Note: Descriptions are shown in the official language in which they were submitted.
This invention relates to a process or the
preparation oE 2-substituted-5-nitroso-4~6-diaminopyrimidines.
It is known that 5-ni-troso-2,4,6-triaminopyrimidines
can be prepared from malonic acid dini-trile and a guanidine
salt. Thus, condensa-tion oE malonic acid dini-trile
and guanidine hydrochloride or nitrate in -the presence
of sodium alcoholate in alcoholic solution gives 2,4,6-
triaminopyrimidine in high yield [W. Traube, Ber. 37,
4544 (1904); Il. Sato et al. J. Chem. Soc. Japan Pure
Chem. Sect. 72, 866 (1951), Chem. ~bstr. 47 5946 (1953)].
This pyrimidine can then be nitrosated wi-th nitrous
acid to form 5-nltroso-2,4,6--triaminopyrimidine [M.F.
Malle-t-te e-t al, JO Am. Chem. Soc. 69, 1814 (197~)].
This process suffers from the disadvantage
that it is too complica-ted for manufacture on a large
scale and that the yield of 5-nitroso-2,4,6-triaminopyrimidine
amounts to a maximum of 75 to 78%, based on the malonic
acid dinitrile.
An attempt to simplify this process has been
made by not isolating -the 2,4,6-triaminopyrimidine in-ter-
mediate product (see Swiss Patent No. 630,616). However
this process still retains various di.sadvantages, namely
tha-t it employs expensive sodium alcoholate, tha-t at
least two mols of salts (sodium chloride and sodium
acetate) are accumulated per mol of malonic acid dinitrile
employed, -that it mus-t be carried ou-t wi-th relatively
dilu-te reaction solu-tions (abou-t 2 litres oE solvent
per mol oE product), and finally tha-t the recovery
of the solven-t af-ter the reaction is very difficult,
since a 4-componen-t solvent mixture (methanol, ethanol,
glacial ace-tic acid, water and by-products) is involved.
Another method of preparing 5-nitroso-2,4,6-
triaminopyrimidine is described by E.C. Taylor, O. Vogl
and C.C. Cheng~ J. em. Chem. Soc. 81, 2442 (1959). By
heating -the potassium sal-t of isoni-troso-malononitrile
with guanidine carbonate in dime-thyl formamide, 5-nitroso-
f
. Ye
.
2,4,6-triaminopyrimidine is ohtained in 88% yield. However,
since the po-tassium sal-t is ob-tained from the silver
salt of isonitroso-maloni-trile, this process can not
be considered for large scale produc-tion.
In French Patent No. l,364,734, a process is
described in which malonic acid dinitrile in aqueous
acetlc ac:id solution is firs-t ni-trosated with sodium
nitrite, -then -the ob-tained isonitroso-malononi-trile
solution is -treated with guanidine carbona-te resul-ting
10 in the evolution of carbon dioxide and precipita-tion
of the guanidine sal-t of isoni-trosomalononi-trile. This
sal-t suspension is then cooled to about 0C, Eiltered
and the guanidine salt isonitrosomalononitrile is dried.
The salt is then hea-ted under reflux in dime-thyl Eormamide
15 after addition of potassium carbona-te, in order to complete
isomerization of 5-nitroso-2,4,6-triaminopyrimidine.
This process constitutes a certain improvement
over the process of Taylor et al, but still exhibits
further disadvan-tages. Thus, the acetic acid mus-t be
20 used in excess (1096 according to the Example). This
excess must be neu-tralized with guanidine carbonate in order
to obtain complete conversion to the guanidine salt of isoni-trosomalono-
nitrile. Cooling of the aqueous solu-tion -to abou-t 0C
gives rise -to technical difficulties, since a crus-t
25 of ice builds up on the inner surface of -the reac-tion
vessel. Cooling to a lesser degree resul-ts in incomple-te
precipi-ta-tion oE -the sal-t.
The drying oE -the guanidine sa]-t oE isoni:trosomalono-
nitrile is risky on technical safe-ty grounds. In -the
30 -treatment oE a crude ison:i:trosolr~lononitrile solution
with guanidine carbona-te one equitlalent o:E carbon dioxide
is given oEE. The reac-tion mix-ture -thereEore has a
tendency -to Eoam during -this procedure so -tha-t the reac-tion
vessel can not be op-timally utilized.
From European paten-t applica-tion No. 115~325~
it is further known -to prepare 2-subs-ti-tu-ted-5-nitroso-
4,6-diaminopyrimidines by treatment of malonic acid
dinitrile with an amidine ln -the presence of a nitrite
salt under acld conditions and in water or alcohol
as solvent -to :Eorm the amidine salt oE the isoni-trosomalono-
nitrile and further converting this salt by hea-ting
5 in dimethyl :Eormamide under basic conditions to form
the desired produc-t. A signi:ficant disadvan-tage of
this process is that the use of dimethyl formamicle libera-tes
dime-thyl ni-trosamine.
I-t i.s an object o:E the presen-t invention to
avoid -the above disadvantages and to provide a process
that enables 2-substituted-5-nitroso-4,6-diaminopyrimidines
to be prepared in a simple, economic and especially
risk free manner and in high yield.
Accordingly, the invention provides a process
Eor preparing a 2-substitu-ted-5-nitroso-~,6-diaminopyrimidine
of the general formula:
NIH2
/~ ~NH
wherein R represents arylr alkyl, alkyl-thio, amino,
substitu-ted amino or arylalkyl, which comprises reac-ting
malonic acid dinitrile with an amidine o:E the general
formula:
NH i
30\ NH2
wherei.n A represents Of So, HSO~, N03, ace-tate or
phosphate and R is as de:Eined above, in water or alcohol and
in acid medium in the presence oE a nitrite salt, so
as to :Eorm the corresponding amidine salt o:E isoni-troso-
malononitrile, and :Eurther converting the amidine salt
with heating in a polar aprotic solven-t selected prom
dimethyl sulFoxide, N-methyl-2-pyrrolidone, N,N-dimethyl-
acetamide, hexame-thylphosphoric acid triamide, 1,3-
dimethyl-2-oxo-hexahydropyri.midine, tetrahydro--thiophene-
l,l-dioxide, 2-methylglutarodinitrile and cyclohexanone,
to form the corresponding 2-substi.tu-ted-5-ni-troso-4,6-
diaminopyrimidine.
Thus, -the malonic acid dini-trile, advantageously
in water or alcohol as solven-t, is nitrosa-ted with an
amidine under acid conditions in the presence of a nitrite
salt, whereby to obtain directly the amidine salt of
isoni-trosomalononi-trile wi-thou-t -the need Eor isola-tion
thereof. The addition of a polar aprotic solvent after
removal of -the water or the alcohol, and heating under
basic conditions resul.ts in formation of the corresponding
2-substituted-5-nitroso-4,6-diaminopyrimidine. According
to the invention, dimethyl sulfoxide, N-methyl-2-pyrrolidone,
N,N-dimethyl ace-tamide, hexamethyl phosphoric acid triamide,
l,3-dimethyl-2-oxo-hexhydropyrimidine or tetrahydrothiophene-
l,l-dioxide is preEerably employed as the polar aprotic solvent,
with dimethyl sulfoxide being most preferred. Apart from
-these solvents, a pyridine base can a.lso be added, such
as ~-picoline, ~-picoline, ~-pi.coline, 2-me-thyl-5-e-thylpyridine
or lutidine.
The reac-tion proceeds according to the general
:Eormula:
NH ilA NC NC NO H No
NaN02 Jo NaA
NH2 CN ON H2N R
NH2
N
11
R N~l2
3~
in which A represents Cl, SO4, HSO~, NO3, acetate or
phospha-te and R represents aryl, alkyl, alkylthio, amino,
substituted amino or arylalkyl.
Examples of suitable arni.dines include acetamidine
hydrochloride, benz.amidine hydrochloride, S-methylisothio-
urea sulfate and guanidine hydrochloride. The preferred
amidine is guanidine hydrochloride.
Suitable nitrite salts include alkali me-tal
and alkal.ine earth me-tal nitrites, preferably sodium
ni-trite.
By -the -term acidic medium is to be unders-tood
a medium having a pEI value o:E less than 6.9.
Regarding the propor-tions of the reactants,
advantageously from 0.1 to 1.1 mol of ni-trite, preferably
from 1.0 to 1.02 mol, is used per mol of malonic acid
dinitrile.
The amount of the solvent for the firs-t reaction
step is not critical and is advantageously from 200
to 2,000 ml per mol of malonic acid dini-trile. Preferably
from 300 to 400 ml of solvent is employed per mol of
malonic acid dinitrile. The reac-tion temperature for
the first s-tep is conveniently be-tween 10 and 50C.
after a reaction time of approximately 0.5 to 15 hours
and after cus-tomary working up, for example by means
of filtra-tion and subsequently drying, the amidine salt
of i.sonitrosomaloni-trile can be ob-tained.
The ami.dine salt o:E isoni-trosomalonitrile can
also be reac-ted withou-t isolation from the reaction
mediwn directly in the second reac-tion s-tep by -the addition
of clime-thyl sulfoxide as solvent. In -the second reaction
step, wi-th dimethyl sul:Eoxide as solvent, :Erom 100 to
2,000 ml, pre:Eerably from 300 -to 800 ml, o:E solvent
is employed per mol of malonic acid dini-trile.
The necessary basic medium can be ob-tained
advantageously by the addition o:E sodium hydroxide,
sodium carbonate, potassium hydroxide, po-tassium carbonate
or a subs-tituted pyridine. Preferred bases are sodium
carbonate and potassium carbonate.
For the final hea-t treatmen-t the reaction mixture
is advan-tageously heated to a tempera-ture oE Erom 100
to 1~0C, preEerably from 130 to 160C, advantageously
for a period of 0.25 to 6 hours, preferably from 1 to
4 hours.
In a preEerred embodimen-t of the invention,
5-ni-troso-2,4,6--triaminopyrimidine is prepared, namely
by reactiny malonic acid dinitrile and guanidine-hydro-
chloride at a pH below 6.9 in the presence of sodiumnitrite -to produce the guanidine salt oE isoni-troso-
malononitrile, which is then converted -to 5-nitroso-2,4,6-
-triaminopyrimidine by heating at 150C in dimethyl sulfoxide
in the presence of sodium carbonate.
The 2-subs-tituted-5-nitroso-4,6-diaminopyrimidines
obtained by the process of the invention can be separa-ted
in conventional manner by filtration or centrifuging,
washed with water and dried. The 2-substituted-5-nitroso-
2,4,6-diaminopyrimidines obtained by the process of
the invention, in particular 5-nitroso-2,4,6--triamino-
pyrimidine~ are versatile intermediate products useful,
for example, for the preparation oE medicamen-ts, such
as triamterene and me-thothrexate, and for the manuEacture
of dyes-tuf:E componen-ts, such as 2,4,5,6-te-traaminopyrimidine.
The following Examples illustrate the inven-tion.
Example 1
To a suspension of 66 g of malonic acid dinitrile
and 100 g oE guanidine hydrochloride in 200 g oE wa-ter,
a solution of 70 g oE sodium nitrile in 120 ml of water
was added dropwise a-t a pH of 4 and at room temperature.
After stirring :Eor 4 hours at room temperature, 21 g
of sodium carbonate and 770 g of a polar apro-tic solvent
were added thereto and the wa-ter was dis-tilled oE:E under
reduced pressure. Subsequently, the reaction mix-ture
was heated for 3 hours at a temperature of 140-150C,
whereby isomerization of 5-nitroso-2,4,6-triaminopyrimidine
took place. Af-ter t:he end oE the reaction, 750 g of
water were added and the product was Eiltered ofE and
washed wi-th wa-ter. The resul-ts of experiments with
various polar aprotic solvents are set out in the following
Table 1.
TABLE 1
. .~
Amoun-t o:E Produc-t Yield
Example Solvent g %
. . _
1-1 Dime-thylsulfoxi.de 138 89.6
1-2 Dimethyl acetamide 118 76.6
1-3 N-Methyl-2-pyrrol.idone 142 92.2
1-4 Tetrahydro-thiophene-l,l147 95.5
dioxide
1-5 3-Picoline 130 84.4
1-6 4-Picoline 144 93.5
1-7 2-Methyl-5-e-thylpyridine 151 98.0
~1-8* Dimethyl Eormamide 128 83.1)
1-9 2-Me-thylglutarodini-trile 111 72.1
1-10 Cyclohexanone 86 55.8
1-11 Hexamethyl phosphoric acid 141 91.6
triamide
1-12 1,3-Dimethyl-2-oxo-hexa- 145 94.2
hydropyrimidine
L
* Comparison tes-t
Example 2
To a suspension o 33 g of malonitrile and
52 g of acetamidine hydrochl.oride in 100 g of wa-ter -there
was added dxopwise at a pH of 4 and at room temperature
a solu-tion of 37.5 y o:E sodium nitrite in 60 g of water.
After -the reaction had proceeded :Eor 4 hours, the reaction
mix-ture was cooled to 0C and the product :Eiltered of-E.
The acetamidine salt o:E isonitrosomalononitrile was obtained
with a mel-ting point o:E 142 -to 143C (decomposi-tion)
in almost quan-ti-tative yield (84% isolated).
Example 3
To a suspension oE 13.2 g of malonitrile and
32 g of benzami.dine hydrochloride in 25 g of water,
there was added dropwise at a pH of 3 -to 5 and at 20C
a solu-tion of 14 g of sodium nitrite in 25 g of water.
After a reacti.on time of 5 hours and cooling to 0C,
the reaction product was :Eil-tered and dried. The benzamidine
salt o:E isonitrosomalonitrile having a melting poin-t
of 150C (decomposi-tion) was obtained in prac-tically
quantita-tive yield (94% isola-ted).
Example 4
To a suspension o:E 33 g of maloni-tril.e and
70 g o:E S-methyl-iso-thiourea sulfate in 100 ml of wa-ter,
there was added dropwise a-t a pH of 4 and a-t room temperature
a solut:ion of 35 g of sodium nitrite in 60 ml of water.
After a reac-tion period of 5 hours, the reaction mixture
was cooled to 4C and :Eiltered. After drying, the S-
methylisothiouronium salt o:E isoni-trosomalononitrile was
ob-tained in very high yield (76~ i.sola-ted), melting
point l.23 to 124C (decomposi-tion).
Example 5
To a suspension of 66 g of malonitrile and
97 g of guanidine hydrochloride in 120 ml of water there
was added at a pH of 4 and at room -temperature a soluti.on
of 70 g o:E sodi.um ni-tri.te in 120 ml. of water. A:E-ter
stirring for 4 hou:rs, the reaction mixture was cooled
to 0C and filtered. A:E-ter drying in a vacuum, the
~;~L~2~L98
guanidine salt of isonitrosomalonitrile was ob-tained
in practically quantitative yield (84% isolated), meltiny
point 160-161C (decomposition).
The Eurther conversion o:E -these amidine salts
oE isoni.trosomalononitrile obtained in Examples 2-to 5 into-the
correspondiny 2-substitu-ted-5-ni-troso-4,6-diaminopyrimidines
can be carried ou-t as described in the literature (E.C.
Taylor et al, J. em. Chem. So. 81, 2442 (1959).
