Process for the production of 3-aminoisoxazoles

3-Aminoisoxazoles of the formula: ##STR1## (wherein R is C.sub.1 -C.sub.6 alkyl, phenyl or halo-phenyl) are prepared by reacting a .beta.-ketonitrile of the formula: EQU R--CO--CH.sub.2 CN (wherein R is as defined above) with a compound of the formula: EQU HY (wherein Y is C.sub.1 -C.sub.6 alkoxy or C.sub.1 -C.sub.6 alkylthio) in the presence of an acid in a solvent to give an iminium salt of the formula: ##STR2## (wherein X is the residue of said acid; R and Y are each as defined above) and further reacting the iminium salt with hydroxylamine in an inert solvent.

The present invention relates to a process for the production of 
3-aminoisoxazoles. 
The following processes for the production of 3-aminoisoxazoles have been 
heretofore known: 
(1) Iwai et al., Chem. Pharm. Bull., 14, 1277-1286 (1966) 
(2) Hoffmann-La Roche, Japanese Patent Publication No. 21147/1966 
(corresponding to U.S. Pat. No. 3,242,189) 
(3) Matsumura et al., J. Takeda. Res. Lab., 30, 475 (1971) 
(4) Okeda et al., Yakugaku Zasshi, 76, 66 (1956) 
These known processes, however, have the following weak points and are not 
altogether satisfactory for industrial preparation: 
(a) isomeric 5-aminoisoxazoles are always produced as by-products along 
with 3-aminoisoxazoles; (b) 5-aminoisoxazoles are usually produced as main 
products; (c) even if 3-aminoisoxazoles are produced as main products, the 
yield is not satisfactory; and (d) it is necessary to employ 
N-acylhydroxylamine as a rather special reactant for obtaining 
3-aminoisoxazoles in a higher yield. 
After diligent investigation of much improved processes for the production 
of 3-aminoisoxazoles free from above defects, the present inventors have 
succeeded in establishing the present invention. 
According to the present invention, there is provided a process for the 
production of 3-aminoisoxazoles of the formula: 
##STR3## 
(wherein R is C.sub.1 -C.sub.6 alkyl, phenyl or halo-phenyl) which process 
comprises reacting a .beta.-ketonitrile of the formula: 
EQU R--CO--CH.sub.2 CN (I) 
(wherein R is as defined above) with a compound of the formula: 
EQU HY (II) 
(wherein Y is C.sub.1 -C.sub.6 alkoxy or C.sub.1 -C.sub.6 alkylthio) in the 
presence of an acid in a solvent to give an iminium salt of the formula: 
##STR4## 
(wherein X is the residue of said acid; R and Y are each as defined above) 
and further reacting the resulting iminium salt with hydroxylamine, 
preferably under basic conditions in an inert solvent. 
The definitions of the above-mentioned substituent groups can be 
illustrated by the following description: 
The alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
t-butyl, pentyl, isopentyl, and hexyl; the halo-phenyl includes 
o-chlorophenyl, p-chlorophenyl, o-bromophenyl and p-fluorophenyl; the 
alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, pentoxy 
and the like; the alkylthio includes methylthio, ethylthio, propylthio, 
isopropylthio, butylthio and the like. 
The present chemical process can be shown in the following reaction scheme: 
##STR5## 
(wherein R, X and Y are each as defined above) 
The first step can be carried out by reacting .beta.-ketonitrile (I) with 
an alkanol or alkyl mercaptan (II) in the presence of an acid. Said 
alkanol or alkyl mercaptan (II) includes methanol, ethanol, isopropanol, 
isobutanol, methyl mercaptan, ethyl mercaptan, isopropyl mercaptan and the 
like. The acid includes hydrogen chloride, hydrogen bromide, sulfuric acid 
and the like. Such a reaction can be carried out according to the 
conventional process for converting nitriles into corresponding 
iminoethers in a suitable solvent (e.g. benzene, toluene, xylene, 
chloroform, methylene chloride) with cooling below room temperature. 
The second step can be carried out by reacting the iminium salt (III) with 
hydroxylamine. This reaction can be effected by reacting the iminium salt 
(III) with hydroxylamine in the presence of a base in a suitable solvent 
and then the resulting oxime is subjected to ring closure by treating with 
an acid. The hydroxylamine is available in its salt forms such as 
hydroxylamine hydrochloride, hydroxylamine sulfate and the like. The base 
includes triethylamine, N-methylmorpholine and alkali alkoxide. The acid 
includes hydrochloric acid, sulfuric acid, acetic acid and the like. The 
solvent includes methanol, ethanol and the like. The reaction is 
ordinarily carried out below 100.degree. C., preferably in the range of 
40.degree. to 80.degree. C. 
The second step can be generally considered to run as shown in the 
following reaction scheme: 
##STR6## 
(wherein R, X and Y are each as defined above) 
The industrial advantages of the present invention over prior art processes 
are as follows: 
(1) 3-Aminoisoxazoles (IV) have been prepared in a high yield, by 
minimizing formation of by-products, 5-aminoisoxazoles, to selectively 
produce oximes (V) and then by subjecting those oximes (V) to ring closure 
with an acid. In contrast to known processes in which relatively large 
amounts of 5-amino isomers are produced, the process of this invention 
affords 5-amino isomers in only about 3 to 4% yield. It is a most 
favorable merit of this invention. 
(2) The operation of the reaction is simple, and those two steps can be 
carried out continuously. Overall yield up to 95% can be easily attained. 
(3) .beta.-Ketonitrile (I) used as a reagent can be easily prepared from 
the corresponding methyl ketone via monochloromethyl ketone intermediate 
as follows: 
EQU RCOCH.sub.3 .sup.Cl.sbsp.2 RCOCH.sub.2 Cl .sup.NaCN RCOCH.sub.2 CN (I) 
(wherein R is as defined above). 
(4) A small amount of 5-aminoisoxazoles, produced as undesirable 
by-products, can be easily removed as an acid material, after being 
hydrolyzed into isoxazole-5-ones (VII) in the ring closure treatment as 
shown in the following reaction scheme. Accordingly, the objective 
products (IV) can be isolated in a high purity. 
##STR7## 
(wherein R is as defined above). 
(5) Thus obtained 3-aminoisoxazoles (IV), for example, 
3-amino-5-t-butylisoxazole (IVa), can be converted into 
1,1-dimethyl-3-(5-t-butyl-3-isoxazolyl)urea (VIII), which is available as 
a potent and selective herbicide, by reacting with N,N-dimethylcarbamoyl 
chloride in the presence of a Lewis acid as follows: 
##STR8## 
(wherein t-Bu is tertiary butyl).

The present invention is further described and illustrated in detail by way 
of the following Examples. 
EXAMPLE 1 
To a suspension of cyanopinacolone (75.102 g) in a mixture of anhydrous 
toluene (150 ml) and anhydrous methanol (26.7 ml) is introduced gaseous 
hydrogen chloride (26.3 g) with cooling at 5.degree. to 10.degree. C. and 
stirring, and the whole mixture is allowed to stand at 10.degree. to 
12.degree. C. for 23 hours. To the reaction mixture is dropwise added 
anhydrous methanol (750 ml), then triethylamine (185.178 g) with cooling 
and stirring to make a complete solution. The reaction mixture is treated 
with hydroxylamine sulfate (51.704 g) and stirred at 50.degree. C. for 2 
hours. Then, conc. hydrochloric acid (112.629 g) is dropwise added to the 
mixture, which is stirred at 50.degree. C. for 1 hour. After evaporating 
the solvent under reduced pressure from the reaction mixture, the residue 
is made alkaline with 48% aqueous sodium hydroxide with cooling, and the 
aqueous solution is shaken with toluene. The organic layer is washed with 
water, subjected to azeotropic distillation under atmospheric pressure, 
and evaporated to dryness to remove the solvent, whereby 
3-amino-5-t-butylisoxazole (79.480 g) is obtained. Melting point is 
106.degree. to 109.degree. C. Yield is 94.5%. 
EXAMPLE 2 
(1) To a suspension of cyanopinacolone (25.034 g) in anhydrous toluene (50 
ml) and anhydrous methanol (8.9 ml) is added gaseous hydrogen chloride 
(9.9 g) with cooling and stirring at 5.degree. to 10.degree. C., and the 
whole mixture is allowed to stand at 5.degree. to 10.degree. C. for 25 
hours. The reaction mixture is mixed with n-hexane and the precipitated 
hydrochloride is filtered and washed with ethyl acetate to give methyl 
4,4-dimethyl-3-oxopentanimidate hydrochloride (37.746 g) as crystals 
melting at 104.degree. to 104.5.degree. C. (decomp.). Yield is 97.5%. 
(2) To a solution of sodium hydrogen carbonate (2.17 g) in water (40 ml) is 
added methylene chloride (50 ml), and then with ice cooling and stirring 
the above obtained methyl 4,4-dimethyl-3-oxopentanimidate hydrochloride is 
added thereto. At once, two layers separate, the organic layer is 
decanted, washed with water, dried over anhydrous sodium sulfate, and the 
solvent is evaporated off under reduced pressure to give crystalline 
residue. This residue is triturated with n-hexane and filtered to give 
4,4-dimethyl-1-methoxy-3-oxo-1-pentenylamine (3.97 g) as crystals melting 
at 79.degree. to 79.5.degree. C. Yield is 98%. 
(3) 4,4-Dimethyl-1-methoxy-3-oxo-1-pentenylamine (1.572 g), anhydrous 
methanol (12 ml), and triethylamine (2.052 g) are mixed together to afford 
a clear solution. Hydroxylamine hydrochloride (0.902 g) is added with 
stirring to the solution, which is heated at 50.degree. to 52.degree. C. 
for 2 hours. The resultant mixture is mixed with conc. hydrochloric acid 
(2.15 ml), stirred at 50.degree. to 52.degree. C. for 1 to 1.5 hours, and 
the methanol is evaporated off under atmospheric pressure. The residue is 
made alkaline with 40% aqueous sodium hydroxide and the solution is 
extracted with chloroform. The organic layer is washed with a small amount 
of water, dried over anhydrous sodium sulfate, and the solvent is 
evaporated to give a crystalline residue (1.361 g). This crude product is 
recrystallized from benzene to give 3-amino-5-t-butylisoxazole as 
colorless crystals melting at 111.degree. to 112.degree. C. Yield is 97%. 
EXAMPLE 3 
Using N-methylmorpholine (1.52 g) instead of triethylamine, the reaction is 
effected as in Example 2(3) above, whereby 3-amino-5-t-butylisoxazole 
(1.21 g) is obtained. Yield is 86.0%. 
EXAMPLE 4 
(1) Using cyanopinacolone, the reaction is effected as in Example 2(1), 
whereby methyl 4,4-dimethyl-3-oxopentanimidate hydrochloride is obtained. 
Yield is 97.5%. 
(2) To a suspension of above obtained methyl 
4,4-dimethyl-3-oxopentanimidate hydrochloride (19.40 g) in anhydrous 
methanol (120 ml), triethylamine (25.3 g) is added dropwise with cooling 
below 15.degree. C. and stirring. The resultant mixture is mixed with 
hydroxylamine sulfate (9.02 g) and stirred at about 50.degree. C. for 2 
hours. Then, conc. hydrochloric acid (26.1 g) is dropwise added to the 
mixture, which is stirred at about 50.degree. C. for 1 hour and evaporated 
under atmospheric pressure to remove the solvent. The residue is made 
alkaline with aqueous 40% sodium hydroxide and the resulting solution is 
shaken with chloroform. The organic layer is washed with water, dried over 
anhydrous sodium sulfate, and then the chloroform is evaporated to give 
3-amino-5-t-butylisoxazole (13.359 g) as crystals melting at 107.degree. 
to 109.degree. C. Yield is 95.4%. 
EXAMPLES 5-8 
Using the starting materials cyanopinacolone (Ia) and II, the reactions are 
effected as in Example 4 to give the 3-amino-5-t-butylisoxazole (IVa) via 
the corresponding iminium salt (III) as shown below. 
Table I 
______________________________________ 
##STR9## 
Ex. II III IVa 
No. Y m.p. (.degree.C.) 
Yield (%) 
Yield (%) 
______________________________________ 
5 EtO 119-120 (d) 97.0 94 
6 i-PrO 122-123 (d) 95.0 92 
7 i-BuO 129-130 (d) 95.0 91 
8 i-PrS 135-137 92.0 90 
______________________________________ 
(Note) The abbreviations in Table I have the following significance. 
Et (ethyl), 
Bu (butyl), 
Pr (propyl), 
d (decomp.), 
i (iso) 
EXAMPLES 9-11 
Using the starting materials (I) and (II), reactions are effected as in 
Example 2, whereby the objective compounds (IV) are obtained via the 
corresponding iminium salts (III) and enaminoketones (VI) as shown below. 
Table II 
__________________________________________________________________________ 
##STR10## 
##STR11## 
III VI IV 
Ex. 
I II m.p. Yield 
m.p. Yield 
m.p. 
Yield 
No. 
R Y (.degree.C.) 
(%) (.degree.C.) 
(%) (.degree.C.) 
(%) 
__________________________________________________________________________ 
9 t-Bu EtO 
119-120(d) 
97 59-60.5 
98 111-112 
97 
10 i-Pr MeO 
99-100(d) 
96 107-108 
98 71.5-72.5 
88 
11 
##STR12## 
MeO 
145-148(d) 
85 110-111 
99 144-145 
81 
__________________________________________________________________________ 
(Note)- 
The abbreviations in Table II have the same significance as in Table I.