Process for the production of 2-alkyl or 2-cycloalkyl-4-methyl-6-hydroxypyrimidines

Production of 2-alkyl or 2-cycloalkyl-4-methyl-6-hydroxy pyrimidines by first reacting diketene and lower alkanoic or cycloalkanoic acid nitriles in the presence of catalytic amounts of Bronsted or Lewis acids, followed by treating the diketene/nitrile reaction product with ammonia in the presence of acid catalysts.

DETAILED DISCLOSURE 
The present invention relates to a new and improved manufacturing process 
for 2-alkyl or 2-cycloalkyl-4-methyl-6-hydroxypyrimidines of the general 
formula 
##STR1## 
wherein R represent an alkyl or a cycloalkyl group. 
Alkyl groups denoted by R are straight-chain or branched-chain groups 
having preferably 1 to 4 carbon atoms, such as, methyl, ethyl, n-propyl, 
isopropyl, n-butyl, secondary butyl, isobutyl or tertiary butyl. 
Cycloalkyl groups denoted by R have 3 to 6 ring carbon atoms. Preferred 
cycloalkyl groups are cyclopropyl, cyclopentyl or cyclohexyl. 
The compounds of formula I have particular importance as intermediates for 
the preparation of, e.g., phosphoric acid esters of substituted 
hydroxypyrimidines as disclosed and claimed in U.S. Pat. No. 2,754,243 
and, in particular, 
O,O-diethyl-O-(2-isopropyl-4-methyl-6-pyrimidyl)-thiophosphate (DIAZINON), 
which has great commercial value by virtue of its well-established 
insecticidal and acaricidal activity and consequent usefulness in pest 
control. 
These substituted hydroxypyrimidines have been produced in commercial 
practice in a laborious multi-step manner as follows: 
##STR2## 
In the above formulae R has the same meaning as given for formula I. 
More recently, this conventional manufacturing process has been improved 
and optimized by way of a continuous ring-closure/neutralization process 
as disclosed and claimed in U.S. Pat. No. 4,014,879, granted 3/29/77 and 
alternate processes for the preparation of the subject hydroxypyrimidines 
have been published in the Japanese patent literature. 
For instance, according to Japanese Patent 557,103, the subject 
hydroxypyrimidines can be prepared by various heat treatments from 
.beta.-acylaminocrotonamides which are made from .beta.-aminocrotonamide 
(derived from diketene and ammonia) and acid anhydrides or acid halides 
and according to published Japanese Patent Application SHo 48-39,942, they 
can be produced by reacting .beta.-aminocrotonamide and an organic acid 
ester in the presence of certain alkaline reactants, such as, alkali 
metals or alkali metal alcoholates. 
However, all of these prior art procedures leave something to be desired 
from the standpoint of efficient and economical large-scale commercial 
manufacturing. 
In the search for better and cheaper process technology for the manufacture 
of the subject hydroxypyrimidines and the phosphoric acid ester 
derivatives made therefrom, it has now been found, surprisingly and 
unexpectedly -- and this forms the principal object of this invention -- 
that these hydroxypyrimidines can be synthesized in a completely novel way 
which involves fewer steps, milder conditions, simpler equipment and less 
expensive reactants. It has been found that this can be accomplished by 
reacting diketene and lower alkanoic or cycloalkanoic acid nitriles in a 
solvent and in the presence of an acid catalyst to form a first-step 
reaction product, i.e., intermediates which are N-acetoacetyl substituted 
(lower) alkanoic or cycloalkanoic acid amides but also include 
acid-catalyzed reaction products of appropriate nitriles and diketene 
capable of being converted to the subject hydroxypyrimidines by reaction 
with ammonia, which intermediates are then converted by ammonia to the 
subject hydroxypyrimidines again in a solvent and in the presence of a 
catalyst in accordance with the following reaction scheme: 
##STR3## 
Again, R in the above formulae has the same meaning as given for formula I 
above. 
More specifically, in this novel and improved process, diketene and the 
lower alkanoic or cycloalkanoic acid nitrile (hereinafter "nitrile") are 
first reacted to yield, as mentioned above, certain intermediates. This 
reaction is carried out in an organic solvent and in the presence of 
catalytic amounts of Lewis and Bronsted acids. 
With respect to the specific reaction procedure and especially the order of 
addition of the reactants, it is advantageous to add diketene slowly to an 
appropriate reaction vessel containing a solution or suspension, heated to 
an elevated temperature, of the nitrile and the catalyst. Alternatively, 
diketene, nitrile, solvent and catalyst are simply mixed together also in 
a conventional reaction vessel at room temperature before heating to an 
elevated temperature. Additionally, the catalysts can be added to the 
reaction mixture in incremental amounts. 
The starting materials for this inventive process, diketene and nitrile 
which are commercially available or accessible, are generally employed in 
equimolar amounts. However, excess amounts of either reactant, up to about 
200 mole % excess, especially of the nitrile can be employed for the 
purpose of yield improvement. 
The reaction time for this diketene/nitrile reaction is typically from 
about an hour to about eighteen hours, and preferably about 6 to 10 hours. 
The organic solvent useful in this diketene/nitrile step can be selected 
from classes which include, but are not limited to, the following: 
aromatic hydrocarbons, such as, benzene, toluene, xylene, chlorobenzene, 
nitrobenzene; chlorinated hydrocarbons, such as, chloroform, carbon 
tetrachloride, ethylene dichloride, trichloroethylene; 
tetrachloroethylene; lower alkanoic acids and esters thereof, such as, 
acetic acid, propionic acid, isobutyric acid, ethyl acetate, ethyl 
propionate, isobutyl isobutyrate; ethers, such as, ether, tetrahydrofuran, 
p-dioxane, 1,2-dimethoxyethane; and ketones, such as, methyl ethyl ketone, 
methyl isobutyl ketone, cyclohexanone; or mixtures thereof. 
As Bronsted acids can be enumerated, without limiting them thereto, the 
following mineral and organic acids: hydrogen chloride, sulfuric acid, 
phosphoric acid, acetic acid, trifluoroacetic acid, isobutyric acid, 
p-toluenesulfonic acid. Lewis acids can be illustrated by, but are not 
limited to, the following acids: boron trifluoride etherate, zinc 
chloride, aluminum chloride. 
Typically, about 5 to 200 mole % of the catalyst per mole of diketene and 
nitrile is employed and preferably about 10 to 30 mole %. 
The reaction temperature in this step can vary within the range of about 
20.degree. C to 150.degree. C and preferably between about 25.degree. C 
and 90.degree. C. It depends often on the solvent chosen. 
The second step which involves treating the reaction product of the 
diketene/nitrile reaction, with or without isolation, with ammonia also in 
a solvent and in the presence of a catalyst and at elevated temperatures, 
accomplishes amination and cyclization of the first-step reaction product 
to 2-alkyl or 2-cycloalkyl-4-methyl-6-hydroxypyrimidine. 
More specifically, this second step, where the first-step reaction product 
is recovered in a conventional manner is carried out by dissolving this 
reaction product in a heated or refluxing solvent containing the catalyst, 
followed by sparging in ammonia and accompanied by removal of water, for 
example, by azeotropic distillation. The conversion of the first-step 
reaction product to the desired hydroxypyrimidine is almost quantitative. 
While amination proceeds rapidly and is completed in a matter of minutes, 
e.g., 5 to 30 minutes as determined by thin layer chromatography, 
cyclization takes longer and may be completed only after 1 to 6 hours. 
As solvents or solvent system there can be used not only the same solvents 
or same solvent system that can be employed in the first step as 
enumerated or mentioned above but also such additional classes as 
aliphatic alcohols, e.g., isobutanol, tertiary butanol, etc. Particularly 
preferred is toluene. 
With respect to the catalysts, it is advantageous to employ acidic 
substances, i.e., Bronsted acids, such as, acetic acid, trifluoroacetic 
acid, isobutyric acid, p-toluenesulfonic acid, phosphoric acid and, most 
preferably, acetic acid and p-toluenesulfonic acid. However, the 
second-step reaction proceeds also without acid catalyst. 
The acidic catalysts when used as is preferable, are employed in catalytic 
amounts which typically range between about 25 to 100 mole % per mole of 
intermediate and preferably between about 30 to 50 mole %. 
The reaction temperature in this second step can vary within the range of 
about 80.degree. to 150.degree. C and preferably between about 95.degree. 
to 115.degree. C. 
It is also entirely feasible to practice the present inventive process in 
one reactor without isolation and recovery of the first-step reaction 
product. Furthermore, it is feasible to practice this process in a 
semicontinuous as well as continuous fashion. 
Isolation and recovery of the desired final product, the 2-alkyl or 
2-cycloalkyl-4-methyl-6-hydroxypyrimidine, is carried out and effected in 
accordance with standard chemical procedures. 
It should be understood that various changes and modifications in the 
procedures described above generally and exemplified below specifically 
can be made, such changes and modifications being within the scope of the 
appended claims. It should further be understood that the following 
example illustrating specific embodiments is not intended to limit the 
disclosure.

EXAMPLE 
Hydrogen chloride was bubbled into a 0.degree.-10.degree. C solution of 8.4 
g of diketene and 6.9 g of isobutyronitrile in 10 ml of ether for 1.5 hr. 
The mixture was stirred at ambient temperature for 16 hr., either 
distilled from the reaction mass at reduced pressure and 100 ml of toluene 
added to the solid residue. The resulting slurry was refluxed while 
ammonia gas was bubbled into it for two hours. After addition of 100 ml of 
chloroform, the mixture was filtered and the filtrate concentrated to 9.0 
g of yellow solid containing 40.3% of 
2-isopropyl-4-methyl-6-hydroxypyrimidine. 
If in the above process wherein the isopropyl embodiment has been 
illustrated, cyclopropane carboxylic acid nitrile is employed in lieu of 
isobutyronitrile, 2-cyclopropyl-4-methyl-4-hydroxypyrimidine is obtained 
in an analogous manner.