HU191592B - Process for preparing isoxazole-derivatives - Google Patents

Abstract

The isoxazole derivative of formula (I> <IMAGE> may be prepared by treating a compound of formula (II> <IMAGE> wherein R<1> stands for an alkyl group containing 1 to 6 carbon atoms, with an oxidizing agent, such as manganese dioxide, potassium iodide and halogen or a hypohalic acid, hydrolizing the resulting compound of formula (II> <IMAGE> wherein R stands for a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, and recovering the product obtained in a manner known per se. Compound (I) is an intermediate for the preparation of thienamycin.

Description

The present invention relates to a novel process for the preparation of the isoxazole derivative of the formula (I).

The compound of formula (I) is disclosed in U.S. Pat. s. Hungarian Patent Application (No. 189,236) discloses thienamycin as a new in-process product.

It has now been found that the isoxazole derivative of formula (I) can also be prepared from the compound of formula (III) in a very simple manner. Compounds of formula (I) wherein R ^{1 is C} 1-6 alkyl are disclosed in U.S. Patent No. 4,269,772. U.S. Pat. No. 4,198,125 discloses thienamycin intermediates, but the reduction method described therein has shown that the compounds of formula (III) are practically unavailable. Examples 5 and 6 of the present disclosure describe how to convert an isoxazole slag of Formula I from a compound of Formula III to a compound of Formula IV wherein R ^{1 is C} 1-6 alkyl, thienamycin (V). hereafter referred to as &quot; 32,400 &quot; According to European patent application, thienamycin can be produced.

The present invention therefore relates to a process for the preparation of an isoxazole derivative of formula (I) which comprises treating a compound of formula (III), wherein R ^{1 is a C} 1-6 alkyl group, with a suitable oxidizing agent, followed by The compound of formula (III) wherein R is hydrogen or (C1-C6) -alkyl is hydrolyzed to give the product.

According to the process of the present invention, a compound of formula (111) is first oxidized.

The oxidizing agent used is preferably a halogen such as iodine, bromine or chlorine in aqueous potassium iodide solution, or a hypohalic acid such as hypochlorous acid instead of halogen. The compound of formula (III) itself is used in a solution of an indifferent organic solvent. The oxidation is carried out at elevated temperature, preferably at the reflux temperature of the reaction mixture. The reaction produces a compound of formula (II) wherein R is hydrogen, which is recovered by extraction and then hydrolyzed to give the compound of formula (I).

Manganese dioxide may also be used as the oxidizing agent, preferably in its active form. The oxidation is carried out in the presence of an indifferent organic solvent. The reaction results in the formation of a compound of formula (11) wherein R is C 1-6 alkyl, which is optionally recovered but preferably directly hydrolyzed.

In both cases, the hydrolysis is conveniently promoted with an acid, although a base may be used. In the latter case, however, production is weaker.

The product of hydrolysis is isolated by evaporation.

The invention is further illustrated by the following non-limiting Examples.

Example 7 [5-Methyl-4- (methoxycarbonyl) -3-isoxazole] -acetic acid

Trans ethyl [5-methyl-4- (methoxycarbonyl) -4,5-dihydro-3-isoxazole] acetate (229 g, 100 mmol) was dissolved in tetrahydrofuran (7.5 mL). A solution of potassium iodide (5.68 g, 34 million) and iodine (2.68 g, 10.5 mmol) in water (25 mL) was added and the reaction mixture was heated under reflux for 6 hours. The excess iodine was then treated with sodium bisulfite and the reaction mixture was extracted with dichloromethane (5 x 10 mL). The combined organic layer was washed twice with 10 mL of saturated brine, and the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated and triturated with ether.

Yield: 1.56 g (79%) of the title compound.

M.p .: 135 ° C

IR (KBr): 3500-2400, 1730 (shoulder), 1710.1600 cm ^-1 . ¹ H-NMR (CDCl ₃ ), δ: 2.63 s (3H), 3.76 s (3H), 3.88 s (2H), 10.10 s (1H).

Example 2 (4-Carboxy-5-methyl-3-yl-oxazole) -acetic acid

An emulsion of 1.99 g (10 mmol) of [5-methyl-4-methoxycarbonyl-3-isoxazole] acetic acid prepared in Example 1 was treated with 10 ml of water and 10 ml of concentrated hydrochloric acid and refluxed for 2 hours. The resulting solution was clarified hot, filtered and the filtrate was concentrated to half. On cooling, the solution crystallizes. The crystals are collected and dried.

Yield: 1.78 g (96%) of the title compound.

230 ° C (from water)

IR (KBr): 3600-2400, 1720.1690, 1610 cm ^1st

¹ H-NMR (D 6 O): δ 2.55 s (3H), 3.85 s (2H).

¹ H-NMR (DMSO-d ₆ ): δ 2.4 s (3H), 3.55 s (2H).

Example 3

Ethyl [5-methyl-4- (methoxycarbonyl) 3-isoxazole] -acetate g trans-Ethyl [5-methyl-4- (methoxycarbonyl) -4,5 dihydro-3-isoxazole] acetate and g of active manganese dioxide are refluxed in 100 ml of anhydrous benzene for 6 hours. The resulting water is continuously removed by 3zeotropic distillation. After completion of the reaction, the reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure.

Yield: 1.8 g (60%) of the title compound.

Mp .: 115 ° C / 0.2 mm Hg.

IR (film): 1715, 1725 cm ^1st

¹ H-NMR (CDCl ₃ ): δ 1.25 t (3H), 2.65 s (3H), 3.80 s (3H), 3.85 s (2H), 4.15 g (2H).

191 59 /

Example 4 [5-Methyl-4- (methoxycarbonyl) -3-isoxazole] -acetic acid

Ethyl [5-methyl-4-methoxycarbonyl-3-isoxazole] -acetate (0.5 g) prepared in Example 3 was heated at reflux for 30 minutes with 3 ml of 20% aqueous hydrochloric acid. The reaction mixture was then evaporated and the residue was crystallized by trituration with ether.

Yield: 0.4 g (90%) of the title compound having the same physical constants as in Example 1.

Example 5 n-Butyl [5-methyl-4-t-butoxycarbonyl) -3-isoxazole acetate g (70.2 g mmol) was prepared as in Example 2 (4-Carboxy-5-methyl-3). (isoxazole) acetic acid in a mixture of 60 ml of n-butanol, 150 ml of benzene and 15 ml of concentrated sulfuric acid is refluxed for 16 hours and the reaction mixture is poured onto ice. The phases are separated and the aqueous phase is extracted with twice 75 ml of benzene. The combined benzene phases are washed twice with 100 ml of water, twice with 75 ml of 5% aqueous sodium bicarbonate solution and again with twice with 75 ml of water each. The benzene solution was dried over calcium chloride and the solvent was distilled off under reduced pressure. The residual oil was 23 g which could be used without further purification. In a given case, it is cleaned by vacuum distillation. (Mp: 130131 ° C / 0.1 mmHg).

Example 6 (2RS, 3RS, 4SR) -4- (Benzylamino) -2-methyl-6-oxotetrahydropyran-3-carboxylic acid hydrochloride g (13.3 mmol), prepared according to Example 5, is prepared as follows: 5-Methyl-4- (n-butoxycarbonyl) -3-isoxazole] -acetate was hydrogenated in 40 ml of 99.5% glacial acetic acid in the presence of 0.5 g of 10% palladium-on-carbon catalyst at room temperature and atmospheric pressure. The catalyst was filtered off, and to the filtrate was added sodium cyano trihydroborate (1.93 g, 27 mmol) with stirring over 20 minutes, and the reaction mixture was stirred at room temperature for 3 hours, then in a water bath for 80 minutes. The reaction mixture was then cooled to room temperature and then

Benzaldehyde (1.6 mL, 16.5 mmol) was added and allowed to stand overnight. Another 1.4 g (20 mmol) of sodium cyanotrihydroborate was then added with stirring for 20 minutes and allowed to stand for 24 hours.

The resulting solution was concentrated in vacuo and 50 ml of n-heptane was distilled off. To the residue was added ether (50 mL) followed by stirring in small portions (40 mL) 10% aqueous potassium bicarbonate solution. The ether layer was separated and the aqueous layer was extracted with ether (2 x 40 mL). The combined ethereal solution was first 40 ml then 20 ml

After washing with 10% aqueous potassium bicarbonate solution, twice with 20 ml of saturated brine each time, the organic phase was evaporated.

The residue was refluxed with concentrated hydrochloric acid (30 mL) for 3 hours, cooled to room temperature, washed with ether (2 x 30 mL), and the hydrochloric acid was evaporated.

The resulting solid residue was triturated with acetone (20 mL), filtered, washed with acetone (10 mL), ether (2 x 10 mL), water (10 mL), and dried.

Yield: 2.1 g (52%) of the title compound.

M.p. 163-164 ° C.

Claims (1)

Claims 1. A process for preparing isoxazole derivatives of formula (I), comprising, reacting a compound of general formula (III) - wherein, R ¹ is 1 to 6 carbon atoms - oxidant hand ^40, and thereafter the formula (II) is the compound of formula (I) wherein R is hydrogen or (C1-C6) -alkyl is recovered and the product of formula (1) is recovered. 2. The process according to claim 1, wherein the oxidizing agent is manganese dioxide or a halogen or hypohalogen acid added to an aqueous solution of potassium iodide. 3. The process of claim 1, wherein the hydrolysis is carried out in the presence of an acid.