DE1445902C - Process for the preparation of 3-aminoisoxazoles - Google Patents

Description

The invention relates to a new, technically advantageous process for the preparation of 3-aminoisooxazoles of the general formula I.

C C - NH,

Il Il

R ₂ -CN

(I)

wherein R ₁ and R _{2 represent} hydrogen atoms or alkyl groups.

Individual 3-Aminoisoxazole are already known, so z. B. 3-Aminoisoxazoles with lower alkyl groups or a phenyl group in the 5-position (see e.g. British Patent 875,458 and Chemische Reports, 96 [1963], pp. 1088-1097).

However, the manufacturing processes known from these literature references are not without disadvantages. The method according to Chem. B'er. is z. B. only for a single 3-aminoisoxazole, namely 3-amino-5-phenylisoxazole experimentally proven. Following the procedure of British Patent Specification 875 458 a derivative is assumed that already contains an isoxazole ring, which is only used in a preliminary stage must be formed by a ring closure reaction. In contrast, in the method according to the invention the desired 3-aminoisoxazole is immediately formed by the ring closure reaction.

The process according to the invention is now characterized in that an α, / 5-dihalocarboxonitrile is used of the general formula II a or an α, / 9-unsaturated α-halocarboxylic acid nitrile of the general Formula Hb

HC

CN

(II a)

HC ^:

■ CN

(lib)

40

45

Xi

where R ₁ and R _{2 have} the above meaning and X ₁ and X _{2 are} halogen atoms, in an alkaline medium at temperatures of up to about 100 ^° C. with N-carbamoylhydroxylamine.

Examples of suitable R ₁ and R ₂ substituents are lower alkyl groups having 1 to 6 carbon atoms, in particular the methyl group. X ₁ and -X ₂ are preferably two halogen atoms of the same type, in particular bromine or chlorine atoms.

The α, / -dihalocarboxylic acid nitriles preferred as starting materials of the general formula II a can easily be selected from the corresponding α, / 3-unsaturated Carboxylic acid nitriles are obtained by addition of halogen, so z. B. the α, / ί-dibromoisobutyronitrile from the methacrylonitrile. The α, / ϊ-unsaturated a-monohalogen compounds of the general formula II b can, for. B. from those just mentioned α, / 3-dihalogen compounds of the general formula II a can be gained by removing a molecule of hydrogen halide.

Isolation of the dihalogen or monohalogen compounds prepared in this way of the general Formula II a or II b before the reaction with the hydroxylamine component is not necessary and, at least for the more unstable representatives of this group of compounds, not an advantage either. In the Rather, one will usually use the crude solutions as they are used in the preparation of the halogenated carboxylic acid nitriles incurred, use directly for the cyclization reaction.

Just like the halogen component, the hydroxylamine component does not need in pure form either to be used. Instead of crystallized, pure N-carbamoylhydroxylamine, one can use without also use crude solutions of the same, as they are in the representation of these compounds, z. B. from hydroxylamine salt solutions, ethyl carbamirate and alkali metal hydroxides.

The cyclization operation can e.g. B. in aqueous, aqueous-alcoholic (ζ. Β. Aqueous-methanolic) or alcoholic solution. The required alkalinity of the reaction medium can be achieved by adding alkalis, such as alkali metal hydroxides, carbonates or alcoholates (e.g. Sodium or potassium hydroxide or sodium ethylate). It is preferable to use pro Mol of dihalocarboxylic acid around 3 moles of alkali and around per mole of monohalocarboxylic acid nitrile 2 moles of alkali.

According to a preferred embodiment of the cyclization operation, the halogen component is added, advantageously with cooling, to an aqueous alkaline solution of the hydroxylamine component. The reaction mixture is then, optionally with the addition of an alkanol, such as methanol, initially kept at about room temperature, preferably with mixing, and then briefly heated, expediently to a temperature of about 80 to 100 ^° C. The resulting basic cyclization products can be in the usual way of Neutral accompanying substances are separated off, for example by extracting the aqueous phase with ethyl acetate or another organic, water-immiscible solvent such as benzene or ether, treating the ethyl acetate extract with a mineral acid, e.g. 2N hydrochloric acid, whereby the basic components are removed from the extract , saturation of the acidic aqueous solution with potassium carbonate and renewed extraction with ethyl acetate.

The 3-aminoisoxazole of the general formula I obtained as the main product of the cyclization reaction can contain small amounts of a cyclization product still containing halogen, e.g. B _{1 contains} a 4,5-dihydro-4-haloisoxazole as a by-product.

The 3-aminoisoxazoles of the general formula I, in particular S-amino-S-methylisoxazole, 3-amino-4-methylisoxazole, 3-amino-4,5-dimethylisoxazole or 3-aminoisoxazcdyo can be used as intermediates for the preparation of corresponding , chemotherapeutically active 3-sulfanilamido-4-R ₁ -5-R ₂ -isoxazoles can be used.

example 1

5 g (0.075 mol) of freshly distilled crotononitrile are mixed with 6 ml of absolute methanol and, while stirring and ice-cooling, 12 g (0.075 mol) of bromine are added dropwise. The mixture is for 12 hours at 0 ° C and a further 24 hours at 20 ⁰ C.

kept in the dark. The red-brown solution, which no longer contains bromine, is then added dropwise over the course of 5 minutes, with stirring, to a solution of 9 g (0.225 mol) of sodium hydroxide and 5.7 g (0.075 mol) of N-carbamoylhydroxylamine in 50 ml of water, with the internal temperature is kept at 8 ^° C. Then, the mixture is shaken for 45 hours at 20 ⁰ C, then heated under reflux for 3 hours in a water bath and then evaporated under reduced pressure to dryness, The last traces of water are distilled off azeotropically with benzene. The dry residue is then extracted twice with 50 ml of hot benzene each time, whereupon the combined benzene extracts are concentrated to about 40 ml. A crude benzene solution of crude 3-amino-5-methylisoxazole is obtained in this way. Content of pure 3-amino-5-methylisoxazole: 4.2 g (57% yield).

Example2

A solution of the sodium salt of N-carbamoylhydroxylamine (prepared from ethyl urethane according to Org. Syntheses, 40, p. 60; calculated content 11.4 g of N-carbamoylhydroxylamine) is cooled with 12 g (0.3 mol) of sodium hydroxide in 20 ml of water offset. At 8 ^° C., a methanolic solution of crude α, ^ - dibromobutyronitrile [prepared from 10 g (0.15 mol) of crotononitrile, 12 ml of absolute methanol and 24 g (0.15 mol) of bromine] is added to the N- Carbamoylhydroxylamine solution, whereupon the mixture is ^{shaken at 20 °} C. for 40 hours and then heated ^{to 90 °} C. for a further 3 hours. The dry residue obtained after evaporation under reduced pressure is extracted twice with 100 ml of benzene each time. The combined benzene extracts are concentrated to 80 ml. An anhydrous benzene solution of crude S-amino-S-methylisoxazole is obtained in this way. Content of pure 3-amino-5-methylisoxazole: 7.75 g (53% yield).

40 B eis ρ ie 1 3

a) To a solution of 16 g (0.4 mol) of sodium hydroxide in 100 ml of water are added 15.2 g (0.2 mol) of crystallized N-carbamoylhydroxylamine and the mixture is saturated with potassium carbonate: This solution is 45.5 g (0.2 mol) α, / 9-dibromobutyronitrile are added and the mixture is shaken ^{at 20 ° C. for 45 hours.} The precipitated, inorganic salts are filtered off. The filtrate is homogenized with ethanol and divided into two equal parts.

b) In order to obtain a bromine-free raw base fraction, the second half of the according to paragraph a) The resulting filtrate was heated on a water bath for 3 hours. The ethanol and part of the steam evaporate Water off. Customary work-up gives 7.6 g of a base fraction (from ethyl acetate) with a Bromine content of only 1.8% of the bromine content calculated for an aminomethyl-dihydro-bromoisoxazole. After recrystallization from benzene, the base is bromine-free. The 3-amino-5-methylisoxazole thus obtained is free from S-amino-S-methyl isomers. Yield 67% (based on N-carbamoylhydroxylamine).

Example4

A solution of 8 g (0.2 mol) of sodium hydroxide and 7.6 g (0.1 mol) of N-carbamoylhydroxylamine in 50 ml of water is saturated with potassium carbonate. After addition of 13.8 g (0.1 mole) of α, / 5-dichloro-buttersäurenitril the mixture is shaken for 3 days at 2O ⁰ C. The oil present is then brought into solution by adding ethanol and the solution is heated for 3 hours on a water bath (without reflux cooling). Customary work-up gives 5.1 g of a base fraction which, in addition to 3-amino-5-methylisoxazole, also contains some chlorine-containing dihydrobase (S-amino-S-methyM ^ -dihydro ^ -chloroisoxazole). Content of pure 3-amino-5-methylisoxazole: 3.8 g (38% yield).

B ei s ρ ie I 5

A solution of crude α, / 3-dibromobutyronitrile is prepared from 5 g (0.075 mol) of crotononitrile, 6 ml of absolute methanol and 12 g (0.075 mol) of bromine. To split off 1 molecule of hydrogen bromide, a solution of 3 g (0.075 mol) of sodium hydroxide in 20 ml of water is added to this solution, while cooling. After one hour, the resulting solution of crude α-bromo-crotonic acid nitrile is added to a solution of 6 g (0.15 mol) of sodium hydroxide and 5.7 g (0.075 mol) of N-carbamoylhydroxylamine in 60 ml of water. The mixture is shaken for 40 hours at 20 ^° C., then heated for 2 hours in a boiling water bath, and finally the basic components are isolated as usual. 5.5 g (75% yield) of crystallized, halogen- and isomer-free S-amino-S-methylisoxazole are obtained.

Example6

40 g of N-carbamoylhydroxylamine are added at 10 ° C. to a solution of 66 g of sodium hydroxide in 320 ml of water. Then, while stirring and cooling, 112 ga, /? - dibromopropionic acid nitrile are added dropwise over the course of about 30 minutes, the reaction temperature being kept at 15 ° C. The mixture is then stirred for a further 3 hours at 20 ^° C., then left for 48 hours at 20 ^° C., then _{blunted to pH 8 with CO 2} and finally extracted with 60 ml of ethyl acetate. When distilled off, the combined dried ethyl acetate extracts leave behind 33 g of oil, which is vacuum distilled; is obtained 29 g of distillate, Siedepunkt- 101 ⁰ C / 10 mm Hg, n = 1.5090% (Beilstein test positive); Melting point about 20 ° C. 29 g of the distillate obtained are heated under reflux for 2 ^l / ₂ hours 25 ml of dry pyridine. Then fractionate at 10 mm Hg. Are thus obtained 27.4 g (62%) of colorless 3-aminoisoxazole of boiling point 101 ⁰ C / 10 mm Hg; nl ° = 1.5090.

Example 7

48 g (1.2 moles) sodium hydroxide and 30.4 g (0.4 mol) of N-carbamoylhydroxylamine are dissolved in 40 ml of water. The solution is cooled to 0 ° C and with 90.8 g of α, / 3-dibromoisobutyric acid nitrile (er, hold by bromination of methacrylic acid nitrile) r, enrelated. The nitrile does not mix with the aqueous ^ phase. Also by adding 400 ml of methanol the mixture will not be homogeneous at first. After 1 hour, the external cooling is removed, whereupon the mixture warms up a little and finally becomes homogeneous. At the same time, yellowing occurs. The alkaline solution is left to stand at 20 ° C. for 5 days and then heated to 90 ° C. for 2 hours. After extraction of the basic components with ethyl acetate, 22 g of crude, bromine-free 3-amino

4-methylisoxazole. By recrystallization from benzene and this substance is obtained from ether in a crystallized, chromatographically uniform form of Melting point 45 to 50 ° C. Yield: 17.9 g (46%).

Example 8

In a round bottom flask equipped with a stirrer, 120 g of 2,3-dibromo-2-methyl-butyronitrile dissolved in 60 ml of methanol and a solution of 20 g of sodium hydroxide in 140 ml of water with stirring and cooling slowly added at 1O ⁰ C. After one hour, a solution of 39 g of N-carbamoylhydroxylamine in 400 ml of 10% sodium hydroxide solution is added and the mixture is stirred at 20 ° C. for a further 40 hours. The mixture is then heated to 90 ° C. for 2 hours, the majority of the methanol evaporating. After cooling, the 3-amino-4,5-dimethylisoxazole precipitates in crystalline form from the alkaline solution. Add 300 ml of ethyl acetate to form two layers. These are separated and the aqueous phase is washed 3 times with a little ethyl acetate. The combined ethyl acetate extracts are dried over sodium sulfate and the ethyl acetate is evaporated, the residue solidifying spontaneously. The NMR spectrum of the crude product indicates that this is still about 25% contaminated with 5-amino-3,4-dimethylisoxazole. The raw yield is about 58%. The melting point of the crude base is 112 to 115 ° C. After recrystallization from benzene / methanol / petroleum ether (4/1/1), the contamination can no longer be detected by thin layer chromatography. Yield of pure 3-amino-4,5-dimethylisoxazole: 20.9 g (40%). Melting point: 115 ° C

B ice pie I 9

700 g of a-ethyl-a, / S-dibromobutyronitrile are dissolved in 350 ml of methanol and, with intensive stirring and cooling, a solution of 115 g of sodium hydroxide in 805 ml of water is added so slowly that the temperature is increased by cooling during the addition 5 to 10 ° C can be maintained. After the end of the entry, stirring is continued for 1 hour at the above temperature, and the mixture is then mixed with a freshly prepared one. Solution of 214 g of N-carbamoylhydroxyiamine. added in 2.35 1 10% sodium hydroxide solution and stirred at 20 ° C for 40 hours. The mixture is then heated to 90 ° C. for 2 hours with stirring, the majority of the methanol being distilled off. It is then cooled and the mixture is exhaustively extracted with ethyl acetate. The combined extracts, dried with sodium sulfate, are concentrated in vacuo and the solidifying residue [200 g, yield 58%; contains some 5-amino-3-methyl-4-äthylisoxazol as an impurity (NMR)] of melting point 72 to 75 ⁰ C from benzene / petroleum ether recrystallized. After recrystallization, the 3-amino-4-ethyl-5-methylisoxazole (colorless crystals) melts at 78 to 81 ° C. The yield of pure substance is 138 g (40% of theory).

Claims (1)

Claim: Process for the preparation of 3-aminoisooxazoles of the general formula I. R ₂ CC - NH ₂ Il Il C N wherein R ₁ and R _{2 are} hydrogen atoms or alkyl groups, characterized in that an α, / S-dihalocarboxylic acid nitrile of the general formula Ha or an a, ß-un saturated a-halocarboxylic acid nitrile of the general formula Hb R ₂ HC- ■ CN (Ha) X ₂ R ₂ HC = = C- X ₁ ■ CN (lib) where R ₁ and R _{2 have} the above meaning and X ₁ and X _{2 are} halogen atoms, in an alkaline medium at temperatures of up to about 100 ^° C. with N-carbamoylhydroxylamine.