CA1137482A - Process for the production of 5-aminoisoxazoles - Google Patents
Process for the production of 5-aminoisoxazolesInfo
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- CA1137482A CA1137482A CA000380883A CA380883A CA1137482A CA 1137482 A CA1137482 A CA 1137482A CA 000380883 A CA000380883 A CA 000380883A CA 380883 A CA380883 A CA 380883A CA 1137482 A CA1137482 A CA 1137482A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
5-aminoisoxazoles substituted in the 4-position by an inert substituent are prepared by reacting a compound of the formula
5-aminoisoxazoles substituted in the 4-position by an inert substituent are prepared by reacting a compound of the formula
Description
~l3'7~8~
This invention relates to the production of 5-amino-isoxazoles of the formula H2N ~ (I) wherein R denotes an inert organic residue, by the~reaction of metallic salts of ~-hydroxyacrylonitriles containing substituents R with acid addition salts of hydroxylamine.
A number of methods for the production of 5-amino-isoxazoles is known.
According to U.S. Patent Specification N 3,917,632, 3-dimethylaminoacrylonitrile is reacted with acid addition salts of hydroxylamine in an inert solvent. Hydroxylamine can be added to cyanoacetylenes in a process described in Chem. Pharm. Bl. (Japan) 14, 1277 (1966) = C.A. 67 (1967) 32627 J. The reaction of toxic sodium cyanide with ~-chloro-acetaldehydeoxime is possible according to Tetrahedron Letters (1969) 4817. The synthesis of 5-amino-4-phenylisox-azole can take place by reaction of free ~-formylphenylace-tonitrile with hydroxylaminehydrochloride according to Arch.
Pharm. 300, 615 (1967).
These various procedures each lead only to the production of selected aminoisoxazoles. For example, the last indicated synthesis can only be effected with the very stable ~-formyl-aryl-acetonitriles which are generally available only in the form of salts from which the free compounds are produced prior to use and purified.
In general, the high cost of materials, trouble-some production routes for the starting materials, the use of highly toxic substances and low yields are disadvantages of hitherto used production methods.
-1- ~
,.
~1~374~;~
I-t is an object of the invention to produce 5-amino-isoxazoles and 5-aminoisoxazoles substituted in the 4-position by a process practicable equally well for all materials so that the very numberous 5-aminoisoxazoles substituted in a wide variety of ways in the 4-position can be produced.
According to the present invention, there is pro-vided a process for the production of 5-aminoisoxazo`les of the formula ~
H N~i
This invention relates to the production of 5-amino-isoxazoles of the formula H2N ~ (I) wherein R denotes an inert organic residue, by the~reaction of metallic salts of ~-hydroxyacrylonitriles containing substituents R with acid addition salts of hydroxylamine.
A number of methods for the production of 5-amino-isoxazoles is known.
According to U.S. Patent Specification N 3,917,632, 3-dimethylaminoacrylonitrile is reacted with acid addition salts of hydroxylamine in an inert solvent. Hydroxylamine can be added to cyanoacetylenes in a process described in Chem. Pharm. Bl. (Japan) 14, 1277 (1966) = C.A. 67 (1967) 32627 J. The reaction of toxic sodium cyanide with ~-chloro-acetaldehydeoxime is possible according to Tetrahedron Letters (1969) 4817. The synthesis of 5-amino-4-phenylisox-azole can take place by reaction of free ~-formylphenylace-tonitrile with hydroxylaminehydrochloride according to Arch.
Pharm. 300, 615 (1967).
These various procedures each lead only to the production of selected aminoisoxazoles. For example, the last indicated synthesis can only be effected with the very stable ~-formyl-aryl-acetonitriles which are generally available only in the form of salts from which the free compounds are produced prior to use and purified.
In general, the high cost of materials, trouble-some production routes for the starting materials, the use of highly toxic substances and low yields are disadvantages of hitherto used production methods.
-1- ~
,.
~1~374~;~
I-t is an object of the invention to produce 5-amino-isoxazoles and 5-aminoisoxazoles substituted in the 4-position by a process practicable equally well for all materials so that the very numberous 5-aminoisoxazoles substituted in a wide variety of ways in the 4-position can be produced.
According to the present invention, there is pro-vided a process for the production of 5-aminoisoxazo`les of the formula ~
H N~i
2 o ~ (1) wherein R is an inert residue and preferably denotes a hydro-gen atom, a straight-chain, branched chain or cyclic alkyl group with 1 to 20 carbon atoms, a straight-chain or branched chain alkyl group containing 1 to 5 carbon atoms substituted by a -CN, -COOR', NH2 or OR' group, wherein R' is a straight-chained, branched or cyclic alkyl group which can be optio-nally substituted or a residue of a monovalent phenol, -(CH2)m-Cyc, wherein Cyc is an alicylic or heterocyclic radical with a mono or polycyclic structure or an aromatic or hetero-aromatic radical with a mono or polycyclic structure, which radical is optionally substituted, and m = O to 5, characterized in that a compound of the formula ) O-CH=C-CN (2) R .
wherein R has the aforesaid meaning, M is an alkali metal, when ~= 1, or an alkali earth metal, when ~=2, is reacted with an acid addition salt of hydroxylamine of the formula H2N OH . HX (3) wherein HX denotes a mono- or polybasic inorganic or organic acid.
~37~2 The products of the process of this invention can - be used as pharmaceutical materials as well as intermediates in their production. They are producible in good quality simply and by a single reaction route.
The process of this invention is particularly advantageous and therefore preferred insofar as it enables compounds to be produced in which R is other than an~aryl group.
The synthesis of 5-amino-4-phenylisoxazole by the process of the invention is distinctly simplified in eontrast of synthesis carried out employing free a-formylacetonitriles described for example in German Offenlegungschrift N 27 53 322 in that metal salts if the product of formylating of substituted acetonitriles ! which are tautomers of hydroxyacrylonitriles, can be employed directly and the expensive process step of isolating the free aldehyde and its purification is spared.
It has in fact been found that only the very stable a-formyl-acetonitriles can be obtained as free compounds, whereas ali-phatic or araliphatic substituted a-formylacetonitriles and such eompounds with further non-aromatic substituents are not obtainable and are deeomposed when attempts to isolate them as free compounds are made.
Even if the free compounds possess good stability, their liberation from the metal salts is disadvantageous sinee waste and impurities occur or an additional purification step is necessary.
The process of this invention avoids such problems in making it possible to use formylated acetonitriles in the metal salt form in which they are first produced in the production of 5-aminoisoxazoles in a simple process route which provides high product yield, independently of the type of substituents in the 4-position. Surprisingly, the process 11374t?~
is not only simple to carry out, but can be carried out under mild conditions and in the absence of auxiliary materials.
The metallic salts moreover offer the advantage simply of yielding inorganic salts as sole by-product and themselves providing the control of the pH value in the region above pH
5, which is necessary for the cyclisation.
The metal salts offer the further advantage of being usable without the need for any previous purification.
Finally, the previous difficult synthesis of 5-aminoisoxazole has been attributed to the production fromsimple nitriles containing 4-substituents. The 5-amino-isoxazoles yieldable according to the process of the invention nevertheless may contain an inertsubstituent in the 4-position, which substituent may be of the type optionally present in those substituted acrylonitriles used as starting materials in the process according to German Offenlegungsschrift N
27 53 322.8.
The substituents R can consist or comprise of chain or cyclic alkyl groups as well as aromatic groups. They may also contain hereto atoms in ring positions or contain func-tional groups in the substituents, insofar as there are inert in the formylation and in the reaction with hydroxylamine or do not hinder the reaction. Such heterocyclic residues R include pyridyl-, piperidyl and other heterocyclic residues, and substituents in radicals R may be amino-, nitrile-, alkoxy of 1 to 8 carbon atoms, aroxy-, acyl, such as for example, carboxyl groups, halogen-, nitro- or alkyl groups of 1 to 8 carbon atoms.
Aromatic groups R can contain one or more aromatic rings which may be fused, non-fused or be separated by aliphatic residues. Aromatic groups R may contain further alkyl groups with from 2 to 8, preferably up to 3 carbon atoms ` 1~37~E~Z
as functional groups or substituents.
Preferred aromatic groups are the phenyl group and the substi-tuted phenyl groups, naphthyl groups and pyridyl groups.
R can, in particular be selected from the group consisting of hydrogen, phenyl, benzyl and an alkyl group of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, said alkyl group being a straight chain or a branched chain.
Among the metal salts of 3-hydroxyacrylonitriles, the sodium salts are preferred.
The process according to the invention can be so carried out that the metal salts of 3-hydroxyacrylonitrile of formula (2) are added as solid materials in suspension or optionally in solution to a suspension or solution of the acid addition salt of hydroxylamine. The metal salt can also be first provided and the acid addition salt of hydroxylamine added thereto, or both salts can be added simultaneously to form the reaction mixture. However, on account of the instability of most metal salts of 3-hydroxy-acrylonitriles of formule (2) in solution it is in generalmore suitable to add the metal salt in portions. Any acid addition salt of hydroxylamine can be employed in the reaction according to the invention. Preferred are those salts of hydrohalic acids which are commercially available, in parti-cular salts with hydrochloric acid, and the salts of sulphu-ric acid are preferred.
The reaction is in general carried out in a polar solvent, for example in water or alcohols admixed with polar aprotic solvents, such as dimethylformamide or dimethylsul-phoxide. If necessary, non-polar solvents such as toluene of mixtures of solvents can find use. Especially suitable are water and alcohols with 1 to 3 carbon atoms.
1~l374~;~
The reaction temperature is usually from -10C to L
+80C. Preferred are temperatures of from ~10C to 40C.
Cooling is necessary to dissipate reaction heat on mixing, E
with the introduction of some metal salts of 3-hydroxyacry-lonitrile. The pressure is not critical and can lie between 1~37~B~
1 and 5 bar, preferably being amb:ient pressure. The reaction is in general complete in 0.5 to 5 hours.
The reactants are mixed in about equimolecular amounts. The excess of one component is possible but an excess of 20~ should not be exceeded. The concentration of the reaction partners should be as high as possible, the limits being given by the solubility of the salts or by the good stirrability of the reaction mixture.
A catalyst or a basic condensation material is not necessary. If necessary, however, a basic condensation material for example an alcoholate or alkali or alkali earth metal hydroxide can be employed. A small amount of alkali metal hydroxide is of value in the event that the reaction partners may be such asto cause the pH of the reaction mixture to drop below 5. At too low ph values, cyclic products cannot be obtained.
The working up of the reaction mixture can be effected by filtration of the reaction product from the reaction solution or by extraction with suitable extraction media such as acetic acid esters.
Before the filtration or extraction, part of the solvent, or in the case of a solvent mixture, one component, or even all of *he solvent, can be removed, for example by distillation in vacuo.
5-Aminoisoxazoles of formula (1) find use as an intermediate in synthesis of medicines and in organic syntheses. Reaction products of formula (1) may thus act as tranquillisers (German Offenlegungsscrift N 22 15 087), as bactericides (United States Patent Specification 3,468,900) and be useful in the production of cyanoacetamide (United States Patent Specification N 3,917,632). Furthermore, 5-aminoisoxazoles can be converted inter alia to substances 1~37~
having anti-inflammatory properties (United States Specifi-~ cation N 3,891,630) and substances with trichomonacital activity. They can be hydrated to achieve ring opening accompanied by splitting off of R, using Pt-catalysts (J.
Org. Chem. 42 (1977) 109).
The following examples illustrate this invention:
87 g (0.75 mol) of sodium-3-hydroxyacylonitrile (78,6% pure) were added in portions over 2 hours to a suspension of 59 g (0.824 mol) of hydroxylaminehydrochloride in 2C0 ml methanol held at 18 to 20C by cooling. The reaction mixture was then stirred at room temperature for
wherein R has the aforesaid meaning, M is an alkali metal, when ~= 1, or an alkali earth metal, when ~=2, is reacted with an acid addition salt of hydroxylamine of the formula H2N OH . HX (3) wherein HX denotes a mono- or polybasic inorganic or organic acid.
~37~2 The products of the process of this invention can - be used as pharmaceutical materials as well as intermediates in their production. They are producible in good quality simply and by a single reaction route.
The process of this invention is particularly advantageous and therefore preferred insofar as it enables compounds to be produced in which R is other than an~aryl group.
The synthesis of 5-amino-4-phenylisoxazole by the process of the invention is distinctly simplified in eontrast of synthesis carried out employing free a-formylacetonitriles described for example in German Offenlegungschrift N 27 53 322 in that metal salts if the product of formylating of substituted acetonitriles ! which are tautomers of hydroxyacrylonitriles, can be employed directly and the expensive process step of isolating the free aldehyde and its purification is spared.
It has in fact been found that only the very stable a-formyl-acetonitriles can be obtained as free compounds, whereas ali-phatic or araliphatic substituted a-formylacetonitriles and such eompounds with further non-aromatic substituents are not obtainable and are deeomposed when attempts to isolate them as free compounds are made.
Even if the free compounds possess good stability, their liberation from the metal salts is disadvantageous sinee waste and impurities occur or an additional purification step is necessary.
The process of this invention avoids such problems in making it possible to use formylated acetonitriles in the metal salt form in which they are first produced in the production of 5-aminoisoxazoles in a simple process route which provides high product yield, independently of the type of substituents in the 4-position. Surprisingly, the process 11374t?~
is not only simple to carry out, but can be carried out under mild conditions and in the absence of auxiliary materials.
The metallic salts moreover offer the advantage simply of yielding inorganic salts as sole by-product and themselves providing the control of the pH value in the region above pH
5, which is necessary for the cyclisation.
The metal salts offer the further advantage of being usable without the need for any previous purification.
Finally, the previous difficult synthesis of 5-aminoisoxazole has been attributed to the production fromsimple nitriles containing 4-substituents. The 5-amino-isoxazoles yieldable according to the process of the invention nevertheless may contain an inertsubstituent in the 4-position, which substituent may be of the type optionally present in those substituted acrylonitriles used as starting materials in the process according to German Offenlegungsschrift N
27 53 322.8.
The substituents R can consist or comprise of chain or cyclic alkyl groups as well as aromatic groups. They may also contain hereto atoms in ring positions or contain func-tional groups in the substituents, insofar as there are inert in the formylation and in the reaction with hydroxylamine or do not hinder the reaction. Such heterocyclic residues R include pyridyl-, piperidyl and other heterocyclic residues, and substituents in radicals R may be amino-, nitrile-, alkoxy of 1 to 8 carbon atoms, aroxy-, acyl, such as for example, carboxyl groups, halogen-, nitro- or alkyl groups of 1 to 8 carbon atoms.
Aromatic groups R can contain one or more aromatic rings which may be fused, non-fused or be separated by aliphatic residues. Aromatic groups R may contain further alkyl groups with from 2 to 8, preferably up to 3 carbon atoms ` 1~37~E~Z
as functional groups or substituents.
Preferred aromatic groups are the phenyl group and the substi-tuted phenyl groups, naphthyl groups and pyridyl groups.
R can, in particular be selected from the group consisting of hydrogen, phenyl, benzyl and an alkyl group of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, said alkyl group being a straight chain or a branched chain.
Among the metal salts of 3-hydroxyacrylonitriles, the sodium salts are preferred.
The process according to the invention can be so carried out that the metal salts of 3-hydroxyacrylonitrile of formula (2) are added as solid materials in suspension or optionally in solution to a suspension or solution of the acid addition salt of hydroxylamine. The metal salt can also be first provided and the acid addition salt of hydroxylamine added thereto, or both salts can be added simultaneously to form the reaction mixture. However, on account of the instability of most metal salts of 3-hydroxy-acrylonitriles of formule (2) in solution it is in generalmore suitable to add the metal salt in portions. Any acid addition salt of hydroxylamine can be employed in the reaction according to the invention. Preferred are those salts of hydrohalic acids which are commercially available, in parti-cular salts with hydrochloric acid, and the salts of sulphu-ric acid are preferred.
The reaction is in general carried out in a polar solvent, for example in water or alcohols admixed with polar aprotic solvents, such as dimethylformamide or dimethylsul-phoxide. If necessary, non-polar solvents such as toluene of mixtures of solvents can find use. Especially suitable are water and alcohols with 1 to 3 carbon atoms.
1~l374~;~
The reaction temperature is usually from -10C to L
+80C. Preferred are temperatures of from ~10C to 40C.
Cooling is necessary to dissipate reaction heat on mixing, E
with the introduction of some metal salts of 3-hydroxyacry-lonitrile. The pressure is not critical and can lie between 1~37~B~
1 and 5 bar, preferably being amb:ient pressure. The reaction is in general complete in 0.5 to 5 hours.
The reactants are mixed in about equimolecular amounts. The excess of one component is possible but an excess of 20~ should not be exceeded. The concentration of the reaction partners should be as high as possible, the limits being given by the solubility of the salts or by the good stirrability of the reaction mixture.
A catalyst or a basic condensation material is not necessary. If necessary, however, a basic condensation material for example an alcoholate or alkali or alkali earth metal hydroxide can be employed. A small amount of alkali metal hydroxide is of value in the event that the reaction partners may be such asto cause the pH of the reaction mixture to drop below 5. At too low ph values, cyclic products cannot be obtained.
The working up of the reaction mixture can be effected by filtration of the reaction product from the reaction solution or by extraction with suitable extraction media such as acetic acid esters.
Before the filtration or extraction, part of the solvent, or in the case of a solvent mixture, one component, or even all of *he solvent, can be removed, for example by distillation in vacuo.
5-Aminoisoxazoles of formula (1) find use as an intermediate in synthesis of medicines and in organic syntheses. Reaction products of formula (1) may thus act as tranquillisers (German Offenlegungsscrift N 22 15 087), as bactericides (United States Patent Specification 3,468,900) and be useful in the production of cyanoacetamide (United States Patent Specification N 3,917,632). Furthermore, 5-aminoisoxazoles can be converted inter alia to substances 1~37~
having anti-inflammatory properties (United States Specifi-~ cation N 3,891,630) and substances with trichomonacital activity. They can be hydrated to achieve ring opening accompanied by splitting off of R, using Pt-catalysts (J.
Org. Chem. 42 (1977) 109).
The following examples illustrate this invention:
87 g (0.75 mol) of sodium-3-hydroxyacylonitrile (78,6% pure) were added in portions over 2 hours to a suspension of 59 g (0.824 mol) of hydroxylaminehydrochloride in 2C0 ml methanol held at 18 to 20C by cooling. The reaction mixture was then stirred at room temperature for
3 hours. The residue, after decanting off of the solvent, was taken up in 100 ml water and extracted with acetic acid ester. After drying and separation off of the acetic acid ester, 61.8 g (98~ of theoretical) of 5-aminoisoxazole were obtained.
Melting point: 72-73C.
lH-NMR-spectrum (DMSO-d6) : ~(ppm) = 4.94 (d, J = 1.4 Hæ, CH), (s. broad, NH2), 8.00 (d, J = 1.4 Hz, -CH=N).
_AMPLE 2 23.2 g (0.20 mol) of sodium 3-hydroxyacrylonitrile (78.6% pure) were added; in portions over 50 minutes to a suspension of 14.6 g (0~21 mol) of hydroxylaminehydrochlo-ride in 50 ml toluene/methanol (1:3 by volume) cooled to not more than 20C and the mixture obtained was stirred for 2 hours at room temperature. After working up as in Example 1, 15.4 g (91.7~ of theoretical) of 5-aminoisoxazole were obtained. Melting point: 68-70C. The lH-NMR-spectrum corresponds to that in Example 1.
11.8 g (0.1 mol) of sodium hydroxyacrylonitrile 1~37~
(77.1% pure) were added ln portions over 40 minutes to a solution of 7.6 g (O.ll mol) of hydroxylaminehydrochloride in 20 ml water which was cooled to up to 20C. The mixture obtained was stirred for 1 hour at room temperature. The reaction mixture was extracted with acetic acid ester and the solvent was stripped off after drying of the reaction mixture. 7.7 g (91.6% of theoretical) of 5-amonoisoxazole were obtained. Melting point: 72C. The H-NMR-spectrum corresponds to that in Example 1.
11.8 g (0.1 mol) of sodium hydroxyacrylonitrile (77,1% pure) were added within 30 minutes in portions to a solution of 9 g (0.55 mol) of hydroxylaminesulphate in 25 ml water which was cooled to 20C. The reaction mixture was held for 3 hours at room temperature. The reaction mixture was extracted with acetic acid ester and the solvent was stripped off after drying of the reaction mixture.
7.4 g (88.1% of theoretical)of 5-aminoisoxazole were obtained.
Melting point: 69-70C.
The H-NMR-spectrum corresponds to that in Example 1.
5 g (0.033 mol) of sodium 3-hydroxy-2-methylacrylo-nitrile (70% pure) were added in portion within 20 minutes to a suspension of 2.5 g (0,037 mol) of hydroxylaminehydro-chloride in 10 ml methanol which was cooled at 20C, and the mixture was stirred for 3 hours at room temperature. After working up as in Example 1, 2.5 g (77.3% of theoretical) of 5-amino-4-methylisoxazole were obtained. Melting point:
61C. H-NMR-spectrum (CDC13): ~ (ppm) = 1.82 (s. 3, CH3), 5.40 (s, broad 2, NH2), 7.91 (s. 1, HC = ).
17.9 g (0.075 mol) of sodium 3-hydroxy-2-benzyl-~3'~4~Z
acrylonitrile (76~ pure) were added in portions within 20 minutes to a suspension of 5.2 g (0.075 mol) of hydroxyl- ~ -aminehydrochloride in 50 ml methanol which was cooled to less than 20C, and the mixture was stirred for 3 hours at room temperature. After working up as in Example 1, 11.0 g (84.3% of theoretical) of 5-amino-4-benzylisoxazole were obtained. Melting point: 125-128C. Molecular weight (mass spectroscopy) 174.
5.95 g (0.033 mol) of sodium-3-hydroxy-2-phenyl-acrylonitrile (92.6~ pure) were added in portions within 15 minutes to a suspension of 2.5 g (0.037 mol) of hydro-xylaminehydrochloride in 10 ml methanol which was cooled to 18C, and the mixture was stirred for 3 hours at room temperature. After separating off the sodium chloride, the methanol was stripped off. The residue was extracted with acetic acid ester, the solution dried and the solvent stripped off. 5.2 g (98.5~ of theoretical) of 5-amino-4-phenylisoxa-zole were obtained. Melting point: 96C.
H-NMR- (DMSO-d6): ~ (ppm) = 7.13 - 7.76 (m, 7, C6H5 and NH2), 8.71 (S, 1, H-C)-_ g _
Melting point: 72-73C.
lH-NMR-spectrum (DMSO-d6) : ~(ppm) = 4.94 (d, J = 1.4 Hæ, CH), (s. broad, NH2), 8.00 (d, J = 1.4 Hz, -CH=N).
_AMPLE 2 23.2 g (0.20 mol) of sodium 3-hydroxyacrylonitrile (78.6% pure) were added; in portions over 50 minutes to a suspension of 14.6 g (0~21 mol) of hydroxylaminehydrochlo-ride in 50 ml toluene/methanol (1:3 by volume) cooled to not more than 20C and the mixture obtained was stirred for 2 hours at room temperature. After working up as in Example 1, 15.4 g (91.7~ of theoretical) of 5-aminoisoxazole were obtained. Melting point: 68-70C. The lH-NMR-spectrum corresponds to that in Example 1.
11.8 g (0.1 mol) of sodium hydroxyacrylonitrile 1~37~
(77.1% pure) were added ln portions over 40 minutes to a solution of 7.6 g (O.ll mol) of hydroxylaminehydrochloride in 20 ml water which was cooled to up to 20C. The mixture obtained was stirred for 1 hour at room temperature. The reaction mixture was extracted with acetic acid ester and the solvent was stripped off after drying of the reaction mixture. 7.7 g (91.6% of theoretical) of 5-amonoisoxazole were obtained. Melting point: 72C. The H-NMR-spectrum corresponds to that in Example 1.
11.8 g (0.1 mol) of sodium hydroxyacrylonitrile (77,1% pure) were added within 30 minutes in portions to a solution of 9 g (0.55 mol) of hydroxylaminesulphate in 25 ml water which was cooled to 20C. The reaction mixture was held for 3 hours at room temperature. The reaction mixture was extracted with acetic acid ester and the solvent was stripped off after drying of the reaction mixture.
7.4 g (88.1% of theoretical)of 5-aminoisoxazole were obtained.
Melting point: 69-70C.
The H-NMR-spectrum corresponds to that in Example 1.
5 g (0.033 mol) of sodium 3-hydroxy-2-methylacrylo-nitrile (70% pure) were added in portion within 20 minutes to a suspension of 2.5 g (0,037 mol) of hydroxylaminehydro-chloride in 10 ml methanol which was cooled at 20C, and the mixture was stirred for 3 hours at room temperature. After working up as in Example 1, 2.5 g (77.3% of theoretical) of 5-amino-4-methylisoxazole were obtained. Melting point:
61C. H-NMR-spectrum (CDC13): ~ (ppm) = 1.82 (s. 3, CH3), 5.40 (s, broad 2, NH2), 7.91 (s. 1, HC = ).
17.9 g (0.075 mol) of sodium 3-hydroxy-2-benzyl-~3'~4~Z
acrylonitrile (76~ pure) were added in portions within 20 minutes to a suspension of 5.2 g (0.075 mol) of hydroxyl- ~ -aminehydrochloride in 50 ml methanol which was cooled to less than 20C, and the mixture was stirred for 3 hours at room temperature. After working up as in Example 1, 11.0 g (84.3% of theoretical) of 5-amino-4-benzylisoxazole were obtained. Melting point: 125-128C. Molecular weight (mass spectroscopy) 174.
5.95 g (0.033 mol) of sodium-3-hydroxy-2-phenyl-acrylonitrile (92.6~ pure) were added in portions within 15 minutes to a suspension of 2.5 g (0.037 mol) of hydro-xylaminehydrochloride in 10 ml methanol which was cooled to 18C, and the mixture was stirred for 3 hours at room temperature. After separating off the sodium chloride, the methanol was stripped off. The residue was extracted with acetic acid ester, the solution dried and the solvent stripped off. 5.2 g (98.5~ of theoretical) of 5-amino-4-phenylisoxa-zole were obtained. Melting point: 96C.
H-NMR- (DMSO-d6): ~ (ppm) = 7.13 - 7.76 (m, 7, C6H5 and NH2), 8.71 (S, 1, H-C)-_ g _
Claims (28)
1. A process for the production of 5-aminoisox-azoles of the formula (I) wherein R denotes a hydrogen atom, a straight-chain, branched chain or cyclic alkyl group with 1 to 20 carbon atoms, a straight-chain or branched chain alkyl group containing 1 to 5 carbon atoms sub-stituted by a -CN, -COOR', NH2 or OR' group, wherein R' is a straight-chained, branched or cyclic alkyl group which may be optionally sub-stituted, or a residue of a monovalent phenol, -(CH2)m-Cyc, wherein Cyc is an alicyclic or heterocyclic radical with a mono or polycyclic structure or an aromatic or heteroaromatic radical with a mono or polycyclic structure, which radical may be substituted and m = 0 to 5, characterized in that a compound of the formula (2) wherein R has the aforesaid meaning, .alpha. is 1 or 2 and M is an alkali metal, when .alpha.= 1, or an alkali earth metal, when .alpha.= 2, is reacted with an acid addition salt of hydroxylamine of the formula H2N OH . HX (3) wherein HX denotes a mono- or polybasic inorganic or organic acid.
2. A process according to claim 1, where the acid HX is a hydrogen halide acid or sulphuric acid.
3. A process according to claim 2, wherein the acid HX is hydrochloric acid.
4. A process according to claim 1, wherein the reaction is carried out in a polar solvent or in a solvent mixture including a polar solvent.
5. A process according to claim 1, which is carried out at a pH maintained at a value of 5 or more by reactants present in the reaction mixture employed or an alkaline compound added thereto.
6. A process according to claim 1, which is carried out at a temperature of from -10 to 80°C.
7. A process according to claim 6, which is carried out at a temperature of from 10 to 40°C.
8. A process according to claim 1, where R is selected from the group consisting of alkyl, phenyl, pyridyl and piperidyl.
9. A process according to claim 1, where R is an aromatic as heteroaromatic radical which may be substituted with alkyl groups of 2 to 8 carbon atoms.
10. A process according to claim 1, where R' may be substituted by amino-,nitrile-,C1-C8 alkoxy-, aroxy-, acyl-, halogen-, nitro-or C1-C8 alkyl-groups.
11. A process for the production of 5-aminoisox-azoles of the formula (1) wherein R denotes an inert residue, characterized in that a compound of the formula (2) wherein R has the aforesaid meaning, .alpha. is 1 or 2 and M is an alkali metal, when .alpha.= 1, or an alkali earth metal, when .alpha.= 2, is reacted with an acid addition salt of hydroxylamine of the formula H2N OH ? HX (3) wherein HX denotes a mono- or polybasic inorganic or organic acid.
12. A process according to claim 11, where the acid HX is a hydrogen halide acid or sulphuric acid.
13. A process according to claim 12, wherein the acid HX is hydrochloric acid.
14. A process according to claim 11, wherein the reaction is carried out in a polar solvent or in a solvent mixture including a polar solvent.
15. A process according to claim 11, which is carried out at a pH maintained at a value of 5 or more by reactants present in the reaction mixture employed or an alkaline compound added thereto.
16. A process according to claim 11, which is carried out at a temperature of from -10 to 80°C.
17. A process according to claim 16, which is carried out a a temperature of from 10 to 40°C.
18. A process according to claim 1, wherein R is an alkyl group with 1 to 20 carbon atoms, said alkyl group being a straight chain or a branched chain.
19. A process according to claim 1, wherein R is selected from the group consisting of hydrogen, phenyl, benzyl and an alkyl group with 1 to 8 carbon atoms, said alkyl group being a straight chain or a branched chain.
20. A process according to claim 19, wherein the acid HX is a hydrogen halide acid or sulphuric acid.
21. A process according to claim 20, wherein the reaction is carried out in a polar solvent or in a solvent mixture including a polar solvent.
22. A process according to claim 21, which is carried out at a pH maintained at a value of 5 or more by reactants present in the reaction mixture employed or an alkaline compound added thereto.
23. A process according to claim 22, which is carried out at a temperature of from -10 to 80°C.
24. A process according to claim 23, wherein the acid HX is hydrochloric acid and sulphuric acid.
25. A process according to claim 24, which is carried out at a temperature of from 10 to 40°C.
26. A process according to any one of claims 2, 4 and 5, wherein a is 1 and M is Na.
27. A process according to any one of claims 20, 21 and 22, wherein .alpha. is 1 and M is Na.
28. A process according to any one of claims 23, 24 and 25, wherein .alpha. is 1 and M is Na.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803024989 DE3024989A1 (en) | 1980-07-02 | 1980-07-02 | METHOD FOR PRODUCING 5-AMINOISOXAZOLES |
| DEP3024989.9 | 1980-07-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1137482A true CA1137482A (en) | 1982-12-14 |
Family
ID=6106202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000380883A Expired CA1137482A (en) | 1980-07-02 | 1981-06-30 | Process for the production of 5-aminoisoxazoles |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0043024B1 (en) |
| JP (1) | JPS5746972A (en) |
| AT (1) | ATE6858T1 (en) |
| CA (1) | CA1137482A (en) |
| DE (2) | DE3024989A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE452961B (en) * | 1985-05-03 | 1988-01-04 | S & L Maskin Ab | TAPPHALLARE |
| RU2638530C2 (en) * | 2016-02-29 | 2017-12-14 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Derivatives of 5-aminoisoxazol - conformationally-rigid analogs of g-amino butyric acid and its production method |
| RU2658837C1 (en) * | 2017-06-30 | 2018-06-25 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Process for the preparation of 5-aminoisoxazole-carboxylic acid |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD29481A (en) * | ||||
| US3468900A (en) * | 1966-08-24 | 1969-09-23 | Hoffman Lab Inc | Process for preparing isoxazole compounds |
| DE1814116A1 (en) * | 1967-12-13 | 1969-08-21 | Takeda Chemical Industries Ltd | Process for the preparation of 3-aminoisoxazole |
-
1980
- 1980-07-02 DE DE19803024989 patent/DE3024989A1/en not_active Withdrawn
-
1981
- 1981-06-15 EP EP81104613A patent/EP0043024B1/en not_active Expired
- 1981-06-15 AT AT81104613T patent/ATE6858T1/en not_active IP Right Cessation
- 1981-06-15 DE DE8181104613T patent/DE3162870D1/en not_active Expired
- 1981-06-30 CA CA000380883A patent/CA1137482A/en not_active Expired
- 1981-06-30 JP JP56100775A patent/JPS5746972A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0043024B1 (en) | 1984-03-28 |
| ATE6858T1 (en) | 1984-04-15 |
| DE3024989A1 (en) | 1982-01-28 |
| DE3162870D1 (en) | 1984-05-03 |
| EP0043024A1 (en) | 1982-01-06 |
| JPS5746972A (en) | 1982-03-17 |
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