JPH0977752A - Process for producing N-unsubstituted isoxazolidine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce in a short reaction time and high yield the subject compound useful for raw materials of pharmaceuticals, agrochemicals and cosmetics, etc. SOLUTION: An olefinic aldehyde compound of formula I [R<1> is a (substituted) divalent aromatic group and R<2> is a (substituted) divalent aliphatic group; R<2> to R<4> is H or an organic group] is allowed to react with a hydroxyoxime of the formula HO-R<5> -CH=N-OH [R<5> is a (substituted) alkylene] in the presence of an organic tin compound to obtain an isooxyazolidine compound of formula II. This compound is hydrolyzed, preferably in an acidic condition, to obtain the objective compound of formula III (R<1a> , R<2a> , R<3a> and R<4a> are R<1> , R<2> , R<3> and R<4> respectively or groups produced by hydrolyzing those groups or H). An example of the compound is 1,3a,4,9b-tetrahydro-3,3-dimethyl- cis-3H-[1]benzopyrano[4,3-C]isoxazole.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing an N-unsubstituted isoxazolidine useful as a raw material for medicines, agricultural chemicals, cosmetics and the like.

[0002]

2. Description of the Related Art N-Unsubstituted isoxazolidine is a useful basic nucleus heterocycle as a raw material for medicines, agricultural chemicals, cosmetics and the like. As its production method, (1) a method utilizing a nitrone-olefin cycloaddition reaction utilizing tautomerization of an oxime; (2) a hydride or an alkyl nucleophile to a C = N double bond of isoxazoline. Addition reaction of agents;
(3) A method is known in which an N-cyclic acetal-substituted nitrone is produced by condensation of ω-hydroxyoxime and an aldehyde by heating in an inert solvent, cycloaddition of an olefin, and subsequent acid hydrolysis is performed. .

However, the methods (1) and (2) are not general because the applicable systems are limited. Further, the method (3) has a wider application range than the methods (1) and (2), but requires heating at a high temperature for a long time, which causes a problem of side reaction control.

[0004]

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide a method for producing an N-unsubstituted isoxazolidine which can be obtained in a high yield in a short reaction time and has a wide range of applications.

[0005]

The inventors of the present invention have conducted an examination focusing on the method (3). When an organotin compound is used as a catalyst, hydroxyoxime and olefin aldehyde can be produced in a short time in a high yield. It was found that an N-cyclic acetal-substituted isoxazolidine is produced by condensation with and is hydrolyzed to obtain an N-unsubstituted isoxazolidine with wide generality, and the present invention has been completed. .

The present invention is represented by the following reaction formula.

[0007]

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(Where R¹May have a substituent
A divalent oil which may have a divalent aromatic group or a substituent
R represents an aliphatic group², R^ThreeAnd R^FourIs a hydrogen atom or organic
Group, R^FiveIs a linear or branched chain which may have a substituent.
R represents a branched alkylene group, R ^1a, R^2a, R^3aAnd R^4a
Is R¹, R², R^ThreeAnd R^FourIndicates or
Groups or hydrogen atoms produced by hydrolysis of these groups
Indicates)

That is, the present invention is represented by the formula (3) obtained by reacting an olefin aldehyde represented by the formula (1) with a hydroxyoxime represented by the formula (2) in the presence of an organotin compound. The present invention provides a process for producing an N-unsubstituted isoxazolidine represented by the formula (4), which comprises hydrolyzing isoxazolidines.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the formula (1) showing olefin aldehydes used as a raw material in the present invention, the divalent aromatic group which may have a substituent represented by R ¹ is phenyl, Examples thereof include groups in which an alkyl group, an alkoxy group, a nitro group, a halogen atom or the like is substituted on a group such as naphthalene or an aromatic heterocycle. On the other hand, examples of the divalent aliphatic group which may have a substituent include an alkylene group substituted with an alkoxy group, a nitro group, an aromatic group or the like. The organic groups represented by R ² , R ³ and R ⁴ include linear, branched or cyclic aliphatic groups, aromatic groups, aralkyl groups, alkoxycarbonyl groups, alkenyloxycarbonyl groups and aromatic oxycarbonyl groups. And so on. Further, these aliphatic group and aromatic group may be further substituted with an alkoxy group, a nitro group, an alkyl group, an aromatic group and the like.

Such olefin aldehydes (1)
For example, the following equation (5)

[0012]

[Chemical 6]

(Wherein R²′, R^Three'And R^Four′ Is hydrogen source
Child, alkyl group, aralkyl group, alkoxycarbonyl
Group, alkenyloxycarbonyl group, or aromatic oxy
Represents a carbonyl group, A is a single bond, an oxygen atom, NR^Ten
(Where R^TenRepresents a hydrogen atom or an amino protecting group), sulfur
Represents a yellow atom or a methylene group, R⁶, R⁷, R⁸And R
⁹Is an alkyl group, alkoxy group, halogen atom, nitro
Group or R⁶And R⁷, R⁷And R⁸Or R⁸And R
⁹Form a benzene ring with adjacent carbon atoms
May be. ) Is preferred.

Further, in the formula (2) showing the hydroxyoxime as the other raw material, the linear or branched alkylene group which may have a substituent represented by R ⁵ is:
Examples thereof include an alkylene group which may have a substituent having 2 to 6 carbon atoms, and an alkylene group which may have a substituent having 3 to 5 carbon atoms is more preferable. Here, the substituent on the alkylene group may be an optically active oxygen functional group derived from a saccharide.

Organotin compounds used as catalysts in the condensation reaction of olefin aldehydes (1) with hydroxyoximes (2) include dialkyltin oxides such as dibutyltin oxide and dioctyltin oxide; dialkyltin dicarboxylic acids such as dibutyltin diacetate. Acid esters and the like can be mentioned.

The reaction of the olefin aldehydes (1) with the hydroxyoxime (2) is carried out in an inert solvent such as toluene or benzene in the presence of a trace amount of the above organotin compound, preferably 1 to 5 mol% based on the raw material. It is preferable to heat and reflux for several hours (3 to 6 hours depending on the amount of catalyst). The molar ratio of the raw material compound used is not particularly limited, but is preferably 1: 1.

Hydrolysis of the isoxazolidines (3) obtained by the above reaction is preferably carried out under acidic conditions. The acid used is preferably a mineral acid such as hydrochloric acid, nitric acid or sulfuric acid.

To extract the desired product from the acidic aqueous solution after the reaction, the neutral layer may be extracted and removed, and then the aqueous layer may be made alkaline. Further, to further purify the desired product, recrystallization, column chromatography or the like may be used.

[0019]

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

Example 1 2- (3-Methyl-2-butenyloxy) benzaldehyde (190 g, 1 mol), 5-hydroxypentanal oxime (120 g, 1.03 mol) and dibutyltin oxide (5 g, 2 mol%) in toluene solution 5 (1L)
Heated to reflux for an hour. After the crystals precipitated by cooling are separated by filtration,
The solvent was evaporated, the crystals and the residue were combined and stirred in ethanol (1.2 L) and 2M hydrochloric acid (600 ml) at room temperature for 16 hours. The reaction was concentrated and then extracted with diethyl ether (2 x 200 ml). The aqueous layer was made alkaline with aqueous ammonia, extracted with methylene chloride, and crystallized to give 20
4 g (90%) of 1,3a, 4,9b-tetrahydro-
3,3-Dimethyl-cis-3H- [1] benzopyrano [4,3-c] isoxazole was obtained.

Melting point 120-121 ° C. ¹ H-NMR; 7.37 (m, 1H), 7.22 (m, 1H), 6.95 (m, 2H), 4.50
(d, J = 6.6Hz, 1H), 4.20 (dd, J = 4.8,5.1Hz, 1H), 3.82 (dd, J =
10.8, 13.2Hz, 1H), 2.55 (m, 1H), 1.44 (s, 3H), 1.30 (s, 3
H). ¹³ C-NMR; 155.1, 131.0, 129.2, 121.4, 119.2, 117.1,
84.8, 63.5, 57.7, 48.1, 28.6, 21.3. MS m / z; 205, 173, 137, 120, 91. Elemental analysis (as C ₁₂ H ₁₅ NO ₂ ); Theoretical value: C, 70.22; H, 7.37; N, 6.82. Analytical value: C, 70.09; H, 7.33; N, 6.79.

Example 2 2-allyloxy-1-naphthaldehyde (2.12)
g), diacetone mannose oxime (2.75 g)
And a toluene solution of dibutyltin oxide (30 mg) (60
(ml) was heated to reflux for 3 hours. The solvent was distilled off and ethyl acetate-
Crystallization from hexane gave 2.98 g (64%) of adduct-1. Chromatography from the mother liquor further added 0.90 g (17%) of adduct-1 and 0.80 g (15%).
%) Of isomer adduct-2 was obtained.

[0023]

[Chemical 7]

The resulting adduct-1 was hydrolyzed in the same manner as in Example 1 to give 1,3a, 4,9b-tetrahyhydro-cis-3H- [1] naphthopyrano [4,3-c] isoxazole. Got

Examples 3 to 9 In the same manner as in Example 1, the compounds shown in Table 1 were obtained.

[0026]

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[0027]

[Table 1]

Examples 10 and 11 The reaction was carried out under the same conditions as in Example 1 except that benzene was used as the reaction solvent, and the following compounds were obtained.

[0029]

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Example 12 A reaction was carried out in the same manner as in Example 1 except that citrorelal and 5-hydroxypentanol oxime were used as the raw materials, hydrolysis was carried out using 1.1 mol of perchloric acid, and the reaction was carried out in methanol at 60 ° C. , The following compound was obtained (yield 76
%).

[0031]

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Example 13 A reaction was carried out in the same manner as in Example 1 except that melonal and 5-hydroxypentanal oxime were used as the starting materials, hydrolysis was carried out using 1.1 mol of perchloric acid, and the hydrolysis was carried out at 60 ° C. in methanol. The following compound was obtained (yield 80%).

[0033]

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Example 14 The following compound was obtained in the same manner as in Example 1 using 2- (3-methyl-2-butenyl) benzaldehyde as the olefin aldehyde (yield 53%).

[0035]

[Chemical 12]

Example 15 2- [N- (β-methyl-
Using 2-butenyl) -N-tosylamino) benzaldehyde, the following compound was obtained in the same manner as in Example 1 (yield 9
0%).

[0037]

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[0038]

According to the present invention, since the reaction between olefin aldehyde and hydroxyoxime is completed at a low temperature and in a short time, there are few side reactions, a high yield and a wide range of N-
Unsubstituted isoxazolidines are obtained.

Claims (1)

[Claims] 1. The following formula (1) (In the formula, R ¹ represents a divalent aromatic group which may have a substituent or a divalent aliphatic group which may have a substituent, and R ² , R ³ and R ⁴ are Indicates a hydrogen atom or an organic group)
The olefin aldehydes represented by the formula (2): HO-R ⁵ -CH = N-OH (2) (In the formula, R ⁵ is a linear or branched chain which may have a substituent. Of the formula (3) embedded image obtained by reacting a hydroxyoxime represented by (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above), the isoxazolidines are hydrolyzed. (In the formula, R ^1a , R ^2a , R ^3a and R ^4a are R ¹ and R respectively.
² , R ³ and R ⁴ , or a group or a hydrogen atom formed by hydrolysis of these groups), a process for producing an N-unsubstituted isoxazolidine.