Note: Descriptions are shown in the official language in which they were submitted.
FMC DOCKET 4307
~' ~0~%~
This invention relates to the field of herbicides, to
novel herbicidal 5-pyrimidinecarbonitriles and intermediates
thereto, to herbicidal compositions containing the herbi-
cidal compounds, and to methods for the control of undesired
plant growth by preemergence or postemergence application of
the herbicidal compounds and compositions.
One of the first herbicides was 2,4-dichlorophenoxy-
acetic acid (2,4-D), which became available in 1944 for the
control of broad-leaved weeds. Since then, a number of other
10classes of herbicides have appeared, some of which are more
selective than 2,4-D! give control at much lower rates of ap-
plication, are less toxic to mammals, longer lasting, easier
to use, cheaper, and do not leave residues harmful to the en-
vironment. All of these characteristics are desirable fea-
tures for a herbicide to possess.
; Heterocyclic organic compounds are among the newer
classes of herbicides. For example, the six-member s-tri-
azipe ring system is the central structural feature in a
number of commercial herbicides. The six member 1,3-diazine
-- 1 --
~7~
` .:,1
~U'~5~;
' ' .:
(pyrimidine~ ring system is less common among the known herbi-
cides, but some 4,6-disubstituted and 2,4,6-trisubstituted
5-nitropyrimidines display herbicidal activity [Ger. Offen.
2,520,381] as do certain 2,6-diamino-5-pyrimidinecarboxamides
[U. S. 3,B45,055]. Among the problems associated with the
pyrimidine herbicides has been their relatively low activity
and the consequent need to apply them in large quan~ities,
producing environmental and other problems.
According to the present invention 5-pyrimidinecarbo-
nitriles, having amino substituents in the 2 and 6 positions
and an alkoxy substituent in the 4 position, are extremely
effective herbicides, which control the growth of a range
of grassy and broad-leaved weads while not affecting d~sir-
able crops such as corn and cotton growing therewith. One
advantage of the 2,4,6-trisub tituted 5-pyrimidinecarbo-
nitriles of this invention is that many of them are effective
at very low rates of application.
The herbicidal 5-pyrimidinecarbonitriles of this in-
vention and the intermediates thereto are represented col
lectively by the following structural formula:
R~N~R2
NCl"~N
R4
,
.
... .
.
10~;~S~6
wherein R is a radical selected from amino, lower
alkylamino, lower cycloalkylamino, di(lower alkyl)amino,
[alpha-cyano(lower alkyl)]amino, and halogen; R4 is a
radical selected from lower alkoxy and halogen; and R6
is a radical selected from amino, lower alkylamino, lower
cycloalkylamino, di(lower alkyl)amino, and halogen; with the
proviso that no more than two of R2, R4 and R6 are halogen;
and provided further that neither R2 nor R6 is tert-butyl-
amino; and when R2 is isopropylamino, R6 is other than n-
butylamino; and when R2 is methylethylamino, R6 i5 other
than isopropylamino; and when R2 is diethylamino, R6 is
other than amino. In defining R2, R4, and R6, the term
"lower" means 1-7 carbon atoms, preferably 1-4 carbon atoms.
These intermediates and the herbicidal 5-pyrimidine-
carbonitriles prepared therefrom can be obtained conveniently
from a 2,4,6-trihalo-5-pyrimidinecarbonitrile. 2,4,6-Tri-
chloro-5-pyrimidinecarbonitrile is available from barbituric
acid and urea via 2,4,6-trihydroxy-5-pyrimidinecarboxamide.
Alpha-aminonitriles are employed in preparing 5-pyrimidine-
carbonitriles containing an [alpha-cyano(lower-alkyl)]amino
group in the R2 position. Alpha-aminonitriles may be pre-
pared by the Strecker synthesis.
The intermediates of this invention contain at least
one, but no more than two, halogen atoms, preferably
chlorine. They are obtained by the displacement of one or
two of the halogen atoms of a 2,4,6-trihalo-5-pyrimidine-
carbonitrile. Among the former, especially use~ul inter-
- 3 -
,
. '
~ S5~
mediates comprise 4,6-dichloro-2~ cyano-1-methyl-ethyl-
amino)-5-pyrimidinecarbonitrile, 4,6-dichloro-2-isopropyl-
amino-5-pyrimidinecarbonitrile and 4,6-dichloro-2-(1-
methylpropylamino) 5-pyrimidinecarbonitrile; whereas
among the latter, 4-chloro-2-(1-cyano-1-methylethylamino)-
6-ethylamino-5-pyrimidinecarbonitrile, 4-chloro-2-(1-cyano-
l-methylethylamino)-6-isopropylamino-5-pyrimidinecarbo-
nitrile, 4-chloro-2-(1-cyano-1-methylethylamino)-6-
cyclopropylamino-5-pyrimidinecarbonitrile, 4-chloro-6-
cyclopropylamino-2 isopropylamino-5-pyrimidinecarbo-
nitrile, and ~-chloro-6~cyclopropylamino-2-(1-methyl~ -
propylamino)-5-pyrimidinecarbonitrile are especially use-
: ful.
In the herbicidal 5-pyrimidinecarbonitriles of this
invention all three of the halogen atoms of the 2,4,6-
trihalo-5-pyrimidinecarbonitrile are displaced, so that
R2 is a radical selected from amino, lower alkylamino,
lower cycloalkylamino, di(lower alkyl)amino, and [alpha-
cyanollower alkyl)]amino; R4 is a lower alkoxy radical;
and R6 is a radical selected from amino, lower alkylamino,
lower cycloalkylamino, and di(lower alkyl)amino; with the
proviso that neither R2 nor R6 i5 tert-butylamino; and
provided further that when R2 is isopropylamino, R6 iq
other than n-butylamino; and when R2 is methylethylamino,
R6 i5 other than isopropylamino; and when R2 is diethyl-
amino, R6 is other than amino.
.
,' ' , ' ' ' ; . :
~ 25S6
Preferred herbicidal compounds result when R2 is
- selected from lower alkylamino (except ter~butylamino~
and [alpha-cyano-~lower alkyl)]amino; and R6 i~ selected from
lower alkylamino (except tert-butylamino) and lower cyclo-
alkylamino.
Especially preferred herbicidal compounds result if R2
is selected from ethylamino, isopropylamino, l-methylpropyl-
amino, 2-methylpropylamino, and l-cyano-l-methylethylamino;
R4 is methoxy or ethoxy; and R6 i~ selected from ethylamino,
isopropylamino and cyclopropylamino.
The herbicidal compositions of this invention each con-
tain an herbicidally effective amount of at least one herbi-
cidal 5-pyrimidinecarbonitrile. The herbicidal compositions
may taXe the form of granules, wettable powders, emulsifiable
concentrates, solutions, or other known forms, depending on
the mode o~ application.
The method of controlling the growth of undesired plant
species within the contemplation of this invention involves
applying to the area to be protected an herbicidal compo-
; 20 sition containing an herbicidally effective amount of at least
one herbicidal 5-pyrimidinecarbonitrile. A variety of method~
of application may be utilized and are well known in the art.
These include preemergence application of an herbicidal com-
position to the 50il before planting seeds therein or to both
the soil and the seeds after the seeds are sown, as well as
postemergence application to growing plants.
; - 5 -
. :
, '
;
iLO~ZriS~
Syntheses of the herbicidal 5-pyrimidinecarbonitriles
and intermediates thereto are illustrated in the following
Examples, wherein all temperatures are in degrees centi-
grade and pressures are in millimeters of mercury.
xample IV
4,6-Dlchloro-2-(1-c~ano-1-methylethylamino)-
5-~yrimidinecarbonitrile
A stirred solution of 6.3 grams of 2/~,6-trichloro-
5-pyrimidinecarbonitrile in 25 ml of acetone was cooled
to -10, and 2.5 grams of 2-amino-2-methylpropionitrile
was added. With the reaction mixture at -10, a solution
of 1.3 grams of sodium hydroxide in 3.5 ml of water was
added dropwise. Upon complete addition, the reaction
mixture was stirred at -10 for 30 minutes. The ace-
tone was removed under reduced pressure; the residue
was extracted with diethyl ether, and the extract was
separated and dried over magnesium sulfate. The extract
was filtered, and the filtrate was evaporated under re-
duced pressure, yielding a residue. The residue was re-
crystallized from methylcyclohexane to give 3.1 grams
of 4~6-dichloro-2~ cyano-1-methylethylamino)-5-pyrimi-
dinecarbonitrile; mp, 154-158J.
Analysis:
Calculated for CgH7C12N5: C,42.21; H,2.73;
N,27.34;
Fou~d: C,42.26; H,2.92;
N,27.35.
~J~
Example VI
4,6-Dichloro-2-isopropylamino-5-p~ _idinecarbonitrile
A stirred solution of 4.2 grams of 2,4,6-trichloro-5-
pyrimidinecarbonitrile in 100 ml of diethyl ether was cooled
to between -5 and -10, and a solution of 2.4 grams of
isopropylamine in 100 ml of diethyl ether was added drop-
wise. Upon complete addition, water was added to the
reaction mixture~ and the ether layer was separated. The
ethereal layer was dried over magnesium sulfate and filtered.
The filtrate was evaporated to drynes~ under reduced
pressure. The residue was recrystallized from methyl-
cyclohe2ane to give 2.4 grams of 4,6-dichloro-2-isopropyl-
amino-5-pyrimidinecarbonitrile; mp, 179-181.
Similar compounds prepared in a like manner are listed
in Table I
Example XIV
4-Chloro-2,6-bis(ethylamino)-5-pyrimidinecarbonitrile
To a stirred solution of 6.3 grams of 2,4l6-tri-
chloro-5-pyrimidinecarbonitrile in 75 ml of acetone
was added dropwise 7.7 grams of an aqueous solution
of 70% ethylamine. Upon complete addition, the reaction
mixture was stirred at room temperature for 60 hours~
The acetone was removed by evaporation under reduced
pressure. The residue was extracted with a mixture of
diethyl ether and water, and 2.9 grams of insoluble
4-chloro-2,6-bis(ethylamino)-5-pyrimidinecarbonitrile,
mp, 190-191, remained.
' ' ' ' '
,:
.
- ,
:
~ ZS5
Analysis:
; Calculated for CgHl~C1~5: C,47.90; H,5.35;
N,31.03;
Found: C,47.70; H,5.40;
N,31.15.
Similar compounds prepared in a like manner are listed
in Table II.
Exam~le XI
4-Chloro-2-(1-cyano-1-methylethylamino~-6-
isopro~lamino-5-~yrimidinecarbonitrile
To a stirred solution of 5.1 grams of 4,6-dichloro-2-
(l-cyano~l-methylethylamino)-5-pyrimidinecarbonitrile in
100 ml of acetone, 2.3 grams of isopropylamine was added
dropwise. The reaction mixture was then stirred at room
temperature for 16 hours. The acetone was removed under
reduced pressure, and the reaction mixture was extracted
with a mixture of diethyl ether and waterr The organic
;~ layer was separated and dried over magnesium sulfate. The
solution was filtered, and the filtrate was evaporated under
reduced pressure, yielding a residue. The residue was re-
crystallized from methylcyclohexane to give 2.7 grams of
4-chloro-2-(1-cyano-1-methylethylamino)-6-isopropylamino-5-
pyrimidinecarbonitrileS mp, 144-147.
Analysis:
Calculated for C12H15ClN6: C,51.70; ~5~42;
; N,30.14;
Found: C,51.05; H,5.20;
N,29.85.
. ' ' ' ' ~ ' .
5~
E~am~le XXIX
4-Chloro-6-cyclopropylamino-2-isopropxlamino-5-
pyrimidinecarbonltrlle
To a stirre~ solution of 9.2 grams of 4,6-dichloro~2-
isopropylamino-5-pyrimidinecarbonitrile in 75 ml of acetone,
2.4 grams of cyclopropylamin~ :in 25 ml of acetone was added
dropwise at room temperature. Upon complete addition 3 2
grams of aqueous 50% sodium hydroxide in 10 ml of water was
added dropwisel also at room temperature. The reaction
mixture was stirred for 4 hours. The solvent was removed
and the residue washed with water. The solid was collected
by filtration and dried to give 702 grams of 4-chloro-6~
cyclopropylamino-2-isopropylamino-5-pyrimidinecarbonitrile
upon recrystallization for methylcyclohexane the melting
point wa~ 157-160C.
Analysis:
Calculated for CllH14ClN5: C,52.66; H,5.71;
N,27.87;
Found: C,52.57~ H,5.71;
N,27.84.
Similar compounds prepared in a like manner are listed
in Table III.
55~
Example XXXV
2~ Cyano-l-methyleth~lamino)-6-isopropylamino-
4-metho~y-5-~yrimidinecarb_nitrile
A solution of 3.8 grams of 4-chloro-2-(1-cyano-1-
methylethylamino)-6-isopropylamino-5-pyrimidinecarbo-
nitrile in methanol was added to a solution of 0.3 gram
of sodium in 20 ml of methanol. The reaction mlxture
was heated under reflux for 4 hours, then allowed to
stand at room temperature for 60 hours. The solution
resulting from the addition of 0.05 gram of sodium to
5 ml sf methanol was added to the reaction mixture. The
reaction mixture was then heated under reflux for 3 hours.
The excess methanol was removed under reduced
pre~sure, and the residue was extracted with a mixture of
diethyl ether and water. The ether layer was separated
and dried over magnesium sulfate. The mixture was filteredr
and the filtrate was evaporated to dryness under vacuum.
The re~idue was recrystallized from a mixture of benzene
and petroleum ether to give 1.1 grams o 2~ ayano-1-
methylethylamino)-6-i~opropylamino-4-methoxy-5-pyrimidine-
carbonitrile; mp, 156-159~,
Analysis:
13 18 6
N,30.64;
Found: C,57.10; ~,6,70
N,30.90,
2,6-Bis(eth~lamino)-4 methoxy-5-~yrlmidinecarbonitrlle
To a stirred solution of 3.4 grams of 2,6-bis(ethyl-
amino)-4-chloro-5-pyrimidinecarbonitrile in 100 ml of
methanol was added dropwise at room temperature a solution
of 0.4 gram of sodium in 20 ml of methanol. The reaction
mixture wa~ heated under reflux for 4 hours, then allowed
to cool to room temperature where it stood for 60 hours.
The solvent was removed under reduced pressure and the
residue taken up in diethyl ether and water. The ether
layer was dried with magnesium sulfate and filtered.
The filtrate was evaporated under reduced pressure to a
re~idue. The residue was recrystallized from a mixture
of petroleum ether and benzene, to give 2.2 grams of
2,6-bis(ethylamino)-4-methoxy-5 pyrimidinecarbonitrile;
mp, 114-116C.
Analysis:
Calculated for ClOH15N5' C~54-28; ~6-83;
N,31.667
Found: C,54~38; H,7.08;
N!3~.93 .
-- 11--
Exam~le LIV
6-Cyclo~ropxlamino-2-isopropylamino-4-meth
~~yrimidinecarbonitrile
To a stirred solution of 0.9 gram of sodium meth-
oxide in 100 ml of methanol was added, in one portion,
4.0 grams of 4 chloro-6-cyclopropylamino-2-isopropyl-
amino-5-pyrimidinecarbonitrile. The reaction mixture
was then heated under re~lux for 3 hours. The methanol
was removed by evaporation under reduced pressure to
give a residue. The residue was washed with water, and
the solid was collected by filtration to yield 3.5 grams
of 6-cyclopropylamino-2-isopropylamino-4-methoxy-5-
pyrimidinecarbonitrile; mp, 142-147.
Analysiss
Calculated or C12H17N50s C~ 58.285 ~,6.92;
Nt28.31;
Found. C,58.04; H,6~98;
N/28.34~
. Similar compounds prepared in a like manner are listed
in Table IV.
The ability of the herbicidally active compounds to
control undesired plant growth was demonstrated as followss
- 12 -
Z5S~
For preemergence tests, rows of the seeds of lima bean
(Phaseolus lunatus~, corn (Zea mays), wild oats (Avena fatua),
lettuce (Lactuca sativa), mustard (Brassica juncea) and crab-
grass (Digitaria sany~inalis) were planted together in 15 cm
by 20 cm by 8 cm flats containing approximately 5 cm of sandy
loam soil. After planting, an aqueous acetone solution of one
of the active compounds was sprayed directly on the soil
and exposed seeds, the active compound being applied uniformly
at 8 96 kg per hectare. A thin layer of soil, approximately
1.3 cm deep, was then applied over the seeds~ The flats
were maintained in a greenhouse, and watered regularly on
the surface of the soil for 10-14 days. At the end of this
period, the phytotoxicity of the compound was recorded.
Individual plant species were examined for percent kill,
and a vigor rating of 0 to 5 was assigned to the surviving
plants, a vigor rating of 5 signifying no chemical injury,
4- slight injury (plants have or are expected to recover),
3- moderate to severe injury (plants expected to recover
in time), 2- moderate to severe injury (plants not expected
to recover), 1- severe injury (plants not expected to
recover), and 0- complete killo Table V lists data col-
lected in preemergence tests with herbicidally active
compounds of the present invention.
In postemergence tests, untreated plants prepared as
described above were maintained in a greenhouse and watered
regularly for a period of 10 - 14 days, until the first tri-
foliate leaves of the bean plants were unfolding. The plants
were then sprayed uniformly with an a~ueous acetone solution
. ~.: . , , ' ' '' '"' ' - '.. : " ' ' ' ' '
zLj~
of one of the herbicidally active compounds at 8.96 kg per
hectare as in the preemergence tes~s. The treated plants
were maintained in a greenhouse and watered regularly for an
additional 10 - 14 days. At the end of that ~ime the phyto-
toxicity of the compound was recorded as in the preemergence
test3. The results of these tests appear in Table VI.
The following herbicidal 5-pyrimidinecarbonitrile
are prepared by the methods de~cribed above. In general,
although these compounds e~hibit herbicidal activity, a
number of them are not as effective as the preferred active
compound~: 6-amino-2-ethylamino-4-methoxy-5-pyrimidinecarbo-
nitrile, 2-(1-cyano-1-methylethylamino)-4-methoxy-6-propyl-
amino-5-pyrimidinecarbonitrile, 6-cyclopropylamino-2-isopropyl-
~ amino-4-methoxy-5-pyrimidinecarbonitrile, 2-diethylamino-
- 4-methoxy-6-methylamino-5-pyrimidinecarbonitrile, 2-di-
ethylamino-6-dimethylamino-4-me~hoxy-5-pyrimidinecarbonitrile,
2-ethylamino-4-methoxy-6-propylamino-5-pyrimidinecarbo-
nitrile, 2-diethylamino-4-methoxy-6-propylamino-5-pyrimi-
dinecarbonitrile, 2-ethylamino-4-methoxy-6-methylamino-
5-pyrimidinecarbonitrile, 6-dimethylamino-2-ethylamino-
4-methoxy~5-pyrimldinecarbonitrile, 6-isopropylamino-4-
methoxy-2-(1-methylpropylamino)-5-pyrimidinecarbonitrile,
2-isopropylamino-4-methoxy-6-tl-methylpropylamino)-5-
pyrimidinecarbonitrile, 2~isopropylamino-4-methoxy-6-
propylamino-5-pyrimidinecarbonitrile, 2-isopropylamino-
4-methoxy-6-(2-methylpropylamino)-5-pyrimidinecarbo~
nitrile~ 6-ethylamino-4-metho~y-2-methylethylamino-5-
pyrimidinecarbonitrile, 4-ethoxy-6-ethylamino-2 (1-
~ 55~
cyano-l-methylethylamino)-5-pyrimidinecarbonitrile, 6-
ethylamino-4-methoxy-2-(2-methylpropylamino) 5-pyrimi-
dinecarbonitrile, 2-(1-cyano-1 methylpropylamino)-4-
etho~y-6-isopropylamino-5 pyrimidinecarbonitrile,
2,6-diethylamino-4-isopropoxy-5-pyrimidinecarbonitrile, 6-
ethylamino-4-methoxy-2~ methylpropylamino)-5-pyrimidine-
carbonitrile, 2-amino-6-ethylamino-4-methoxy-5-pyrimidine-
carbonitrile, 2-amino-6-cyclopropylamino-4-methoxy-5-pyrimi-
dinecarbonitrile, and 2-amino-6-isopropylamino-4-methoxy-
5-pyrimidinecarbonitrile.
The herbicidal 5-pyrimidinecarbonitriles of this inven~
tion may be utilized in diverse formulations to produce the
herbicidal compositions contemplated herein. The herbicidal
compositions contain between about 0.5% and 95% active 5-
pyrimidinecarbonitrile, toge~her with between about 44 and
98.5% agriculturally acceptable carrier, and between about
1~ and 15~ surfactant, by weight. As is well known in the
art, the formulation and mode of application of an herbicidal
composition may affect its activity in a given application.
Thu~, the herblcidal 5-pyrimidinecarbonitrile~ disclosed here-
in may be formulated into granules, wettable powders, emulsi-
fiable concentrates, solutionsl or other known forms, de-
pending on the mode of application.
Granular formulations are particularly useful for aerial
application. These formulations may be of several types.
Large particles of an absorbent carrier such as attapulgite
or kaolin clay, corncobs, expanded mica, and so forth,
may be impregnated with solutions of the active compounds.
- 15 -
. . . :
:
lZ5S~
The active 5-pyrimidinecarbonitriles in solution or as a
slurry may also be sprayed onto the surface of the absorb-
ent particles. The core of the particle may be water-
soluble or insoluble. A particularly useful type of
particle is one in which a wettabl~ powder is applied as
a surface coating to an insoluble granule such that the
wettable powder may be dispersed on contact with
moisture. Granules may be produced by compacting dusts
or powders, by extrusion through a die, or by use of a
granulating disk. Granular formulations may vary widely
in concentration, containing as little as 0.5% or as much
- as about 20% active compound.
Wettable powders in the form of finely divided particles,
which disperse readily in water or other dispersants, are
useful formulations for both preemergence and postemergence
herbicides. A wettable powder typically contains a carrier
such as a readily wetted inorganic diluent; for example,
Fuller's earth, kaolin clays or silicas mixed with about 5%
to 80~, but preferably at lea~t 50%, herbicidally active com-
pound and lesser amounts of surfactants.
Emul~ifiable concentrates, which are homogeneous l~quid
or paste compositions dispersible in water or other dispersants,
- may consist entirely of the active 5-pyri~idinecarbonitriles
of this invention ~ogether with a liquid or solid surfactant.
They may also contain agriculturally acceptable liquid car-
riers such as xylene, naptha, isophorone or other organic
solvents.
- 16 --
~z~56
Typical surfactants used in agricultural formulations
include, for e~ample, the alkyl and aralkyl sulfonates and
sulfates and their sodium salts, polyethylene oxides,
sulfonated oils, fatty acid esters of polyhydric alcohols,
and other types of surface active agents, many of which are
available in commerce. Surfactants, when used, normally com-
prise from about 1~ to 15% by weight of the herbicidal
composition~
The herbicidal compositions of this invention may be
applied without further dilution or as dilu~e solutions,
emulsions, or suspensions in water or other suitable diluents.
The herbicidal compositions may be applied to the area where-
in control i6 desired by spraying the compositions onto the
undesired vegetation or the surface of the soil if they are
liquids, ox by distribution from mechanical equipment in the
case of solids~ The surface-applied material may also be
blended into the upper layer of soil by cultivation, or
left as applied in order to galn the optimum results~
The herbically active compounds of this invention may
be formulated and applied together with insecticides, fungi-
cides, nematicides, fertilizers and other agricultural
chemicals. In formulating and applying the herbicidal com-
positions of this invention, either alone or with other
agricultural chemicals, herbicidally effective amounts of
the active compounds are employed. The amount constituting
an effective amount is variabley but generally, a uniform
application of between about 0.1 and 9 kilograms per hectare
is effective, for example, 0.28 to 4.48 kilograms per hectare.
- 17 -
~ 2,S56
The intermediates and herbicidal 5-pyrimidinecarbo-
nitrile of this invention, represented by the structural
formula
R~ ~,R
NC
- R~
wherein
(a) R2 is a radical selected from amino, lower
alkylamino, lower cycloalkylamino, di(lower
alkyl)amino, [alpha-cyano(lower alkyl)]amino,
and halogen;
(b) R4 is a radical selected from lower alkoxy
and halogen; and
(c) R is a radical selected from amino, lower
alkylamino, lower cycloalkylamino, di(lower
alkyl)amino, and halogen;
with the proviso that no more than two of R2, R4, and R6 are
halogen; and provided further that neither R2 nor R6 is tert-
butylamino; and when R2 is isopropylamino, R6 is o~her than n-
butylamino; and when R2 is methylethylamino, R6 is other than
: isopropylamino; and when R2 is diethylamino, R6 is other than
amino, are prepared by a process characterized by treating a
2,4,6-trihalo-5-pyrimidinecarbonitrile with an organic amine
at a temperature below 0C. to produce a 2-amino-4,6-dichloro-
5-pyrimidinecarbonitrile; and then treating said 2-amino-4,6-
- 18 -
:~0'~5~
dichloro-5-pyrimidinecarbonitrile with the same or a different
amine at a temperature higher than 0C. to produce a 4-chloro-
2,6-diamino-5-pyrimidinecarbonitrile; and then treating said
4-chloro-2,6-diamino-5-pyrimidinecarbonitrile with an alkali
metal alkoxide in alcohol to produce a 4-alkoxy-2,6-diamino-
5-pyrimidinecarbonitrile.
-- 19 --
Z~S~i
o I ~ o CO ~_
a~
Z . , .. . . o
U~
I ~ ~ ~ ~
_ I ~ ~ ~ OD
, ~ ,~ ~ o
o m .
E~ .~
C~ .
~ 0~ 1 ~ U~ ~ ~
_~ O I Ll~ O U: ~D
0 0~ 1 OD ~ 0~ a:
C Z U~ O
a~ ~ ~ I c~
~1 ~ QD I 1` 1`'~1
r~ I o o. ~1
~ ~ .
O ~ ~ ~ ~ el~
U ~ I O o O O
I` I
C~
o~
~ I~r ~ ~ ~r
H
~ 1
O o o o o o o
Cl:l P~ O ~ ) 0
~:1 11
E~ ~ ~ ~~1
~ I ~ I I I I
.,1U~ OU~ ~ ~`JCO
:
Z
~ r~
V C~
~ S~J
m m
.~.
~; ~ ^ ~ ~ -~
eG
c)
N
m ~- m m m :r
m ~ m m
æ z z z z; z
a)
R
~ a~ HI I ~ H
O ~C H1--1 X X X
~ q~
~ O
-- 20 --
~ .
l O'.?'~
`
..
z
.. ~ U~ I` I`
o ~
~n
In O ~
:~ ~) ct~ ~r o u~
I
~ ~ u~
.~ o u~ o ~r
~D O
~; . .
:~
~1 ~ u~
~--l o ~
~ p:
C~
~D ~ O O~
o
~ L
H
H
.,1 U ' O ~)
~:1 O O ~ o o
a~ ~, ~ O ~ f)
E~ ~ ~`3 ~r
C I ~ I I
.,1 ~1 0 ~1 0
.~ ~ CO ~ ~D ~ ' , ,,
r-l ~`I , ~1
~U
~ O
~'
~ ~ E3
U~ C~
0 ~1
~ O
:C _. ~ ~ ~
z z æ o ~
o
m p~
~ ~ b ~
. :~ m m
~ (~ C~ V o
m
Z Z; Z C)
aJ
~ ~ ~1
C ~ H m
~ a X ~
O ~C ~ ~ H
e ~ ~ ~e x
o
C~ o
-- 21
~ .
In Ln ~ ~ O ~ O ~ a~
~ ~ ~0 0 OD a~
: zi
c~ ~ u~ a~ ~ ~ ~ I_ I~ u~ o u~ co
:
~ OD O ~ ~ o o1-- c~
O ~ ~tCO ~In o ~ r~ o ocr
E'~ ~:
tq u~
O ~ ~O_I ~ ~ U~ ~ U~CO~D
r~ r ~ o c~ oa~
I` ~ a) o ~o~ ~ ~r ~ ~ I
u~
o ~ u~ ~u~ ~ ~ ,1 a~ o ~~1 o
o ~ o o 1` ~ ~ ~u~r~
~ z
0~ ~ ~DIn~1 ~ ~ r~ 1`u~ o noo
~J ~ `I1~ 1~ ~ ~ N ~ ~ ~~`I
aJ .~1
_~
w ~1 ~
c~ ~ I` 0~ ~1 ~ ~ cn ~ a~ 1~ ~o o~
:
~1 ~
C~ ~ o ~ o ~ o o CO O
Cr~ ~1 Ir7 ~ a~ N Ot~ ~ O
. ~ . , . . . . ~ . .
t- ~ o o 1` 1` ~ ~ ~- ~ I
O o o o o o o o o o o o o O
~ ~D ~ ~U~ O O ~ ~ u~ Or~
\-1 1:~ I I~r I I I I I I I I I I
H ~1 r~ (~ ~ CD O ~ 1~ U~~r ~\ a~
~ ~ ~ W1~.-1 ~ ~ ~ ~ 1_
E~ ,~ ~ ~ ~ ~ ~ ~1
~: ~_, o
E~ 5
5~
_ _ ~ -- ~ ~ ~0 V
P~ o v v v v v v m
_ ~ ~ _ ~ _ ~ ~ o ~ o
~ ~ ~ ~ ~ X
C~ V Vc~
~p~ q ~ OCC
z Z Z Z Z æ Z Z V ~; u
tl: ~ Z
Z ~
V :Z
.~,
~r:
v ~ æ z Z æ væ
~; _ _ _
_ ~ ~ ~ ~ ~ ~ _ _ _ _
~ ) v ~ m
~ V ~ V V C~
a~ m P~ m :~
zz; æ æ :z; z æ æ æ æ x z
~ H H
O ~I Q H H H H H ~ H
Ql O E~ H1-1 H H H X H H H H ~> ;~
Ei ~ H H ~ - H X~C X
O X X ~ X ~ X X ~ X ~ ~ X
V :d
-- 22 --
-' ~V~
co o~~ o In c~ ,1
~o~r ~ o
ol ~ ~ ~ ~ ~ ~
N ')N t') ~`J ~1
~ I r~ o t~
O ~ ~a~
~ D::
ul u~
a~
o ~ ~ ~a~
I`~ ~~D ~1 1`
. ~ . . . .
u~
u~
O OD1~ 0 ~ U~
~ cn o ~ NOD ~ ~1
~ ~ ~; CO ~ ~D ~ I`
~ ~ ~ ~ ~ r~
W ,~ o ~D ~ ~ ~ r- r
~ ~`J 1` 0 ~ D O
c~ m
U~ ~ ~D U^) In ~9 ~D
C~
o a~ ~ o ~o
U~
. . . . ~ .
~ u) ~r u~
_
~ .,~ o ~ o C~
:~ o O O O O O O O
~ ~ a~ u~ ~ cou~
r~ U~ ~O ~ U~r-l 1~1 . r~ .
~ ~r ~ ~ ~
C C ~
o ~ ~ ~ o U~ ~ ~ o
~ ~ ~ ~ In ~ ~I r~
_, ~ ~ ~ ~ ~, ~ ~, ,,
a~
HH ~:
H
o~' o~
~¢ u~
E-l ~ 0~ 0 ~0 ~ ) 0~0 ~)
c ~ ~ o: tq ~ C m
rl U ~ C~
" ~ Z ~ ~ Z Z C~ ~ Z
Z o
~¢ E3 ~
r~
P~ _ _ ~ Q, ^ U
~_ ~ ~ o ~
~ m c~
m ~ u u
U ~ ~ ",C> _ ~
-- m m m ~ D:
U V ~ V ~ ~)
m m -- m ~ m
æ z :z æ t) z z
~1 H H a
0 4-1 ~ H H H H m
o ~ ~ ~' ~ H m H
~) ld
-- 23
'~';~
l~Z~
~ ~ ~ O ~ ~ co ~ o
N ~ ~ ~D (~7r~ r-l O ~1 CO t`l ~')
Z . . . . . . . . . .
~ .
:5 0~ D O ~ O~ ~ O ~ O ~D
O ~ ~~1 ~ ~ CS~
~q
O
U~
~ ~ a~ 3 o ~ a~
r-~ ~ O ~ C10 0 ~~
0 C~ u~ o o~ O '
r-l
a~ o ~ o~ o
_I 1` ~ ~D 1~ 0 00 ~ ~D O
~ Z
a) ~ ~cna~ u~ ~ o~ oo ~ ~ ~ OD u7
c~
IJ
~ ~ I o a~
cn ~ ~ o ~ ~D ~ 00 00
:r
~D 1` ~0 ~ 1` 1` ~D ~D U~ r~
~)
~r~ ~ U~
C~
~ D O O~ r ~ 1` o
~ I~
~ ~C~ ~ V C~ U C~ C~
O o o o o _ ~ o o o o o o o
C: I I I l~
.,~ ou~
~r ~ ,1-,1
~3 ~1 ~--I ~ ~ ~ ~1
Q)
m~:
~3
~7 ~ ~ ~ . .
m::: m m m m m ~ m 5:
~C~ V
m mP~ m cc P~
Z Z æ z z z z z æ z z; z
æ
::~
C~
Z
C`~ C~ C~ ~ ~ ~ ~ ~ ~
~; ~ _ ~
~ ~ ~ m m ~ m
m mc~ u
'~ ~ 8 '~ 8 8 8 8 8 8 8 8
z z x z z z æ z z z z z
Q~ H
~1 H H
0 4-J ~ H ~1--1 H ~q H
O E3 H H ~ ~ H lc H H ~:- H
E~ (a #~ I H H ~ :-
O X X ~q ~C X X
x~c x ~ x X
- 2A -
55~;
oo ~ I`cn In I~D Ln
o~ ~ ~r ~ ODr~ ~ I~O 1-- ,
Z
O ~ cr~
,
~ a~ n ~ 5 ~ ~
O u~ In ~ o ~ I r~ u~
. . ~ . . . . . . . .
~n
U~
r~ I~ O O ~ l~ i --
~1 ~ ~ ~ 1~ oo o n I
a ~ . . . . . . . . . I
~ ~ ~ ~o ~1 a~ ~ I co oo
O ~ ~ o o cn I
J~ ao ~ ~0 _1 ,1 ~ C~ ao o I ~ ~
~ ~ ~ ~ u~ O ~ O~ D ~ 5 OD co
a~
a
~1 ~ ~7 ~ ~ a~ er ~ ~ 0~ 1 ~ D
~ ~ a~
U ~
~) . . . . . . . . I
O~ ~ ~` ~ ~0 CO ~ O~ ~ I OD
~1 C~ U ~ ~ V C~
~IJ O o o o o o o o o o o o o
Pl ~` ~ o t~ ~ ~ 1-- o ~) o~
~ ~r ~ ~ ~r ~ ~ ~ In ~ r~ ~1
,~ ~ ~ ,1 ~ ~ ~ ~ ~ ~ ~ ~ _I
C: ~1 t~ o o ~r ~ ~ ~1 1` a~ o
O ~ ~ ~ r~ o
C~ ,~ ~ ~ ~ ~ ~1 ~ ~ ~1
_ a)
~:
~ _.
H ~ t~
m _ ,,
C~ ~ ~ ~ ~)
~ ~ ~¢ ~ ~ Q~ ~ _ ,~
:4 m ~) o ~ o o ~ ~ ~
~ D
E~ ~ ~ ~ ~, ~ ~ ~ C~ O ~
m t) o o 5: ~:) o o o -- ~ -- o o
m
m ~ ~ m
~ z ~ zc, ~ z; æ z c~
C~
m c~
Z -- o o
~ ~
C~
z æ z z z
1~ ~ QI
_ _ ~ _ _ _ ~ ~) ~ O C~
~ ~ ~ ~ ~ ~ m m
m m m P~
C~ ~ ~ ~ o o
_ _ _ _ -- -- m
U C~
m ~ m
z æ z æ z; z z z z z o c~
::1~1 H
0 4-1 Q 1-1 H H
Pl O Ei H H X H H H
O X ~ ~ H H H H ~ ~ H H
X
.
-- 25 --
IZ556
~ I`
æ ~
~ a~ o~
O ~ ~D
In I~ I_
U~
U~ U~
~, ~ _,
~)
a~
~ lo ~
~ ~; ~
aJ ~ N
.,.
~1 ~ C~
~cr ,~
~ ~ r~ O
~) ~V
U~
I~ ~ ~
C~
a~
~ U~ O
C .
0 t)
C ~1 N O O
~ C I I ~
o ~ a~ ~
_ ~: ~.Qc'
H
1~ ~
Ul O O-- .~:
rl C 5~ ~J
~
~' ~U
P: ~
~1
. ~
~ 0
c~
~a z z d)
c a) o
~1 C
o ~ ~ a
~o ~ q
o ~s x x
z~s~;
~ ~ I~ o ~r ~1 ~J ~1 ~ ~ O ~ ~ ~ O
:
0 ~;a~ o o~ a~ ~ o x c~ o n x
~) -~
P IO O ~ ~1 o ~ ~ ~P o o ~ In o ~ ~ o
~C .
U~ ~
~ ~ IooooooooooC~oooooo
P; æ ~41 o ~ ~n O co O O c~ OO~ O~ O
H
æ
~; Pl o o ~ r o ~ ~ r u7 o
~'C " ~ .
a l O O O O O O O O O O O O O ~0 0 0 0
~ ~ f o~
o
I O O O O O O O O O O O O O C O O o
E~ ~
H
1:
o I O O O O O O O O ~ O O O O lUo O C~ o
H
m .
I C: O O O O O O O O C: O O 0 ~0 0 0 0
P~ ~
o
13 0 H 1-1 H H
O ~--1 H H ~ 1 H ~ H H
Ei X X ~ ~ ~~ X H 1--1 H H ~ H
X X ~ X ~ X ~ X ~q
~: O
- 27 -
u~ ~1 o o o ~ o o ~ ~ o o
u~
h
O O O O O O O G O O O O
OOO OO OO~
~J
O O ~ ~ ~ O
~1 o o
U~ ~ 4~
O
O O O O O O O O Lr) O U~ O
u u~ ~4 o o o oo o o ~ 1~ o a 1~
~ ~ ~ 1 0
H 5~ ~1
Z :~
m ~ I o O O ~ O 0 ~7 ~ N O 1~ (~
~ g
~ ~ O
H I O O O O O O O O L~ O O O
Q a) ~ O O O o O 1- o CO ~
~-~ ~1
:3
PC
_ ~ ~
ro l ~ ~1 o o ~ o ~ O
.~ o o
~ ~ OOOOOOOOOOOO
O ~ ~ 1~S O ~ O U~ ~ o ~ ~9
_ H ~: ~ ~
~ ~a ~
> H ~ .
~1 u~ o ~ er ~ er u~
~Ç ~ ~
E~ ~ O ~ O
C~ ~) oooooooooooo ~ :,
H ~5 O ~D ~ . O --
~1 Q~ h
~; ~ ~ ~ o tl~ a;
I ~ o ~ ~ ~ er u~ u~ O ~r a1 ~ ~ .
a, I ~-r~
Sil
C~ O-rl a) ~ ~:
Z ~ o o o o u7 o o o o o o o
~7 ~1 ~4 O O ~` O ~1 la 0 ~r t~l
~-rl
~: . a) e
E~
~Y ' .c
~ ~ o
o ~ ~ ~ ~
o o
~S ~ ~ rl r~
o r-l H rl C ~1
E~ ,_1 H H ~ 1 H ~ ~ H
t~
O *
-- 2 8 --
ul P¦ u~ o o o o o o o o ~1 ~`1 O O O O O O O O O N O O ~ Il- ~
~11
~ oooooooooolnoooooooooooooo
~ ~I ooooooooa~c~ooooooooo~oo
C~
~1ooooooo~oooooooooooo~oo~ln
ooooooooooooooooooooa~oooo
~n ~; oooooooa~oooooooooooo~o
~ I ooooooo~lo~l~ooooooooo~oo~U~
~ :1
H ~ ¦ O O O O O O O O O O O O O O O O O O O O O O O O O
a ~ ~ 0OOOOOO :noo~ooooooooooo c:~ou
æ ~ ,, ,, ,, ~ _, ,, ,, ,, _I ~1 ,, ,, _, _1 ,1 ,, ~1 ,~ ,
H
~1 ~r U? O N O O _I Ln ~r ~:P ~ ~ ~ ~ U~ L0 O O U~ O O ~ U~
O O OOOOOOOOOOOOOOOOOOOOOOOOO
l~il P~ r-l ~; o a~ o o c~ o o Is~ O O
H 3 H
E-l u
~ P ~ n o ~ o o u~
~:
~a o 0OOOO~OOOO~O~OOOOOOOOOOOO
~; O 1~ 1~ ~ O O
H -1 ~1 ~1
P~ C
m ~ ~1 ~~~~~
m
~ ~0000000000000000000000000
V ,, ~4l oc~o o O U~ 0000 0
I ~ _I ~1 _I ~1 ~ _t ~ ~1 ~1
~:
E~
o
~ o
E3 ~ H H H H
o r-l H H ~- ~ 5 ~ H H r-l I H H
ID ta ~ x X ~ ~ ~ " ~ Hl ~ 1 ~ P ~ H 1--1 i~l H
~ X ~ ~ ~ ~ ~ ~G ~C ~ ~ X ~ ~C ~ ~ X Y 3C ~ 1
C) ~
O
-- 29 --
S6
u~ ~1 ~ o o ~
~ ~: I o o o o
~) ,.
~1 ~ '
U~ ~J O
~ ~o o o o
H U~ P~; O o o ~ O
E~ ~ ,~
H
o a
~ ~ O o o O
.'C ~
O
Z ~ .,1
H J'JO O O O p
a a)P~ o O O O
~: ~ ~
~; ~1 ~~ ~
~n O
In J~ ~ S
~ O O
o ~ ~~ O O O O ~ ~O
_ H ~3: t~ o ~ t`~ ~
H H ::1
~ ,E~
~ ~ ~ .,1 ~
~ ~ C_~ ,~
?~ O o o o JJ _I
~) ~ ~
H al ~a
C~
~1 ~
~1 ~:1 0~
æ ~ ~ 1 0 0 0 0
D: ~ o o ~
O
~q
E-l K C~
U~ J~
O ~ ~ O
4 ~:: 1::: h
O ~ ~ ~ C
cL ~ r o o o
~ a) .. ,. .,~ .. , ..
o r-l H U~ ~ ~ ~ ~
t,) p H ~ a 0 ~0
i~3 H X ~`1H rl rl 1~ U t~
0 ~a ~ H ~ ~ Ll C rl rl ,~
0 4~ ~¢
O
-- 30 --
~ ' ' , ~. ' ' '
,
