Preparation of pyrazolo[5,1-b]quinazolones

Pyrazolo[5,1-b]quinazolones are prepared by reacting isatoic anhydrides with pyrazolones at from 100.degree. to 180.degree. C. in an inert organic solvent with simultaneous azeotropic removal of the water formed in the course of the reaction.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a novel process for preparing 
pyrazolo[5,1-b]quinazolones by reacting isatoic anhydrides with 
pyrazolones in an inert organic solvent at from 100.degree. C. to 
180.degree. C. with simultaneous azeotropic removal of the water formed in 
the course of the reaction. 
2. Discussion of the Background 
It is known to prepare 2-methylpyrazolo[5,1-b]quinazolone by reacting 
isatoic anhydride with 3-methyl-pyrazol-5-one in the melt or in a 
high-boiling solvent at from 200.degree. C. to 250.degree. C. (Angew. 
Chem. 74 (1962), 839). 
J. Heterocycl. Chem. 18 (1981), 117 and J. Med. Chem. 24 (1981), 735 
disclose the preparation of further pyrazolo[5,1-b]quinazolones. The 
starting materials used are likewise isatoic anhydrides and pyrazolones. 
This reaction takes place in N,N-dimethylformamide as solvent in the 
presence of sodium hydride as base at from -10.degree. C. to 0.degree. C. 
Neither procedure is easy to carry out on an industrial scale. On the one 
hand, special measures are required in order to be able to perform the 
reaction at a very high temperature in a melt or in a high-boiling 
solvent; on the other hand, the use of sodium hydride as a base is not 
without its problems and necessitates a great deal of attention to safety. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide a new process for 
preparing pyrazolo[5,1-b]quinazolones which starts from industrially 
readily accessible starting materials and which should give the target 
products in good yield without recourse to extraordinary technical 
resources. 
We have found that this object is achieved with a process for preparing a 
pyrazolo[5,1-b]quinazolone of the formula I 
##STR1## 
where R.sup.1, R.sup.2 and R.sup.3 are identical or different and each is 
independently of the others hydrogen, halogen, C.sub.1 -C.sub.4 -alkoxy, 
nitro, C.sub.1 -C.sub.4 -alkyl, trifluoromethyl, carboxyl, cyano, 
carbamoyl, C.sub.1 -C.sub.4 -monoalkyl- or -dialkyl-carbamoyl, 
phenylcarbamoyl, sulfamoyl, C.sub.1 -C.sub.4 -monoalkyl- or 
-dialkylsulfamoyl, phenylsulfamoyl, hydroxysulfonyl or C.sub.1 -C.sub.4 
-alkanoylamino and X is C.sub.1 -C.sub.4 -alkyl or substituted or 
unsubstituted phenyl, by reacting an isatoic anhydride of the formula II 
##STR2## 
where R.sup.2, R.sup.2 and R.sup.3 are each as defined above, with a 
pyrazolone of the formula III 
##STR3## 
where X is as defined above, which comprises performing the reaction at 
from 100.degree. C. to 180.degree. C. in an inert organic solvent with 
simultaneous azeotropic removal of the water formed in the course of the 
reaction. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
All the alkyls appearing in the abovementioned formulae may be, not only 
straight-chain, but also branched. 
Where substituted phenyl appears in the formulae I or III, suitable 
substituents are for example C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 
-alkoxy, halogen, in particular fluorine, chlorine or bromine, nitro and 
cyano. 
R.sup.1, R.sup.2, R.sup.3 and X are each for example methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl or sec-butyl. 
X is further for example phenyl, 2-methylphenyl, 4-methylphenyl, 
4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 
2-methoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 
2,6-dimethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 
2,4-dichlorophenyl, 2- or 3-nitrophenyl or 3- or 4-cyanophenyl. 
R.sup.1, R.sup.2 and R.sup.3 are each further for example fluorine, 
chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
isobutoxy, sec-butoxy, monomethylcarbamoyl, dimethylcarbamoyl, 
monoethylcarbamoyl, diethylcarbamoyl, monopropylcarbamoyl, 
dipropylcarbamoyl, monoisopropylcarbamoyl, diisopropylcarbamoyl, 
monobutylcarbamoyl, dibutylcarbamoyl, N-methyl-N-ethylcarbamoyl, 
monomethylsulfamoyl, dimethylsulfamoyl, monoethylsulfamoyl, 
diethylsulfamoyl, monopropylsulfamoyl, dipropylsulfamoyl, 
monoisopropylsulfamoyl, diisopropylsulfamoyl, monobutylsulfamoyl, 
dibutylsulfamoyl, N-methyl-N-ethylsulfamoyl, formylamino, acetylamino, 
propionylamino, butyrylamino or isobutyrylamino. 
The process according to the invention is preferred for those 
pyrazolo[5,1-b]quinazolones of the formula I where X is methyl or phenyl 
and R.sup.1, R.sup.2 and R.sup.3 are each hydrogen, nitro, methoxy, 
phenylsulfamoyl, chlorine or bromine. 
The process according to the invention is carried out in an inert organic 
solvent at from 100.degree. C. to 180.degree. C., preferably at from 
120.degree. C. to 160.degree. C. 
In general, atmospheric pressure is employed. In some cases, however, it 
may also be of advantage to carry out the reaction under superatmospheric 
pressure (from 0 up to 5 bar gauge). 
A suitable inert organic solvent is in particular xylene, dichlorobenzene, 
nitrobenzene or methyl benzoate. 
In general this solvent is used in an amount of from 3 to 10 parts by 
weight per part by weight of isatoic anhydride II. 
Isatoic anhydride II and pyrazolone III are customarily used in a molar 
ratio of from 1.2:1 to 0.8:1. 
It is also possible to perform the process according to the invention in 
the presence of 1 to 50 percent by weight, preferably 5 to 30 percent by 
weight and particularly 10 to 20 percent by weight, based in each case on 
the pyrazolone of the formula III, of anhydrous sodium carbonate or 
potassium carbonate. 
Advantageously, the novel process is carried out by introducing inert 
solvent and pyrazolone III initially, heating with stirring to the 
temperature according to the invention and adding isatoic anhydride II. 
After the evolution of carbon dioxide has ceased, the reaction mixture may 
be admixed with catalyst and is in general stirred at the temperature 
according to the invention for from 1 to 10 hours, during which the water 
formed in the course of the reaction is azeotropically distilled out of 
the reaction mixture, the function of entrainer being performed by the 
inert solvent. Isatoic anhydride II and pyrazolone III may also be used as 
an aqueous paste, in which case the water is azeotropically distilled out 
of the reaction mixture together with the water of reaction. 
The amount of solvent distilled off during the reaction may be recycled 
into the reaction mixture in the form of fresh or regenerated solvent. 
On completion of the reaction, which proceeds via a ring-opened 
intermediate of the formula IV 
##STR4## 
where R.sup.1, R.sup.2, R.sup.3 and X are each as defined above, the 
resulting pyrazolo[5,1-b]quinazolone of the formula I is separated off, 
washed with the particular solvent, methanol and warm water and dried. 
It is also possible to remove the solvent by steam distillation and to 
isolate the pyrazolo[5,1-b]-quinazolone from an aqueous suspension. In 
this alternative, impurities go into solution at above pH 7 and thus can 
be removed in the course of filtration. 
Using the process according to the invention, which may be carried out not 
only continuously but also batchwise, the pyrazolo[5,1-b]quinazolones can 
be obtained in good yields without recourse to extraordinary technical 
resources and the solvent used in this synthesis may in general be reused 
following regeneration (distillation). 
Pyrazolo[5,1-b]quinazolones are useful intermediates for the synthesis of 
dyes and pigments. 
The Examples which follow serve to illustrate the invention in more detail.

EXAMPLE 1 
100 g of 3-methylpyrazol-5-one were introduced in 1,000 g of xylene. After 
heating to 115.degree. C., 200 g of 5-chloroisatoic anhydride were slowly 
added to the mixture. After CO.sub.2 evolution had subsided, the mixture 
was stirred for 20 minutes, then heated to 140.degree. C. and maintained 
at that temperature until no further water of reaction distilled off. This 
is followed by cooling down to 70.degree. C., filtration, washing first 
with 550 g of methanol and then with warm water, and drying to leave 200 g 
of a colorless powder of the formula 
##STR5## 
EXAMPLE 2 
160 g of 3-phenylpyrazol-5-one were added to 750 g of xylene and heated to 
115.degree. C. 160 g of isatoic anhydride were then slowly added to the 
mixture. After CO.sub.2 evolution had ceased, the mixture was stirred for 
20 minutes, heated to 140.degree. C. and maintained at that temperature 
for 6 hours. It was then cooled down to 95.degree. C. and diluted with 
1,000 ml of water, and the solvent was distilled off by steam 
distillation. Thereafter it was diluted with 2,000 ml of water, admixed 
with 40 g of 50% strength by weight sodium hydroxide solution and 
subsequently stirred for 1 hour. This was followed by filtration, washing 
neutral with water and drying to leave 220 g of a yellowish powder of the 
formula 
##STR6## 
EXAMPLE 3 
100 g of 3-methylpyrazol-5-one and 200 g of 6-chloroisatoic anhydride were 
heated in 700 g of nitrobenzene at 150.degree. C. for 4 hours. The 
reaction mixture was then cooled down to 80.degree. C. and filtered. The 
filter residue was washed with 500 g of methanol and then with 3,000 ml of 
warm water and dried to leave 195 g of a colorless powder of the formula 
##STR7## 
EXAMPLE 4 
50 g of 3-methylpyrazol-5-one were introduced in 350 g of xylene and heated 
to 115.degree. C. At that temperature 80 g of isatoic anhydride were 
slowly added and stirred in until the evolution of CO.sub.2 had ceased. 10 
g of anhydrous sodium carbonate were then added, and the mixture was 
heated to 135.degree. C. and stirred until no further water of reaction 
passed over. The mixture was cooled down to 100.degree. C., 200 ml of 
water were added, and xylene was driven off by means of steam. Thereafter 
the aqueous suspension was cooled down to 70.degree. C. and brought to a 
pH of from 7 to 7.5 with 5 g of 96% strength by weight sulfuric acid. The 
mixture was then filtered, and the filter residue was washed with warm 
water until the run-off was colorless, and dried to leave 85 g of a 
product of the formula 
##STR8## 
EXAMPLE 5 
100 g of 3-methylpyrazol-5-one and 200 g of 4-chloroisatoic anhydride were 
heated in 800 g of dichlorobenzene at 155.degree. C. for 3 hours. After 
cooling down to 80.degree. C., the mixture was filtered, and the filter 
residue was washed with 500 g of methanol and then with 3,000 ml of warm 
water and dried to leave 180 g of a colorless powder of the formula 
##STR9## 
EXAMPLE 6 
200 g of 3-methylpyrazol-5-one were introduced in 1,500 g of methyl 
benzoate, heated with stirring to 115.degree. C. and then slowly admixed 
with 300 g of 3,5-dichloroisatoic anhydride. The reaction mixture was then 
stirred at 170.degree. C. for 3 hours while the water of reaction was 
distilled off. After cooling to 90.degree. C, the reaction mixture was 
filtered, and the filter residue was washed with 1,000 g of methanol and 
3,000 ml of warm water and dried to leave 250 g of a light-colored powder 
of the formula 
##STR10## 
The compounds listed in the Table below with reaction conditions and yield 
were obtained in a similar manner. 
__________________________________________________________________________ 
Example Temp. 
Yield 
No. Formula Solvent [.degree.C.] 
[%] 
__________________________________________________________________________ 
7 
##STR11## nitrobenzene 
160 73 
8 
##STR12## nitrobenzene 
165 85 
9 
##STR13## dichlorobenzene 
170 82 
10 
##STR14## nitrobenzene 
170 84 
11 
##STR15## methyl benzoate 
160 75 
12 
##STR16## nitrobenzene 
160 78 
13 
##STR17## nitrobenzene 
160 84 
14 
##STR18## methyl benzoate 
160 89 
15 
##STR19## xylene 140 87 
16 
##STR20## nitrobenzene 
170 83 
17 
##STR21## nitrobenzene 
170 85 
18 
##STR22## nitrobenzene 
170 75 
__________________________________________________________________________