DE1445902A1 - Process for the preparation of aminoisoxazoles - Google Patents

Description

RAH 4440/81 I.

F. Hoffmann-La Roche & Co. Aktiengesellschaft , Basel (Switzerland) Process for the preparation of aminoisoxazoles

The invention relates to a new, technically advantageous one Process for the preparation of 3-amino-: 1.iOzazoles of the general formula

R ² R ¹ I. I. C. - C I. I. 0 0-KH ₂

(D

1 2
• where R and R each represent a hydrogen atom, an alkyl, aralkyl or aryl group.

The method according to the invention is characterized in that "τ""™ is an α, ß-dihalocarboxylic acid! Tril of the general formula

R ² R ¹

II
HC C-CN (Ha)

X ²

or an α, ß-unsaturated α-halocarboxylic acid nitrile of the general formula

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R ²

HC ^ = ^ C - CN (IXb)

1 2

■ where in the formulas Ha -and lib R and R the above

1 2

Have meaning and X and X are halogen atoms,

in. alkaline medium with hydroxylamine or one in the amino group protected hydroxylamine to a 3-amino-isoxazole of the general formula I cyclized »

1 2
The R or “R” substituents are, for example

lower alkyl groups with 1-6 "carbon atoms, especially methyl, also benzyl _9, phenethyl and phenyl into consideration» The

1 2

Both symbols R and R can have the same or different meanings »For example, they can both mean a hydrogen atom or both an alkyl, aralkyl or aryl group, which can be the same or different, or one symbol can be a hydrogen atom and the other

12 represent an alkyl, aralkyl or aryl group «X and X are preferably two halogen atoms of the same type, in particular bromine or chlorine atoms "

Examples of corresponding starting materials of the formulas Ha and Hb _s used in the inventive cyclization

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the same 3-amino-isoxazole (formula I) are obtained a) the α, ß-dibromobutyronitrile and b) the a-bromo-crotonic acid nitrile. When using monohalocarboxylic acid nitriles of the formula Hb, only the cyclization products result those 3-amino-isoxazoles of the formula I in which R is hydrogen atom means »

The preferred as starting materials a, ß-Dihalogenarbonsäurenitrile of formula Ha can be easily prepared from the corresponding α, β-unsaturated carbonitriles are obtained by Halogenanlagerung, such "B" the α, ß-dibromo-isobutyronitrile from methacrylonitrile, the α.β- Unsaturated α-monohalogen compounds of the formula Hb, Z ₀ B _{0 can be obtained} from the abovementioned α, β-dihalogen compounds of the formula Ha by removing a molecule of hydrogen halide.

An isolation of the di- Halogen or monohalogen compounds of the formulas Ha or Hb 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. Rather, as a rule, you will the crude solutions as they are used in the manufacture of halogenated ones Carboxylic acid nitriles accumulate, use directly for the cyclization reaction,

BATH ORIGINAL

If one uses "in the cyclization operation according to the invention free hydroxylamine, so he can ink himself. Circumstances (most likely when using compounds of the formula Ha with R = hydrogen) in addition to the 3-amino compounds of the formula I in The corresponding 5-amino isomers also form a minor amount, the formation of these by-products practically does not occur utter when dealing with N-protected hydroxylamine, in particular with an H-acyl-hydroxylamine, works. The N-acyl protecting group can, for example, be derived from aliphatic or aromatic carboxylic acids, such as formic acid, acetic acid, propionic acid or benzoic acid. Accordingly, for example, U-formyl-, IT- = acetyl- or U-benzoyl-hydroxylamine can be used as the hydroxyl use lamine component »A particularly preferred ST = The acyl derivative of hydroxylamine is N-carbamoyl-hydroxylamine (Hydroxyurea) “This.hydroxylamine derivative guarantees you particularly uniform, specific and in high yield to the 3-amino compounds of the formula I leading ßeaktionsverlauf "

Like the halogen component, the hydroxylamine component does not need to be used in pure form either. Instead of crystallized, pure N-carbamoyl-hydroxylamine one can also use crude solutions of the same without further ado, as they are when these compounds are represented, ■ ζ "B" from hydroxylamines salt solutions, carbamic acid ethyl ester and alkali hydroxides, will be obtained "

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The cyclization operation can, for example, be carried out in aqueous, aqueous-alcoholic (e.g. aqueous-methanolic) or alcoholic Solution can be carried out »The required alkalinity of the reaction medium can be achieved by adding alkalis, such as Alkali metal hydroxides, carbonates or alcoholates (e.g. "B" Sodium or potassium hydroxide or sodium ethylate) can be obtained » Preferably, around 3 moles of alkali are used per mole of dihalocarboxylic acid nitrile (formula II a) and around 3 moles of alkali metal are used per mole of monohalocarboxylic acid nitrile (Formula II b) around 2 moles of alkali.

According to a preferred embodiment of the cyclization operation, the halogen component (formula Ha or «lib) 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 approximately room temperature, preferably with thorough mixing, and then briefly heated, expediently to a temperature of about 80-100 ° C. neutral accompanying substances are separated, for example by extraction of the aqueous phase with ethyl acetate or another organic, water-immiscible solvent (such as benzene, ether, etc.), treatment of the ethyl acetate extract with a mineral acid (e.g. 2N hydrochloric acid, which gives the extract the basic components are removed), saturation of the acidic aqueous solution with potassium carbonate and renewed extraction with ethyl acetate.

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The 3-amino-isoxazole of the formula I. obtained as the main product of the cyclization reaction can be small amounts of one more halogen-containing cyclization product as a by-product. This by-product is presumably a 4 * 5-dihydro-4-halo-isoxazole the formula

R ² R ¹

CH CX ¹ (III

I I

0 C

wherein R, R and X dj. _{e have the} above meaning »

The 3-amino-isoxazoles of the formula I, especially that 5-Amino-5-methyl-isoxazole, the 3-amino-4-methyl-isoxazole, the 3-Amino-4 »5-dimethyl-isoxazole or 3-amino- = isoxazole, can as intermediate products for the production of corresponding, chemo-

1 2

therapeutically active 3-sulfanilamido-4-R -5-R -isoxazoles can be used, into which they can be converted in a manner known per se by coupling with a benzenesulfohalide. The 3-amino-isoxazoles of the formula I do not need to be isolated for the subsequent coupling. You can also in solution, for example, are used in benzene solution, as obtained by the cyclization. Likewise , the dihydro-halogen bases of the formula III which may be present do not need either

- ■ »..-""- to be removed, since under the conditions of the coupling reaction

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anyway - and even particularly easy dehydrohalogenation takes place, so that the coupling products are exclusively halogen-free 3-

1 2

Sulfanilamido-4-R -5-R -isoxazole result »The accompanying substances of the formula III can, if desired, also on known type dehydrohalogenated to the isoxazoles of the formula I by the action of alkali, optionally with heating will"

example 1

5 g (0.075 mol) of freshly distilled crotononitrile are mixed with 6 ml of absolute methanol, and 12 g (0.075 mol) of bromine are added dropwise while stirring and while cooling with ice. The mixture is stored in the dark for ^{12 hours at 0} ° C. and for a further 24 hours at 20 ^{° C.} Then the red-brown solution, which no longer contains bromine, is 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 F-carbamoyl-hydroxylamine in 50 ml of water, the internal temperature being kept at 8 ^° C. Then, the mixture is shaken for 45 hours at 2O ⁰ C, then heated under reflux for 3 hours in a water bath and then concentrated by evaporation under reduced pressure to dryness. The last remnants 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 approx. 40 ml. A crude benzene solution of is obtained

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crude ^ -amino - ^ - xaethyl-isoxazole. From the raw material thus obtained 3-Amino-5-methyl-isoxazole can be converted into benzene Solution with p-acetaminobenzenesulfonyl chloride (in the presence of pyridine) and subsequent hydrolysis of the p-ethamino group win 10.8 g of pure 3-sulfanilamido-5-ethyl-isoxazole.

Example 2

A solution of the sodium salt of H-carbamoyl-hydroxylamine [prepared from ethyl urethane according to Org. Syntheses 40 , page 60} calculated content 11.4 g of N-carbamoyl-hydroxylamine] is cooled with 12 g (0.3 mol) of sodium hydroxide in 20 ml water added. At 8 ^° C., a methanolic solution of crude α, β-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 F- carbamoyl-hydroxylamine Lb'sung, and the mixture is shaken for 40 hours at 20 ⁰ C and then heated for 3 hours at 90 ⁰ C. 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. This gives an anhydrous benzene solution of crude 3-amino-5-methyl-isoxazole, from which 20 g of crude 3-sulfanilamido-5-methyl-isoxazole can be obtained.

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Example 5

To a solution of 7 g (0.175 mole) of sodium hydroxide in 40 ml of water "is added at -10 ⁰ C in portions 5.2 g (0.075 mol) of hydroxyl-amine hydrochloride. These are added 11.35 g (0.05 mol ) of crude α, β-dibromo-buttersäurenitril. the mixture is shaken for 48 hours at 20 ⁰ C. Subsequently, brings to play unresolved, oily with ethanol in the solution and the solution heated for 3 hours in a water bath. then to the solution is saturated with potassium carbonate and isolated the basic fractions. to give 2.9 g of a partially crystalline Rohbasenfraktion [Beilstein test negative]. from 500 mg of this Rohbasenfraktion obtained during the distillation under reduced pressure [0.2 mm, bath temperature '70 ⁰ C] 430 mg of a distillate crystallizes on trituration and has a melting point of up to 65 ^° C. On the basis of the thin-layer chromatogram, the distillate contains a mixture of 3-amino-5-methyl-isoxazole and 5-amino-3-methyl-isoxazole.

Example 4

a) 15.2 g (0.2 mol) of crystallized N-carbamoyl-hydroxylamine are added to a solution of 16 g (0.4 mol) of sodium hydroxide in 100 ml of water and the mixture is saturated with potassium carbonate. 45.5 g (0.2 mol) of α, β-dibromobutyronitrile are added to this solution and the ^{mixture is shaken at 20 °} C. for 45 hours. The inorganic salts which have separated out are filtered off. The piltrate is homogenized with ethanol and divided into two equal parts.

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b) The first half is oime under reduced pressure Temperature increase freed from the ethanol. After the non-basic components have been separated off, a bromine-containing base fraction is obtained of 8.40 g [Beilstein and Ehrlich reaction positive], which in addition to 3-amino-5-methyl-isoxazole also contains some amino-methyl-dihydro-bromine- isoxazole [very likely 3-amino-5-methyl-4,5-dihydro-4-bromo-isoxazole] contains. This base fraction contains $ 17 of the for an amino-methyl-dihydro-bromo-isoxazole calculated bromine. From the The crude base mixture thus obtained can be 13.5 g of crystalline Gain 3-sulfanilamido-5-methyl-isoxazole.

c) In order to obtain a bromine-free crude base fraction, "the second half of the filtrate obtained in accordance with paragraph a) is heated on a water bath for 3 hours. The ethanol and some of the water evaporate. After conventional work-up, 7» 6 g of one are obtained Base fraction [from ethyl acetate] with a bromine content of only 1.8 $ of the bromine content calculated for an amino-methyl-dihydro-bromo-isoxazole ". After recrystallization from benzene, the base is bromine-free. The 3-amino-5-methyl-isoxazole thus obtained is free from the 5-amino-3-methyl isomer. Yield $ 67 (based on N-Oarbamoyl-hydroxylamines).

Example 5

6.9 g (0.05 mol) of N-benzoyl-hydroxylamine and 11.4 g are added to a solution of 4 g (0.1 mol) of sodium hydroxide in 25 ml of water (0.05 mol) α, β-dibromobutyronitrile and shake the mixture

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at 20 ⁰ C. After 5 days of heating the mixed with 50 ml of ethanol mixture 2 hours on the water, after separation is obtained of the non-basic components 1.5 g of a Rohbasenfraktion, which can be distilled to about 30 $, and due to the Thin-layer chromatogram does not contain any 5-amino-3-methyl-isoxazole in addition to the 3-amino-5-methyl-isoxazole.

Example 6

A solution of 8 g (0.2 mol) of sodium hydroxide and 7.6 g (0.1 mol) of N-carbamoyl-hydroxylamine in 50 ml of water is mixed with Saturated potassium carbonate. After adding 13.8 g (0.1 mol) of α, β-dichloro-butyric acid nitrile the mixture is shaken at 20 ° C. for three days. Then the existing OeI is by Zugbe of ethanol brought into solution and the solution heated for 3 hours on a water bath [without reflux cooling], according to the usual Working up gives 5.1 g of a base fraction which, in addition to 3-amino-5-methyl-isoxazole, also contains some chlorine-containing dihydrobase ^ -Amino ^ -methylH - ^ - dihydro ^ -chloroisoxazole]. the end 0.98 g of the crude 3-amino-5-methyl-isoxazole thus obtained can be converted into 1.93 g of crude, halogen-free 3-sulfanilamido-5-methyl-isoxazole obtain.

Example 7

A solution of crude is made from 5 g (0.075 mol) of grotonic acid nitrile, 6 ml of absolute methanol and 12 g (0.075 mol) of bromine α, β-dibromobutyronitrile. For splitting off a molecule

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Hydrogen bromide is added to this solution, while cooling, with a solution of 3 g (0.075 mol) of sodium hydroxide in 20 ml of water. 15 mol) ETatriumhydroxyd and 5.7 g (0.075 mol) N ~ carbamoyl-hydroxylamine in 60 ml of water «the mixture is then shaken for 40 hours at 20 ⁰ C s heated for 2 hours in a boiling water bath and sehliesslich the basic fractions are isolated in a conventional «One receives 5s5 g of crystallized, halogen- and isomer-free 3-amino-5-methyl-isoxazole ·» -

Example -8

To a solution of 8 g (0.2 mol) of sodium hydroxide in 50 ml of water is added 8.5 g (0.1 mol.) Of H-acetyl-hydroxylamine (CELCOJffiOH « ¹ / 2H ₂ 0). The solution obtained is with 22.7 g (0.1 mole) of _α-dibromo-9 ß = buttersäurenitril in 50 ml of methanol and then further added with 50 ml of methanol still "The homogeneous solution obtained is allowed to stand at 2O ⁰ C, then for 2 hours in a boiling water heated and then cooled. »The base mixture contained in the resulting solution is isolated by ethyl acetate extraction» 4 g of a base mixture are obtained from the ethyl acetate extract, which mainly contains 3-amino-5-methylisoxazole in addition to bromine-containing base, but no 5-amino-3 ~ methylisoxazole contains "This base mixture is about 75 $ distillable in a bulb tube" The yellow oil obtained as distillate partially crystallizes "The Beilstein reaction to halogen is

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still positive. 1.15 g of halogen-free 3-sulfanilamido-5-methyl-isoxazole can be obtained from 0.98 g of the distilled base by reaction with p-acetaminobenzenesulfochloride and treatment of the coupling product with sodium hydroxide solution. 3-SuIfanilamido-5-methyl-isoxazole is precipitated from the alkaline solution by acidification, yield: 1.15 g; Melting point: 164-170 ⁰ C. The product is halogen-free.

Example 9

40 g of N-carbamoyl-hydroxylamine are added at 10 to a solution of 66 g of sodium hydroxide in 320 ml of water. Then, while stirring and cooling, 112 g of α, β-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 Bssigester extracts leave 33 g of oil, which is vacuum distilled? Boiling point-101/10 mm, nf = 1.5090 (Beilstein test positive); Melting point about 20 ^° C. 12.0 g of the distillate obtained are refluxed with 10 ml of dry pyridine for 2 hours. Then fractionate at 10 mm Hg. This gives 11.4 g of colorless 3-aminoisoxazole with a boiling point of 101/10 mm? nf = 1.5O9O "

Example 10

48 g (1.2 mol) of sodium hydroxide and 30.4 g (0.4 mol) of N-carbamoyl-hydroxylamine are dissolved in 40 ml of water. The solution is ^{cooled to 0} ° C. and treated with 90.8 g of α, β-dibromo-isobutte ^ -

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acids! tril (obtained by bromination of methacrylic acid nitrile) added = the citrile does not mix with the aqueous phase «, the mixture is not homogeneous even by adding 400 ml of methanol» compartment 1 hour, the external cooling is removed, whereupon the mixture is a little warmed up and finally becomes homogeneous. Simultaneously occurs yellowing a _o is allowed to the alkaline solution for 5 days at 20 ⁰ C are then heats it for 2 hours at 9O ⁰ Cc-extraction of the basic components with Essigester obtained 22 g of crude, bromine-free 3-amino-4-methyl-isoxazolo recrystallization from benzene and ether there is obtained from this substance in crystalline, chromatographically uniform shape of melting point 45-50 ⁰ C

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Claims (1)

Claims / 1 "- Process for the preparation of ^ -Aminq-isoxazoles the general formula R ² R ¹ I I C = C (I) I I 0 C-NH. 1 2
where R and R each represent a hydrogen atom, an alkyl, aralkyl or aryl group, characterized in that one is a halocarboxylic acid nitrile of the general formula Ha or Hb ? 1 2 R ^ R ^X ΈΓ HC C-CF HC = C-CF (Ha) (Hb) 12 1 • where R and R have the above meaning and X so- how X mean halogen atoms, in alkaline medium with hydroxylamine or one in the amino group cyclized protected hydroxylamine. 809813/1 123 2 "Method according to claim 1, characterized in that A, β-dibromobutyronitrile is used as the halocarboxylic acid nitrile used" 3 "Method according to claims 1-2, characterized that you can ET-carbamoylhydroxylamine as a protected hydroxylamine used 809813/1123