PROCESS FOR THE MANUFACTURE OF ISOXAZOLE DERIVATIVES

PROCEDE DE PRODUCTION DE DERIVES DE L'ISOXAZOLE

English Abstract

Abstract of the Disclosure:
A process for the preparation of 5-methyl-isoxazole-4-
carboxylic acid anilides of the formula
<IMG>
in which an aniline of the formula
<IMG>
is reacted with a 5-methyl-isoxazole derivative of the formula
<IMG>
The compounds are pharmacologically active and have a strong
antiphlogistic and analgesic action.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 5-methyl-isoxazole-4-
carboxylic acid anilide of the formula I
<IMG> (I)
wherein R1, R2 and R3 can be identical or different and represent
alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2 or 3 carbon
atoms, alkylthio having 1, 2 or 3 carbon atoms and each of these
groups can be completely or partially substituted by identical
or different halogen atoms, or R1, R2 and R3 represent halogen,
nitro, cyano or carbalkoxy having 1, 2 or 3 carbon atoms in the
alkyl group and in which R1 and R2 also represent hydrogen,
in which case, however, R3 cannot be methyl, but in which case
R3 additionally represents phenyl which may be monosubstituted or
disubstituted by any of fluorine, chlorine, bromine, iodine,
alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1, 2 or 3
carbon atoms, or phenoxy which may be monosubstituted or disub-
stituted by any of fluorine, chlorine, bromine, iodine, alkyl
having 1, 2 or 3 carbon atoms or alkoxy having 1, 2 or 3 carbon
atoms, or in which R1 represents hydrogen and R2 and R3 con-
jointly represent a methylenedioxy group or, conjointly with the
phenyl ring carrying them, represent a naphthalene ring,
in which an aniline of the formula V

<IMG> (V)
wherein R1, R2 and R3 are as defined above, is reacted with a
5-methyl-isoxazole derivative of the formula VI
<IMG> (VI)
wherein X represents a halogen atom, a YO- group or a ZO-CO-O-
group, Y representing phenyl which may be monosubstituted,
disubstituted or trisubstituted by fluorine, chlorine, bromine,
iodine, methyl, ethyl, methoxy, ethoxy, nitro or cyano; or the
acyl radical corresponding to the formul V and Z representing
(C1-C4)-alkyl, benzyl or phenyl.
2. A process as claimed in claim 1 in which the preparation
is carried out in the presence of an inert solvent.
3. A process as claimed in claim 1 in which a carboxylic
acid chloride of the formula VI is reacted with an aniline of
the formula V in the presence of an acid binding agent at a
temperature in the range of from 0 to 160°C.
4. A process as claimed in claim 1, claim 2 or claim 3,
in which R1 represents hydrogen, R2 represents fluorine and R3
represents fluorine, chlorine or trifluoromethyl.

5. A process as claimed in claim 1, claim 2 or claim 3,
in which R1 represents hydrogen and R2 and R3 represent
fluorine in the 3 and 4 positions.
6. A process as claimed in claim 1, claim 2 or claim 3,
in which R1 represents hydrogen, R2 represents fluorine in the
3 position, and R3 represents chlorine in the 4 position.
7. A process as claimed in claim 1, claim 2 or claim 3,
in which R1 represents hydrogen and R2 and R3 represent fluorine
in the 2 and 4 positions.
8. A process as claimed in claim 1, claim 2 or claim 3
in which R1 represents hydrogen, R2 represents fluorine in the
2 position and R3 represents trifluoromethyl in the 5 position.

Description

-` ~0~0S6
Our copending Canadian Patent Application No. 254,134
relates to 5-methyl-isoxazole-4-carboxylic acid anilides of the
formula I CONH ~ 2
~ C~3 (I)
in which Rl, R2 and R3 can be identical or different and denote
alkyl having 1, 2 or 3 C atoms, alkoxy having 1, 2 or 3 C atoms,
alkylthio having 1, 2 or 3 C atoms, each of which groups can be
completely or partially substituted by identical or different
halogen atoms, such as fluorine, chlorine, bromine or iodine, or
denote halogen, such as fluorine, chlorine, bromine or iodine, or
nitro, cyano or carbalkoxy having 1, 2 or 3 C atoms in the alkyl
group, and in which Rl and R2 also denote hydrogen, in which case,
however, R3 cannot be methyl, but in which case R3 additionally
denotes phenyl which may be monosubstituted or disubstituted by
any of fluorine, chlorine, bromine, iodine, alkyl having 1, 2 or
3 C atoms or alkoxy having 1, 2 or 3 C atoms, ox phenoxy which
may be monosubstituted or disubstituted by any of fluorine,
chlorine, bromine, iodine, alkyl having 1, 2 or 3 C atoms or
alkoxy having 1, 2 or 3 C atoms, or in which Rl denotes hydrogen
and R2 and R3 conjointly denote a methylenedioxy group or, con-
jointly with the phenyl ring carrying them, denote a naphthalene
ring, and, furthermore, it relates to a process for the manufac-
ture of the compounds of the formula I, wherein an acetoacetic
acid anilide of the formula II
/~=~y, R3
CH3-CO-CH~-CONH ~ R2 (II)
~3~
.

0~5~S6
in which Rl, R2 and R3 have the abovementioned meaning, is warmed
with an orthoformic acid ester of the formula III
HC (OR)3 (III)
in which R denotes a Cl- to C4- alkyl, and advantageously with an
acid anhydride, the resulting 2-alkoxymethylene-acetoacetic acid
anilide of the formula IV
~ R3
CH3-CO-IC-CONH ~ R2 (IV)
~ ~ OR Rl
in which R, R1, R2 and R3 have the abovementioned meanings, is
isolated and this is subsequently treated with hydroxylamine in
an organic solvent.
In a further development of the process according to the
aforesaid specification, a simplified process for the manufacture
of 5-methyl-isoxazole-4-carboxylic acid anilides of the formula I
CONH~ ~ I )
CH R
in which Rl, R2 and R3 can be identical or different and denote
alkyl having 1, 2 or 3 C atoms, alkoxy having 1, 2 or 3 C atoms,
alkylthio having 1, 2 or 3 C atoms, each of which groups can be
completely or partially substituted by identical or different
halogen atoms, such as fluorine, chlorine, bromine or iodine, or
denote halogen, such as fluorine, chlorine, bromine or iodine, or
nitro, cyano or carbalkoxy having 1, 2 or 3 C atoms in the alkyl
group, and in which Rl and R2 also denote hydrogen, in which case,
however, R3 cannot be methyl, but in which case R3 additionally
denotes phenyl which may be monosubstituted or disubstituted by
-- 2
.

109S056
any of fluorine, chlorine, bromine, iodine, alkyl having 1, 2 or
3 C atoms or alkoxy having 1, 2 or 3 C atoms, or phenoxy which
may be monosubstituted or disubstituted by any of fluorine,
chlorine, bromine, iodine, alkyl having 1, 2 or 3 C atoms or
alkoxy having 1, 2 or 3 C atoms, or in which Rl denotes hydrogen
and R2 and R3 conjointly denote a methylenedioxy group or, con-
jointly with the phenyl ring carrying them, denotes a naphthalene
ring, has now been found, wherein an aniline of the formula V
~ ~ ~2 (V)
in which Rl, R2 and R3 have the abovementioned meanings, is reacted
with a 5-methylisoxazole derivative of the formula VI
~;o
~ C ~ X (VI)
~ ~ CH
in which X denotes a halogen atom, preferably chlorine or bromine,
a YO- group or a ZO-CO-O- group, Y representing phenyl which may
be monosubstituted, disubstituted or trisubstituted by fluorine,
chlorine, bromine, iodine, methyl, ethyl, methoxy, ethoxy, nitro
or cyano, or the acyl radical corresponding to the formula V and
Z representing (Cl-C4)-alkyl, benzyl or phenyl.
Advantageously, the reaction is carried out in a parti-
tioning agent or solvent which has an inert behaviour towards the
reactants. For example, these can be nitriles, such as acetoni-
trile, ethers, such as diethyl ether, tetrahydrofurane or dioxane,
and alcohols, such as methanol, ethanol, propanol or isopropanol.
A preferred process forthe preparation of the compounds
-- 3 --
::
,` .

05~
of the formula I is the reaction ofthe carboxylic acid chloride
of the formula VI with an aniline of the formula V. It is advan-
tageous here to carry out the reaction in the presence of acid
binding agents, such as potassium carbonate or sodium carbonate,
alkali metal or alkaline earth metal hydroxides or alcoholates,
organic bases, for example triethylamine, pyridine, picoline or
quinoline or an excess of the particular aniline employed, at
temperatures between 0 and 160C, preferably between 20 and 80C.
The reaction times can be from a few minutes up to two hours.
The 5-methylisoxazole-4-carboxylic acid derivatives of
the formula VI, required as starting materials for the process
according to theinvention, are obtained in a manner which is in
itself known (compare German Patent 634,286) by reaction of
ethoxymethylideneacetoacetic acid ester with hydroxylamine to
give a 5-methyl-isoxazole-4-carboxylic acid ester, by acid saponi-
fication of the ester thus obtained, preferably using a mixture
of glacial acetic acid and concentrated hydrochloric acid in a
ratio of 1:1, to give 5-methyl-isoxazole-4-carboxylic acid and by
conversion of this carboxylic acid by customary methods into the
carboxylic acid halides, esters or anhydrides. The 5-methyl-
isoxazole-4-carboxylic acids can also be activated by reaction
with a carbodiimide, for example dicyclohexylcarbodiimide.
Possible carboxylic acid derivatives of the formula ~I
are 5-methylisoxazole-4-carboxylic acid phenyl ester, in particu-
lar also the 2,4-dichloro-phenyl ester and the 2,4,6-trichloro-
phenyl ester, and furthermore 5-methylisoxazole-4-carboxylic
acid anhydrides, in particular those in which X denotes the
methoxycarbonyloxy radical, the ethoxycarbonyloxy radical or the

l~S05~
benzyloxycarbonyloxy radical.
The compounds of the formula I are pharmacologically
active. They have a strong antiphlogistic and analgesic action.
Preparation examples
1. 5-methylisoxazole-4-carboxylic acid 4-fluoro-anilide of
the formula I
al) A solution of 7.3 g (0.05 mole) of 5-methylisoxazole-4-
carboxylic acid chloride of the formula VI in 20 ml of acetoni-
trile is added dropwise, whilst stirring, at room temperature to
0.1 mole of 4-fluoroaniline of the formula V (11.1 g), dissolved
in 200 ml of acetonitrile. After stirring for a further 15
minutes, the crystals which have precipitated are filtered off
and rinsed with twice 20 ml of acetonitrile and the combined
filtrates are brought to dryness under reduced pressure. This
gives 10.8 g (98% of theory) of an oily residue which crystal-
lizes after trituration.
Melting point after recrystallization from water:
117 to 118C.
a2) When 0.05 mole of triethylamine (10.1 g) is used as
the acid-binding agent instead of the 4-fluoroaniline of the
formula V, the oily residue is digested with water. The crystals
thus obtained are filtered off and washed with water. ~ft~r dry-
ing in air, this gives 10.6 g (96% of theory~ of colorless
crystals whichj after recrystallization from water, melt at 117
to 118C.
b) 0.1 mole of 4-fluoroaniline of the formula V ( 11.1 g)
and 0.1 mole of 4-bromophenyl 5-methylisoxazole-4-carboxylate of
the formula Vl (28.2 g) dissolved in 50 ml of acetonitrile are
heated under reflux for 90 minutes. Subsequently the solution
- 5 -
. .
, ,
:

5056
is evaporated under reduced pressure and the residue is digested
with petroleum ether. This gives 15.6 g (71% of theory) of an
oily residue which crystallizes after spreading out. Melting
point after recrystallization from water: 117 to 11~C.
c) 0.1 mole of 4-fluoroaniline of the formula V (11.1 g)
and 0.1 mole of ethoxycarbonyl 5-methylisoxazole-4-carboxylate
of the formula VI (19.9 g), dissolved in 60 ml of tetrahydro-
furane, are heated under reflux for 60 minutes. The reaction
mixture is then brought to dryness and this gives 17.1 g (78% of
theory) of a crystalline residue which, after recrystallization
from water, melts at 117 to 118C.
The compounds listed in Table 1 were prepared by the
process indicated above.
Table 1: 5-methylisoxazole-4-carboxylic acid anilides of the
formula I
No. Rl R2 R3Melting point C
1 H H 4-F 117 - 118
2 H H 4-C1 151
3 H H 4-Br 162 - 163
4 H H 4-I 173 - 173.5
H 3-Cl 4-Cl 146
6 H 3-C1 -OP 123 - 124
7 H _o 2125 - 126
B -H 3-F 4-F 107 - 109
9 H 3-F 4-C1 105 - 107
10 H 2-F 4-F 123
11 H 2-F 5-CF3 111 - 113
-- 6 --
: ,

~0'~505~
The numbers in Table 1 denote:
1. 5-Methylisoxazole-4-carboxylic acid 4-fluoro-anilide
2. 5-Methylisoxazole-4-carboxylic acid 4-chloro-anilide
3. 5-Methylisoxazole-4-carboxylic acid 4-bromo-anilide
4. 5-Methylisoxazole-4-carboxylic acid 4-iodo-anilide
5. 5-Methylisoxazole-4-carboxylic acid 3,4-dichloro-anilide
6. 5-Methylisoxazole-4-carboxylic acid 3-chloro-4-fluoro-
anilide
7. 5-Methylisoxazole-4-carboxylic acid 3,4-methylenedioxy-
anilide
8. 5-Methylisoxazole-4-carboxylic acid 3,4-difluoro-anilide
9. 5-Methylisoxazole-4-carboxylic acid 4-chloro-3-fluoro-
anilide
10. 5-Methylisox~zole~4-carboxylic acid 2,4-difluoro-anilide
11. 5-Methylisoxazole-4-carboxy~ic acid 2-fluoro-5-trifluoro-
methyl-anilide.
-- 7 --
"