Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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I1 ~2~58
I The lnventlon relates to a process for the preparatlon
! f 2-3ubstltuted 5-nltroso-2,6-dlamlnopyrimldlnes.
.1 .
It 19 known that 5-nltroso-2,4,6-trlamlnopyrlmldlne
can be prepared from malonlc nltrlle and a guanldlne salt.
2,4,6-Trlaminopyrlmidlne ls obtalned ln moderate yleld
by the condensatlon of malonlc dlnltrlle and guanldlne
hydrochlorlde or nltrate ln the presence of a sodlum alcoholate
ln alcohollc solutlon [W. Traube, Ber. 37, 4544 (1904); H Sato
et al., J. Chem. Soc. Japan Pure Chem. Sect. 72, 866 (1951); and
Chem. Abstr. 47, 5946 (1953)]. Thls pyrlmldlne 13 then
nltrosated to 5-nltroso-2,4,6-trlamlnopyrlmldlne, uslng nltrous
acld ~M.F. Mallette et al., J. Am. Chem. Soc. 69, 1814 (1947)].
such processes have the dlsadvantages that they are too
troublesome when relatlvely large amounts have to be prepared
and that the maxlmum yleld of 5-nltro~o-2,4,6-triamlnopyrlmldlne
18 75 to 78 percent, relatlve to malonlc dlnltrlle.
Attempts have been made to slmpllry the process by not
,! 1301atlng the lntermedlate product 2,4,6-trlamlnopyrlmldlne (see
Swlss Patent Speclflcatlon No 630,616). However, the proce3s
stlll has varlous dlsadvantages: expenslve sodlum alchololate
has to be used; at least two mols of salt (NaCl and Na acetate)
are produced per mol Or malonlc dlnltrlle employed; the reactlon
has to be carrled out uslng relatlvely dllute solutlons
(approxlmately 2 llters of solvent per mol of product); and
flnally, the recovery of the solvent ls a very dlfflcult
~LZ4~958
procedure, slnce a 4-component solvent mlxture (methanol,
ethanol, glaclal acetlc acld, water and by-products) ls present.
Another route for the preparatlon of 5-nltroso-2,4,6-
trlamlnopyrlmldlne ls descrlbed by C. Taylor, 0. Vogl and C.C.
ln J. Am. Chem. Soc. 81, 2442 (1959). 5-Nltroso-2,4,6-
trlamlnopyrlmldlne ls obtalned ln 88 percent yleld by heatlng
the potasslum salt Or lsonltroso-malononltrlle wlth guanldlne
carbonate ln dlmethylformamlde. Slnce the potasslum salt ls
prepared from the sllver salt of lsonltrosomalononltrlle, the
process ls unsultable for large-scale lndustrlal productlon.
French Patent Speclflcatlon No. 1,364,734 descrlbes a
proceas ln whlch malonic dinitrile in aqueous acetic acid
solution is ~lrst nitrosated with sodium nitrite, and then the
resultant isonitrosomalononitrile solution is treated with
guanldlne carbonate, C02 belng evolved and the guanldlne salt of
lsonltrosomalononltrlle belng obtalned. The salt suspenslon 18
then cooled to approxlmately 0C. and flltered, and the
guanldlne salt Or lsonltrosomalononltrlle ls drled. After the
addltlon of R2C03 to the salt ln dlmethylformamlde, the mlxture
ls heated under reflux ln order to effect lsomerlzatlon to
5-nltroso-2,4,6-trlamlnopyrlmldlne.
Such process represents a certaln degree of progress
compared wlth the process accordlng to Taylor et al., but lt
stlll has several dlsadvantages. Thus, the acetlc acld has to
be used ln exoe~s (10 percent, accordlng to the example). Thls
excess has to be neutrallzed wlth guanldlne carbonate ln order
for the formatlon of the guandlne salt of lsonltrosomalono-
nlerlle eO 6 to cc~pleelon~
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41~58
Cooling the aqueous suspension to approxlmately 0C.
lnvolves technical dlfficulties, slnce a crust of ice ls formed
on the inside of the reaction vessel. When the mixture i9
cooled to temperatures whlch are not quite so low, the salt is
not completely preclpltated.
From the polnt of view of safety, drying the guanidine
salt of lsonitrosomalononitrile involve rlsks.
In the treatment of crude lsonltrosomalononltrlle
solution wlth guanidine carbonate, one equlvalent of C02 ls
liberated. The reaction mixture therefore has a tendency to
foam during the operation and accordingly the reactlon vessel
cannot be optimally utilized.
An obJect of the lnventlon ls to avold the
above-mentloned disadvantages. Another object Or the lnventlon
18 to provlde a process whlch makes lt posslble to prepare
2-substituted 5-nltroso-4,6-dlamlnopyrlmldlnes ln a slmple and
economlcal manner and ln hlgh yleld.
The invention involves a process for the pre-
paration of 2-substituted 5-nitroso-4,6-diaminopyrimi-
dines of the formula:
5~3
¦ NH2
NO
R~ NH2
wherein R is aryl, alkyl, alkylthio, amino, substituted amino or
arylalkyl. Malonlc dinitrile is reacted with an amidine of the
formula:
/~IH HA
R
NH2
wherein A is Cl, l/2 S04, HS04, N03, acetate or phosphate and R
has the above meaning, ln water or alcohol, in an acidlc medium,
and in the presence of a nitrite salt, to provide the
correspondlng amidlne salt of isonitrosomalononitrile. The
amidlne salt of the lsonltrosomalononitrile, in
dimethyl~ormamide or a pyrldine base, and in a basic medium, is
converted by heat treatment to the corresponding 2-substituted
5-nitroso-4,6-dlamlnopyrlmldlne.
In the process of the lnventlon, the malonlc
dinitrlle, in water or alcohol as the solvent, is nltrosated
wlth an amldine in an acidic medium and in the presence of a
nitrite salt. The amidine salt ox isonitrosomalononitrile is
dlreotly ~orme~ In tle quequ: o :lcqùollo :u:p:n:lon. Such
~4~5~3
.1,
salt is not isolated; lnstead, the mixture ls rendered basic.
Then, after dimethylformamide or a pyridine base has been added,
the water or the alcohol is distilled off under reduced
pressure. After the water or the alcohol has been virtually
completely removed, the reactlon mixture ls subjected to heat
treatment, advantageously heated under reflux. The
correspondlng 2-substituted 5-nltroso-4,6-diaminopyrlmldlne ls
formed. As used herein acldic medium or acldic pH means a pH
value of below 6.9. Also as used herein, baslc medium or basic
pH means a pH value of above 7.1.
The inventlon reactlon take place accordlng to
general equatlon: _
NH . HA No NC NO H2N+
R _ + ¦ + NaN02 --I \ baa
NH2CN L CN H2N R
NH2
N
JON 1NH2
whereln A ls Cl, 1/2 S04, HS04, N03, acetate or phosphate and R
denotes aryl, alkyl, alkylthlo, amlno, substltuted amlno or
j arylalkyl.
I Examples of amldlnes are acetamldlne hydrochlorlde,
;'l benzamldlne hydrochlorlde, S-methylisothlourea sulfate and
guanldlne hydrochlorlde. The alkall metal or alkallne earth
metal nitrltes, preferably sodlum nltrlte, can be used as the
nltrlte salt. Regardlng the proportions, advantageously 0.1 to
4i958
1.1 mol of nltrlte, preferably 1.01 mol of nltrlte, ls used per
mol of malonlc dlnltrlle.
The amount of solvent (water or ethanol) for the flrst
stage of the reactlon ls not crltlcal, and is advantageou31y 200
to 2,000 ml per mol of malonlc dlnitrlle. Preferably 300 to 400
I ml of solvent are employed per mol of malonlc dlnltrlle.
¦ In the second stage of the reactlon, wlth
dlmethylformamlde or a pyrldlne base as the solvent, 100 to
2,000 ml, preferably 300 to 500 ml, of solvent can be employed
; per mol of malonodlnltrlle.
In a preferred embodlment, 5-nltroso-2,4,6-
trlamlnopyrlmldlne 18 prepared as follows: malonlc dlnltrlle
and guanldlne hydrochlorlde are reacted at a pH of below 6.9 ln
the presence of sodlum nltrlte to glve the guanldlne salt of
lsonltrosomalononltrlle, and the guanldlne salt of
isonitrosomalononitrile 18 converted to 5-nltroso-2,4,6-
trlamlnopyrlmldlne by bolllng under reflux ln dlmethyformamlde.
After the lsomerlzatlon reactlon, the red suspenslon
of 5-nltroso-2,4,6-trlaminopyrlmldlne ln dlmethylformamlde can
be dlluted wlth water, and the product can be separated off by
flltratlon or centrlfuglng, and washed wlth water. For many
, reaction the molst product can be used. If necessary, lt can
be drled by heatlng by any convenlent method. 5-nltroso-2,4,6-
trlamlnopyrlmldlne 18 a versatlle lntermedlate product for
example for the preparatlon of medlcaments, such as, trlamterene
and methotrexate, and for the preparatlon of dyestuff
components, such as, 2,4,5,6-tetramlnopyrlmldlne.
Thls lnventlon also lncludes a composltlon of malonlc
1,
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dlnltrile, water or alcohol, a nltrlte salt and an amldine
havlng the formula:
NH HA
R _
NH2
i
whereln A ls Cl, l/2 S04, HS04, N03, acetate or phosphate and R
18 aryl, alkyl, alkylthlo, amlno, substltuted amlno or
arylalkyl. The pH 18 acldlc.
The following Examples illustrate the
invention.As used hereln, all percentages, ratlos, proportlons
and parts are on a welght basls unless otherwlse stated hereln
or otherwlse obvlous herefrom to one ordlnarlly skllled ln the
art.
EXAMPLE 1
A solutlon Or 70 g Or sodlum nltrlte ln 120 g of water
j was added dropwlse at room temperature to a suspenslon of 66 g
malononltrlle and 96 g of guanldlne hydrochlorlde ln 200 g Or
water, and the PH was kept at 4 by the addltlon of hydrochlorlc
acld. After the reactlon had contlnued ror 4 hours at room
temperature, 21 g of sodlum carbonate and 400 g of
dlmethylformamlde were added. The water was dlstllled Orr under
reduced pressure. Thereafter, the reactlon mlxture was heated
at 140C. for l hour, lsomerlzatlon to 5-nltroso-2,4,6-trlamlno-
,
95~3
."
I pyrlmldlne taklng place. After the reactlon was complete, 400ml of water were added, and the product was filtered off and
washed wlth water. After the product had been drled, 140 g of a
pure raspberry-red 5-nltroso-2,4,6-trlamlnopyrlmldlne were
obtained. The melting polnt of the product was above 340C. and
the yleld was 91 percent.
EXAMPLE 2
A solutlon of 37.5 g of sodium nitrite in 60 g of
water was added dropwlse to a suspenslon of 33 g of malono-
nltrile and 52 g of acetamldlne hydrochloride ln lO0 g of water
at pH 4 and at room temperature. After the reactlon had
contlnued for 4 hours, the reactlon mlxture was cooled to 0C.
and the product was flltered off. The acetamldlne salt of
lsonltrosomalononltrlle, havlng a meltlng polnt 142 to 143C.
(decomposltlon), was obtalned ln vlrtually quantltatlve yleld
(84 per¢ent lsolated).
EXAMPLE 3
A solutlon of 14 g of sodlum nltrlte ln 25 g of water
was added dropwlse to a suspenslon of 13.2 g of malononltrlle
and 32 g of benzamldine hydrochlorlde ln 25 g of water at pH 3
I to 5 and at 20C. After the reactlon had contlnued for 5 hours
l and the mlxture had been cooled to 0C., the reactlon product
was flltered off under suctlon and drled. The benzamldlne salt
of lsonltrosomalononltrlle, havlng a meltlng polnt of 150C.
(decomposltlon), was obtalned ln vlrtually quantltatlve yleld
(94 percent lsolated).
EXAMPLE 4
i A solutlon of 35 g of sodlum nltrlte ln 60 ml of water
I 9
1,
lZ41958
was added dropwise to a suspenslon of 33 g of malononltrile and
70 g of S-methyllsothlourea sulfate ln 100 ml of water at pH 4
and at room temperature. After the reactlon had contlnued for 5
hours, the reactlon mixture was cooled to 4C., and the product
was flltered off. After the product had been drled, the
S-methyllsothlouronlum salt of lsonltrosomalononltrlle was
obtalned ln very hlgh yleld (76 percent lsolated). The salt had
a meltlng polnt of 123 to 124C. (decomposltlon).
EXAMPLE 5
A solutlon of 70 g of sodlum nltrlte ln 120 ml of
water was added dropwlse to a suspenslon of 66 g of
malononltrlle and 97 g of guanldlne hydrochlorlde ln 120 ml of
water at pH 4 and at room temperature. The mlxture was stlrred
for 4 hourR and then was cooled to 0C., and the product was
flltered off. After the product had been drled under vacuum,
the guanldlne salt of lsonltrosomalononltrlle was obtalned ln
vlrtually quantltatlve yleld (84 percent lsolated). The salt
hmd a meltlng point of 160~ to 161C. (decompo9ltlon1.
