JP2640822B2 - Method for producing isoxazolidines - Google Patents

Description

The present invention relates to a novel process for producing isoxazolidines.

Isoxazolidines can be widely used as intermediates for the synthesis of physiologically active substances such as pharmaceuticals and agriculture, and as chemicals such as stabilizers, functional substances or synthetic intermediates thereof. Therefore, it is useful in the chemical industry.

(Prior Art) Conventionally, as a method for producing isoxazolidine, Journal of Chemical Society, p.432, 1942,
Ethoxycarbonyl isoxazolidine (II
It is only described that, using I), isoxazolidine hydrochloride (IV) was obtained by hydrolysis with hydrochloric acid.

However, a method for producing an isoxazolidine represented by the following general formula (II) by hydrolyzing an acyl isoxazolidine derivative represented by the following general formula (I) as described in the present invention is completely described in the literature. There is no.

(Problems to be Solved by the Invention) In order to obtain isoxazolidine hydrochloride (IV) by hydrolyzing ethoxycarbonyl isoxazolidine (III), the method described in the above-mentioned literature was used in this reaction. Equimolar carbon dioxide gas is generated as ethoxycarbonyl isoxazolidine (III). Generation of large amounts of carbon dioxide can cause an explosion of the reactor. In particular, if the reactions occur in a chain due to the catalytic action of impurities contained therein or the local heating of the reaction vessel, there is a risk of causing a major accident due to an explosion. Therefore, it is not preferable as an industrial production method.

On the other hand, ethoxycarbonylisoxazolidine (III), which is a precursor of isoxazolidine (IV), can be obtained by reacting N-hydroxyurethane with 1,3-dibromopropane (Journal of Chemical Society of 1942). 432). However, in order to obtain N-hydroxyurethane as a raw material, the reaction must be based on a highly toxic reaction between chloroethyl formate and hydroxylamine, which is obtained by a reaction between phosgene and ethanol. Therefore, in a conventional reaction route using ethoxycarbonyl isoxazolidine, it is inevitable to use phosgene having extremely high toxicity to humans and animals, which is problematic as an industrial production method.

In view of these circumstances, an object of the present invention is to establish a new process for producing isoxazolidines suitable for industrial-scale production using raw materials that are not explosive and have no toxicity to humans and animals. is there.

(Means for Solving the Problems) In order to achieve the above objects, the present inventors have intensively studied a number of reactions. As a result, the following general formula (I) [Wherein, R ₁ represents an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, or an arylalkyl group (where aryl is a benzene nucleus, a naphthalene nucleus, a pyridine nucleus, a thiophene nucleus, or a furan nucleus. And these nuclei may be substituted with up to three identical or different halogen atoms, lower alkyl groups, lower haloalkyl groups, lower alkoxy groups and nitro groups), and R ₂ represents lower alkyl And n is 0
Represents an integer of ~ 3, and A is Or The compound represented by the general formula (II) is hydrolyzed to obtain a compound represented by the general formula (II): [In the formula, R ₂ represents a lower alkyl group, and n represents an integer of 0 to _3. ] It has been found that isoxazolidine compounds represented by the formula:

The hydrolysis reaction of the present invention can be carried out by simply adding water to the compound of the formula (I) and heating the compound. However, usually, in order to accelerate the reaction, an acid or a base is further used. Hydrolysis is good. In this case, (I)
Hydrolysis with an acid is preferred because it is convenient in operation to handle the compound of formula (II) as a salt of an acid after hydrolyzing the formula compound. As the acids that can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid are preferable, and as the base that can be used, sodium hydroxide, potassium hydroxide, sodium carbonate, and the like can be given.

When the hydrolysis is carried out using acids, an aqueous solution containing at least 1 equivalent mol, preferably 1.5 to 3 equivalent mol of an acid to the compound of the formula (I) is mixed with the compound of the formula (I) and heated. I just need. The reaction temperature can be freely selected from room temperature to the boiling point of water, but usually the reaction is completed by heating from room temperature to the boiling point. After completion of the reaction, when the mineral acid is hydrochloric acid and R has a low molecular weight, the hydrochloride of the compound of the formula (II) is obtained by distilling off the acid residue together with water, and this is dissolved in alcohol, alkoxide, caustic soda. Alternatively, the compound is liberated with potassium hydroxide or the like to remove salts, and then the alcohol is distilled off to obtain the compound of formula (II). When R is not of low molecular weight and the mineral acid is hydrochloric acid, after hydrolysis, the acid residue is removed by extraction with toluene, tetrahydrofuran or chloroform, etc., and water is distilled off to obtain the compound of formula (II). Is obtained. When the mineral acid is other than hydrochloric acid, usually after hydrolysis, the excess mineral acid is neutralized with caustic soda, caustic potash, or sodium carbonate, etc. After the acid residue is extracted, water is distilled off to obtain a mixture of the compound of the formula (II) and an inorganic salt, which is liberated in alcohol to obtain the compound of the formula (II).

When the hydrolysis is carried out using a base, the hydrolysis is carried out by mixing the compound of formula (I) with an aqueous solution containing at least 1 equivalent mol, preferably 1 to 2 equivalent mol of alkali relative to the compound of formula (I). . Heating can be selected up to the boiling point of water, but usually 50 ° C to 60 ° C is often sufficient. After completion of the reaction, the compound of formula (II) is obtained by distilling off water. In some cases, a mineral acid such as hydrochloric acid, sulfuric acid, and phosphoric acid is added to the obtained reaction solution to form a salt, and the compound is treated in the same manner as in the case of the acid decomposition to obtain the compound of formula (II). .

The compound of formula (I) as a raw material is, for example, described in Journal of Organic Chemistry, Vol. 36, No. 284.
Page (1971) or a method similar thereto,
That is, it is obtained by reacting an acylhydroxylamine with a 1,3-dibromopropane derivative.

Examples 1 to 5 show production examples of the compound of the formula (II) by the production method of the present invention. Production examples of the compound of the formula (I) are shown in Reference Production Examples 1 to 3. Table 1 shows the members of the formula (I) compounds used in the present invention and (II)
The production examples of the formula compounds are shown together.

(Example 1) 3-methylisoxazolidine (reaction No.
4) Preparation of n-hexanoyl-3-methylisoxazolidine 1
A mixture of 8.5 g and 50 ml of 4N-hydrochloric acid was heated and refluxed for 10 minutes.
After cooling, 25 ml of 4N sodium hydroxide was added, and water was distilled off under reduced pressure. 100 ml of tetrahydrofuran was added to the residue, and the crystals were separated by filtration. After air-drying, the crystals were placed in 100 ml of a 1N-sodium methoxide solution, and the crystals were separated by filtration and methanol was distilled off under reduced pressure. The residue was distilled under reduced pressure to give the title compound as a colorless oil having a boiling point of 58-59 ° C / 21 mmHg, 7.1 g.
(81.6% yield).

(Example 2) Production of isoxazolidine (reaction No. 9) Using 44.7 g of benzoyl isoxazolidine, the reaction was carried out in the same manner as in Example 1, treated and distilled, and the title compound was found to be colorless with a boiling point of 70-72 ° C / 40 mmHg. As an oil, 14.
7 g (79.7% yield) was obtained.

Example 3 Production of Isoxazolidine (Reaction No. 15) 4-Methoxyphenylsulfonylisoxazolidine
A mixture of 24.3 g and 120 ml of 1N sodium hydroxide was stirred at 60 ° C. for 30 minutes. After cooling, 20 ml of 1N-hydrochloric acid was added and water was distilled off under reduced pressure. After adding 100 ml of tetrahydrofuran to the residue and filtering off the crystals, the residue was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was distilled under reduced pressure to give the title compound as a colorless oil having a boiling point of 70-72 ° C / 40 mmHg, yielding 5.9 ge
(Yield: 72.6%) was obtained.

(Example 4) 5-Methylisoxazolidine (reaction No.
26) Production of 26.3 g of α-naphthylsulfonyl-5-methylisoxazolidine, reacted, treated and distilled in the same manner as in Example 1 to give a colorless oil having the title compound having a boiling point of 70-72 ° C./31 mmHg. As a result, 7.0 g (84.7% yield) was obtained.

Example 5 3-ethylisoxazolidine (reaction No.
21) Preparation of benzylsulfonyl-3-ethylisoxazolidine
Using 21.9 g, reacted and treated as in Example 1,
After distillation, 8.5 g (yield 97.9%) of the title compound was obtained as a colorless oil having a boiling point of 64-65 ° C./22 mmHg.

(Reference Production Example 1) Production of benzoyl isoxazolidine (used for reaction No. 9) A mixture of 13.7 g of benzohydroxamic acid, 15.8 g of 1-bromo-3-chloropropane, 29.0 g of anhydrous potassium carbonate and 200 ml of dimethylformamide was added at 80 ° C for 1 hour. Stirred for hours. After cooling, the salts were filtered off and the filtrate was concentrated under reduced pressure. Chloroform was added to the residue, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 16.8 g of the title compound as a pale yellow oil. Purification by silica gel column chromatography gave a colorless oil,
It showed ²³ _D ▼ = 1.4434.

(Reference Production Example 2) Production of p-toluenesulfonyl isoxazolidine (used for reaction No. 12) 18.7 g of p-toluenesulfonylhydroxylamine,
A mixture of 15.8 g of 1-bromo-3-chloropropane, 11.5 g of potassium hydroxide and 200 ml of ethanol was stirred at 50 ° C. for 3 hours. After cooling, tetrahydrofuran, toluene and water were added, and the organic layer was separated. Dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 19.1 g of the title compound as pale brown crystals. Recrystallization with a mixed solvent of hexane and ethyl acetate gave white crystals, melting point 93-
94.5 ° C.

(Reference Production Example 3) Production of 3-methyl-2-pyridinecarbonylisoxazolidine (used for Reaction No. 33) 15.2 g of 3-methyl-2-pyridylcarbonylhydroxylamine, 20.2 g of 1,3-dibromopropane, 8.8 sodium hydroxide When the reaction and treatment were carried out in the same manner as in Reference Production Example 1 using g and 200 ml of ethanol, 15.5 g of the title compound was obtained as a pale brown oil. Purification by silica gel column chromatography gave a colorless oil,
It showed ²³ _D ▼ = 1.4683.

(Effect of the Invention) When the production method of the present invention is carried out, there is no generation of gas accompanying the hydrolysis reaction as compared with the conventional method of hydrolysis of ethoxycarbonyl isoxazolidine,
The reaction proceeds smoothly and there is no danger of explosion. for that reason,
The desired isoxazolidine can be obtained safely and in high yield.

Further, according to the production method of the present invention, the present invention can be applied to the production of not only isoxazolidine known hitherto, but also various isoxazolidines having various substituents thereon.

Further, according to the production method of the present invention, unlike the case where ethoxycarbonylisoxazolidine as a conventional raw material is used, acylisoxazolidines which are a raw material can be obtained safely and easily without using phosgene.

Therefore, according to the production method of the present invention, the target product can be obtained safely and in a high yield, and thus is useful as an industrial production method for isoxazolidines.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07D 413/12 307 C07D 413/12 307 333 333 (56) References JP-A-59-53474 (JP) , A) JP-A-61-286352 (JP, A) "Fram Organic Chemistry [I]], 4th edition, translated by Yukawa Yasuhide, February 15, 1986, Hirokawa Shoten, p. 333, John McMurry," Org ". anic Chemistry ", 1984, Brooks / Cole Publishing Company, USA. 794-795 Synthetic Reagents, edited by Shin Ogawara et al., June 1, 1980, Kodansha, p.51

Claims (1)

(57) [Claims] (1) General formula [Wherein, R ₁ represents an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, or an arylalkyl group (where aryl is a benzene nucleus, a naphthalene nucleus, a pyridine nucleus, a thiophene nucleus, or a furan nucleus. And these nuclei may be substituted with up to three identical or different halogen atoms, lower alkyl groups, lower haloalkyl groups, lower alkoxy groups and nitro groups), and R ₂ represents lower alkyl And n is 0
Represents an integer of ~ 3, and A is Or Is represented by the following formula: [Wherein, R ₂ represents a lower alkyl group, and n represents an integer of 0 to 3].