production of oxazolines - Google Patents

Abstract

PURPOSE: To obtain the subject compound by using a water-containing reaction raw materials and catalyst as it is without drying and dehydrating in advance by reacting a specific nitrile with an amino alcohol in the presence of a Lewis acid, etc. CONSTITUTION: The objective compound of formula II (e.g. 2-methyl-4- phenyloxazoline) is produced by reacting (A) a nitrile of the formula R<1> -CN [R<1> is a (substituted)alkyl, an aralky] or an aryll (e.g. acetonitrile) with (B) an amino alcohol of formula I [R<2> to R<5> are each H, a (substituted)alkyl, an aralkyl or an aryl] (e.g. 2-aminoethanol) in the presence of (C) a Lewis acid (e.g. aluminum trichloride) and (D) a molecular sieve in a solvent (e.g. toluene) at 60-150 deg.C. Preferably, the molar ratio of A:B is (0.5-2):1 and the amounts of the components C and D are 0.1-3 times mol and 0.5-10 times weight based on the component B, respectively.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing oxazolines.

[0002]

2. Description of the Related Art Oxazolines are known as intermediates for medicines, agricultural chemicals, functional materials and the like.
A method is known in which nitriles and amino alcohols are reacted in the presence of a catalyst such as zinc acetate while maintaining the water content in the reaction system at 1.0% by weight or less (JP-A-5-140129). ing.

However, in the case of this method, in order to maintain the water content in the reaction system, each reaction raw material or catalyst must be dried and dehydrated in advance, which is an advantageous method as an industrial production method. I couldn't say. Further, in this method, there was no recognition about the production of racemic or optically active oxazolines.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present inventors, in the reaction of nitriles and amino alcohols, the reaction raw material or catalyst containing water is not dried in advance before the reaction, without dehydration, the reaction easily proceeds as it is, Further, as a result of studying a method for easily producing racemic or optically active oxazolines having an asymmetric carbon in the molecule, the present invention has been completed.

[0005]

Means for Solving the Problems The present invention is represented by the general formula 3 R ¹ -CN (In the formula, R ¹ represents an optionally substituted alkyl group or an aralkyl group or an aryl group.) Nitriles and general formula 2 (In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an aralkyl group or an aryl group). With a Lewis acid and a molecular sieve in the presence of the general formula 1 (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and a method for producing the oxazolines.

The target compound and each reaction raw material in the present invention are represented by the above-mentioned general formulas 1, 2 and 3, respectively. In these general formulas, the alkyl group is methyl, ethyl, n-propyl or isopropyl. Group, n-
A butyl group, an isobutyl group, a t-butyl group, an n-amyl group, a neopentyl group, an n-hexyl group, a cyclohexyl group, an n-octyl group, an n-nonyl group and the like, and an aralkyl group is a benzyl group, 2-phenylethyl group. Group, 2-naphthylethyl group, diphenylmethyl group, etc., and the aryl group is exemplified by phenyl group, naphthyl group, biphenyl group, furyl group, thiophenyl group, etc., and these groups are further substituted with a substituent. In this case, as the substituent, a halogen atom such as chlorine and bromine, a lower alkyl group such as a methyl group, an ethyl group, an isopropyl group, an n-butyl group, a t-butyl group, an n-amyl group and an n-hexyl group, a methoxy group. Group, ethoxy group, n-propoxy group,
Lower alkoxyl group such as t-butoxy group, aryloxy group such as phenoxy group, n-propylthio group, t-
Examples thereof include lower alkylthio groups such as butylthio group, arylthio groups such as phenylthio group, nitro group and hydroxyl group.

As specific compounds of each of these reaction raw materials,
Examples of the nitriles represented by the general formula 3 include acetonitrile, n-propionitrile, n-butyronitrile, 2-chloro-n-butyronitrile, cyclohexanecarbonitrile, benzonitrile, α-tolunitrile,
Examples of amino alcohols represented by the general formula 2 include p-nitrobenzonitrile and the like, such as 2-aminoethanol, 1-amino-2-propanol, and 2-amino-.
3-methyl-1-butanol, phenylglycinol,
Phenylalaninol, 2-amino-1,2-diphenylethanol, isoleucinol, valinol, norephedrine, 2-amino- (4-methoxyphenyl)-
1-propanol, 2-amino- (4-chlorophenyl) -1-propanol, 3-phenoxy-2-amino-1-propanol and the like can be mentioned respectively, and these amino alcohols can be substituted with the substituent R ² in the general formula ² and When R ⁴ or / and R ³ and R ⁵ are different, the compound may be a racemate or an optically active form.

The Lewis acid used in this reaction is
Examples include aluminum trichloride, boron trifluoride, zinc chloride, iron chloride, iron bromide, tin chloride, aluminum triisopropoxide, zinc acetate and the like.
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 the amino alcohols as the raw material.

As the molecular sieve, those which are usually used as a dehydrating agent such as beads or pellets 3A, 4A, 5A are used, and the amount thereof varies depending on the amount of water in the reaction system. , Usually 0.01 to 100 times the weight of the raw material amino alcohol,
It is preferably in the range of 0.5 to 10 times by weight.

In this reaction, the starting nitriles and amino alcohols are usually used in a molar ratio of 0.5.
˜3: 1, preferably 0.5 to 2: 1, and there is no problem even if these raw material compounds contain water. The reaction is usually carried out in a solvent, and an inert solvent is used in the reaction using a Lewis acid such as toluene, xylene, hexane, octane, or chlorobenzene as a solvent. It may be used as a solvent itself or as a mixture with these solvents. In this case, the nitriles are used in a solvent amount beyond the above-mentioned use range.

The reaction temperature is 50 to 250 ° C., preferably 6
The reaction time is in the range of 0 to 150 ° C., and the reaction time is not particularly limited, and the end point of the reaction can be the time when the amino alcohol as a raw material disappears.

After completion of the reaction, the molecular sieves are removed by filtration or the like, and an alkaline aqueous solution such as a saturated sodium hydrogencarbonate aqueous solution is added to the filtrate, the precipitated solid is removed by filtration or the like, and then concentrated, and water is added thereto. After adding toluene, ethyl acetate, diethyl ether,
The target compound can be isolated by extracting with an organic solvent such as dichloromethane and concentrating the organic layer, and if necessary, it can be purified by distillation or column chromatography.

Thus, the oxazolines represented by the general formula 1, for example, 2-methyl-4-phenyloxazoline, 5-methyl-2-phenyl-2-oxazoline, 2
-Ethyl-4-phenyl-5-methyloxazoline, 2
-Phenyl-4-t-butyl-5-ethyloxazoline, 2-benzyl-4-t-butyl-5-oxazoline, 2-propyl-4-ethyl-5,5-dimethyloxazoline, 2-methyl-4-isopropyl When oxazoline or the like is produced and the starting amino alcohol is a racemate or an optically active substance, a racemic or optically active oxazoline corresponding to the starting material can be obtained.

[0014]

EFFECTS OF THE INVENTION According to the method of the present invention, nitriles and amino alcohols can be used as a reaction raw material in one step without dehydration in advance even if water is present in the raw material compound. In addition to oxazolines having no asymmetric carbon, racemic and optically active oxazolines can be easily produced.

[0015]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited thereto.

Example 1 (R)-(-)-Phenylglycinol 10 (72.9)
Acetonitrile containing 4% by weight of water
g and dissolve it in beaded molecular sieve 4
After adding 80 g of A, the mixture is stirred for 30 minutes under a nitrogen stream. 10 g (73.4 mmol) of zinc chloride is added to this solution, and the mixture is stirred for 7 hours while heating under reflux. After the reaction,
The reaction mixture was filtered to remove the molecular sieves, and the separated molecular sieves were washed with acetonitrile (50 g x
Wash with 2). The filtrate and the washing solution are combined, 400 g of a saturated sodium hydrogen carbonate aqueous solution is added thereto, the mixture is stirred at room temperature for 30 minutes, and the precipitated solid is separated by filtration. After the filtrate is concentrated until almost all the acetonitrile is removed, the concentrated solution is poured into 400 g of water and extracted with ethyl acetate (300 g × 2). The obtained extracted organic layer was washed with 100 g of water, dried over anhydrous sodium sulfate and then concentrated, and the concentrated liquid was purified by silica gel column chromatography with chloroform-acetone (20: 1) and 4R-2-methyl-4-. 9.21 g (57.2 mmol) of phenyloxazoline was obtained. Yield 78.5%

Example 2 (S)-(+)-2-Amino-3-methyl-1-butanol 10 (96.9 mmol) was dissolved in 300 g of acetonitrile containing 4% by weight of water, and this was dissolved in beads. After 80 g of the molecular sieve 4A was added, the mixture was stirred for 30 minutes under a nitrogen stream. 10 g of zinc chloride (7
(3.4 mmol), and the mixture is stirred with heating under reflux for 7 hours. After completion of the reaction, post-treatment was carried out in the same manner as in Example 1 to obtain 4S-.
2-Methyl-4-isopropyloxazoline 8.75 g
(69.1 mmol) was obtained. Yield 71.3%

Comparative Example 1 4R-2-methyl-4-phenyloxazoline 0 was reacted and worked up in the same manner as in Example 1 except that the molecular sieve was not used, but the molecular sieve was not removed. 0.551 g (3.42 mmol) was obtained. Yield 4.7%

Comparative Example 2 Acetonitrile having a water content of 2% by weight was used as the acetonitrile, and the reaction and post-treatment were carried out in the same manner as in Example 1 except that the molecular sieve was not used (however, the molecular sieve was not removed). 4R-2-methyl-4
-1.11 g (6.92 mmol) of phenyloxazoline was obtained. Yield 9.5%

Claims (1)

[Claims] 1. A nitrile represented by the general formula 3 R ¹ —CN (wherein R ¹ represents an alkyl group which may have a substituent, an aralkyl group or an aryl group) and a general formula 2 (In the formula, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an aralkyl group or an aryl group). With a Lewis acid and a molecular sieve in the presence of the general formula 1 (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.) A process for producing an oxazoline compound.