DE2032809A1 - Process for the preparation of 3 Hydroxyisoxazoldenvaten - Google Patents

Description

Patent attorney
Bertin iö, lUteefcUaiua 2

June 29, 1970 P.5105

Sankyo Company, limited in ϊ ο k y ο (Japan).

Process for the preparation of 3-hydroxyisoxazole derivatives.

The invention relates to a new and improved process for the preparation of J-Hydroxyisoxazolde * derivatives of the formula

OH

/ (D

where R is an alkyl group such as methyl, ethyl, η-butyl and represents tert-butyl or a phenyl group.

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It is known that the 3-hydroxyisoxazole derivatives (I) are useful as agricultural fungicides, and that they are themselves are also useful as intermediates for a synthesis of organic phosphates, which are an insecticidal Have activity (Japanese Patent Publication No. 2440/67 and British Patent Publication ITo. 1 115 585).

Several processes for the preparation of the 3-hydroxyisoxazole derivatives have heretofore been proposed. A sol-

^ ches typical well-known procedure is the procedure, which by I. Iwai et al. in Chemical from Pharmaceutical Bulletin, Volume 14, page 1277 (1966) and in Japanese Patent Publication No. 25660/67, corresponding to British Patent No. 1 113 618 was described and claimed. The aforementioned known method consists in the reaction of an acetylenecarboxylic acid alkyl ester with hydroxylamine in the presence of an alkali metal hydroxide to form the aforementioned 3-hydroxyisoxazole derivatives to manufacture. Although this known method for a. economically feasible process can be sustained, there are some drawbacks that should be overcome or improved.

W It is particularly difficult under the existing circumstances in the art, to get the Acetylencarbonsäurealkylester used as starting material in a commercial scale and at low cost. Another known method is disclosed in Japanese Patent Publication No. 14704/68 and in French patent no. 1 534 601 has been published. According to this known process, the 3-hydroxyisoxazole derivatives are prepared by reacting a compound selected from the group consisting of a saturated "(", ß-dihaloaliphatic carboxylic acid alkyl ester and

■■ "* ^; , iV:

an unsaturated 06- (or B-yeonohaloaliphatic carboxylic acid alkyl ester with hydroxylamine in the presence of an alkali metal hydroxide. However, this process is disadvantageous from an economic point of view because the yield of the desired product is not very high (about 60 to BO ) 3 yield). It is therefore understandable that these known methods could not be considered in the art to be the most advantageous methods.

AIp a result of intensive research on a {

economically advantageous process for manufacture the 3-hydroxyisoxazole derivative (I) has now been unexpectedly found that the desired product can be easily prepared in high yields by reaction a β, β-dihalocarboxylic acid ester, which is relatively is cheap and easy to obtain on an industrial scale, with a hydroxylamine in the presence of one Alkali or alkaline earth metal hydroxide.

It is therefore a main aim of the present study to show a new and improved process for the preparation of the 3-hydroxyisoxazole derivatives (I).

Further features and advantages of the invention emerge from the following description. "

According to the present invention, the 3-hydroxyisoxazole derivative of the formula (I) prepared by reacting a β / β-dihalocarboxylic acid ester of the formula

X ■

I.
RG- GE ₂ - COOR ¹ (II)

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ÖAD ORIGINAL

wherein R has the meaning described above, wherein R * is a Alkyl group such as methyl, ethyl and η-butyl represents, and and wherein X represents a halogen atom such as chlorine or bromine with hydroxylamine in the presence of an alkali or alkaline earth metal hydroxide. When carrying out the process according to the invention, the reaction can preferably be carried out by using an organic solvent such as methanol, dioxene, tetrahydrofuran and acetone, and preferably

^ e utes an aqueous organic solvent, such as aqueous Methanol, aqueous ethanol and aqueous dioxane.

Preferred examples of the alkali or alkaline earth metal hydroxide to be used in the reaction are sodium hydroxide, Potassium hydroxide, calcium hydroxide and the like. Although the reagent, hydroxylamine, is in the form of a free one Base can be introduced, it is useful and preferred, the inorganic or organic acid addition salt of which to use, for example the Hydrochloric !, the sulfate and the like. The reaction can generally the starting ester (II) and hydroxylamine (as a free base) in a molar ratio of about 1: 1 up to about 1: slightly above 1 can be used. It is

In the reaction, it is expedient to use the alkali or alkaline earth metal hydroxide in an amount of about 4 mol to about 6 mol or more per mol of the starting ester (II). The reaction temperature is not critical, but it is expedient that the reaction initially at room temperature or under cooling, for example in the range of about -1O ⁰ C to about 25 ⁰ C, and then above room temperature, preferably at about 5O ⁰ C to about 80 ⁰ C is carried out with heating, because it can be assumed that the reaction proceeds in two stages, which is indicated below with chemical formulas:

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R - O - OE ₂ - COOR ¹

R - C - OH ₂ - C

NHOH

/ ■

In the above formulas, R, R ¹ and X have the meanings described above.

In the present process, alkali or alkaline earth metal salts of the desired product (I) are in situ educated. The 3-hydroxyisoxazole derivatives (i) are obtained by customary methods, for example by adding an acid to the reaction mixture, distilling off of the organic solvent and collecting the in the aqueous Residue formed precipitate by filtration. The desired product can be purified by extraction the precipitate with a suitable solvent, such as benzene or ether, drying the extract, distilling off of the solvent and recrystallization of the residue from a suitable solvent, such as n-hexane. The starting materials (II) in the present process are new compounds, and they are produced with high Yield (above 90 #) by reaction of a ß-ketocarbon

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acid esters of the formula

R - CO - CH ₂ - COOR ¹ (III)

wherein R and RV have the meanings described above, with a phosphorus pentahalide at a low temperature. In carrying out the aforementioned process, the reaction can be carried out in the presence or in the absence of an inert solvent. As the inert solvent, there can be used carbon disulfide, carbon tetrachloride, diehlorethane, benzene, n-hexane and the like. The reaction is performed at a low temperature, preferably to avoid at about -2O ⁰ C to 5 ⁰ C to side reactions. As the phosphorus pentahalide, phosphorus pentachloride or phosphorus pentabromide can be used in an amount of 0.5 mol or more per mol of the β-ketocarboxylic acid ester (III). After the reaction has ended, water or alcohol is added to the reaction mixture in order to decompose the phosphorus halide formed. The resulting mixture is washed with water and the solvent is distilled off from the reaction mixture, whereby the β, β-dihalocarboxylic acid ester (II) is obtained in high yield. The product can be purified by rectification or recrystallization.

Manufacture of the starting material

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(1) Preparation of methyl β, β-dichlorobutyrate

To 40 ml of 1,2-dichloroethane, 24 g.Phoephorpenta-. Chloride added. To the resulting solution is added dropwise 20 g Hethylacetoacetat with stirring and under cooling to -1O ⁰ C to -5 ⁰ O. Hach completion of the addition, the reaction mixture is stirred for 6 hours at -5 ⁰ C. Methanol is added to the reaction mixture in order to decompose the phosphorus oxychloride formed. The resulting mixture is washed with water and the diehlöathan is distilled off, giving 26.4 g (90 # yield) of the desired product. The product thus obtained is rectified and die.Fraktion which boils at 178.5 to 180 ⁰ C, is collected to give the desired product.

Analysis values

for C ₅ H ₈ O ₂ Cl ₂ : C * 35.11 # i H »4.71J *; Cl * 41.46? T found: C «35.45 #; H = 4.89t; Cl «41.32? I

OfJ

Specific gravity dgQ 1 »2449 Refractive index n | 1.4470

(2) Production of methyl ß-phenyl-ßjß-dichloropropionate

35 g of rhosphorus pentachloride are added to 60 ml of 1,2-dichloroethane. 50 g of methyl benzoylacetate are added dropwise to the resulting solution with stirring and with cooling to -10 ⁰ to -5 ^{0 C.} After the addition is completed, the reaction mixture is stirred for 5 hours at -5 ° C. and left to stand at this temperature overnight. To the reaction mixture becomes

Added methanol in order to decompose the phosphorus oxychloride formed. The resulting mixture is washed with water and the dichloroethane was distilled off to give 55 g (85 i> yield) of the desired product. The product obtained in this way is recrystallized from η-hexane, whereby the pure product is obtained.

Analysis values

calculated for C ₁₀ H ₁₀ O ₂ Cl ₂ :

0 * 51.53 #; H = 4.32 #; 01 = 30, found 0 = $ 51.60; H = 4.35 #; 01 = 30.11 /.

The following examples are given for the purpose of illustrating the process according to the invention, but without to limit the scope of the invention.

example 1 3-hydroxy-5-n) ethyliBoxazole

10 g of methyl ß, ß-dichlorobutyrate are added ^{dropwise at -5 0} C to a solution consisting of 4.47 g of hydroxylanjine hydrochloride, 6.35 g of sodium hydroxide, 16 ml of water and 100 ml of methanol. The solution obtained is stirred at this temperature for one hour and then at room temperature for a further hour. 5.4 g of sodium hydroxide are dissolved in the solution, and the resulting solution is refluxed for 4 hours. ! laugh at the ab-

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cool, the reaction mixture is acidified by adding hydrochloric acid and the methanol is distilled off under reduced pressure. The separated 3-hydroxy-5-niethylisoxazol is extracted with benzene and the extract concentrated to dryness to give 5.21 g (90 i> yield) of a pale-yellow needles. The product obtained in this way is identified with an authentic sample using the mixed melting point and the infrared spectrum.

Example 2 3-Hydrox.v-5-phenyliBoxazole

A solution of 23 g of methyl ~ ß-phenyl-ß, ß-diehlorpropionat in 200 ml of methanol is added dropwise at -5 ⁰ O to a solution consisting of 10 g of hydroxylamine sulfate, 12 g of sodium hydroxide and 25 ml of water. The resulting solution is stirred for one hour at the same temperature and then for a further hour at room temperature. 10 g of 50 percent strength by weight aqueous sodium hydroxide are added to the reaction mixture, and the resulting solution is refluxed for 5 hours. The methanol is distilled off under reduced pressure and 200 ml of water is added to the residue. The aqueous solution is acidified by adding 50 percent sulfuric acid to separate out 3-hydroxy-5-phenylisoxazole, which is collected by filtration and dried to give 14.3 g (90 % yield) of crystals. The crude product obtained in this way is ^{recrystallized from Be 1} ZoI to give needles which melt at 166 to 167 ° C. The product will

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with an authentic sample with the help of the melting point and the infrared spectrum identified »

Claims;

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Claims (4)

Patent claims: | 1 J Process for the preparation of a 3-hydroxyisoxazole derivativea the formula -OH IT
R '"O ^ wherein R is an alkyl group or a phenyl group .., characterized by the reaction of a ß, ß-dihalocarboxylic acid ester the formula X ■■ '- .. ■ R - -C - CH ₉ - COOR ¹ wherein R has the meaning described above, wherein R ^{1 represents} an alkyl group and wherein X represents a halogen atom, with hydroxylamine in the presence of an alkali or alkaline earth metal hydroxide. 2. The method according to claim 1, characterized in that the reaction is carried out in an aqueous! «! Ethanol. 5. The method according to claim 1, characterized in that that the alkali metal hydroxide is ITodium hydroxide. 4., The method according to claim 1, characterized in that that X is CrJ.or. " 009884/2244