Process for the preparation of 4(3H)-quinazolinones

A new process for the preparation of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinones from anthranilic acid derivatives is described herein. Additional reactants used in the process are 4-aminotetrazole and a trialkoxymethane or the reaction can be carried out using the imidic ester obtained from these two compounds.

BACKGROUND OF THE INVENTION 
3-(1H-Tetrazol-5-yl)-4(3H)-quinazolinone and related compounds have been 
described in U.S. Pat. No. 4,419,357 as useful as mediator release 
inhibitors. The compounds are prepared by a several-step procedure 
starting with an appropriate 2-nitrobenzoyl chloride. The indicated acid 
chloride is reacted with 5-aminotetrazole to give the corresponding 
carboxamide and the nitro group is then reduced to give the corresponding 
2-amino-N-(1H-tetrazol-5-yl)benzamide. This benzamide is then heated with 
triethoxymethane to give the quinazolinone referred to originally. This 
procedure is generally similar to one described in the literature for 
preparing other related quinazolinones. While this method may ordinarily 
be adequate for obtaining the compound in question, it does suffer from a 
number of disadvantages, particularly when larger supplies of compound are 
desired. Thus, the nitrobenzoyl chloride starting material used in the 
original procedure is relatively expensive and reactive; solids handling 
problems are involved with the intermediates in question and the overall 
yield is only about 50%. 
Other different methods for the preparation of substituted 
4(3H)-quinazolinones have been described in the literature and one general 
approach makes use of anthranilic acid derivatives. Thus, Levy et al., J. 
Chem. Soc., 1956, 985, describes the reaction of methyl anthranilate with 
a benzimidoyl chloride to give a quinazolinone. A number of intermediates 
are suggested although they are not specifically isolated. A similar 
procedure is described in Bayer German Pat. No. 1,809,174, although the 
intermediates proposed there are not the same as those set forth by Levy 
et al. In both of these procedures, however, the benzimidoyl chloride used 
as a starting material would be relatively stable and easy to prepare as 
compared to the intermediate formimidoyl chloride which would be needed to 
prepare the tetrazolyl compounds mentioned earlier. Actually, it is 
questionable whether the appropriate formidoyl compound could be obtained 
at all for the indicated tetrazole series. 
In a somewhat different approach, Rajappa et al., Tetrahedron, 29, 1299 
(1973), describes the reaction of anthranilic acid with a bicyclic imino 
ether to give a complex tetracyclic system which contains the 
quinazolinone structure. Rajappa et al., were interested in other 
questions and provided no details with regard to this process or any 
background leading up to their use of it. It is noted, however, that their 
process was limited to the acid (anthranilic) and heat alone was 
sufficient to bring about the cyclization involved in the preparation of 
the Rajappa compounds. 
Finally, in a still different approach, Arques et al., Anales de Quimica, 
156 (1982), describes the reaction of methyl anthranilate first with the 
dimethylacetal of dimethylformamide followed by an amine to give a 
3-substituted 4(3H)-quinazolinone. Arques also provides a brief summary of 
other methods for preparing 4(3H)-quinazolinones. 
SUMMARY OF THE INVENTION 
A new procedure for the preparation of 4(3H)-quinazolinones has been found 
which is particularly suitable for the preparation of the tetrazolyl 
quinazolinones referred to initially. This procedure is convenient and it 
gives the desired compounds in good yields. The quinazolinones involved 
are acidic and form salts with alkali metals, ammonia and amines. Such 
salts are equivalent to the free tetrazoles and they can also be obtained 
by the present procedure. Specifically, the procedure involves a process 
for the preparation of quinazolinones of the formula 
##STR1## 
wherein X represents hydrogen or one or two methyl, halogen or methoxy 
groups or a methylenedioxy group, and the alkali metal, ammonium and amine 
salts thereof, which comprises: 
(a) Reacting an anthranilic acid derivative of the formula 
##STR2## 
wherein X is defined as above and Z is alkyl of 1-4 carbon atoms or 
ammonium or OZ is NH.sub.2 ; with a 5-(alkoxymethyleneamino)tetrazole 
which has the structural formula 
##STR3## 
wherein the Alkyl group contains 1 to 4 carbon atoms, in an inert solvent 
to give a formamidine of the formula 
##STR4## 
(b) Cyclizing said formamidine to the quinazolinone product directly when Z 
or OZ contains nitrogen or, when Z is alkyl of 1-4 carbon atoms, by the 
use of an alkali metal base, ammonium hydroxide or an amine and, 
(c) When the cyclization product is obtained in the form of a salt and the 
free tetrazole is desired, acidifying said cyclization product with a 
mineral acid to give the desired quinazolinone. 
The amines referred to above with regard to salts or the cyclization are 
mono-, di- and tri-alkylamines wherein each alkyl group contains up to 
four carbon atoms. 
The present invention further encompasses the novel imino ether and 
formamidine intermediates used in the present process. 
Thus, it has been found that 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone and 
related compounds (Formula I) can be obtained readily from certain 
anthranilic acid derivatives (Formula II) and an appropriate imino ether 
of 5-aminotetrazole (Formula III). This gives the corresponding 
formamidine derivative (Formula IV) which then cyclizes to give the 
desired quinazolinone product. The tetrazole substituent group is acidic 
so that when the cyclization reaction is carried out under alkaline 
conditions or a cation is available in the reaction mixture as a result of 
the particular anthranilic acid derivative used, the product is obtained 
as the tetrazole salt. It is then necessary to acidify this salt if the 
free tetrazole is desired. Mineral acids such as hydrochloric acid are 
preferred for this acidification. 
In the first step of the process, the anthranilic acid derivative and the 
imino ether (used either as the compound itself or as prepared in situ) 
are heated in an inert solvent such as carbon tetrachloride, 2-propanol or 
other solvents and the indicated mixed formamidine forms. When Z or OZ 
contains nitrogen, the formamidine cyclizes directly to the desired 
product but, when esters are used (Z is alkyl), it is necessary to treat 
the formamidine with base either with or without isolation of the 
formamidine. When Z is alkyl and the formamidine is isolated, it is then 
treated with base in an appropriate solvent to give the desired 
quinazolinone. Hydroxylic solvents such as methanol or 2-propanol are 
preferred although other solvents such as toluene and dimethylformamidine 
can be used. Bases which can be used in the cyclization step, with or 
without isolation of the formamidine, include sodium carbonate, sodium 
hydroxide, sodium methoxide, sodium t-butoxide, ammonium hydroxide, 
n-propylamine, diethylamine, trimethylamine and triethylamine. As noted 
earlier, when base is present in the reaction mixture, the product is 
obtained as the tetrazole salt. Heating is optional for the cyclization 
step. 
The imino ether used in the first step of the process is prepared by 
heating 5-aminotetrazole and an appropriate trialkoxymethane in excess 
trialkoxymethane or in an inert solvent such as hexane, carbon 
tetrachloride or N,N-dimethylformamide. If desired, the imino ether can be 
specifically isolated and then used in the present process. However, it 
hydrolyzes rapidly on exposure to atmospheric moisture so that it is 
usually preferable to prepare the imino ether in situ and use it 
immediately in the process of the invention. In view of this fact, this 
reactant may not be named specifically in many of the examples but it is 
actually formed in the reaction mixture and then reacts further as 
described. The examples involved should thus be read with this fact in 
mind. 
A preferred embodiment of the present invention involves carrying out the 
process using anthranilic acid esters (i.e., Z is alkyl of 1-4 carbon 
atoms). A further preferred embodiment involves the use of methyl 
anthranilate in the process, with the imino ether prepared in situ and the 
entire process carried out in a single pot. In this further preferred 
embodiment of the present invention, specifically directed to the 
preparation of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone, it is possible to 
combine the preparation of the imino ether with the process described 
earlier and carry out the complete synthesis of the 3(4H)-quinazolinone 
without isolating any of the intermediates. Thus, triethoxymethane, 
5-aminotetrazole and methyl anthranilate are mixed in an inert solvent and 
heated. Examples of useful solvents are 2-propanol, carbon tetrachloride, 
toluene or ethyl acetate. The formamidine described earlier forms in the 
reaction mixture and base is then added as discussed earlier and the 
mixture is heated to bring about cyclization and give the desired 
4(3H)-quinazolinone. The success of this process is particularly 
unexpected in that, in spite of the fact that the initial reaction mixture 
contains two different amine compounds, the triethoxymethane has been 
found to react selectively with the 5-aminotetrazole to give the 
corresponding imino ether and this imino ether then reacts readily and 
cleanly with the amino group of the anthranilic acid ester to give the 
formamidine described earlier. The process proceeds here to give the 
indicated compounds in good yields so that it would be a particularly 
attractive method for preparing the specific compound in question. 
It can be seen that the process here is advantageous over that described 
initially in that anthranilic acid derivatives are more readily available 
than the 2-nitrobenzoic acid compounds which serve as the starting 
material in the prior art procedure discussed earlier. In addition, the 
present synthesis can be completed in much less time than the procedure 
used originally.

The following examples are presented to illustrate the present invention. 
They should not be construed as limiting it in any way. 
EXAMPLE 1 
A mixture was prepared from 50 g of 5-aminotetrazole, 347 g of 
triethoxymethane and 500 ml of hexane and this was heated under nitrogen 
so that distillation took place at a moderate rate (head temperature about 
60.degree.-68.degree. C.). Distillate was collected over a period of 6 
hours with hexane being replaced in the reaction mixture as necessary. The 
mixture was then cooled to room temperature and the fine white needles 
that formed were collected by filtration, washed with hexane and vacuum 
oven dried with heating to give 5-(ethoxymethyleneamino)tetrazole. This 
material hydrolyzes rapidly on exposure to atmospheric moisture so that it 
should be used promptly for any further reactions desired or it should be 
stored using appropriate conditions. 
EXAMPLE 2 
A mixture of 10 g of 5-aminotetrazole, 18 g of triethoxymethane and 200 ml 
of carbon tetrachloride was heated under nitrogen with stirring until 
distillate appeared. Then, a moderate rate of distillation was maintained 
for 6 hours with carbon tetrachloride being replaced in the reaction 
mixture as necessary. At this point, analysis of the crystals present 
showed complete conversion of aminotetrazole. The white crystals were then 
filtered from the hot solution and washed briefly with carbon 
tetrachloride to give a wet cake of 5-(ethoxymethyleneamino)tetrazole 
which was used immediately as is. 
EXAMPLE 3 
A mixture of 25 g of 5-aminotetrazole monohydrate and 356 g of 
triethoxymethane was heated under nitrogen with stirring at 100.degree. C. 
for 4 hours during which time a distillate was collected. Then, 30 ml of 
cyclohexane was added and the mixture was cooled first to room temperature 
and then briefly with an ice-water bath. The white crystals which formed 
were separated by filtration and vacuum oven dried to give 
5-(ethoxymethyleneamino)tetrazole. 
EXAMPLE 4 
A mixture was prepared from 12.2 g of 5-aminotetrazole monohydrate, 71.3 g 
of triethoxymethane, 22.3 g of methyl anthranilate and 100 ml of carbon 
tetrachloride and this was refluxed under nitrogen with stirring for 16 
hours. The mixture was then cooled to room temperature and the white 
crystals which formed were separated by filtration, washed with carbon 
tetrachloride and dried to give N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine melting at about 
199.degree.-200.degree. C. 
EXAMPLE 5 
A mixture of 5 g of 5-aminotetrazole and 150 ml of 2-propanol was heated to 
80.degree. C. under nitrogen. To the resulting heterogeneous mixture was 
added 7 g of trimethoxymethane and 9.3 g of methyl anthranilate. The 
mixture was stirred for 35 minutes and then cooled to 30.degree. C. The 
white crystals which formed were separated by filtration, washed with 
2-propanol and vacuum oven dried to give N.sup.1 
-(1H-tetrazol-5-yl)-N.sup.2 -(2-carbomethoxyphenyl)formamidine. 
EXAMPLE 6 
A mixture was prepared from 9.5 g of 5-aminotetrazole, 16.5 g of 
triethoxymethane and 50 ml of N,N-dimethylformamide and heated under 
nitrogen and a solution of 16.9 g of methyl anthranilate in 15 ml of 
N,N-dimethylformamide was added to the hot mixture and stirred for 15 
minutes. The mixture was then cooled to room temperature and stirred for 
16 hours. The white crystals which formed were separated by filtration, 
washed first with N,N-dimethylformamide and then with 2-propanol, and 
vacuum oven dried to give N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine which was identical with authentic 
material. 
EXAMPLE 7 
A mixture of 5 g of 5-aminotetrazole, 46.7 g of triethoxymethane, 10.5 g of 
methyl anthranilate and 105 ml of hexane was heated at reflux under 
nitrogen for 48 hours. The mixture was cooled to room temperature and the 
white crystalline product was separated by filtration, washed with hexane 
and vacuum oven dried to give product containing traces of methyl 
anthranilate. This was triturated with additional hexane, followed by 
filtration and drying to give pure N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine. 
EXAMPLE 8 
A mixture of 12.1 g of 5-aminotetrazole monohydrate, 42 g of 
triethoxymethane, 21 g of methyl anthranilate and 50 ml of 2-propanol was 
stirred at room temperature under nitrogen for 2 days. The white solid 
which formed was separated by filtration, washed with 2-propanol and 
vacuum oven dried to give N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine which was identical with authentic 
material. 
EXAMPLE 9 
To a mixture of 5 g of 5-(ethoxymethyleneamino)tetrazole in 50 ml of ethyl 
acetate, stirred at room temperature under nitrogen, there was added a 
solution of 10.2 g of methyl anthranilate in 50 ml of ethyl acetate and 
the mixture was stirred for 24 hours. The white solid which formed was 
separated by filtration, washed with ethyl acetate and vacuum oven dried 
to give crude N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine. This was recrystallized from a mixture 
of N,N-dimethylformamide and ethyl acetate to give pure product identical 
with authentic material. 
EXAMPLE 10 
Methanol (15 ml) was cooled to about 0.degree. C. in an ice-acetone bath 
and 0.3 g of N.sup.1 -(1tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine was added under nitrogen with stirring 
to give a heterogeneous mixture. Stirring under nitrogen was continued and 
about 66 mg of sodium methoxide was added portionwise to give a 
homogeneous solution. Additional sodium methoxide was added to bring the 
pH to between 7-8. The solvent was then evaporated under reduced pressure 
to give the sodium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone. The 
product obtained by this procedure was identical in all respects with 
material prepared by the procedure described in the literature. 
EXAMPLE 11 
A mixture was prepared from 2.9 g of the sodium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolin-4-one, 25 ml of methanol and 15 ml 
of water and stirred at room temperature. To this mixture was added 4 ml 
of 3N hydrochloric acid and stirring was continued for 15 minutes. The 
white solid which formed was separated by filtration, washed with water 
and vacuum oven dried to give 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone 
which was idential with authentic material. 
EXAMPLE 12 
A slurry of 3 g of N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine in 10 ml of methanol was stirred at 
room temperature. A solution of 0.8 ml of 14.8M ammonium hydroxide in 5 ml 
of methanol was added to the mixture which was stirred for 1 hour. The 
white solid which formed was separated by filtration, washed with aqueous 
2-propanol and vacuum oven dried to give the ammonium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone. 
EXAMPLE 13 
A cooled (0.degree. C.) slurry was prepared from 10 g of N.sup.1 
-(1H-tetrazol-5-yl)-N.sup.2 -(2-carbomethoxyphenyl)formamidine and 25 ml 
of water and this was stirred while 8.2 ml of 5N sodium hydroxide was 
added dropwise. The mixture was brought to room temperature and 200 ml of 
2-propanol was added. It was then heated to 70.degree. C., a further 90 ml 
of 2-propanol was added, and the mixture was stirred for 4 hours at 
70.degree. C. It was then cooled to room temperature and stirred for 16 
hours. The white crystals which formed were separated by filtration and 
washed with aqueous 2-propanol and vacuum oven dried to give the sodium 
salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone. 
EXAMPLE 14 
A solution was prepared from 0.3 g of N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine and 10 ml of N,N-dimethylformamide. A 
slurry of 67 mg of sodium methoxide in 1.4 ml of N,N-dimethylformamide was 
added and the mixture was stirred under nitrogen for 30 minutes. The 
solvent was then evaporated under reduced pressure to give the sodium salt 
of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone. 
EXAMPLE 15 
A mixture was prepared from 0.3 g of N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine and 15 ml of methanol and cooled to 
0.degree. C. under positive pressure of nitrogen. Solid sodium methoxide 
(0.66 g) was added portionwise and the mixture was stirred for 15 minutes. 
The solvent was evaporated in vacuo to give crude sodium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone (93% pure by HPLC). 
EXAMPLE 16 
A mixture was prepared from 0.4 g of N.sup.1 -(1H-tetrazol-5-yl)-N.sup.2 
-(2-carbomethoxyphenyl)formamidine and 40 ml of toluene and this was 
heated to 60.degree. C. under nitrogen. A solution of 20% sodium 
t-butoxide in tetrahydrofuran (0.7 ml) was added, the mixture was stirred 
at 60.degree. C. for 1 hour, and then cooled to room temperature. The 
off-white solid which formed was separated by filtration, washed with 
hexane and vacuum oven dried to give crude sodium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone with a purity of greater than 90% 
as shown by HPLC. 
EXAMPLE 17 
N.sup.1 -(1H-Tetrazol-5-yl)-N.sup.2 -(2-carbomethoxyphenyl)formaidine (5 g) 
was mixed with 25 ml of 2-propanol. The resulting slurry was stirred at 
room temperature and 2 g of triethylamine was added. The mixture was 
heated at reflux for 24 hours and then cooled to room temperature. The 
white crystals which formed were separated by filtration, washed with 
2-propanol and dried to give the triethylammonium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 
112.degree.-115.degree. C. Evaporation of the solvent from the filtrate in 
vacuo gave a residue which was triturated with carbon tetrachloride, 
filtered and dried to give additional crude triethylammonium salt. 
EXAMPLE 18 
A mixture was prepared from 10 g of 5-aminotetrazole, 18.2 g of 
triethoxymethane, 18 g of methyl anthranilate and 90 ml of 2-propanol and 
this was heated at 70.degree. C. under nitrogen and stirred for 1.5 hours. 
The mixture was then cooled to room temperature, 23 ml of distilled water 
was added, and the resulting mixture was then stirred for 15 minutes 
before 24 ml of 5N aqueous sodium hydroxide was added. The resulting 
mixture was first stirred at room temperature for 15 minutes and then 
heated to reflux. A clear pale yellow solution resulted and 180 ml of 
2-propanol was added at such a rate that the temperature remained above 
70.degree. C. Reflux was then maintained for 1 hour before the mixture was 
cooled to room temperature with stirring. Crystallization took place 
during this time and the crystals which formed were separated by 
filtration, washed with 2-propanol and dried in a vacuum oven to give the 
sodium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at greater 
than 300.degree. C. The purity of the product, as determined by HPLC, was 
greater than 99.9% and the yield was 80% as the trihydrate. The product 
can be isolated as the trihydrate, in anhydrous form, or as some 
intermediate hydrate, depending on the duration and amount of heating used 
in the drying process. 
EXAMPLE 19 
A mixture of 5 g of 5-aminotetrazole, 9.8 g of triethoxymethane, 9.9 g of 
methyl anthranilate and 50 ml of carbon tetrachloride was prepared and 
heated at reflux under nitrogen for 16 hours. Anhydrous sodium carbonate 
(3.1 g) was added to the hot mixture followed by the slow addition of 50 
ml of distilled water. The mixture was then stirred for 30 minutes, cooled 
to room temperature and filtered to remove solid materials. The aqueous 
layer was then separated and it was heated to 75.degree. C. To this hot 
solution was added 100 ml of 2-propanol while maintaining the temperature 
above 70.degree. C. Reflux was continued for an additional 30 minutes and 
the mixture was then cooled to room temperature. The crystals which formed 
were separated by filtration, washed with 2-propanol and dried to give the 
sodium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone.multidot.2.7 
hydrate. 
EXAMPLE 20 
A solution was prepared from 10 g of 5-aminotetrazole and 100 ml of 
N,N-dimethylformamide and heated to 90.degree. C. Triethoxymethane (21.3 
g) was added and the mixture was stirred at 90.degree. C. under nitrogen 
for 3 hours. A solution of 16 g of anthranilamide in 20 ml of 
N,N-dimethylformamide was then added, the resulting mixture was cooled to 
85.degree. C., and then it was stirred at 85.degree. C. for 1 hour. The 
mixture was cooled to room temperature over 16 hours during which time 
crystallization took place. The crystals which formed were separated by 
filtration to give 2.3 g of product and the filtrate was concentrated to 
give a further 5.3 g of product. The solid obtained in this way was the 
ammonium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 
236.degree.-240.degree. C. 
EXAMPLE 21 
A slurry of 0.5 g of the ammonium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone in 10 ml of methanol was stirred 
at room temperature, acidified with 0.7 ml of 3N hydrochloric acid, and 
stirred for 15 minutes. 2-Propanol (5 ml) was added and the resulting 
mixture was stirred for an additional 15 minutes. The white powdery 
crystalline solid which formed was collected by filtration, washed with 
cold methanol and dried to give 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone 
which was identical with the material prepared according to the procedure 
described in the prior art. 
EXAMPLE 22 
A mixture was prepared from 10 g of 5-aminotetrazole and 50 ml 
N,N-dimethylformamide. This was heated to 100.degree. C. and 17 g of 
triethoxymethane was added. The resulting mixture was stirred at 
100.degree. C. under nitrogen for 2 hours and then a solution of the 
ammonium salt of anthranilic acid (prepared from 16 g of anthranilic acid 
and 7.8 ml of 14.8M ammonium hydroxide in methanol, followed by removal of 
the methanol) in 40 ml of N,N-dimethylformamide was added. The mixture was 
stirred for 1 hour at 100.degree. C., then cooled to room temperature and 
finally cooled in an ice bath to induce crystallization. The white 
crystals which formed were separated by filtration, washed with 
N,N-dimethylformamide and then with carbon tetrachloride, and vacuum oven 
dried to give the ammonium salt of 
3-(1H-tetrazol-5-yl)4(3H)-quinazolinone. 
EXAMPLE 23 
A solution was prepared from 11.7 g of methyl anthranilate and 80 ml of 
anhydrous methanol and cooled to 0.degree. C. under nitrogen. To this 
stirred solution was added 10 g of 5-(ethoxymethyleneamino)tetrazole as a 
solid. The reaction mixture was stirred for 20 minutes and then 14.2 ml of 
5N sodium hydroxide was added and stirring was continued for 10 minutes. 
The mixture was filtered to remove some insoluble solid and the solvent 
was evaporated from the filtrate in vacuo to leave a residual glassy 
solid. This was taken up in water/2-propanol (35 ml, 1:1) and heated to 
70.degree. C. An additional 80 ml of 2-propanol was added and heating was 
continued for 20 minutes. The mixture was then allowed to cool to room 
temperature over 16 hours. The crystals which formed were separated by 
filtration, washed with aqueous 2-propanol and vacuum oven dried to give 
the sodium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone hydrate. 
EXAMPLE 24 
A mixture of 10.1 g of 5-aminotetrazole monohydrate, 60 g of 
triethoxymethane and 155 ml of hexane was heated under nitrogen until 
distillate appeared. Slow distillation was continued for 7 hours (head 
temperature 60.degree.-80.degree. C.) with hexane added to replenish the 
material removed. To the hot mixture was added 14.8 g of methyl 
anthranilate and, after 1.5 hours, the mixture was allowed to cool to room 
temperature and stirred for 48 hours. To the resulting mixture was added 
80 ml of methanol followed by slow addition of sufficient 5N sodium 
hydroxide to bring the pH to approximately 8. The mixture was then stirred 
briefly and the white solid was separated by filtration, washed with 
aqueous 2-propanol and vacuum oven dried to give the sodium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone. 
EXAMPLE 25 
A mixture was prepared from 12 g of 5-aminotetrazole monohydrate, 36.5 g of 
triethoxymethane, 38.5 g of methyl anthranilate and 100 ml of ethyl 
acetate under a positive pressure of nitrogen. The mixture was heated at 
60.degree. C. for 6 hours and then 50 ml of 2.3N sodium hydroxide was 
added to the hot solution. Agitation was discontinued to allow phase 
separation and the organic phase was removed. To the hot aqueous phase was 
added 300 ml of 2-propanol and this mixture was stirred for 2 hours as 
precipitation occurred. The mixture was cooled for 16 hours and the white 
crystals were separated by filtration, washed with aqueous 2-propanol and 
vacuum oven dried to give the sodium salt of 
3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone which was identical with 
authentic material. 
EXAMPLE 26 
Under a positive pressure of nitrogen, a mixture was prepared from 10 g of 
5-aminotetrazole, 19.6 g of triethoxymethane, 19.8 g of methyl 
anthranilate and 150 ml of toluene. This heterogeneous mixture was heated 
until distillate appeared and slow distillation was continued for 5 hours 
with replenishment of the toluene in the reaction vessel as necessary. The 
mixture was then cooled to 65.degree. C. and 6.4 g of anhydrous sodium 
carbonate was added followed by the slow addition of 50 ml of water. The 
mixture was then heated for 30 minutes and the aqueous phase was 
separated. This aqueous phase was heated to 80.degree. C. and to the hot 
mixture was slowly added 300 ml of 2-propanol. This mixture was stirred at 
80.degree. C. for 30 minutes, then cooled to room temperature and stirred 
for 12 hours. The white crystalline solid which formed was separated by 
filtration, washed with aqueous 2-propanol and vacuum oven dried to give 
the sodium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone trihydrate 
which was identical with authentic material. 
When the procedures described above are repeated using substituted 
anthranilic acid derivatives or other anthranilic acid esters, the 
corresponding 4(3H)-quinazolinones are obtained.