PROCESS FOR THE PRODUCTION OF 5-AMINOISOXAZOLES

METHODE DE PREPARATION DE 5-AMINOISOXAZOLES

English 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
<IMG>
wherein R is a said inert substituent, M is an alkali metal
(.alpha. = 1) and an alkaline earth metal (.alpha. = 2), with an acid
addition salt of hydroxylamine.

Claims

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A process for the production of 5-aminoisox-
azoles of the formula
<IMG> (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
<IMG> (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

11. A process for the production of 5-aminoisox-
azoles of the formula
<IMG>
(1)
wherein
R denotes an inert residue, characterized in that a
compound of the formula
<IMG> (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.
12

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.
13

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.
14

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
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:
EXAMPLE 1
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.
EXAMPLE 3
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.
EXAMPLE 4
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.
EXAMPLE 5
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 = ).
EXAMPLE 6
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.
EXAMPLE 7
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 _