Aqueous process for the preparation of 5-methyl-n-(aryl)-1,2,4-triazolo(1,5-A)pyrimidine-2-sulfonamides

5-Methyl-N-(aryl)-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamides are prepared by the cyclization of N -(3-(((aryl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amines with 4-methoxy-3-butene-2-one or its synthetic equivalents in the presence of an aqueous base. By controlling the pH of the condensation between 8.5 and 10.5, by-product formation can be substantially reduced.

FIELD OF THE INVENTION 
The present invention relates to a process for the preparation of 
5-methyl-N-(aryl)-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamides by the 
aqueous alkaline cyclization of 
N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amines with 
4-methoxy-3-butene-2-one or a precursor thereof. 
BACKGROUND OF THE INVENTION 
Aryl substituted 5-methyl-N-(aryl)-1,2,4-triazolo 
[1,5-a]pyrimidine-2-sulfonamides (I), 
##STR1## 
such as those described in U.S. Pat. No. 4,755,212, are valuable 
herbicides for the selective control of weeds in agronomic crops. U.S. 
Pat. No. 4,734,123 recommends as the final step in the preparation of 
these compounds the cyclization of 
N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amines (II) with 
appropriately substituted 1,3-dicarbonyl compounds or their synthetic 
equivalents, for example: 
##STR2## 
Accordingly the cyclizations may be conducted under acidic, neutral or 
basic conditions in a variety of solvents including, for example, acetic 
acid, ethanol, butanol, dimethylformamide, dimethylsulfoxide or 
tetrahydrofuran. Among the difficulties encountered with such cyclizations 
are depressed yields associated with decomposition of both product and 
starting material and with formation of undesired isomers, e.g., the 
7-methyl isomer. 
##STR3## 
The discovery of a high yield process with a high selectivity to the 
desired 5-methyl isomer would be of great interest. Furthermore, the 
replacement of flammable and toxic organic solvents with environmentally 
benign water would be of considerable benefit. 
SUMMARY OF THE INVENTION 
The present invention relates to a process for preparing 
5-methyl-N-(aryl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamides of the 
formula: 
##STR4## 
wherein 
X represents F, Cl, Br or C.sub.1 -C.sub.4 alkyl, 
Y represents F, Cl, Br or NO.sub.2, and 
Z represents H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy, 
which comprises contacting an 
N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl) amine of the formula: 
##STR5## 
wherein 
X, Y and Z are as previously defined, with 4-methoxy-3-butene-2-one or a 
synthetic equivalent thereof in an aqueous alkaline medium and controlling 
the pH of the mixture between about 8.5 and about 10.5. 
By conducting the cyclization in water at a pH between about 8.5 and about 
10.5, a high yield of the desired 5-methyl isomer with very little 
contaminating 7-methyl isomer is obtained.

DETAILED DESCRIPTION OF THE INVENTION 
As used herein, the terms "C.sub.1 -C.sub.4 alkyl" and "C.sub.1 -C.sub.4 
alkoxy" refer to straight-chained or branched hydrocarbon groups of up to 
four carbon atoms, provided that all substituent groups are sterically 
compatible with each other. The term "sterically compatible" is employed 
to designate substituent groups which are not affected by steric hindrance 
as this term is defined in "The Condensed Chemical Dictionary", 7th 
edition, Reinhold Publishing Co., N.Y. page 893 (1966) which definition is 
as follows: "steric hindrance: A characteristic of molecular structure in 
which the molecules have a spatial arrangement of their atoms such that a 
given reaction with another molecule is prevented or retarded in rate". 
Sterically compatible may be further defined as reacting compounds having 
substituents whose physical bulk does not require confinement within 
volumes insufficient for the exercise of their normal behavior as 
discussed in Organic Chemistry of D. J. Cram and G. Hammond, 2nd edition, 
McGraw-Hill book Company, N.Y., page 215 (1964). 
The preferred "C.sub.1 -C.sub.4 alkyl" and "C.sub.1 -C.sub.4 alkoxy" groups 
are --CH.sub.3, --CH.sub.2 CH.sub.3, --OCH.sub.3 and --OCH.sub.2 CH.sub.3. 
The most preferred group is --CH.sub.3. 
The N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amines (II) are 
known compounds and are described in U.S. Pat. No. 4,734,123. Of these 
starting materials, X and Y are preferably F or Cl. Most preferably, both 
X and Y are F. Z is preferably H. 
4-Methoxy-3-butene-2-one is also a commercially available compound. 
Alternatively, 4-methoxy-3-butene-2-one can be generated in situ from 
appropriate precursors. For example, under basic conditions, 
4,4-dimethoxybutanone eliminates methanol to generate 
4-methoxy-3-butene-2-one. 
##STR6## 
In the aqueous cyclization reaction, the 
N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl) amine is condensed 
with 4-methoxy-3-butene-2-one or one of its synthetic equivalents, such 
as, for example, 4,4-dimethoxybutan-2-one. 
In principal one equivalent of each reagent is required; in practice an 
excess of the 4-methoxy-3-butene-2-one or its synthetic equivalent is 
preferred. Generally, from 1.1 to 1.5 equivalents of the 
4-methoxy-3-butene-2-one are employed, while about 1.2 equivalents are 
preferred. 
Theoretically, the reaction can be conducted under acidic, neutral or basic 
conditions. It has been found, however, that under aqueous alkaline 
conditions, i.e., pH .gtoreq.8.5, the cyclization is highly selective to 
the desired 5-methyl isomer. Furthermore, at pH .gtoreq.11, the 
4-methoxy-3-butene-2-one rapidly decomposes and the desired products, 
5-methyl-N-(aryl)-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamides, are 
subject to hydrolysis, i.e., the reverse reaction of cyclization. 
Therefore, in order to insure high yields of the desired isomer under 
aqueous reaction conditions, it is critical to maintain the pH of the 
reaction between 8.5 and 10.5, more preferably between 8.5 and 9.5. The pH 
of the reaction can be controlled by continuous monitoring and adjusting 
as the reaction proceeds or, preferably, by using a buffer. 
Suitable water-soluble bases that can be employed in the reaction include 
the alkali metal hydroxides, carbonates, and bicarbonates. Alkali metal, 
particularly sodium, hydroxide and carbonate and mixtures thereof are 
preferred as bases while carbonate and bicarbonate are preferred as 
buffers. The actual cyclization reaction is catalytic in base and the 
amount used is not critical: 0.2 to 1.0 equivalents of base are routinely 
employed for this condensation. Because of the relative acidity of the 
N-(3-(((aryl)amino)-sulfonyl)-1H-1,2,4-triazol-5-yl)amine (I) starting 
material, an additional equivalent of base is first required for 
neutralization. 
##STR7## 
In a typical reaction, one equivalent of NaOH is added to neutralize the 
starting material and then about 0.2 equivalents of Na.sub.2 CO.sub.3 are 
added to catalyze the cyclization. The Na.sub.2 CO.sub.3 also serves to 
buffer the reaction medium. If the reactive 4-methoxy-3-butene-2-one is 
generated in situ, for example, by the reaction of 4,4-dimethoxybutanone 
with caustic, additional NaOH is not required since the reaction is 
catalytic in base. 
The cyclization reaction is generally run from ambient temperature to about 
90.degree. C., preferably from 60.degree. to 80.degree. C. 
The cyclization can be conducted in brine as well as in water. In fact, it 
is often convenient to perform the cyclization using crude 
N-(3-(((aryl)-amino)sulfonyl)-1H-1,2,4-triazol-5-yl) amine in the brine 
from which it can be prepared. In this process, the 
5-methyl-N-(aryl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide is 
prepared in three steps from 5-amino-3-mercapto-1,2,4-triazole by: 
(a) chlor-oxidation to form 5-amino-3-chlorosulfonyl-1,2,4-triazole: 
(b) coupling with a substituted aniline to prepare 
N-(3-(((aryl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl) amine; and 
(c) cyclization to give the desired product. 
This is a particularly preferred process for the compound in which the aryl 
group is a 2,6-difluorophenyl moiety, viz., where X and Y are F, and Z is 
H. 
##STR8## 
Each step may be conducted in water without isolation of the intermediate 
product. 
In a typical example of this process, the 
N-(3-(((2,6-difluorophenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine is 
present in brine as a mixture of neutral compound and monosodium salt. To 
prepare this stream for cyclization, the pH is adjusted upward to a 
condition of mono- and disodium salts. This can be done, for example, by 
adjusting to pH to about 9.0 with Na.sub.2 CO.sub.3. The cyclization is 
then initiated by addition of 1.2 equivalents of dimethoxybutane or 
methoxybutenone and held at a temperature of about 60.degree. C. until 
conversion is complete. The product, as the monosodium salt, is insoluble 
in brine and precipitates during the course of the reaction. Purification 
may be accomplished by isolating the solid monosodium salt by filtration. 
Most impurities are rejected in the filtrate and wash. The conversion to 
neutral product is most advantageously accomplished by dissolution of the 
monosodium salt in hot water and by slow acidification to generate a 
crystalline precipitate. Acidification with acetic acid has proven very 
controllable, forming an acetate buffer which prevents acid hydrolysis of 
the product. 
The following examples are presented to illustrate the invention and are 
not to be construed as a limitation thereon. 
High pressure liquid chromatography (HPLC) was performed with one or the 
other of the following systems: 
(a) on a chromatograph composed of an Hitachi L6200 pump, Kratos 
Spectroflow 757 variable wavelength detector at 214 nm, Spectra Physics SP 
4290 integrator and Rheodyne 7125 injector with a 20 .mu.l sample loop and 
a Jones Chromatography (Littleton Co.) Apex Octyl 5.mu., 25 cm.times.4.6 
mm reverse phase column in which the column was eluted at 1.8 cc/min with 
8 volume percent acetonitrile and 0.1 volume percent H.sub.3 PO.sub.4 in 
water: or 
(b) on a Hewlett Packard 1090 liquid chromatograph with UV detection at 214 
nm, a 5 .mu.l injector loop and a 25 cm Jones C-8 column in which the 
column was eluted at 1.8 cc/min with 19 volume percent 
acetonitrile and 0.1 volume percent H.sub.3 PO.sub.4 in water. 
EXAMPLE 1 
Cyclization with Dimethoxybutanone and Na.sub.2 CO.sub.3 
##STR9## 
N-(3-(((2,6-difluorophenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine (2 
grams (g), 7.3 millimoles) was suspended in 15 milliliters (mL) of water 
and was mixed with 1.2 g (10.9 millimoles) of Na.sub.2 CO.sub.3. The 
slurry was heated to 50.degree. C. and 1.44 g (10.9 millimoles) of 
4,4-dimethoxybutan-2-one were added. After 5 hours (hrs), the reaction was 
judged complete by HPLC analysis and the solid product was filtered and 
washed with water. The wet cake was dissolved in water and acidified with 
18 percent HCl until the pH reached about 4 at room temperature. The 
resulting slurry was stirred for 20 hrs and the product was recovered by 
filtration and dried to give 1.82 g of white solid with a 
5-methyl/7-methyl isomer ratio of greater than 100. 
EXAMPLE 2 
Cyclization with Dimethoxybutanone and Na.sub.2 CO.sub.3 /NaOH 
N-(3-(((2,6-difluorophenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine 
(27.5 g, 0.1 moles) dissolved in 100 mL of 1N NaOH solution (0.1 moles) 
was mixed with 5.3 g (0.05 moles) of Na.sub.2 CO.sub.3 and the mixture was 
heated to 70.degree. C. Dimethoxybutanone (19.8 g, 0.15 moles) was added 
and the mixture was stirred at 70.degree. C. for 1 hr. The slurry was 
cooled and filtered, and the filter cake was washed with 100 mL of water 
and dried to yield 30.3 g (86 percent yield) of dry monosodium salt having 
a 5-methyl/7-methyl isomer ratio of 46. 
EXAMPLE 3 
Cyclization with Dimethoxybutanone and Na.sub.2 CO.sub.3 /NaOH 
N-(3-(((2,6-difluorophenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine 
monohydrate (14.6 g, 0.05 moles) was combined with 50 mL of 1N NaOH (0.05 
moles) and 5.2 g (0.05 moles) of Na.sub.2 CO.sub.3 in 50 mL of water, and 
the mixture was heated to 80.degree. C. to give a clear solution. The 
cyclization was initiated by the addition of 9.7 g (0.075 moles) of 
4,4-dimethoxybutan-2-one. The reaction was maintained at 80.degree. C. and 
monitored by HPLC. After about 10 minutes (min), the product rapidly 
precipitated in an oatmeal-like consistency. After 75 min, the reaction 
was complete and had a 5-methyl/7-methyl isomer ratio of 36. The reaction 
mixture was cooled to 3.degree. C. and vacuum filtered to recover the 
monosodium salt. The filter cake was washed with about 30 mL of ice water 
and then resuspended in 100 mL of water. The suspension was heated to 
90.degree. C. to give a clear solution which was acidified by the 
dropwise addition of 4.5 g of acetic acid in 25 mL of water over 30 min. 
The resulting slurry was cooled to 3.degree. C. and vacuum filtered. The 
product was washed with 50 mL of ice water and then 50 mL of methanol. 
After vacuum drying, the product weighed 14.2 g (87 percent yield) and had 
a purity of 99.8 percent by HPLC area percent analysis. 
EXAMPLE 4 
Cyclization with Dimethoxybutanone and Na.sub.2 CO.sub.3 /NaOH in Brine 
N-(3-(((2,6-difluorophenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine 
(27.5 g, 0.1 moles) slurried in 77 g of water was mixed with 100 mL of 1N 
NaOH solution (0.1 moles) and 35 g of NaCl in a 500 mL 3-necked flask 
equipped with a thermometer, mechanical stirrer and a dropping funnel. 
Sodium carbonate (2.1 g, 0.02 moles) was added to the reaction mixture and 
the flask was heated to 60.degree. C. 4,4-Dimethoxybutan-2-one (95 
percent, 16 g, 0.12 moles) was added and the reaction mixture was stirred 
for 7 hrs at 60.degree. C. After this time, all of the starting material 
had been consumed. The 5-methyl/7-methyl isomer ratio of the cooled 
reaction mixture was about 42. The white precipitate was filtered and the 
filter cake was washed with 100 mL of 20 percent NaCl solution. The wet 
cake was reslurried in 250 mL of water and neutralized by the dropwise 
addition of 1N HCl (100 mL, 0.1 moles) at 80.degree. C. The mixture was 
cooled to 0.degree. to 10.degree. C. and the white solid product was 
isolated by filtration and dried at 90.degree. C. under vacuum to a 
constant weight. A 91 percent yield (35.4 g) of product was obtained. 
EXAMPLE 5 
Preparation of 
5-Methyl-N-(2,6-difluoro-phenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfona 
mide from 5-Amino-3-mercapto-1,2,4-triazole without Intermediate Isolation 
##STR10## 
5-Amino-3-mercapto-1,2,4-triazole (23.5 g; 0.2 moles) and 160 mL of 6.25 N 
HCl (1.0 mole) were charged to a 500 mL 3-necked flask equipped with 
mechanical stirrer, dropping funnel and chlorine sparge tube. While 
maintaining the reaction temperature between 20.degree. and 30.degree. C., 
12 g (0.105 moles) of 30 percent H.sub.2 O.sub.2 were added dropwise over 
10 min. Following the addition, the reaction was briefly warmed to 
50.degree. C. and then cooled to 0.degree. C. using an ice/ethanol bath. 
Chlorine (39 g; 0.56 moles) was sparged into the reaction over 2 hrs at 
0.degree. C. and 60 mL of deionized water were added near the end of the 
reaction to maintain a stirrable slurry. After confirming complete 
conversion to the sulfonyl chloride by HPLC, 3 g of Na.sub.2 S.sub.2 
O.sub.5 were added to reduce any excess chlorine. 
The 5-amino-3-chlorosulfonyl-1,2,4-triazole reaction mixture was added all 
at once to 310 g (2.4 moles) of wet 2,6-difluoroaniline and the reaction 
exothermed to about 45.degree. C. Coupling was complete after 20 min The 
reaction was neutralized with 176 g (2.2 moles) of 50 percent NaOH to give 
a pH of 6.0. 2,6-Difluoroaniline was recovered by steam distillation using 
a Dean-Stark trap as receiver allowing the aqueous phase of the distillate 
to continuously return to the pot. After 283.5 g of 2,6-difluoroaniline 
were recovered, the resulting slurry contained 
N-(3-(((2,6-difluorophenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine 
with only a trace of the aniline remaining. The slurry was cooled to 
60.degree. C. in preparation for cyclization. 
The pH of the slurry was adjusted from 5.3 to 9.2 by the addition of 10.6 g 
of Na.sub.2 CO.sub.3. The cyclization was initiated by heating to 
60.degree. C. and by adding 34 g 0.25 moles) of 95 percent 
dimethoxybutanone. The temperature was held at 60.degree. C. for 4 hrs, 
during which time the product precipitated. After 4 hrs, the reaction was 
cooled to 20.degree. C. and vacuum filtered. The filter cake was washed 
with 200 mL of 20 percent NaCl brine and was reslurried in 300 mL of 
water. After heating to 90.degree. C., the slurry was acidified by the 
dropwise addition of 100 mL of 2N HCl over 1 hr. After cooling to room 
temperature, the solid product was collected by vacuum filtration and 
washed with about 200 mL of water. Vacuum drying at 100.degree. C. gave 
53.3 g of 
5-methyl-N-(2,6-difluorophenyl)-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfona 
mide.