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Патент USA US3031467

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3,031,459?
United States Patent
Patented Apr. 24, 1962
2
1
heterocyclic radicals, such as morpholyl hexamethylen
3,031,450
imino or piperidyl radicals; at least one of said substitu
.
ents R5, R6, R7 and R8 being a halogen atom; substituent
R represents the following: hydrogen; bromine; iodine;
SUBSTITUTED rYRn/rrDo.-[5,4-d]-PYRn\tIDINEs
Franz Gottwalt Fischer, Wurzburg, and Josef Roch and _'
August Kottler, Biberacli (Kiss), Germany, ass'ignors to
an hydroxyl or substituted hydroxyl group, such'as an
Dr. Karl Thomae G.m.b.H., Biberach (Riss), Germany
No Drawing. Filed Apr. 12, 1960, Ser. No. 21,609
alkoxy, aryloxy, or'acyloxy group; a mercapto or sub-'
stituted mercapto 'group, such as an alkyl-mercapto or'
Claims priority, application Germany Apr. 30, 1959
0 Claims. (Cl. 260-2475)
aryl-mercapto group; ‘an amino or substituted amino
group, such as a mono or di-alkylamino, ~arylamino, or
This is a continuation-in-part'of copending application 10 -acylamino group; a guanidyl or substituted guanidyl
group; a hydrazino or substituted hydrazine group, such ~
Serial No. 571,146, ?led March 13, 1956, now aban
as an alkyl-, aryl—, or acyl-hydrazino group; or a nitrogen‘
cloned.
containing heterocyclic radical, such as a morpholine or
This invention relates to substituted pyrimido-[5,4-d]
pyrimidines and a method of preparing them.
piperidine radical; and substituent X represents hydrogen
More speci?cally stated, the present invention broadly 15
relates to substitution derivatives of pyrimido-[5,4-d]
pyrimidine (often also referred to as “h0mopurine”) hav
ing the structural formula -
20
or an alkali metal.
,
'
The pyrimido-pyrimidine compounds of Formula II
used as starting materials for the preparation of the com
pounds of Formula lI are produced according to methods
known in the chemical arts; for instance, by halogenating
the corresponding hydroxy pyrimido-pyri'midine com
pounds or by ring closure of suitable reaction compo
nents.
Hydroxy pyrimido-pyrimidine compounds are prepared,
for instance, according to the method described in Ger
man Patent No. 845,940 and United States Patent
R2
.
2,826,580.
(I)
Halogen is preferably introduced into such hydroxy
wherein two, three or ‘all four of the substituents R1
pyrimido-pyrimidine compounds by heating them with in
organic acid, halides, most advantageously by heating
through R; are basic groups, that is, primary, secondary
or tertiary amino groups; and, if only two or three of 30
them with phosphorus halides, such as phosphorus oxy
said substituents are basic groups, the remaining substitu
chloride and phosphorus pentachloride. For instance, the
ent or substituents are hydrogen, halogen, hydroxy, mer
following halogenated pyrimido-pyrimidines are obtained
capto, lower alkyl, pheny-l, phenoxy, lower alkoxy, lower
by such reactions:
alkoxy-lower alkoxy, (di-lower alkyl-aminoHower alk
oxy, lower alkyl-mercapto, phenyl-mercapto, benzy-l-mer 35 2,4,6,8-tetrachloro~pyrimido-pyrimidine;
capto or carboxy-lower alkyl-mercapto.
The term “tertiary amino groups” as used herein is also
understood to include substituents wherein the nitrogen
is part of a heterocyclic ring, such as morpholyl, piperidyl,
4,6,8-trichloro-pyrimido-pyrimidine;
4,6,8-t1ichloro-Z-mercapto-pyrimidopyrimidine;
4-methyl-mercapto-2,4-dichloro-pyrimido-pyrimidine; and
others.
pyrrolidyl, piperazyl, tetrahydropyridyl and tetrahydro
40
quinolyl, which in turn may carry substituents of its own,
especially lower alkyl substituents. v
'
Halogenation of pyrimido-pyrimidine compounds con
taining exchangeable hydrogen atoms can be accomplished
The substituted ho'mopurines ‘according to the present
by the action of free halogen or of halogen-yielding com
invention may be prepared by the following methods:
pounds, such as N-halogenated succinimides and thelilte,
45 in inert solvents. It is also possible to prepare halogen
Method A
substituted pyrimido-pyrimidine compounds which may
By reacting substituted pyrimido-[5,4-d]-pyrimidines
be used as starting material for the process according to
having the structural formula
the present invention by suitable ring closure reactions, _ .
such as by ‘a reaction of pyrimidine-4-carboxylic acids, I
which halogenated in the pyrimidine nucleus and sub
stituted in the 5-position, with suitable reactants capable
% \ /N\
I
‘i.
of forming the pyrimido-pyrimidine ring system.
‘FR’
R’bosN/C\ C aN
in.
Such '
ring closure reactions are also disclosed in the, above‘
identi?ed United States patent.
(II)
55
.
The following starting materials, having the general
structural Formula II may be used in the reaction accord-,
with, a compound of the vformula
ing to our invention without, however, limiting the in
vention thereto;
X--R
(III)
In Formulas II and HI, substituents R5, R6, 11,, and Re, 60 6-chloro-4,8-dihydroXy-pyrimido#pyrimidine;
12 carbon atoms, which may also be interrupted by hetero
2,6-dichloro-4,8-diamino-pyrimicloapyrimidine;
2,6-dichloro-4,8-dianilino-pyrimido-pyrimidine;
6-chloro-4,8-disernicarbazidmpyrimido-pyrimidine;
atoms, such asrsulfur or oxygen; hydroxyl or substituted '
hydroxyl ‘groups, such as alkoxy, aryloxy, or acyloxy 65
groups; mercapto or substituted mercapto groups, such as
2,6—dichloro-4,8-di-phenyloxy-pyrimido-pyrimidine; ‘
which 'may be alike or different from each other, represent
the following; Hydrogen; hydrocarbon radicals with 1 to .
6-ehloro-2-mercapto~4,8-dimorpholino-pyrimido=
pyrimidine;
alkylamino, -arylamino, -aralkylamino or -acy1amino
2,.6-dichloro-4,8-di-pherryl-mercapto-pyrimido~pyrimidine;
’
4,6,8-trichIoro-Z-mercaptO-pyrimido-pyrimidine;
groups; guanidyl or substituted guanidyl groups; hy 71
drazino or substituted hydrazine groups, such as alkyl-,
4,6,8-trichloro-pyrimido-pyrimidine;
alkyl mercapto, aralkylmercapto or aryl mercapto groups;
amino or substituted amino groups such as mono- or di
iaryle, or ac'yl-hydrazino groups; or nitrogen containing
6-rnethyl-mercapto-2,4-'dichloro-pyrimidodpyrimidine;
6-chloro-4,S-diiodo-pyrimido-pyrimidine;V ’
2,4,6,S-tetrachloro-pyrimidoepyrimidine.
3,031,450
4
3
Compounds having the general structural Formula III
effect the reaction with compounds of Formula III in
which are suitable for reaction with the above-indicated
such a manner that not only the halogen but also the
other substituents are exchanged by group R of the re
and similar halogen derivatives of pyrimido-pyrimidine of
the Formula Hare, among others, the following:
Alkali metal hydroxides,
action component of Formula III. Thus, it is, for instance,
possible to convert 2,6-dichloro-4,8-dihydroxy-pyrimido
pyrimidine, 2,6-dichloro-4,S-diamino-pyrimido-pyrimidine,
Alcohols,
and 2,6-dichloro-4,8-dipiperidino-pyrimido-pyrimidine into
2,4,6,8-tetra-anilino-pyrimido-pyrimidine by reaction with
Alkali metal alcoholates,
Phenols,
Alkali metal phenolates,
Ammonia
Primary or secondary amines,
aniline.’
10
Guanidines,
Hydrazines,
Amino alcohols,
Alkali metal hydrosul?des,
‘
Method B
Another method of preparing the substituted homo
purines according to the present invention comprises react
ing substituted pyrimido-[5,4-d]-pyrimidines having the
15
structural formula
Mercaptans,
Thiophenols,
Alkali metal thiophenolates,
Morpholine,
Piperidine.
The exchange of halogen against hydrogen is effected
20
Z2
(IV)
by the action of reducing agents, for instance by the
with ammonia, a primary amine or secondary amine; the
action of phosphorus diiodide (P214) and hydrogen iodide
or of catalytically activated hydrogen. It is also possible 25 term “secondary amine” also includes heterocyclic com
pounds in which the nitrogen is a part of the heterocycle,
to exchange a speci?c halogen atom in such compounds
such as piperidine, pyrrolidine, morpholine and the like.
1 by a different halogen atom. Chloro-pyrimido-pyrimidine,
for instance, can be readily converted into the corre
sponding iodo compound by reaction with sodium iodide
in acetone as a solvent medium.
Reaction of compounds having the structural Formula
II with compounds having the structural Formula III is
carried out, in many instances, in the presence of an
acid-neutralizing agent, such as an alkali metal hydroxide,
an alkali metal carbonate, or a tertiary amine. If de
sired, an excess of the reaction component of Formula III
may be employed for this purpose, provided such reac
tion component has acid-neutralizing properties.
The reaction according to the present invention can be
carried out without or in the presence of solvents or dilu
ents that are inert toward the reaction components. Suit
able solvents or diluents are, for instance, acetone and
other dialkyl ketones, dioxane, benzene, xylene,‘ or di
In Formula IV from one to all four of substituents Z1
through Z4, which maybe identical or different from each
30 other, are selected from the group consisting of hydroxyl,
substituted hydroxyl, thiol, substituted thiol, amino, sub
stituted amino, ring-nitrogen-containing heterocyclic radi
cals which are attached to‘ the pyrimido-pyrimidine
nucleus through the ring-nitrogen atom, or a quaternary
" ammonium group.
If two or three of substituents Z1,
Z2, Z3 and Z4 inFormula IV have the above-de?ned
meanings, the remainder may also be selected from the
group consisting of hydrogen and hydrocarbon radicals.
The reaction between compound IV and the ammonia,
preliminary amine or secondary amine is preferably car
ried'out at elevated temperatures and in the presence of
an excess of the particular amine employed. If desired
or necessary, it may also be performed in the presence
of an inert solvent and/or a reaction accelerator and under
methyl formamide. If required, the reaction may be
facilitated by operating under pressure. Water and alco 45 superatmospheric pressure.
hols may also be used as solvents or diluents, especially
in the absence of alkali metal hydroxides and at a low
reaction temperature, since, under such conditions, no sub
stantial reaction takes place between said solvents or
diluents and the halogen-containing pyri-mido-pyrimidine
compounds.
An excess of the reaction component of
Formula III may also ‘be employed as solvent or diluent,
provided it is liquid under the reaction conditions.
The substituted pyrimido-pyrimidine compounds of the
Formula IV which are used as starting materials in this
process may conveniently be prepared by the process de
scribed in German Patent 845,940 and U.S. Patent
2,826,580, but starting with the corresponding S-arnino
uracil-4-carboxylic acids wherein the pyrimidine ring car
ries substituents Z1 to 2,, as previously de?ned, instead
of with the 5-amino-uracil-4-carboxylic acids disclosed
in said patents.
The reaction temperature is between —20° C. and
The pyrirnido-pyrimidine compounds IV used as start
+250“ C. If required, reaction accelerators, such as
ing materials in the present process may also be prepared
copper or copper salts, strong inorganic acids or catalysts
by ?rst preparing a trihydroxy-substituted or tetrahy
of the Friedel-Crafts type, can be added during the reac
droxy-substituted pyrimido-pyrimidine by the method de
tion.
scribed in said Germ-an and U.S. patents, then halogen
If at least two of the substituents R5, R6, R7 and R8
of the compounds of Formula II are halogen, the reaction 60 ating the tri- or tetrahydroxy compound to form the cor
responding trihalo- or tetrahalo-substituted pyrimido
according to the present invention may alsobe carried out
pyrimidine, and then exchanging the halogen for sub
stepwise. While, for instance, the halogen in 4- and 8
stituents Z1 to Z4, as previously de?ned, by Method A
position is predominantly exchanged when working at a
described herein. The exchange of all of the halogen for
low temperature, such as room temperature or with cool
radicals Z, to Z4 may be accomplished all at once or
ing, it is possible to replace all halogen atoms which may
stepwise.
be present, that is, also those in 2- and 6-position, by
Primary and secondary amines which may be used as
other groups when operating at a higher temperature, for
reactants in the reaction with compounds of the formula
instance at a temperature between 150° and 200° C. In
IV include the following: alkyl-amines, lower alkenyl
this manner it is possible to produce pyrimido-[SA-d}
pyrimidine compounds which contain different substitu 70 amines, hydroxyalkyl-amines, alkoxyalkyl-amines, di
entS R1,
R3 and R4.
When using certain halogen-containing starting mate
rials which, in addition, contain other substituents such as
hydroxyl groups, substituted hydroxyl groups, amino
groups, and/ or substituted amino groups, it is possible to
aIkylaminoaIkyI-amines, aryloxy-alkyl-amines, aralkyl
amines, substituted aralkylamines whose substituent
groups are inert under the reaction conditions, aromatic
amines, substituted aromatic amines whose substituents
are inert under the reaction conditions, polyhydroxyalkyl
3,031,450 -
6
5
tate evidently consisted essentially of N-hydroxymthyl
aniline hydrochloride. 200 ccjwater were added to the
resulting suspension. The hydrochloride went into solu
tion and, simultaneously, 2,6-dichloro-4,S-di-(N-hydroxy
ethyl-aniline) pyrimido-pyrimidine was precipitated in
amines, et-heri?ed polyhydroxyalkyl'amines, pyrrolidine,
piperidine, morpholine, hexamethyleneimino, piperazine,
substitution derivatives of these heterocyclic amines whose
substituents include primarily halogen, alkyl, hydroxyl
and alkoxy groups, hydrazine, alkyl-hydrazines and
guanidines.
the form of a yellow precipitate which was at ?rst some
what sticky but rapidly solidi?ed. The yield amounted
As indicated above, Method B ‘may be carried out in the
to 8.1 gm., corresponding to 86% of the theoretical yield.
presence of a reaction accelerator. Examples of such
For analytical purposes the compound was repeatedly
reaction accelerators are acid addition salts of the amine
reactant used, copper powder or copper salts.
l0 recrystallized ‘from methanol, thereby yielding a bright
yellow microerystalline powder consisting of small prisms.
It has also been stated above that the reaction may be
its melting point was l89—l90° C.
carried out under superatmospheric pressures; this expe
Analysis—C22H20O2N6Cl2; molecular Weight: 471.3.
dient is particularly advantageous when one or ‘both of
the reactants are relatively volatile substances.
Calculated: 56.05% C; 4.27% H; 17.83% N. Found:
Examples of suitable inert solvents for the present 15 56.12% C; 4.52% H; 17.61% N.
The following 2,6-dichloro-4,8-diamino pyrimido-py
method are water, alcohol, acetone, dioxan, benzene and
xylene. However, as previously indicated, a particularly
preferable embodiment of this expedient is the use of an
excess of the ammonia, primary amine or secondary
rimidine compounds were prepared by proceeding in an
analogous manner as described above under (a):
(b) With morpholine: 2,6-dichloro-4,8-dimorpholino
pyrimido~pyrimidine, melting point: 276~277° C.
arnine reaction component as the solvent medium because
(0) With p-chloro-aniline: 2,6-dichloro-4,8-di-(p-chloro
anilino) pyrimidopyrimidine, melting point: 307-309° C.
(d) With B-hydroxy-ethylamine: 2,6-dichloro-4,8-di(;3
, under these circumstances the introduction of a foreign
substance into the reaction mixture is not necessary.
The basic substituted pyrimido-pyrimidines of the For
mula I obtained by Methods A and B above may be
transformed into their water-soluble acid addition salts, 25
hydroxy ethylamino) pyrimido-pyrimidine, melting point:
246-248° C.
V
(e) With ,H-diethylamino-et'hylamine: 2,6-dichloro-4,8
and particularly into pharmacologically non-toxic acid
addition salts, vby customary methods, i.e. by reaction
with the corresponding acid. Examples of pharma
bis(,8-diethylamino ethylamino)
melting point: 128-430“ C.
pyrimido~pyrimidine,
_
(f) With methyl - dodecyl - amine: 2,6 - dichloro - 4,8
cologically non-toxic acid addition salts of the basic sub
stituted homopurines according to the present invention 30 bis - (methyl dodecylamino) pyrirnido - pyrimidine, melt
ing point: 76—77° C.
are the acid addition salts ‘formed with the following in
organic and organic acids: Hydrochloric acid, hydro
(g) With isoamyl - amine: 2,6 - dichloro ;- 4,8 - bis
bromic acid, sulfuric acid, phosphoric acid, acetic acid,
tartaric acid, lactic acid, succinic acid, citric aid, nicotinic
(isoamylarnino) pyrimido-pyrimidine, melting point: 94
12 gm. of phosphorus diiodide (P214) were added in
small portions to a suspension, heated on a steam bath,
(k) With methyl - cyclohexyl - amine! 2,6 - dichloro
4,8 - di - (methyl cyclohexyl amino) pyrimido - pyrimi
95° C.
35 , (h) With benzylamine: 2,6 - dichloro - 4,8 - bis - (ben
acid and camphor-sul-fonic acid.
zylamino) pyrimido - pyrimidine, melting point: 2294
The following examples serve to illustrate the present
230° C.
invention without, however, limiting the same thereto.
(i) With p-dimethylamino - aniline: 2,6 - dichloro
EXAMPLE 1
4,8 - bis - ,(P - dimethylamino aniline) pyrimido - py
40 rimidine, melting point: did not melt at or below 350° C.
4,8-Dianilin0 Pyrimido-Pyrimidine
(j) With diallylamine: 2,6 - dichloro - 4,8 - bis - (di
This compound was prepared ‘from 2,6-dichlor-4,8
allylamino) pyrimido - pyrimidine, melting point: 100—
dianilino pyrimido-py'rimidine by a reaction with hydro
101° C.
'
gen iodide and phosphorus diiodide.
dine, melting point: 179—l81° C.
of 3.8 gm. (0.01) 2,6-dichloro-4,85dianilino pyrimido
pyrimidine in 40 cc. hydroge iodide (d=1.7) in the
(I) With 5 - chloro - ethylamine: 2,6 - dichloro - 4,8
di - (B - chloro ethylamino) pyrimido - pyrimidine: did
course of about half an hour. Heating was continued for
not melt at temperatures up to 350° C.
one hour. The mixture was then cooled and the pre
(m) With butyl ~ ethanolamine: 2,6 - dichloro - 4,8
50
cipitated crystals were ?ltered off on a vacuum ?lter.
bis - (butylethanolamino) pyr-imido - pyrimidine, melt
The precipitate was extracted with 200 cc. of hot dioxane.
ing point: 140—141° C.
2.8 gm. of red, brilliant rhombic crystals remained after
extraction. The yield was about 90% of the theoretical
yield. The crystals were twice recrystallized from di
(It) With benzyl - ethanolamine: 2,6 - dichloro - 4,8
bis - (benzyl-ethanolamino) pyrimido - pyrimidine, melt
ing point: 173—175° C.
methyl formamide, whereby very slightly yellowish, small 55
(0) With 2,3 - dihydroxy-propylamine:
needles having a melting point of 255-256“ C. were ob
2,6 - dichloro
4,8 - bis - (2,3 - dihydroxy-propylamino) pyrimido - py
tained which were analyzed as follows:
rimidine, melting point: 208—210‘’ C.
CIBHMNG; molecular weight: 314.3. Calculated:
(p) With ammonia: 2,6 - dichloro - 4,8 - diamino py
68.77% C; 4.49% H; 26.74% N. Found: 68.61% C; 60 rimido - pyrimidine: did not melt at 350° C. or below.
4.45% H; 27.04% N.
(q) With carbethoxy - methylamine: 2,6 - dichloro
4,8 - di - (carbethoxy - methylamino) pyrimido - pyrim
EXAMPLE 2
idine, melting point: 207~209° C. with decomposition.
v2,6-Dichl0ro-4,8-Diamino Pyrimido~Pyrimidine
Compounds
'
Such compoundswere obtainedby reacting tetrachloro
pyrimido-pyrirnidine at room temperature with various
amines.
EXAMPLE 3
65
2,6-Dickl0r0-4,8-Dianilin0 Pyrimido-Pyrimidine
This compound was prepared from 2,6-dichloro—4,8-di
iodo pyrimido-pyrimidine and aniline.
(a) 2,6-dichloro-4,8-di~(N-hydroxy ethyl anilino) py
4.5 gm. (0.01 mol) 2,6-dichloro-4,8-diiodo pyrimido
rimido-pyrimidine: 10.0 gm. (0.08 mol) N-hydroxy ethyl 70 pyrimidine were dissolved in 100 cc. dry dioxane. The
aniline, dissolved in 15 cc. dioxane, were poured into a
solution of 5.4 gm. (0.02 mol) 2,4,6,8-tetrachtloro pyrim
ido-pyrimidine in 50 cc. dry dioxane, while stirring. A
solution was added dropwise, while stirring and cooling
with ice, to a solution of 3.7 gm. (0.04 mol) aniline in
anhydrous benzene in the course of half an hour. Yellow
crystals started to precipitate out very rapidly. Stirring
yellowish crystalline precipitate rapidly separated out, ac
companied by a slight vgeneration of heat. The precipi 75 was continued for half an hour. The precipitated crude ,~
.
3,031,450
8.
product was ?ltered'off on a vacuum ?lter, triturated with
4,8-bis-(diethylamino) pyrimido-pyrimidine were heated‘
slightly acid water (dilute hydrochloric acid), again ?l
in a sealed tube with 3.4 gm. (0.04 mol) morpholine to
tered on a vacuum ?lter, washed and dried. 2.3 gm., cor
180° C. for one and a half hours.
responding to 61% of the theoretical yield, were obtained.
For analytical purposes, the compound was recrystallized
product was obtained in solid form only after reprecipitat
The pasty reaction
ing it twice from very dilute hydrochloric acid and allow
ing it to stand for a prolonged period of time. 2.8 gm
three times from dioxane, whereby very slightly yellowish,
small needles having a melting point of 287-288° C.
were obtained on drying in a vacuum at room tempera~
ture. For analytical purposes, the compound was re
crystallized twice from a mixture of methanol and water
were obtained.
Analysis.—C18H12N6C12; molecular weight: 383.2. Cal
culated: 56.41% C; 3.16% H; 21.93% N; 18.50% Cl.
(2:1) whereby ivory-colored, lustrous scales (small ir
regular leaflets) having a melting point of 73-75° C.
Found: 56.61% C; 3.42% H; 21.79% N; 18.81% Cl.
were obtained.
EXAMPLE 4
.Analysis.—C18H29ON-1; molecular weight: 359.5. Cal
culated: 60.14% C; 8.13% H; 27.27% N.
2,4,6,8-Tefraanilin0 Pyrimido-Pyrimidine
This compound was prepared from 2,4,6,8-tetrachloro
pyrimido-pyrimidine and aniline.
2.7 gm. (0.01 mol) tetrachloro pyrimido—pyrimidine,
having a melting point of 255-258° C., were re?uxed
with 45 gm. aniline for 25 minutes. On pouring the re
sulting dark brown solution into 500 cc. of 1 N hydro
Found:
59.89% C; 8.26% H; 27.28% N.
The
following
_
4,6,8 - triarnino — pyrimido-pyrimidine
compounds were obtained by proceeding in a manner
analogous to that described above under (a), but using
dilierent amines:
20
chloric acid, crude tetraanilino pyrimido-pyrimidine pre
cipitated out in the form of a brownish amorphous pre
cipitate. Yield: 4.0 gm. corresponding to 80% of the
theoretical yield. The compound was recrystallized three
times from dioxane, whereby canary yellow, small needles
(b) 6 - methylamino - 4,8—bis-(ethylamin0)pyrimido
pyrimidine having a melting point of 94—96° C. from 6
chloro-4,8-bis - (ethylamino) - pyrimido - pyrimidine and
methylamine.
(c) 6 - morpholino - 4,8 ~ di-(ethyl-ethanolamino)-py
rirnido~pyrimidine having a melting point of 120-122”
C. from 6-chloro-4,8-di-(ethyl-ethauolamino)-pyrimido
having a melting point of 300-302° C. were obtained.
pyrimidine and morpholine.
Analysis.-C30H24N2; molecular weight: 496.6. Cal
(d) 6 - anilino - 4,8-diamino-pyrimido-pyrimidine hav
culated: 72.56% C; 4.87% H; 22.57% N. Found:
ing a melting point of 170-173° C. from 6~ch1oro-4,8-di
71.70% C; 4.80% H; 23.27% N.
amino-pyrimido-pyrimidine and aniline.
Said compound was also obtained by proceeding in 30
(e) 6 - diethanolamino - 4,8 - bis - (allylamino) - py
the same manner but re?uxing the following compounds
rimido-pyrimidine having a melting point of 104-106" C.
with aniline:
from 6 - chloro-4,8-bis-(allylamino)-pyrimido-pyrimidine
2,6-dichloro-4,S-dianilino pyrimido-pyrimidine,
2,6-dichloro-4,8-diamino pyrimido-pyrimidine,
2,6-dichloro-4,8~clihydroxy pyrimido-pyrimidine, and
2,6-dichloro~4,S-dipiperidino pyrimido-pyrimidine.
anddiethanolamine.
rimidine having a melting point of 292-294” C. from 6
chloro-4,8-diamino-pyrimido-pyrimidine and dimethyl
amine.
The starting material, 2,4,6,8-tetrachloro pyrimido-py
rimidine, was obtained by re?uxing 2,6-dichloro-4,8-dihy
droxy pyrimido-pyrimidine with phosphorus oxychloride.
EXAMPLE 5
'
(f) 6 - dimethylamino - 4,8 - diamino - pyrimido - py
(g) 6 - diethanolamino - 4,8 - dipiperidyl - pyrimido
40 pyrimidine having a melting point of 100-105 ° C. (sinter
ing started at 95° C.) from 6-chloro-4,8-dipiperidyl-py
rimido-pyrimidine and diethanolamine.
,
(h) 6 - (,8 - hydroxy - ethylarnino) - 4,8-dimorpholyl
6-Chl0r0-4,8-Dimorphoiino Pyrimido-Pyrimidine
pyrimido-pyrimidine and morpholine.
pyrimido-pyrimidine having a melting point of 106-108°
C. from 6-ch1oro-4,8-dimorpholyl-pyrimido-pyrirnidine
and ?-hydroxy-ethylamine.
A mixture of 2.0 gm. (0.023 mol) morpholine and
2.0 gm. (0.02 mol) triethylamine, dissolved in 20 cc.
pyrimido - pyrimidine having a melting point of 64-66°
This compound was obtained from 6-chloro-4,8-diiodo
(i) 6 - methyl - ethanolamino-4,8-bis-(methylamino)
dioxane, was added to a solution of 4.2 gm. (0.01 mol)
6-chloro-4,8-diiodo pyrimido-pyrimidine in 50cc. dioxane,
while stirring and cooling. The mixture was allowed to
stand for about half an hour. Subsequently, 400 cc.
water were added thereto. The initially precipitated
50
C. from 6-chloro-4,8~bis-(methylamino)-pyrimido-pyrim
idine and methyl-ethanolamine.
(j) 6 - morpholyl - 4,8 - di-(3-methoxypropyl~amino)
pryrimido-pyrimidine having a melting point of 80-82" C.
from 6 - chloro - 4,8 - di - (3 - methoxypropyl-amino)-py
rirnido-pyrimidine and morpholine.
morpholine hydrochloride was again dissolved by addition
(k) 6 - diisopropanolamino-4,S-dimorpholyl-pyrimido
of water, and crude 6-chloro-4,8-dirnorpholino pyrimido 55
pyrimidine having a melting point of 106-108” C. from
pyrimidine precipitated out. Yield: 2.7 gm. correspond
6-ch1oro-4,8-dimorpholyl-pyrimido-pyrimidine and diiso
ing to 80% of the theoretical yield.
propanolamine.
For analytical purposes, the compound was recrystal
(l) 6 - diethanolamino - 4,8-di-(p-nitro-anilino)-pyrim—
lized three times from dioxane and yielded long colorless
ido-pyrirnidine
having a melting point of 310-311° C.
needles having a melting point of 199-200° C.
60
from 6-chloro - 4,8-di- (p-nitro-anilino) -pyrimido~pyrimi
Analysis.-C14H1qO2N6Cl; molecular weight: ‘336.8.
dine and diethanolamine.
Calculated: 49.93% C; 5.08% H; 24.96% N. Found:
(m) 6 - piperidino - 4,8-di-(?-hydroxy-ethylamino-py
49.41% C; 4.29% H; 24.81% N.
rimido-pyrimidine having a melting point of 17 8-179° C.
The starting material, 6-chloro-4,8-diiodo pyrimido-py
rimidine was prep-ared by reacting 4,6,8-trichloro py 65 from 6-chloro-4,8-di- (,B-hydroxy-ethylamino) -pyrimido
pyrimidine and piperidine.
rirnido-pyrimidine with sodium iodide.
(n) 6 - diethanol amino-4,8-dimorpholyl-pyrimido-py
EXAMPLE 6
rimidine having a melting point of ISO-152° C. from 6
4,6,8-Triamin0 Pyrimido-Pyrimidine Compounds
chloro-4,S-dimorpholyl-pyrimidopyrimidinea and dietha
These compounds were prepared by reacting 6-chloro 70
4,8-dia1nino pyrimido—pyrimidine compounds with vari
nolamine.
.
(0) 6 - morpholyl - 4,8-bis-(ethylamino)-pyrimido-py
ous amines at elevated temperature and, if required,
rimidine having a melting point of 151-153" C. from 6
under pressure.
.
(a) 6 - morpholino - 4,8 - bis - (diethylamino) py
chloro - 4,8 - bis-(ethylamino)-pyrimido-pyrimidine
rimido - pyrimidine: 6 gm. (about 0.02 mol) 6-chloro 75
and
morpholine.
(p) 6 - morpholyl - 4,8 - diamino-pyrimido-pyrimidine
3,031,450
10'
9
having a melting point of 266—267° C. from 6-ch1'oro
small needles were obtained which did not melt, even at a
4,8-diamino-pyrimido-pyrimidine and morpholine.
temperature of 360° C.
Analysis.—C14H1BO4N6; molecular weight 334.3. Cal
culated: 50.29% C; 5.43% H; 25.14% N. Found:
48.83% C; 5.57% H; 24.60% N.
EXAMPLE 9
EXAMPLE 7
2,4,6,8-Tetraamino-Pyrimlia'o-Pyrimidine Compounds
These compounds were prepared by reacting 2,4,6,8
6-Chloro-4,8-Diamino-Pyrimido-Pyrimidine Compounds
'tetrachloro-pyrimido-pyrimidine with various amines at
elevated temperature and, if required, under pressure and
in the presence of copper powder or copper ‘salts as 're
action acceleration.
Thesecompounds were obtained by reacting 4,6,8-tr'i-V ,
10 chloro-pyrimido-pyrimidine with various amines atfroom.
temperature and, if required, accompanied by cooling.
(a) 2,4,6,8 - tetra - (dimethylamino) -pyrimido-pyrimi
(at) 6 - chloro - 4,8 - di - allylamino pyrimido-pyrimi
dine: 2.7 gm. (0.01 mol) tetrachloropyrimido-pyrimidine
dine: 4.6 gm. (0.08 mol) allylamine dissolved in 15 cc.
dioxane were added, while stirring, to a solution of 4.8
were added in small portions, while stirring, to 50 cc. of
a dimethylamine solution in absolute ethanol (contain
gm. (about 0.02 mol) 4,6,8-trichloro-pyrimido-pyrimi
ing 0.14 mol of dimethylamine), whereby the dichloro
dine in 50 cc. dry dioxane. The temperature ofthe mix
ture increased slightly due to the exothermic reaction.
After allowing the mixture to stand for a short period of
diamino compound precipitated out. 0.1 gm. copper sul
fate was added to the resulting suspension and the mix
ture was heated in a sealed, thick-walled glass tube to .
200° C. for one hour.
The reaction solution was di
luted with water and the‘crude reaction product was
reprecipitated by dissolving it in 200 cc. 0.2 N hydro
chloric acid, purifying the solution with animal charcoal,
and precipitating the reaction product with concentrated
ammonia. Yield: 1.7 gm. corresponding to 56% of the
theoretical yield. For analytical purposes, the com
pound was recrystallized three times from absolute eth
20
which was ?ltered off on a vacuum ?lter and dried at.
room temperature in a vacuum.
' 6-chloro-4,8-di-allylamino-pyrimido-pyrimidine was puri
25 ?ed by recrystallizing it twice from ethanol. The result
ing ?ne, colorless needles melted at 114—l16° C.
The following 6-chloro-4,8-diamino-pyrimido-pyrimi
dine compounds were preparedby proceeding in the same
manner as described above under (a), but reacting 4,6,8
yellow, irregular needles having a melting point of 164
Analysis.—C14H24NB; molecular weight: 304.4. Cal
culated: 55.22% C; 7.95% H; 36.81% N. Found:
55.33% C; 7.86% H; 36.78% N.
Yield: 4.8 gm., corre- .
sponding to 87% of the theoretical yield. The crude
anol and dried at 130° C. in a vacuum of 0.1 mm. Bright
165° C. were obtained.
time, water was added, whereby the crude reaction-prod
uct precipitated as a yellowish amorphous precipitate
30
trichloro-pyrimido-pyrimidine with various other amines,
as indicated:
'
The following 2,4,6,8-tetraamino-pyrimido-pyrimidine
(b) With methyl-ethanol-ami-ne: 6-chloro-4,8-di- (meth
yl-ethanol-amino)-pyrimido-pyrimidine having a melting
compounds were prepared by following the procedure de
scribed above under (a), but reacting tetrachloro-pyrim
(c) With diisoproganol-amine: 6-chloro-4,8-bis-(diiso
propanol-arnino)-pyrimido-pyrimidine having a melting
point of 90-92° C.
ido-pyrimidine with various other amines, as indicated:
point of 177—179° C.
(b) With allylamine: 2,4,6,8-tetra-(a1lylamino)-pyrim
(0) With methyl-ethanolamine: 2,4,6,8-tet-ra-(methyl
point of 155—156° C.
'
'
(d) With methylamine: 6—chloroi-4,8-bis-(methylamii
' ido-pyrimidine having a melting point of 201-202" C.
ethanolamino)-py1imido-pyrimidine having a melting
‘
40
15o)-pyrimido-pyrimidine having a melting point of 227
29° C.
‘
(2) With diet-hanol-amine: 6~ohloro-4,8-bis-(diethanol
amino)—pyrimido-pyrimidine having a melting point of
,
(d) With B-hydroxy-ethyl amine: .2,4,6,8-tetra-(;3-hy
135—l36° C.
droxy ethylamino)-pyrimido-pyrimidine having a melting
point of l80—182° C.
(1‘) With p-nitro-aniline: 6-chloro-4,8-bis-(p-nitro-ani
lino)-pyrinrido-pyrimidine which did not melt on heating
(e) With piperidine: 2,4,6,8-tetrapiperidyl-pyrimido—
up to 350° C.
pyrimidine having a melting point of 163—165° C.
-
(g) With 3-methoxy-propyl-amine: 6-chloro-4,8-di-(3
(f) With Morpholine: 2,4,6,8-tetramorpholyl-pyrim
methoxy - propylamino) - pyrirnido - pyrimidine having a
ido-pyrimidine having a melting point of 266—268° C.
(g) With p-chloro-aniline: 2,4,6,8-tetra-(p-chloro-ani
lino)-pyrimido-pyrimidine having a melting point above
melting point of 98~100° C.
330° C.
of 290-292° C.
‘
(h) With o-methoxy-aniline: 6-chloro-4,8-di~(o—meth—
oxy-anilino)-pyrimido-pyrimidine having a melting point
(h) With ammonia: 2,4,6,8—tetraamino-pyrimido-py~
(i) With dibenzyl~aminez 6-chloro-4,8-bis-(dibenzyl
rimido-pyrimidine; did not melt at a temperature up to
amino)-pyrimido-pyrimidine having a melting point of
350° C.
55 l60~163 ° C.
(i) With, methylamine: 2,4,6,8-tetra-methylamino-py
rimido-pyrimidine having a melting point 013202-204" C.
7
(j) With ethylene-imine: 6-chloro-4,8-di-(ethylene-imi
‘ 'no)-pyrimid0-pyrimidine: this compound assumed a yel
lowish color at 130° C. and decomposed at about 170° C.
EXAMPLE 8
2,6-Dim0rph0lyl-4,8-Dihydroxy-Pyrimid0-Pyrimidine
The compound was prepared by reacting 2,6-dichloro
4,8-dihydroxy-pyrimido-pyrimidine with morpholine in
(k). With semicarbazide: 6-chloro~4,8-disemicarbazido
60 gggrrméio-pyrimidine, which did not melt on heating up to
the presence of copper powder.
2.3 gm. (0.01 mol) 2,6-dichloro-4,8-dihydroxy pyri-.
mido-pyrimidine were heated to about 200° C. with 17.4 65
gm. (0.2 mol) morpholine and a spatula-point-full of
copper powder in a sealed heavy-walled glass tube for
about 2 hours. The reaction mixture was dissolved in 200
cc. of water. The aqueous solution was ?ltered, and
‘EXAMPLE 10
2,6 -Bis- ( ,H-Diethylamino-Ethoxy ) -4,8-Bis- (Die?thy l~
amino) -Pyrimid0-Pyrimidine
This compound was prepared by reacting 2,6-dic‘hloro
4,8-bis-(diethylamino)-pyrimido-pyrimidine with ?-dieth
yl-amino ethanol in the presence of metallic sodium.
the pyrimido-pyrimidine compound was precipitated in 70
3.4 gm. (0.01 mol) 2,6-di'ch1oro-4,8-bis-(diethyl-ami
the form of a yellow, amorphous precipitate by adding
no) ~pyrimido-pyrimidine, werere?uxed with a solution
concentrated hydrochloric acid to the ?ltrate. Yield: 2.5
of 0.5 gm. sodium metal in 35 gm. of?-diethylamino
gm. corresponding to 75% of the theoretical yield. The
ethanol for three hours, whereby no visible change took H
compound was reprecipitated three times from hot dilute
place. The reaction mixture was admixed with 400' cc.
sodium hydroxide solution,rwhere-by very ?ne, yellowish,
water... The mixture was acidi?ed by adding concen—
3,031,450 ‘
1l
12
trated hydrochloric acid, puri?ed with animal charcoal
solution of 1 gm. (0.04 mol) 6-methyl mercapto-2,4-di-'
chloro-pyrimido-pyrimidine, having a melting point of
and ?ltered.
Concentrated ammonia was added to the
?ltrate, whereby the reaction product precipitated in the
100-—103° C., in 100 cc. of dioxane, while stirring. The
form of a heavy oil.
mixture was allowed to stand for about 14' hours.
It was separated from the solution
by decanting. On adding water thereto and allowing
100
cc. of water were added and the resulting solution was
the mixture to stand for some time while cooling, the
concentrated by evaporation in a vacuum.
compound solidi?ed. It was ?ltered oil: on a vacuum
?lter and dried in a vacuum at room temperature. Yield:
tated yellow ?akes were ?ltered o? on a vacuum ?lter,
The precipi
washed and dried. Yield: 0.6 gm. corresponding to 48%
of the theoretical yield. For analytical purposes the
3.2 gm. corresponding to 64% of the theoretical yield.
For analytical purposes, the compound was puri?ed by 10 compound was recrystallized four times from methanol.
Yellow, small, irregular crystals melting at 130-132” C.
dissolving it in petroleum ether, treating the solution with
animal charcoal, and slowly evaporating the solvent. A
were obtained.
Analysis.—-C15H20O2N6S; molecular ‘weight: 348.4.
colorless, soft mass having a melting point of 35.5-37.0°
Calculated: 48.26% C; 5.78% H. Found: 49.07% C;
Analysis.—C26H48O2I-I8; molecular weight: 504.7. Ca1 15 5.32% H.
The starting material, 6-methyl mercapto-2,4-dichloro
culated: 61.87%' C; 9.58% H; 22.21% N. Found:
pyrimido-pyrim-idine, was obtained by re?uxing the sodi
61.83% C; 9.53% H; 22.56% N.
’
um salt of G-methyl mercapto-2,4-dihydroxy-pyrimid0~
The starting material, 2,6-dichloro-4,8-bis-(diethylami
pyrimidine and phosphorus pentachloride in phosphorus
no)-pyrimido-pyrimidine, was obtained by reacting 2,4,6,
C. was obtained.
8-tetrachloro-pyrimido-pyrimidine with diethylamine.
20
oxychloride.
Using a procedure analogous to that described above,
EXAMPLE 14
2,6-bis-(B-diethylamino-ethoxy) - 4,8 --dipiperidyl-pyn'm
ido-pyrimidine, melting point 60—61‘’ C., was obtained
' 2,6 -Diethoxy-4,8-Bis-( ,B-Dz'ethylamino-Etlzylamino) -
Pyrimido-Pyrimidine
from 2,6-dichloro - 4,8 - dipiperidyl-pyrimido-pyrimidine
and B-diethylamino-ethanol.
25
EXAMPLE 11
rimidine with sodium ethylate.
4.3 gm. (0.01 mol) 2,6-dichloro-4,8-bis-(p-diethylamino
‘I " l6-Ch[Ora-2-Mercapt0-4,8-Dim0rpholyl-Pyrimidoi
Pyrimidine
This compound was prepared from 4,6,8-trichloro-2
mercapto-pyrimido-pyrimidine and morpholine.
3.4 gm. (0.04 mol) morpholine ‘were dissolved in 10
cc. dioxane. The resulting solution was added, while
cooling, to a solution of 2.7 gm. (0.01 mol) 4,6,8-tri
chloro-2-mercapto-pyrimido-pyrimidine in 50 cc. dry di
oxane. Immediately, a crystalline suspension was formed
ethylamino)-pyrimido-pyrimidine were heated for one
30 hour at 190~200° 'C. in a sealed thick-walled glass tube
with 50 cc. of an absolute ethanolic solution of sodium
alcoholate (0.02 mol). After cooling, ?ltering off the
precipitated sodium chloride on a vacuum ?lter and
washing said sodium chloride with absolute ethanol, the
ethanol was evaporated in a vacuum.
which was allowed to stand for half an hour and was
Yield: 1.6 gm. cor
form.
40
powder having a melting point of 240° C. was obtained.
45
Found: 45.46% C;
at room temperature. Yield: 4.1 gm. (92% of the theoret
needles having a melting point of 78.0—78.5° C. were ob
tained. '
Analysis.—C22I-I4(,O2N8;
molecular weight:
448.6.
Calculated: 58.92% C; 8.92% H; 24.99% N. Found:
59.13% C; 8.86% H; 24.70% N.
The starting material, 4,6,8-trichloro-Z-mercapto-pyrim
ido-pyrimidine was prepared by re?uxing 4,6,8-trihydroxy
The starting material, 2,6-dichloro-4,8-bis(?-diethyl—
2-mercapto-pyrirnidopyrimidine in the form of its sodi
um salt with phosphorus pentachloride and phosphorus
oxychloride.
?ltered on a vacuum ?lter, washed and dried in a vacuum
ical yield). The compound was puri?ed by reprecipitat
ing it four times from hot dilute hydrochloric acid and’
recrystallizing iit-ifrom petroleum ether. Small colorless
from glacial acetic acid, whereby a yellow amorphous
Calculated: 45.58% C; 4.64% H.
4.42% H.
The oil solidi?ed on admixture with 200 cc. of
It was triturated with water in a mortar,
- ice water.
responding to 43% of the theroetical yield. For ana
lytical purposes, the product was recrystallized twice
Analysis.—C14H1qO2N5ClS; molecular Weight: 368.8.
The remaining
pyrimido-pyrimidine compound was ?rst obtained in oily
then admixed with 5 times its volume of water. The
precipitated crude reaction product was ?ltered off on
a vacuum ?lter, washed and dried.
This compound was prepared by reacting 2,6-dichloro
4,8 - bis - (e-diethylamino - et-hylarnino) - pyrimido - py
amino-ethylamino)-pyrimido-pyrimidine, was obtained by
reacting 2,4,6,8-tetrachloro-pyrimido-pyrimidine with B
diethylamino ethylamine.
'
EXAMPLE 12
EXAMPLE 15
6-Chlor0-2-Mercapt0-4,8-Dipieridyl-Pyrimid0
Pyrimidine
_2,6-Dihydr0xy-4,8-Diamino-Pyrimid0-Pyrimidine .
mercapto-pyrimido-pyrimidine and piperidine. The pro
This compound was prepared by reacting 2,6-dichloro
4,8-diamino-pyrimi-do-pyrimidine with concentrated sul
cedure was the same as that described in Example 11,
furic
This compound was prepared from 4,6,8-trichloro-2- ‘
but in place of morpholine, an equimolecular ‘amount of '60
piperidine was used.
C. was obtained.
'
1
Y
-
-
I
I
-
2.3 gm. (0.01 mol) 2,6-dichloro-4,8-diamino-pyrimido
Yield: 1.1 gm., corresponding to .
30% of the theoretical yield. On recrystallizing the crude
reaction product twice from butanol, van orange-colored
amorphous powder having a melting point of 242-243"
acid.-
30 cc. concentrated sulfuric acid were poured over
pyrimidine; hydrogen chloride was evolved. The mixture
was heated to 50° C. for 30 minutes. After dilution with
120 cc. water, the resulting solution was heated, ?ltered,
65 and subsequently allowed to stand at 0° C. for several
Analysis.—C16I-I21N6ClS; molecular weight: 364.7.
Calculated: 52.70% C; 5.80% H. Found: 52.13% C:
5.72% H.
EXAMPLE 13
6-Methyl MercaptO-Z,4-Dimorph0lyl-Pyrimido
Pyrimidine
This compound was prepared from 6-methyl mercapto
2,4-dichloro~pyrimido-pyrimidine and morpholine.
2.6 gm. (0.03 mol) morpholine were poured into a 75
hours. The precipitated sulfate of 2,6-dihydroxy-4,8-di
amino-pyrimido-pyrimidine was obtained in long, clus
tered, interlaced, colorless needles which were ?ltered
oil on a vacuum ?lter.
About 1 gm. of these needles
was obtained. The free 2,6-dihydroxy-4,8-diamino
pyrimido-pyrimidine was prepared therefrom by dissolv
ing the sulfate in 100 cc. of hot water and precipitating
the free base by neutralizing the solution with ammonia.
The precipitate was a microcrystalline, colorless powder.
Analysis.—-C6H6O2N6; molecular Weight: 194.2. Cal
3,031,450
1.3’
4,8-Diamin0-Pyrimido-Pyrimidine Compounds
These compounds were prepared by reacting 4,8-di
chloropyrimido-pyrimidine with various amino-com
pounds in the following manner:
,
14
(j) 4,8-di- (N-hydroxy-ethyl-p-nitroeinilino ) -pyrimido
culated: 37.11% C; 3.11% H. Found: 36.22% C;
3.70% H.
EXAMPLE 16
pyrimidine was obtained from 4,8-dichloro-pyrimido-py
rimidine and N-hydroxy ethyl~p~nitro aniline. The yield
was 73% of the theoretical yield. ‘On recrystallization
U! from dimethyl formamide, the compound was obtained in
the form of a yellow, amorphous powder having a melt
ing point of 265~267° C.
(k) 4,8 - di - (methyl-ethanol-arnino)-pyrimido-pyrimi
-
Four times'the molecular. amount of the corresponding
dine, melting point 162—165° C., was obtained from 4,8
amino compound, if required in solution in dioxane, was 10 dichlo‘ro-pyrimido-pyrimidine and methyl-ethanol amine.
poured into a solution of 4,8-dichloro-pyrimido-pyrimi-'
(l) 4,8 - bis - (diethanolamino) - pyrimido - pyrimidine,
dine in dioxane. The startingmaterial was obtained by
meltingpoint 156° C., was obtained from 4,8-dichlor0
re?uxing the sodium salt of 4,8-dihydroxy-pyrimido
pyrimidospyrimidine and diethanolamine.
pyrimidine with phosphorus pentachloride in phosphorus :
(m) 4,8-di-(ethylene-imino)-pyrimido-pyrimidine, no,
oxychloride. It had a melting point of 232° C.
15 melting point up to 350° C., Was obtained from 4,8-di
The reaction mixture of 4,8-dichloro-pyrirnid0 pyrimi
chloropyrimido-pyrimidine and ethyleneimine.
dine and the corresponding amino compound was ad
EXAMPLE 17
mixed with water, whereby the desired 4,8t-diamino
2,6-Dim0rpholyl-4,8-Di-(Ethyl-Mercapto)
pyrimido-pyrimidine was precipitated. Its yield was
Pyrimido-Pyrimidine
determined. To purify the precipitate for analytical 20
purposes, it was reprecipitated from dilute hydrochloric
‘This compound was obtained from 2,6-dichloro-4,8-di
acid and recrystallized from a suitable solvent as indicated
(ethylanercapto).-pyrirnido-pyrimidine and morpholine.
hereinafter.
3.2 gm. (0.01 mol) 2,6-dichloro-4,8-di-(ethyl-mer
(a) 4,8-dimorpholyl-pyrimido-pyrimidine was obtained
capto)pyrimido-pyrimidine, obtained as described above,
from 4,8-dichloro-pyrimido-pyrimidine and .morpholine.
The yield was 98% of the ‘theoretical .yield. The com
pound was obtained in the form of very small,,_c0lorless
prisms which have a melting point of 197—*19'8°'C., after '
recrystallization ‘from benzene.
25 were heated in a sealed thick-walled glass tube at 200°
C. for 2 hours with 20 cc. morpholine, 20 cc. water, and
1 cc. copper sulfate solution saturated in the cold. The
reaction mixture was allowed to cool, admixed with
about 200 cc. water and acidi?ed with concentrated hy
_
(b) 4,8-dipiperidyl-pyrimido-pyrimidine was obtained 30 drochloric acid. The undissolved 2,6-dimorpholyl-4,8-di
from 4,8-dichloro-pyrimidopyrimidine and piperidine.
-(ethyl-mercapto)-pyrimido-pyrimidine was ?ltered oil on
a vacuum ?lter, washed, and dried at 110° C. Yield: 1.3
The yield was 93% of the theoretical yield. On recrys-'
tallization from methanol, colorless bright ?akes melting
gm., corresponding to 31% of the theoretical yield. For
analytical purposes the compound was recrystallized twice
at 132~134° C. were obtained.
(0) 4,8-dianilino-pyrimido-pyrimidine was obtained
from 4,8-dichloro-pyrimido-pyrimidine and aniline. The
from dimethyl formamide whereby orange-colored, micro
crystalline prisms having a melting point of 293—295° C.
yield was 93% of the theoretical yield. On recrystalliza
were obtained.
tion from dimethyl formamide, faintly yellowish, small
needles melting at 257—258° C. were obtained.‘
(d) 4,8-diamino-pyrimido-pyrimidine was prepared‘ by
reacting 4,8-dichloro=pyrimido-pyrimidine with ammonia.
The yield was 99% of the theoretical yield. On reprecipi
tation from dilute hydrochloric acid, very small, color-
40
(e)
A
4,8-bis-(methylamino)pyrimido-pyrimidine was
6.31% H.
EXAMPLE‘ l8
6~Carboxy~Methyl-Mercapt0—4,8-Di-Pr0pylamin0
less needles, which did not melt at temperatures up to 360°
C., were obtained.
I
‘Analysis.—C18H2(,-O2N6S2; molecular weight: 422.6.
Calculated: 51.16% C; 6.20% H. Found: 51.06% C;
Pyrimido-Pyrimidine
45
prepared from 4,8-dichloro-pyrimido-pyrimidine and
This compound was prepared by reacting 6-chloro-4,8,—
di-propylamino-pyrimido<pyrimidine with thioglycolic acid
in the presence of pyridine.
'
methylamine. The yield was 92% of the theoretical
2.8 gm. (0.01 mol) of 6-ch1oro-4,8-di-propylamino
yield. On recrystallization from water, a colorless, crys
pyrimido-pyrimidine having a melting point of 88—90° C.
talline powder melting at 265° 'C. was obtained.
50
were heated at 200° C. for 2 hours with 0.2 gm. (0.1
(1‘) 4,8-bis-(dimethy1amino)pyrimido-pyrimidine was
obtained by reacting 4,8-dichloro-pyrimido-pyrimidine
mol) thioglycolic acid and 9.7 gm. (0.1 mol) pyridine in
with dimethylamine. The yield was 97% of the theoreti~
a sealed heavy-walled glass tube. The reaction mixture
was removed from the tube by rinsing with 150 cc. water.
cal yield. On recrystallization from water, bright needles
melting at 115° C. were obtained.
(g) 4,8-dihydrazino-pyrimido-pyrimidine was obtained -
55
by reacting 4,8-dichloropyrimido-pyrimidine with hy
solution in the form of a brown precipitate which was
initially of pasty consistency, by acidifying the aqueous
drazine. The yield was 93% of the theoretical yield.
After reprecipitation from dilute hydrochloric acid, an
ivory-colored, microcrystalline powder consisting of very
small needles and melting at 226° C. was obtained.
- (h) 4,8-bis-(N,N'-diphenyl-guanidyl) pyrimido-pyrimi
6 - carboxy - methyl - mercapto - 4,8 - di - propylamino
pyrimido-pyrimidine was precipitated from the aqueous
solution. Yield: 3.2 gm., corresponding to 95% ‘of the
60
theoretical yield. For analytical purposes the compound
was reprecipitated twice from dilute sodium hydroxide
solution and then recrystallized twice from a small amount
of methanol. Brownish, small prisms having a melting
dine was prepared from 4,8-dichloro-pyrimido-pyrimiden
point of 172-174° C. were obtained.
and N,N'-diphenyl ‘guanidine. The yield was 80% of
the theoretical yield. On reprecipitation from dilute hy 65 Analysis.-—C14H20O2N6S; molecular weight: 336.4.
Calculatedr 49.98% C; 5.99% H. Found: 50.13% C;
drochloric acid, the compound was obtained in the form
.of a yellow, microcrystalline powder which sintered at
6.02% H.
, 200°‘ C. and had a melting point of 245° C.
(i) 4,8-di- ( IS-hydroxy-ethylarnino) pyrimido-pyrimidine
The starting material, 6-chloro-4,S-di-propylamino
pyrimido-pyrimidine, was obtained ‘by reacting 4,6,8-tri
was prepared from 4,8-dichloroepyri-mido-pyrimidine and 70' chloro-pyrimidopyrimidine with propylamine.
p-hydroxy ethylam'ine. The yield of the analytically pure
compound was 72.2% of the theoretical yield. On recrys
tallization from methanol, colorless. rectangular lea?ets
and prisms having a- ‘melting point of '204—205‘’1 C. ‘were’,
obtained.
EXAMPLE 19
2,4,6,8-TetraaminmPyrimido-Pyrimidine Compounds
These compounds were obtained by reacting the corre
sponding
2,6 - dichloro - 4,8v - diamino -' pyrimido
3,031,450
16
15
EXAMPLE 20
pyrimidine compounds with various amines at elevated
temperatures, as described hereinafter.
(a) 2,6 - bis - (diethanol
2,4,6,8-Tetraamin0-Pyrimido-Pyrimidine Compounds
amino) - 4,8 - dipiperidyl
pyrimido-pyrimidine: 36.7 gm. (0.1 mol) 2,6-dichloro
4,8-dipiperidyLpyrimidO-pyrimidine having a melting 5
point of 241—242° C. were heated to 200° C. with 100
gm. diethanol amine and the mixture was kept at said
These compounds were prepared by reacting the corre
sponding 2,6 - dichloro - 4,8 - diamino - pyrimidopyrimi
dine compounds with various amines at elevated tem
perature under pressure, as described in detail herein
after.
temperature for 10 minutes. After cooling, about 500 cc.
(a) 2,6 - dimorpholyl - 4,8 - di - (ethyl - ethanol
of water were added to the reaction mixture, whereby the
reaction product precipitated out as a viscous mass.’ After 10 amino)~pyrimido-pyrimidine: 7.6 gm. (0.02 mol) 2,6-di
chloro - 4,8 - di - (ethyl - ethanol - amino) - pyrimido
decanting the water, said mass was triturated with a
pyrimidine were heated with 20 cc. morpholine at 200°
small amount of acetone, whereby a solid-yellow pre
C. for one hour in a sealed thick-walled glass tube. The
cipitate was formed. Yield: 26.5 gm., corresponding to
52.4% of the theoretical yield. For analytical purposes
reaction mixture was diluted with 200 cc. water.
the compound was recrystallized four times from acetic
acid ethyl ester, whereby dark yellow, ?ne, small needles '
having a melting point of l62—163° C. were obtained.
2,6 - dimorpholyl - 4,8 - di - (ethyl - ethanol - amino)
Crude
py’rimido-pyrimidine was precipitated in the form of a
yellow, amorphous solid.
It was ?ltered oil on a vac
uum ?lter, washed, and dried at 110° C. Yield: 8.7
Analysis.-C24H4OO4N8; molecular weight: 504.6.
gm., corresponding to 91% of the theoretical yield. For
Calculated: 57.12% C; 7.99% H; 22.21% N. Found:
20 analytical purposes the compound was recrystallized four‘
57.16% C; 7.83% H; 22.26% N.‘
times from methanol. The resulting light yellow, micro
The starting material, 2,6-dichloro-4,8dipiperidyl-py
crystalline, small needles were dried at 130° C./0.1 mm.
rimido-pyrimidine, was prepared by reacting 2,4,6,8-tetra
Their melting point was 190-1910 C.
chloro-pyrimido-pyrimidine with piperidine at room tem
Analysis.-C22H36O4N8; molecular weight: 476.6. Cal
culated: 55.44% C; 7.61% H; 23.52% N. Found:
perature.
Other 2,4,6,8~tetraamino-pyrimido-pyrimidine com
pounds were obtained "from various 2,6-dichloro-4,8-di7
55.42% C; 7.67% H; 23.32% N.
amines in place of diethanolarnine and proceeding in the
using various other amines, the following new 2,4,6,8
30
(b) 2,6 - bis - (cliethanolamino) - 4,8 - bis - (diethyl
pared:
'
(b) 2,6 - dimorpholyl - 4,8 - di - (propyl - ethanol
amino)-pyrimido-pyrimidine having a melting point of
167-168° C. was obtained by reacting 2,6-dichloro-4,8-bis
amino)-pyrirnido-pyrirnidine having a melting point of
41-143° C. was obtained by reacting 2,6-dichloro-4,8-di
(diethylamino) -pyrimido-pyrimidine with diethanolamine.
(propyl-ethanol-amino)-pyrimido-pyrimidine with mor
(c) 2,6 - bis - (diethanolamino) - 4,8 - dipyrrolidyl
pholine.
pyrimido-pyrimidine having a melting point of 186-l87°
C. was obtained by reacting 2,6-dichloro-4,8-dipyrrolidino
pyrimido-pyrimidine with diethanol amine.
(c) 2,6 - dimorpholyl - 4,8 - di - (methyl - ethano1~
amino)~pyrimido-pyrimidine having a melting point of
207—209° C. was obtained by reacting 2,6-dichloro-4,8
di-methyl-ethanol-amino) ~pyrimindo-pyrimidine with mor-v
(d) 2,6 - bis — (diethanolamino) - 4,8 - bis - (diallyl
amino):pyrimido-pyrimidine having a melting point of
110° C. was obtained by reacting 2,6-dichloro-4,8-bis
>
tetra-amino-pyrimido-pyrimidine compounds were pre
same manner as described under (a).
.
'
In the same manner as described above under (a), but
amino-pyrimido-pyrimidine compounds by using other
40
(diallylamino)~pyrimido-pyrimidine with diethanolamine.
pholine.
(d) 2,6 - dimorpholyl - 4,8 '- bis - (diethanolamino)
pyrimido-pyrimidine having a melting point of 209-210°
C. was obtained by reacting 2,6-dichloro-4,8-bis-(dieth
(e) 2,6 - bis - (diethanolamino) - 4,8 — bis - (dimethyl
amino)-pyrimido-pyrimidine having a melting point of
182—183° C. is obtained by reacting 2,6-dichloro-4,8
bis-(dimethylamino)-pyrimido-pyrimidine with diethanol
anolamino)-pyrimido-pyrimidine with morpholine.
(2) 2,6 - dipiperidyl - 4,8 - bis ~ (diethanolarnino)
pyrimido-pyrimidine having a melting point of l82-l84°
C. was obtained by reacting 2,6-diehloro-4,8-bis-(dieth
amine.
(f) 2,6 - bis - (diethanolamino) - 4,8 - bis - (dibutyl- _
anolamino)-pyrimido-pyrimidine with piperidine.
amino)-pyrimido-pyrimidine having a melting point of
(1‘) 2,6 -bis - (diethanolamino) - 4,8 - bis - (diethanol
124—l26° C. was obtained by reacting 2,6—dichloro-4,8
bis-(dibutylamino)-pyrimido-pyr-imidine with diethanol 50 amino)-pyrimido-pyrimidine having a melting point of
18-160° C. was obtained by reacting 2,6-dichloro-4,8
amine.
bis-(diethanolamino)-pyrimido~pyrirnidine with diethyl
(g) 2,6 - di - (methyl - ethanol — amino) - 4,8 - di
amine.
piperidyl-pyrimidopyrimidine, which starts to sinter at
114° C. and melts at 122-124° C., was obtained by re
acting
2,6-dichloro-4,8-dipiperidyl-pyrimidopyrimidine
with methyl-ethanol-amine.
(g) 2,6 - dimorpholyl - 4,8 - bis - (dimethylamino)
55 pyrimido-pyrimidine having a melting point of 92-193"
C. was obtained by reacting 2,6-dichloro-4,8-bis-(dimeth
I
ylamino)-pyrimido-pyrimidine with morpholine.
(h) 2,6 - di - (propyl - ethanol - amino) - 4,8 - di
(h) 2,6 - dipiperidyl - 4,8 - bis -'(isoarnylamino)
morpholyl-pyrimidopyrimidine having a melting point of
l38-139° C. was obtained by reacting'2,6-dichloro-4,8
pyrimido-pyrimidine having a melting point of 192-194"
C. ‘was obtained by reacting 2,6-dichloro-4,8-bis-(isoam
60
dimorpholyl-pyrimido-pyrimidine with propyl-ethanol
ylamino)-pyrimido—pyrimidine with piperidine'.
amine.
I
(i) 2,6 ~ bis - (diisopropanol - amino)
V
" (i)
- 4,8 - di
piperidyl-pyrimido-pyrimidine having a melting point of
obtained by reacting 2,6-dichloro-4,8-dipyrrolidyl-pyrimi
182-1830 ‘C. was obtained by reacting 2,6-dichl0ro-4,8 65
piperidyl-pyrimido-pyrimidine with diisopnopanol-amine.
having 7 a
ethanol-amino)-pyrimido-pyrirnidine with piperidine.
melting point of 88-90c C. was obtained by reacting 2,6
dichloro - 4,8 - di - (dodecyl - ethanol - amino) - pyrimido—'
pyrimidine with methyl-ethanol-amine.
70
These compounds were prepared by reacting 4,6,8-tri
chloro-pyrimido-pyrimidine with various amines at ele
75 vated temperatures, if desired at elevated pressures, and
C. was obtained by reacting 2,6-dichloro-4,S-dimorpholyl- ’
pyrimido-py-rimidine with diethanol amine.
EXAMPLE 21
4,6,8-Tfiamino-Pyrimido-Pyrimidine Compounds
(k) 2,6 -, bis - (diethanolamino) ~' 4,8 - dimorpholyl
pyrimido-pyrimidine having a melting point of 202-204“
do-pyrimidine with piperidine.
‘
p
(j) 2,6-dipiperidyl - 4,8 - di - (benzyl - ethanol-amino)
pyrimido-pyrimidine having a melting point of 161-163°
C. was obtained by reacting 2,6-dichloro-4,8-di-(benzyl
(1') 2,6 - di - (methyl - ethanol - amino) - 4,8 - di
(dodecyl-ethanol-amino)-pyrimido-pyrimidine
2,6 - dipiperidyl - 4,8 - dipyrrolidyl - pyrimido
pyrimidine having a melting point of 254-2560 C. was
3,031,450
17
inafter.
_
18
(0) With sodium IS-diethylamino-ethanolate: 6-(?-di
in the presence of copper salts as described in detail here
ethylamino-ethoxy) - 4,8 - dimorpholyl - pyrimido - pyrim
'
idine; melting point 100-103° C.
(a') With sodium fi-ethoxy-ethanolate: G-(?-ethoxy-eth
(a) 4,6,8-tri-(methylamino)-pyrimido-pyrimidine: 4.8
gm. (0.02 mol) 4,6,8-trichloro-pyrimido-pyrimidine were
heated to 200° C. for about 2 hours with 50 cc. of an
oxy)-4,8-dimorpho1yl-pyrimido-pyrimidine; melting point
absolute alcohol solutionof methylamine (about 0.2 mol)
11 1-1 12° C.
I
.
.
(e) With sodium ,G-propoxy-ethanolate: 6-(B-propoxy
and 0.1
copper sulfate in a sealed thick-walled glass
ethoxy)-4,8 - dimorpholyl - pyrimido - pyrimidine; melting
tube. The reaction mixture was diluted with about 300
point l22-123° C.
cc. water, ?ltered, and concentrated by evaporation to
EXAMPLE 23
1/3 of its volume. After allowing the mixture to stand 10
for several hours the crude 4,6,8-tri-(methylamino)
2,6-Dimorpholyl-4,8-Di( B-Propoxy-Ethoxy ) vpyrimido-pyrimidine was precipitated in the form of a
brown solid similar in texture to cotton.
Pyrimido-Pyrimtidine
Yield: 4 gm.,
This compound was obtained by reacting 2,6-dichloro
corresponding to 91% of the theoretical yield. For an
alytical purposes the compound was recrystallized three 15 4,8-di-([i-propoxy-ethoxy)-pyrimido-pyrimidine with mor
times from water and the resulting colorless very ?ne,‘
8.1 gm. (0.02 mol) 2,6-dichloro-4,8-di-(?-propoxy
wool-like ?bers were dried at 130° C./0.1 mm. Melting
pholine.
point: 188-189" C.
.
'
ethoxy)—pyrimido-pyrimidine having a melting point of
‘
Analysis.-C9H13Nq; molecular weight: 219.3.
.
Calcu
78-81“ C. Were heated to 100° C. for 2 hours with 20 cc.
lated: 49.31% C; 5.97% H. Found: 49.00% C; 20 morpholine in a sealed thick-walled glass tube. The reac
tion product was removed from the tube by rinsing with
5.79% H.
The following 4,6,S-triamino-pyrimidopyrimidine com
200 cc. water, ?ltered off on a vacuum ?lter, washed and
dried. Yield: 9.9 gm., corresponding to 98% of the
pounds were prepared by following the procedure de
theoretical yield. For analytical purposes the compound
scribed above under (a), but using in place of methyl
25 was reprecipitated from N hydrochloric acid and recrys
amine other amines as indicated.
(b) With ethylamine: 4,6,8-tri-(ethylamino)-pyrimido
pyrimidine; melting point 83-85 ° C.
.
(0) With propylamine: 4,6,8-tri-(propylamino) -pyri
mido-pyrinn'dine; melting point 84-86° C.
(d) With dimethylamine: 4,6,8-tri-(dimethylamino)—
pyrimido-pyrimidine; melting point 92-93” C.
(e) With ?-hydroxy-ethylamine: 4,6,8-tri-(?~hydroxy
ethylamino)- pyrimido pyrimidine; melting point 83
tallized twice from a mixture of methanol and water
(1:4). A bright yellow, microcrystalline powder was
formed. Melting point: 155-l57° C.
Analysis..—C24H38O6N6; molecular weight: 506.6. Cal
30 culated: 56.90% C; 7.56% H. Found: 56.4% C;
7.47% H.
'The starting material, 2,6-dichloro-4,S-di-(?propoxy
ethoxy)-pyrimido-pyrimidine, was prepared by reacting
2,4,6,8-tetrachl0ro-pyrimido-pyrimidine with a solution of
85° C.
(1‘) With morpholine: 4,6,8-trimorpholyl-pyrimido-pyr
imidine; melting point 182-184“ C.
(g) With aniline: 4,6,8Ptrianilino-pyrimido-pyrimidine;
melting point 203-204“ C.
,
35
while cooling.
pyrimido-pyrimidine; melting point 274-275° C.
(i) With o-methoxy-aniline: 4,6,8-tri-(o-methoxy-ani
lino)-pyrimido-pyrimidine; melting point 2l4-2l5° C.
40
_
Preparation of Various 2,4,6,8éTetraamino-Pyrimid0-Py
rimidines From the Corresponding 2,6-Dichl0ro-4,8
Diamino-Pyrimidwl’yrimidines by Reaction With the
Corresponding Amines at Elevated Temperatures
(a) 2,6 - bis - (diethanolamino) - 4,8 - di -_ (4’ - methyl
EXAMPLE 22
6-Alkoxy-4,8-Dimorpholyl-Pyrimido-Pyrimidine '
Compounds
These compounds were prepared by reacting 6-chloro
4,8~dimorpholino-pyrimidopyrimidine with the corre
sponding alcoholate solutions, if required at elevated pres
sure, as described below.
,
EXAMPLE 24
-
(h) With p-chloro-aniline: 4,6,8-tri-(p-chloro-anilino)
sodium metal in the monopropyl ether of ethylene glycol,
'
>
(a) 6-ethoxy-4,8~dimorpholyl-pyrimido-pyrimidine: 6.7
gm. (0.02 mol) 6-chloro-4,8-dimorpholyl-pyrimido
pyrimidine were heated to 180° C. for 2 hours with
50 cc. of a sodium alcoholate solution containing 0.5
piperidyl)~pyrimido-pyrimidine: 4.0 gm. (0.01 mol) 2,6
45
dichloro-4,8-di-( 4’-methyl-piperidyl ) -pyrimido-pyrimidine
(melting point 166-167“ 0, obtained from 2,4,6,8-tetra
chloro-pyrimidopyrimidine and 4-methyl-piperidine in di
oxan at room temperature) were admixed with 16 gm.
(about 0.15 mol) diethanolamine and the mixture was
50 heated for 45 minutes at 190-195 ° C. A honey-colored
melt was obtained which was taken up in about 150 cc.
water. The raw reaction product separated out as an ini
tially greasy yellow mass which, however, solidi?ed after
standing for some time.
The solidi?ed mass was sep
gm. (0.022 mol) sodium in a sealed thick-walled glass 55 arated by vacuum ?ltration, triturated with‘ a small
amount of water in a mortar, again vacuum ?ltered,
tube. The crude reaction product was removed from
washed with Water and dried. The yield was 5.0 gm.
said tube by rinsing with a small amount of water and
(94% of theory). For analysis, the product was dis
_then recrystallized, after it ‘had. been ?ltered oiic [on a
' solved in dilute. acetic acid and reprecipitated from this
‘vacuum ?lter, from a mixture of ethanol and water (1:4).
Yield: 519 gm., corresponding to 85% of the theoret 60 solution by adding sodium acetate. Thereafter, it was re
ical yield. , ' For analyltical purposes the compound was
crystallized from ethylene chloride. Deep yellow, partly
recrystallized twice from about 100 cc. ethanol, repre
rhombic shaped, ?at prisms having a melting point of
cipitated from hot 0.5 N hydrochloric acid, and again re
crystallized from ethanol. The resulting almost color
less, very short, rhombic prisms were dried at 65° C./ 0.1
mm. Melting point: 129-132" C.
Analysis.-C16H22O3N6; molecular weight: 346.4. Cal
culated: 55.48% C; 6.40% H. Found: 55.11% C;
174-175 ° C. were obtained.
[6.20% H.
Analysis.-C26H44N3O4: molecular weight: 532.7. Cal
culated: 58.62% C; 8.33% H. Found: 58.90% C;
8.66% H.
Following a procedure analogous to that described
under (a) above, the following 2,4,6,8-tetraamino-py
rimido-pyrimidines were prepared from the indicated
By proceeding in the same manner as described above 70 starting materials:
under (a) but using other sodium alcoholate solutions as
indicated below, the following 6-alkoxy-4,8-dimorpholyl
pyrimido-pyrimidine compounds were obtained:
(b) With sodium butanolate:
6-butoxy-4,8-dimor
pholyl-pyrimidopyrimidine; melting point 109-l11° C.
(b) 2,6 - bis - (diethanolamino) - 4,8 - di - (3' - methyl
piperidyl)~pyrimido-pyrimidine, melting point 188-190”
C., from 2,6-.dichloro-4,8-di-(3’-methyl-piyeridyl)-pyrim
ido-pyrimidine (melting point 181-183° C.) and dietha
nolamine.
'
3,031,450
19
Y
as a yellow precipitate, while the 3-methyl-piperidine
hydrochloride which separated out during re?uxing re
dissolved. ’After vacuum ?ltering, washing the ?lter cake
and drying it in vacuo at room temperature the yield of
reaction product was 4.6 gm. (86% of theory). For
analysis, the product was puri?ed by dissolving it in
dilute acetic acid and reprecipitating it from this solu
tion by adding a sodium acetate solution thereto, and then
recrystallizing it twice from ethyl ‘acetate. The pure
(c) 2,6, - bis - (diethanolamino) - 4,8 - di - (2’ - methyl
piperidyl)-pyrirnido-pyrimidine, melting point 208-209"
C., from 2,6-dichloro-4,8-di-(2’-methyl-piperidyl)-pyrim
ido—pyrimidine (melting point l44-145° C.) and dieth
anolamine.
(at) 2,6 - bis - (diethanolamino) - 4,8 - bis - (2',6' - di
methyl-morpholyl) 7 pyrimido - pyrimidine, melting point
181-183° C., from 2,6-dichloro-4,8-bis-(2',6’-dimethyl
morpholyl)-pyrimido-pyrimidine (melting point 197-199°
C.) and diethanolamine.
10 product was obtained in the form of a brilliant yellow
microcrystalline powder having a meltingpoint of 138
(e) 2,6 - bis - (diethanolamino) - 4,8 - bis - (2',6' - di
methyl piperidyl)-pyrimido-pyrimidine, melting point
140° C.
223-226° C., from 2,6-dichloro-4,8-bis-(2’,6’-dimethyl
AnalysiS.-C26H44N8O4; molecular weight: 532.7. Cal
culated: 58.62% C; 8.33% H. Found: 58.50% C;
piperidyl)-pyrimido-pyrimidine (melting point 160-162"
C.) and diethanolamine.
15
6'-tetrahydro-pyridyl)~pyrimido-pyrimidine, melting point
150-152" C., from 2,6-dichloro-4,8-bis-(1',2',5',6’-tetra
hydro-pyridyl)—pyrimido-pyrimidine (melting point 209
211° C., decomposition) and diethanolamine.
.
under (a) above, the following 2,4,6,8-tetraamino-pyrimi
do-pyrimidineswere prepared from the starting materials
indicated in each case.
20
(b) 2,6 - di - (4' - methyl-piperidyl) - 4,8 - bis - (dietha
nolamino)-pyrimido-pyrimidine,- melting point 191-193°
C., from 2,6-dichloro-4,8-bis-('diethanolamino)-pyrimido
pyrimidine and 4-methyl-piperidine.
(g) 2,6 - bis - (diethanolamino) - 4,8 - di - (3' - hy
droXy-piperidyl)-pyrimido-pyrirnidine, melting point 202
204° C., from 2,6-dichloro-4,8-di-(3’-hydroXy-piperidyl)
pyrimido-pyrimidine (melting point 208-210“ C.) and di
ethanolamine.
8.52% H.
l"By following a procedure analogous to that described
(f) 2,6 - bis - (diethanolarnino) '- 4,8 - bis - (1’,2’,5',
(0) 2,6 - di - (2’ - methyl - morpholyl) - 4,8 - bis - (di
_ethanolamino)-pyrimido-pyrimidine, melting point 161
‘
yl-morpholyl)-pyrimido-pyrimidine, melting point 183
163° C., from 2,6-dichloro-4,8-bis-(diethanolamino)-py
rimido-pyrimidine and Z-methyl-morpholine.
185° C., from 2,6-dichloro-4,8-di-(2’-methyl-morpholyl)
pyrimiclo-pyrirnidine (melting point 182-184“ C.) and di
bis-(diethanolarnino)-pyrimido-pyrimidine, melting point
(h) 2,6 - bis - (diethanolamino) - 4,8 - di - (2' - meth
ethanolamine.
(d) 2,6 - lbis - (2',6' - dimethyl - morpholyl) - 4,8
30 236-238° C., from 2,6-dichloro-4,8-bis-(diethanolamino)
'
pyrimido-pyrirnidine and 2,6-dimethyl-morpholine.
(i) 2,6 — bis - (diisopropanolamino) - 4,8 - dimor
pholyl-pyrimido-pyrimidine, melting point 216-218° C.,
(e) 2,6 - bis - (1',2’,5’,6' - tetrahydro - pyridyl) - 4,8
bis - (diethyanolamino) - pyrimido - pyrimidine, melting
from 2,6 - dichloro-4,8-dimorpholyl-pyrimido-pyrimidine
(melting point 276-277 ‘’ C.) and disopropanolamine.
point 171-173° C., from 2,6-dichloro-4,8-bis~(diethanol
amino)-pyrimido-pyrimidine and 1,2,5,6-tetrahydro-pyri
(k) 2,6 - d - (ethanol - isopropanol - amino) - 4,8 - di
morpholyl-pyrimido-pyrimidine, melting point 159-161“
C., from 2,6-dichloro-4,8-dimorpholyl-pyrimidopyrimi
dine.
‘
‘
(1‘) 2,6 - di - (methyl - ethanol -amino) - 4,8 - di - (N'
dine and ethanol-isopropanol-amine.
methyl - piperazyl) - pyrimido - pyrimidine, melting point
(l) 2,6 - di - [ethanol - butanol - (2’) - amino] - 4,8
dimorpholyl-pyrimido~pyrimidine, melting point 173-175 ° 4.0
C., from 2,6-dichloro-4,8-dimorpholyl-pyrimido-pyrimi
dine and ethanol-butanol-(Z')-arnine.
188-189“ C., from 2,6-dichloro-4,8-di-(N’-methyl-piper~
azyl)-pyrimido-pyrimidine (decomposition at about 205°
C.) ‘and methyl-ethanol-amine.
(g) 2,4,6,8 - tetra - (N' - methyl - piperazyl) - pyrimi
do-pyrimidine, melting point 121-123° C., from 2,6-di
(m) 2,6 - di - [ethanol - butanol - (2’) - amino] - 4,8
dipiperidyl-pyrimido-pyrimidine, melting point 173-175 °
C., from 2,6-dichloro-4,8-dipiperidyl-pyrimidopyrimidine
45
(melting point 245-247° C.) and ethanol-butanol-(2')
chloro - 4,8 - di - (N' - methyl - piperazyl) - pyrimido
pyrimidine and N-methyl-piperazine.
(h) 2,6 - di - (N’ - methyl - piperazyl) - 4,8 - dipiper
amine.
idyl-pyrimido-pyrimidine, melting point 130-132° C.,
(n) 2,6 - di - (methyl-glucamino) - 4,8 - dimorpholyl
from 2,6-dichloro-4,8-dipiperidyl-pyrimido-pyrimidine and
pyrimido-pyrimidine, melting point 191-193" C., from
2,6-dichloro-4,S-dimorpholyl - pyrimido - pyrimidine
and 50
N-methyl-piperazine.
methyl-glucamine.
EXAMPLE 26
(0) 2,6 - bis - (diethanolamino) - 4,8 - di - (hexameth
yleneimino)-pyrimido-pyrimidine, melting point 208-209“
C., from 2,6-dichloro-4,8-di - (hexamethyleneimino) - py
rimido-pyrimidine (melting point 170-172“ C.) and di
ethanolamine.
55
of
'
2,6 - dichloro - 4,8 - di' - (4’
methyl-piperidyl)-pyrimido~pyrimidine: 12 gm. (about
0.12 mol) 4-rnethyl-piperidine were slowly poured into
melting
point 205-208° C., from 2,6-dichloro-4,8-bis-(1',2',3',4’
Vtetrahydro-quinolyl)-pyrimido-pyrimidine (melting point
Amines at Room Temperature
(a) Preparation
(p) 2,6 - bis - (diethanolamino) - 4,8 - bis - (1’,2',3’,
_4'-tetrahydro-quinolyl) - pyrimido — pyrimidine,
Preparation of Various 2,6-Dichloro-4,8-Diamino-Py
rimido-Pyrimidines From 2,4,6,8-Tetrachloro-Pyrim
ido-Pyrimidines By Reaction With the Corresponding
60 a solution of 8.1 gm. (0.03 mol) 2,4,6,8-tetrachloro-py
rimido-pyrirnidine in 120 cc. dioxane at room tempera
244-246° C.) and diethanolamine.
ture (while cooling, if necessary), accompanied by stir
EXAMPLE 25
ring.
After all of the 4-methyl-piperidine had been
added the reaction mixture was allowed to stand for a
Preparation of Various 2,4,6,8-Tetraamino-Pyrimz‘do-Py
rimidines From 2,6-Dichl0ro-4,8-Diamine-Pyrimido-Py 65 short period of time, whereby a crystal suspension was
rimidine By Heating Them Under Re?ux With the Cor
responding Amines
(a) Preparation of 2,6-di-(3'-methyl-piperidyl)-4,8-bis
(di-ethmolamino)-pyrirnido-pyrimidine: 4.1 gm. (0.01 70
mol) - 2,6-dichloro-4,8—bis-(diethanolarnino).-pyrimido-py
'rimidine (melting point 189-190° C.) were refluxed for
about one hour with 12 cc. 3-methyl-piperidine.
The
' reaction mixture was then allowed to cool and was taken
obtained. In order to dissolve out the 4-methyl-piperi
dine hydrochloride formed as a side product by the re
action, the suspension was taken up in about 400 cc.
water. The principal desired reaction product, which
Was insoluble in the aqueous medium, was separated by
vacuum ?ltration, washed with water and dried. The
yield was 10.0 gm. (84% of theory). For puri?cation
purposes the raw product was recrystallized twice from
ethyl acetate, yielding violet-‘blue prisms having a melt
up in 200 cc. water. The reaction product separated out 75 ing point of 166-1670 C.
3,031,450
291
22
dine with diethanolamine for half an hour at 150° C.)
Following a’ procedure analogous to that described un
were heated. for, about 1 hour at 190-195" C; together
der (a) above, the following 2,6-dichloro-4,S-diamiho
pyrimido-pyrimidines were prepared from the starting
pyrimido-pyrimidine, melting point 144-145° C., from
with- 15 gm. diisopropanolamine: The melt obtained
thereby was taken up in 100cc. water, whereupon the
reaction product separated out as a rapidly solidifying
yellow mass. The precipitate was separated by vacuum
2,4,6,8-tetrachloro~pyrimidoapyrimidine and 2-methyl-pi
peridine.
mortar, again vacuum ?ltered, washed“ with water and
materials indicated in each case.
(b) 2,6 - dichloro - 4,8- di -- (2’ - methyl - piperidyD
?ltration, tn'turated with a small amount of waterv in a
dried. The, yield was 4.3' gm. 81% of theory). For
analysis, the raw product was recrystallized‘twicefrom
(0) 2,6 - dichloro - 4,8 - di - (3' - methyl- piperidyl)
pyrimido-pyrimidine, melting point 181-183" C., from
2,4,6,8-tetrachloro-pyrimido-pyrimidine and 3-methy1-pi
ethylene chlorinde,yielding'yellow prisms having a melt
ing point of 172'-174°" C.
Analysis.—C26H44N8O4; molecular weight: 532.7. Ca1
culated:‘58.62% C;,8.33.% 'H. Found,:.58~.9.0%. C;;8.70.%
peridine.
(:1) 2,6 - dichloro - 4,8 - bis - (2’,6’ - dimethyl - piper
idyl)~pyrimido-pyrimidine, melting point 160-162° C.,
from 2,4,6,8-tetrachloro-pyrimido-pyrimidine and 2,6-di
methyl-piperidine.
Following; a’ procedure, analogous to ‘that. described
under (a) above, the ‘following additional 2,4,6,8,-tetra
(e) 2,6 - dichloro - 4,8 - bis - (2',6’ - dimethyl - mor
pholyl)-pyrimido-pyrimidine, melting point 197-199° C.,
aminoqpyrimido-pyrimidines were prepared from the start
from 2,4,6,8-tetrachloro-p'yrimido-pyrimidine and‘ 2,6-di-,
ing materials indicated in each- case.
20
methyl-morpholine.
'
(b) 2 - (ethanolI - isopropanol-- amino) - 6‘ - dietha
nolarnino- 4,8- dipiperidyl‘ - pyrimido - pyrimidine, melt
(f) 2,6 '- dichloro - 4,8- di - (3' - hydroxy- piperidyl)
pyrimido-pyrimidine, melting point 208—210° C., from
2,4,6,S-tetrachloro-pyrimido-pyrimidine and 3~hydiroxy~
ing point 1'46-148° C., from 2,6-dichloroe4,8¥dipiperidyl
pyrimido-pyrimidine, ethanol-isopropanol-amine and di
piperidine.
ethanolamine.
(c)' 2- - (N' - methyl - piperazyl)» 6 - diethanolamino~
(g) 2,6 - dichloro - 4,8 - di - (.1',2",5’,6' - tetrahydro
4,8~dipiperidyl-pyrimido-pyrimidine, melting point 146
pyridyl)-pyrimido-pyrimidine, melting point 209-2‘11° C.
(decomposition), from 2,4,6,S-tetrachlormpyrimido-py
148° C., from 2,6-dichloro-4,8-dipiperidyl-pyrimido-py
rimidine, diethanolamine and‘ N—methyl-piperazine.
rimidine and 1,2,5,6-tetrahydro-pyridine.
(d) 2 - dimethylamino - 6 - diethanolamino - 4,8‘- - di
(11) 2,6 - dichloro - 4,8 - di-(2’amethyl-morpholyl)
piperidyl-pyrimido-pyrimidine, meltingpoint~135£~137° C.,
pyrimido-pyrimidine, melting point 182-184" C., from
2,4,6,8-tetrachloro-pyrimido-pyrimidine and Z-methyl
morpholine.
from 21,6-dichloro-4,8-dipiperidyl-pyrimido-pyrimidine, di
ethanolamine and dimethylamine;
'
I,
(e) 2- morpholyl - 6 - diethanolamino- 4,8 - dipiper
(i) 2,6 - dichloro - 4,8 - bis - (1’,2',3’,4'-tetrahydro
quinolyl)-pyrimido-pyrimidine, melting point 244-246° ‘
idyl-pyrimido-pyrimidine; melting point 128-1'30° C.,
C., from 2,4,6,8-tetrachloro-pyrimido-pyrimidine'and 1,2,
from 2,6-dichloro-4,8-dipiperidyl-pyrimidmpyrimidihe, di
3,4-tetrahydroquinoline.
ethanolamine and morpholine.
isoquinolyl)-pyrimido~pyrimidine, melting point 195-197°
C., from 2,4,6,8~tetrachloro-pyrimido-pyrimidine and 1,2,
3,4-tetrahydro-isoquinoline.
-
pyrimidine, melting point 145-147? C., from 2-chloro
4,6,8-tripiperidyl-pyrimido-pyrimidine (melting point 143
4.0 145° C.) and diethanolamine.
(g) 2,6 - bis - (diethanolarnino)v - 4,8 - dipiperidyl
(l) 2,6 - dichloro - 4,8 - di - (methyl - glucarnino)
pyrimido-pyrimidine, melting point 175-177° C., from
2,4,6,8-tetrachloro-pyrimiddpyrimidine and methyl-gluc
amine.
(m) 2,6 - dichloro - 4,8 - di - (4’ - sulfarnino - aniline)
pyrimido-pyrimidine, melting point 164-166° C., from
2,6-dichloro-4,8-dipiperidyl-pyrimido-pyrimidine and ' di
ethanolamine. Melting points of various addition salts
45 of the tetraamino-pyrimido-pyrimidine product:
° C.
pyrimido-pyrimidine, which has no sharply de?ned melt
ing point up to 350°C, from 2,4,6,8~tetrachloro-pyrimido
pyrimidine and 4-sulfamino-aniline.
Hydrochloride
_________________________ __ ‘196-198
I-Iydrobromide
_________________________ __ 187-189
Sulfate ________________________________ __
(n) 2,6 - dichloro - 4,8 - di - (hexamethylene - imino)
pyrimido-pyrimidine, melting point 170-172° C., from
2,4,6,8-tetrachloro-pyrimido~pyrimidine and hexamethyl—
ene-imine.
'
(f) 2 - diethanolamino - 4,6,8 - tripiperidyl - pyrimido
(k) 2,6 - dichloro - 4,8 - Ibis - (1',2',3',4' - tetrahydro
EXAMPLE 28
168-170
.
Preparation of 2,4,8-Trimorpholyl-6-Phenyl-Pyrimido
Pyrimidine
‘
(0) 2,6 - dichloro - 4,8 - di - (N’ - methyl - piperazyl)
pyrimido-pyrimidine, which decomposes at about 205° C. 55
without sharply de?ned melting point, from 2,4,6,8-tetra
chloro—pyrirnido-pyrimidine and N-methyl-piperazine.
3.1 gm. (‘0.01 mol) ~2,4,8-trichloro-6-phenyl-pyrimido
pyrimidine, melting point 223-225 ° C., obtained by re
?uxing 2,4,8 - trihydroxy - 6 - phenyl - pyrimido - pyrim
idine with phosphorus pentachlon'de in phosphorus oxy
(p) 2,6 - dichloro - 4,8 - di - (5’ — ethyl - 2' - methyl
piperidyl)-pyrimido-pyrimidine, melting point 96-98° C.,
chloride, were heated under re?ux with 12 cc. morpholine
from 2,4,6,8-tetrachloro-pyrimido-pyrimidine ‘and S-ethyl 60 for 75 minutes. The reaction mixture was then taken up
2-methyl-piperidine.
in about 50 cc. water, whereupon thelreaotion product
separated out in the form of a light orange precipitate.
The precipitate was separated by vacuum ?ltration,
washed and dried. The yield was 3.9 gm. (84% of
theory). For analysis, the raw product was recrystal
EXAMPLE 27
Preparation of Various 2,4,6,8;Tetraamino-Pyrimido
Pyrimidines from 2,6-D‘ichl0r0-4,8-Di-Amin0-Pyrim-_
ido-Pyrimidines through 2-Chlore-4,6,8-Triamin0-Py
lized twice from isopropanol, yielding orange microcrys
talline needles having a melting point of'236-237“ C.
Analysis.—C24H30N7O3; molecular. weight: 464.6. Cal
culated: 62.06% C; 6.51% H. Found: 62.45% C; 6.56%
rimido-Pyrimidines by Reaction with the Correspond
ing Amines First at Moderately Elevated Temperatures
and Then at Higher Temperatures, if Desired Under
Pressure
70
(a) Preparation of 2-(diisopropanol-am-ino) -6-(dietha
.
EXAMPLE 29
nol-amino)-4,8-dipiperidyl-pyrimido-pyrimidine: 4.4 gm.
,
Preparation of 2-M0rph0lyl-4,8-Di-(B-Hydroxyethyl
amino) ~6-Phenyl-Pyrimido-Pyrimidine
(0.01 mol) 2-chloro-6-diethanolamino-4,8-dipiperidyl-py
rimido-pyrimidine (melting point 162-164" C., obtained
by heating 2,6-dich1oro-4,8-dipiperidyl-pyrimido-pyrimi
H.
75
3.3 gm. (0.011 mol) 2-chloro-4,8-di-(,B-hydroxyethyl
3,031,450
23
.
.
.
24
.
amino)-6-phenyl—pyrimido-pyrimidine, melting point 198
200° C., obtained by reacting 2,6,8-trichloro-6-phenyl
.
once from a mixture of ethylene chloride and acetone
(1:1). The pure product was a yellow microcrystalline
powder having a melting point of 157-159° C.
Analysis.—C20H35O?N7S; molecular Weight: 501.6.
Calculated: 47.89% C; 7.03% H. Found: 47.95% C'
pyrimido-pyrimidine with ?-hydroxyethyl-amine in dioxan
at room temperature, were re?uxed with 15 cc. mor
pholine for one hour. The reaction mixture was then
taken up in about 100 cc. water, whereupon the reaction
7
7.15 % H.
(0) Preparation of 2,4,6-trimorpholyl-S-ethylthio-py
product rapidly separated out in the form of a light yellow
precipitate. The yield was 3.6 gm. (87% of theory).
Recrystallized ‘from ethanol, the product was obtained in
the form of a light ‘yellow powder composed of micro
10 2,4,6 — trimorpholyl-S-ethylthio-pyrimido-pyri1nidine were
crystalline needles having a melting point of 244-245 ° C.
EXAMPLE 30
obtained from 4.2 gm. (0.01 mol) 2,6-dimorpholyl-4,8
morpholine after repr-ecipitating the reaction product
Preparation of Various 2,4,8-Triamino>Pyrimido-Pyrim
idines from 2-Chlor0-4,8-Diamino-PyrimidoePyrimi
once from dilute hydrochloric acid. For analysis, the
raw product was recrystallized once from aqueous di
rimido-pyrimidine: Following a procedure analogous to
that described under (a) above, 2.6 gm. (56% of theory)
di-(ethylthio)-pyrimido-pyrimidine and about 40 cc.
dines 0r 2,4,8-Trichloro-Pyrimido-Pyrimidines‘ by Re
methyl-formamide, yielding microcrystalline, light yellow
?uxing with ,the Corresponding Amines
(a) Preparation of 2,4,8etrimorpholyl-pyrimido-pyrim
needles having a melting point of 212-214“ C.
idine: 10.1 gm. (0.03 mol) 2-chloro-4,8-dimorpholyl
6.35% H.
pyrimido-pyrimidine were re?uxed for one hour with 40
(d) Preparation of 2,6-bis-(diethanolamino)~4-mor
cc. morpholine. A clear, reddish-brown solution formed
very rapidly. It was allowed to cool, whereby morpholine
pholyl-8-ethylthio-pyrimido-pyrimidine:
The mixture was taken
up in about 200 cc. water, whereby the morpholine hy
drochloride redissolved while 2,4,8-trimorpholyl-pyrim
ido-pyrimidine precipitated out in the ‘form of ‘a yellow,
pasty mass which soon solidi?ed after standing.
Using a pro
cedure analogous to that described under (a) above,
hydrochloride, a side product of the reaction, separated
out as a crystalline precipitate.
’
Analysis.-C2oH29NqO3S; molecular Weight: 447.6.
Calculated: 53.67% C; 6.53% H. Found: 53.15% C;
2,6 - bis - (diethanolamino) - 4 - morpholyl - 8 ~ ethyl
25
thiopyrimido-pyrimidine was prepared from 2,6-bis-(di
ethanolamino)-4,8-di-(ethylthio) -pyrimido - pyrimidine
and morpholine. The puri?ed product had a melting
point of 166-168“ C.
The
(e) 2,6 - (diethanol - amino) - 4 - pyrolidyl - 8 - ethyl
solidi?ed precipitate was separated by vacuum ?ltration, 30 .thioapyrimido-pyrim‘idine, melting point 175-177“ C.,
washed and dried.
The yield was 11.3 gm. (97% of
theory). Recrystallized from a mixture of methanol and
ethanol (5:3), the product was obtained in the form of a
from 2,6-bis-(diethanol-amino)-4,8-di - (ethylthio) - py
rimido-pyrimidine and pyrrolidine.
yellowish amorphous powder having a melting point of
EXAMPLE 32
186-189° C.
35
Preparation of Various 2,4,6,8-Tetraamin0
The same results were obtained when 7.1 gm. (0.03
Pyrimido-Pyrimidines
mol) of 2,4,8-trichloro-pyrirnido-pyrimidine were sub
stituted‘ for the 2-chloro-4,8-dimorpholyl-pyrimido-pyrim
(a) Preparation of 2,6-bis—(diet-hanolamino)-4,8-di
idine in the above process.
piperidyl-pyrimido-pyrimidine: 4.8 gm. (0.01 mol) 2,6
40 bis - (diethanolamino) - 4 - piperidyl - 8 - ethylthio
EXAMPLE 31
pyrimido-pyrimidine were heated with 150 cc. piperidine
Preparation of Various 2,4,6-Trz'amino-8-Thi0
in a sealed tube for about four hours at 200° C. The
'
clear yellow solution obtained thereby was extensively
Pyrimido-Pyrimidines
concentrated by evaporation in vacuo, and the concen
(a) Preparation of 2,6-bis-(diethanolamino)~4-piper
trate was taken up in about 150 cc. water.
idyl-8-ethylthio-pyrimido-pyrimidine: 4.6 gm. (0.01 mol)
pre
cipitated out in the form of a brownish-yellow mass _
which gradually solidi?ed. The yield was 3.4 gm. (67%
of theory). Recrystallized from ethylene chloride, the
pure product was obtained in the form of yellow prisms
about 300 cc. water, the reaction product separated out
‘as a pasty, yellowish-brown precipitate.
2,6-bis-(di
ethanolamino)-4,8-dipiperidylpyrimido-pyrimidine
2,6-bis-.(diethanolamino)-4,8-di~ (ethylthio) - pyrimido
pyrimidine were heated for about three hours at ‘180°
C. in a closed tube with 40 cc. piperidine. After rinsing
the reaction mixture thus obtained out of the tube with
having a melting point of 163-165 ° C.
The same result was obtained when 4.6 gm. (0.01
It was immedi
ately reprecipitated once from dilute'hydrochloric acid
with the aid of ammonia. The yield was 3.0 gm. (63%
mol) 2,6 - bis - (diethanolamino) _ 4,8 - di - ethylthio)
pyrimido-pyrimidine were used in place of the indicated
of theory). For analysis, the raw product was repre
cipitated once from 10% acetic, acid with the aid of a 55 amount of 2,6-bis-(diethanolamino)~4-piperidyl-8-ethyl
thio-pyrimido-pyrimidine.
10% aqueous solution of sodium acetate and then re
The hydrochloride, hydrobromide and sulfate addition
salts of the reaction product were prepared by reacting
the free base with the corresponding acid. Their melt
crystallized twice from ethylene chloride. The pure
product was obtained in the form of microcrystalline
needles having a melting point of 143—144° C.
Analysis.——C21H35O4N7S; molecular weight: 481.6.
Calculated: 52.37% C; 7.32% H. Found: 52.15% C;
ing points were as follows:
Preparation of 2,4,6-tris-(diethanolamino)-8
7
°C.
Hydrochloride
7.15% H.
(b)
60
_ Hydrobromide
_________________________ __ 196-198
_________________________ __
Sulfate
bis - (diethanolamino) - 4,8 - di - (ethylthio) - pyrimido
Using a procedure analogous to that described under
(a) above, ‘and re?uxing the reaction mixture, if neces
sary, the following tetraamino-pyrimido-pyrimidines were
produced from the starting materials indicated in each
pyrimidine were heated with 15.7 gm. (0.15 mol) di
ethanolamine for about 1% hours at 180° C. The melt
obtained thereby was taken up in 150 cc. water.
After
__
184-189
ethylthio-pyrimido-pyrimidine: 4.6 gm. (0.01 mol) 2,6
168-170
neutralizing the solution with glacial acetic acid and al
case.
lowing it to stand for several hours, the reaction product 70
(b) 2,4,6. - tris - (diethanolamino) - 8 - piperidyl
precipitated out in the form of a ?ne yellow precipitate.
pyrimido-pyrimidine, melting point 174—175° C., from
It was separated by vacuum ?ltration, washed and dried.
2,4,6- - tris- (diethanolamino) - 8 - ethylthio - pyrimido
The yield was 3.0 gm. (60% of theory). For puri?ca
pyrimidine and piperidine.
tion, the raw product was extracted once with a small
(c)
2,6 - bis - (diethanolamino) - 4,8 _ di - ([3 - hy
amount of boiling ethylene chloride and recrystallized 75 droxyethyl-amino)-pyrimido-pyrimidine, melting point
3,031,450
25
238-2410
C.,
from
ing solution wa-s allowed to stand for several hours. The
reaction product separated out as ‘a brownish crystalline
(ethylthio)pyrimido-pyrimidine and ?-hydroxyethyl
amine.
(d)
precipitate. The yield was 1.4 gm. (56% of theory).
Recrystallize'cli from methanol, the pure product was ob
2,6 - bis - (diethanolamino) - 4,8 - ‘di - (hexa
methylene imino)-pyrimido-pyrimidine, melting point
170—172°
C.,
from
tained in the form of colorless, brilliant crystals having
a melting point of 203-205° C.
2,6-bis-(diethanolamino)-4,8-di
(ethylthio)-pyrimido-pyrimidine
26
was then taken up‘ in’ about 60 cc. water and the result
2,6-bis-(diethanolamino)-4,8;di
and. hexamethylene
The same result was obtained when 3.5 gm. (0.01
imine.
mol) 4,8-di-(benzylthio-pyrimido-pyrimidine was used in
piperidyl)-pyrimido~pyrimidine, melting point 188-190° 10 place of the indicated amount of 4,8-dithio-pyrimido
pyrimidine. The yield was 1.5 gm. (60% of theory) of
C., from 2,6-bis-(diethanolamino)-4,8-di-(ethylthio)
raw 4,8-di-(13-hydroxyethylamino)pyrimido-pyrimidine.
pyrimido-pyrimidine and 3-methyl-piperidine.
Using a procedure analogous to that described under
(1‘) 2,6 - bis - (diethanolamino) - 4,8- di - (2' - methyl
(e) 2,6 - bis - (diethanolamino) - 4,8 - di ~ (3' - methyl
piperid'yl)-pyrimido-pyrimidine, melting point 208—209°
C., from 2,6-bis-(diethanolamino)-4,8-di-(ethylthio)
pyrimido-pyrimidine and Z-methyl-pipe-ridine.
(a) above, the following additional 4,8-diaminoépyrim
15 ido-pyrimidine were produced from 4,8-di-(ethylthio)
pyrimido-pyrimidine and the amine indicated in each case.
(b) 4,8-dianilino-pyrimido~pyrimidine, melting point
(g) 2,6 - bis - (diethanolamino) - 4,8 - di - (4’ - methyl
255-256“ C. with aniline.
piperidyl)-pyrimido-pyri1nidine, melting point 174-175 °
C., from 2,6-bis-(diethan0lamino)-4,8-di-(ethylthio)
pyrimido-pyrimidine and 4-methyl-piperidine.
pyrimidine, melting point 265-267° C., with N-hydroxy
20
(h) 2,4,6,8 - tetramorpholyl - pyrimido - pyrimidine,
ethyl-p-nitro-aniline.
melting point 266-268° C., from 2,6-dimonpholyl—'4,8
di-(ethylthio)-pyrimido—pyrimidine and morpholine.
~
'
(d) 4,8 - di - (benzyl - ethanol - amino) - pyrimido -
pyrimidine, melting point 126-128° C., with benzyl
ethanol-amine.
(i) 2,6 - di-(N’ - methyl - piperazyl) - 4,8 - dipiperidyl
pyrimido-pyrimidine, melting point 130-132” C., from 25
.
(e) 4,8 - di - (ethylamino) - pyrimido - pyrimidine,
melting point 144-146" C., with ethylamine.
2,6 - di - (N’ - methyl - piperazyl) - 4,8 - di - (ethyl
thio) -pyrimido-pyrimidine and piperidine.
EXAMPLE 34
(k) 2,6 - bis - (diethanolamino) - 4,8 - bis - (1'2’,5’,
Preparation of 2,4,6,-8-Tezra-(p-Hydroxyethyl-Amino)
6'-tetrahydropyridyl)-pyrimido-pyrimidine, melting- point
Pyrimiido-Pyrimidipne from Various Other Substituted
Pyrimido-Pyrimidines and ,B-Hy‘droxyethyl-Amine
ISO-152° C., from 2,6-bis-(diethanolamino)-4,8-di 30
(ethylthio)-pyrimido-pyrimidine and 1,2,5,6-tetrahydro
pyridine.
(a) From 2,6 - di - (ethylthio)-4,8-di-(B-hydroxyethyl
amino)-pyrimido-pyrimidine: 4.2 gm. (0.01 mol) 2,6-di
(l) 2,6 - bis - (diethanolamino) - 4,8 - di - (3' -.hy
droxy-piperidyl) - pyrimido - pyrimidine‘,
melting point
202-204° C., from 2,6 - bis - (diethanolamino) - 4,8-di
(ethyltlhio)pyrimido-pyrimidine and §-hydrobdy-piperi
dine.
(in) 2,6 - bis - (diisopropanolamino) - 4,8 - dimor
pholyl-pyrimido-pyrimidine, melting point 2l6-218° C.,
from
~
(c) 4,8-di-(N-hydroxyethyl-p-nitro anilino)-pyrimido
2,6 - bis - (diisopropanolamino)-4,8-di-(ethylthio)
pyrimido-pyrimidine and morpholine.
(ethylthio) - 4,8 - di. - (ti - hydroxyethyl - amino) - py
rimido-pyrimidine were heated with 50 cc. ,B-hydroxy
ethyl-amine for about 15 hours at 220° C. in a sealed
The dark solution obtained thereby was then evap
- tube.
orated. almost to dryness in vacuo. The residue was ad
mixed with about 50 cc. water and the resulting mixture
40 was allowed to stand for an extended period of time.
The raw reaction product separated out in the form of
dipiperidyl-pyrimido-pyrimidine, melting point 172-174“
C., from 2-diisopropanolamino-6-diethanolamino-4,8-di
(ethylthio)-pyrimido-pyrimidine and piperidine.
a brownish crystalline precipitate, which was separated
'by a vacuum ?ltration, washed and dried. The yield
was 1.6 gm. (43% of theory). Recrystallized from wa
ter the pure product was obtained in the form of faintly
(0) 2,6 - di - [ethanol - butanol - (2’) - amino] -4,8 —
brownish prisms having a melting point of 180-182“ C.
(n) 2 - diisopropanolamino - 6 - diethanolamino - 4,8 -
dimorpholyl - pyrimido - pyrimidine, melting point 173
2,4,8 - tri - (B - hydroxyethyl - amino) - 6 - (ethylthio) -
175° C., from 2,6-di-[ethanol-butanol-(Z')~amino]-4,8
pyrimido-pyrimidine was identi?ed as an intermediate
product of this reaction.
-
di-(ethylthio)-pyrimido-pyrimidine and morpholine.
(p) 2 - ethanol - isopropanol - amino) - 6 - diethanol
amino-4,8-dipiperidyl-pyrimido-pyrimidine, melting point
The same result was obtained when 3.7 gm. (0.01 mol)
50
2,4,6,8 - tetra - (ethylthio) - pyrimido - pyrimidine were
146-148° C., from 2-(ethanol-isopropanol-amino)-6-di
substituted in the above procedure for the indicated
ethanolamino - 4,8 - di - (ethylthio) - pyrimido - pyrim
amount of 2,6 - di - (ethylthio) - 4,8-di-(?-hydroxyethyl
amino)-pyrimido-pyrimidine, and the reaction mixture
idine and piperidine.
(q) 2,6 - bis - (diethanolamino) - 4,8 - bis - (2’, 6' -
dimethyl-morpholyl)-pyrimido-pyrimidine, melting point
The yield of raw 2,4,
6,S-tetra-(B-hydroxyethyl)-pyrimido-pyrimidine was 1.1
‘ was re?uxed ‘for about 32 hours.
gm. (29% of theory). 2,4,8-tri-([5’-hydroxyethyl
181-183° C., from 2,6 l-bis - (diethanolamino) - 4,8 - .di
(ethylthio)-pyrimido-pyrimidine and 2,6-dimethyl-mor
‘ pholine.
(r) 2,6 - dipiperidyl - 4,8 - bis - (diethanolarnino) -
pyrimido-pyrimidine, melting point 182-184° C., from 2,
amino)-6-(ethylthio)-pyrimido-pyrirnidine was identi?ed
as a side product of this reaction.
60
(b) From 2,6-di-(,B-hydroxyethyl-amino)-4,8-di-phen
ylthio)-pyrimido-pyrimidine: 4.8 gm. (0.011 mol) 2,6-di
6 - di - (ethylthio) - 4,8 - bis - (diethanolamino) - py
(,B - hydroxyethyl - amino) - 4,8 - di - (phenylthio)
rimido-pyrimidine and piperidine.
pyrimido-pyrimidine were re?uxed with 20‘ cc. ?-hydroxy
ethyl-amine for about one hour. The resulting solution
(s) 2,6 - dipyrrolidyl - 4,8 - bis - (diethanolamino) -
pyrimido-pyrimidine, melting point 178—l8l° C., from
65 was poured into about 40 cc water and the aqueous mix
2,6 - di - (ethylthio) - 4,8 - bis - (diethanolamino) - py
ture was allowed to stand for several hours.
rimido-pyrimidine and pyrrolidine.
tetra - (,B-hydroxyethyl-amino)pyrimido-pyrimidine sep
EXAMPLE 33
Preparation of Various 4,8-Diamin0-Pyrimido
Pyrimidines
(a) ‘Preparation of 4,8 - di - (B-hydroxyethyl-amino)
pyrimido-pyrimidine: 2.0 gm. (0.01 mol) 4,8-dithio-py
-
2,4,6,8
arated out in the form of a crystalline precipitate, which
was separated by vacuum ?ltration, washed and dried.
70 The yield was 2.8 gm. (76% of theory).
hydroxyethyl - amino)
- 8
2,4,6-tri-(?
- phenylthio - pyrimido -
pyrimidine, melting point about 138° C., was isolated
as an intermediate product of this reaction.
The same result was obtained when 4.4 gm. (0.01
rimido-pyrimidine were re?uxed with 20 cc. B-hydroxy
ethyl-amine for about one hour. The reaction mixture 75 mol) 2,6 - di--(?-hydroxyethyl-amino )'-4,‘8-di- (phenoxy) -
3,031,450
28
27
pyrimido-pyrimidine were substituted {or the indicated
amount of 2,6-di- (?-hydroxyethyl-amino)-4,8~di-(phenyl
were substituted for the indicated amount of 2,6-dianilino
thio)-pyrimido-pyrimidine in the above procedure. The
yield of raw product was 3.1 gm. (84% of theory).
4,8-di-(ethoxy)-pyrimido-pyrimidine in the above pro
‘cedure:
The yields of raw product were from 4.6 to 4.8 gm.
(c) From
2,6 - dianilino - 4,8 - di - (benzyloxy) -pyrirnido-pyrimidine
2,4,6,8 - tetrapyridyl - pyrimido-pyrimidine
chloride: 5.9 gm. (0.01 mol) 2,4,6,8-tetrapyridyl-pyrirn
(92-96% of theory).
- ‘
Using a procedure analogous to that described under
ido-pyrimidine-chloride were re?uxed with 30 cc. [St-hy
(a) above, and under pressure, if necessary, the follow
droxyethylamine for about one hour. The solution thus
ing tetraamino-pyrimido-pyrimidines were prepared from
obtained was poured into about 60 cc. water and the
'
aqueous mixture was allowed to stand for several hours. 10 the starting materials indicated in each case.
(b) 2,4,6,8 - tetra-(methylamino)pyrimido-pyrimidine,
2,4,6,8 - tetra - (B - hydroxyethyl - amino) - pyrimido melting point 227—228° C., from 2,6-di-(methylamino)
pyrimidine separated out as a crystalline precipitate.
4,8-dithio-pyrimido-pyrimidine ‘and methylamine.
The yield was 1.2 gm. (33% of theory).
The same result was obtained when 0.01 mol 2,4,6,8
(c) 2,4,6,8-tetra - (allylamino) - pyrimido - pyrimidine,
tetra-(triethylammonium)-pyrimido-pyrimidine chloride
melting point 201—202° C., from 2,6-di-(allylamino)-4,8
dithio-pyrimido-pyrimidine and allylamine.
was substituted for the indicated amount of 2,4,6,8-tetra
pyridyl-pyrimido-pyrimidine chloride in the above pro
cedure.
(d) - 2,4,6,8-tetra—(benzylamino) -pyrimido - pyrimidine,
melting point 176-178° C., from 2,6-di-(benzylamino)
4,8-di-(ethylthio)-pyrimido-pyrimidine and benzylamine.
The yield of raw product was 1.3 gm. (35% of
theory).
The tetra-substituted pyrimido-pyrimidine compounds
20
(e) 2,4,6,8-tetra-(methyl-ethanol-arnino)-pyrimido-py
rimidine, melting point 155-156° C., from 2,6-di-(methyl
ethanol-amino)-4,8-dimorpholyl-pyrimido-pyrimidine and
used as starting materials in the above procedures were
obtained as follows:
A solution of 5.4 gm. (0.02 mol) 2,4,6,8-tetrachloropy
methyl-ethanol-amine.
‘
rimido-pyrimidine in 100-150 cc. dry dioxane was heated
(f) 2,4,6,8-tetra - (diethanolamine) - pyrirnido - pyrimi
to about 60° C. 16 cc. pyridine were then added drop 25 dine, melting point 213—214° C., from 2,6-bis-(diethanol
wise to this solution over a period of 15 minutes. The
amino),4,8-dipiperidyl~pyrimido-pyrirnidine and di-ethan
reaction product separated out rapidly as a green precipi
tate which was initially oily but solidi?ed after standing
olamine.
EXAMPLE 36
for some time. The dioxane was separated by decanta
tion or by vacuum ?ltration and the residue or ?lter cake, 30
respectively, was triturated with acetone, separated by
Preparation of Various 2,4,8-Triamin0-Pyrimido
Pyrimidines
(a) Preparation of 2,4,8-trimorpholyl-pyrimido-pyrimi
vacuum ?ltration, washed with acetone and dried in vacuo
dine: 4.0 gm. (0.01 mol) 2-morpholyl-4,8-di-(carboxy
at room temperature. The 2,4,6,8-tetrapyridyl-pyrimido
methylthio)-pyrimido-pyrimidine were heated with 70 cc.
pyrimidine chloride thus obtained was a greenish powder
which was readily soluble in water and produced a red 35 (0.8 mol) morpholine for about three hours at 200° C. in
a sealed tube. The solution obtained thereby was exten
solution with aqueous alkalies, which is typical of pyridyl
sively evaporated. The residue was taken up in about
200 cc. Water, whereby 2,4,8-trimorpholyl-pyrimido-py
rimidine separated out in the form of a faintly yellow
salts. The corresponding tetra-(ethylammonium) com
pound was prepared in similar fashion, except that the re—
action mixture was heated slightly.
It was obtained as
a light brown powder having a melting point of 245
40 ish-brown, amorphous precipitate. The yield was 2.1 gm.
247° C.
(71% of theory). Recrystallized from ethanol, the pure
(d) From 2,6-di-(?-hydroxyethyl-amino)-4,8-diamino
pyrimido-pyrimidine: 0.01 mol 2,6-di-(13-hydroxyethyl
amino)-4,8~diaminopyrimido-pyrimidine: 0.01 mol 2,6-di
product was obtained as a colorless powder having a
(B-hydroxyethyl-amino) ~4,8-diamino-pyrimidopyrimidine
45 (a) above, and re?uxing the reaction mixture if necessary,
were re?uxed with 20 cc. ,B-hydroxyethylamine for about
one hour. The resulting solution was then poured into 50
the following triamino-substituted pyrimido-pyrimidines
cc. water and the ‘aqueous mixture was allowed to stand
each case:
melting point of 182-184" C.
Using a procedure analogous to that described under
were prepared from the starting materials indicated in
.
(b) 2,4,8-trianilino-pyrimido-pyrimidine, melting point
for several hours. 2,4,6,8-tetra-(,B-hydroxyethyl-amino)
pyrimido-pyrimidine separted out as a slightly discolored 50
203-204" C., from 2-anilino - 4,8 - di - (carboxy - methyl
crystalline precipitate.
thio)-pyrimido-pyrimidine and aniline.
(c) 2,4,8-tri-(o-methoxy-anilino)-pyrimido-pyrimidine,
The same result was obtained when 0.01 mol 2,6-di-(?
hydroxyethyl-amino) -4,8-bis- (diethanol-amino) -pyrimido
melting point 214-215° C., from 2-(o-methoxy-anilino)
pyrimidine or 0.01 mol 2,6-di-(?-hydroxyethyl-amino)
4,8-di-morpholyl-pyrimido-pyrimidine was substituted for
4,8-di-(ethylthio) - pyrimido - pyrimidine and o-methoxy
aniline.
(d) 2,4,8-tri-(benzylamino)-pyrimido-pyrimidine, melt
the 2,6-di-(,B-hydroxyethyl-amino)-4,8-diamino-pyrimido
ing point 128-130° C., from 2-benzylamino-4,8-di-(eth
pyrimidine in the above procedure.
ylthio)-pyrimido-pyrimidine and benzylamine.
(e) 2,4,8-tri- (ii-hydroxyethyl-amino) -pyrimido-pyrimi
The yields of raw product were, on the average 2.7
gm. (73% of theory).
EXAMPLE 35
Preparation of Various 2,4,6,8-Tetraamino-Pyrimido
Pyrimidines
(a) Preparation of 2,4,6,8-tetraanilino-pyrimido-pyrimi
dine: 4.0 gm. (0.01 mol) 2,6-dianilino-4,8-di-(ethoxy)
pyrimido-pyrimidine were re?uxed with 25 cc. aniline for
about one hour. The dark brown solution obtained there
by was poured into about 500 cc. 0.5 N hydrochloric acid,
60 dine, melting point 113-115 ° C., from Z-(B-hydroxy-ethyl
amino) - 4,8 - di - (phenylthio) - pyrimido-pyrimidine and
B-hydroxyethyl-amine.
EXAMPLE 37
65
Preparation of 2,4,8-Tri-(Methyl-Ethanol-Amino)~6
Ethylthio-Pyrimido-Pyrimidine
3.7 gm. (0.01 mol) 2,4,6,8-tetra-(ethyl-thio)-pyrimido
pyrimidine were re?uxed with 50 cc. methyl-ethanol
amine for 4 hours. The resulting solution, while it was
whereby the raw tetraanilino-pyrimido-pyrimidine sepa 70 still warm, was taken up in about 500 cc. water, whereby
the reaction product separated out in the form of a light
yellow precipitate which was initially somewhat pasty
but then crystallized rapidly. The precipitate was sepa
rated out in the form of a brownish amorphous precipi
tate. After repeated recrystallization from dioxane the
pure product was obtained in the form of bright yellow
needles having a melting point of 300-302" C.
The same result was obtained when 3.5 gm. (0.01 mol)
rated by vacuum ?ltration, washed and dried in vacuo at
room temperature. The yield of raw product was 3.7 gm.
29
30
(91% of theory). Recrystallized, from methanol, the
' ('a) 2,6 - di - (ethylthio)#4,8ldipyrolidyl-pyrimido-py
-
rimidine, melting point 184-186" C., ‘from 2,4,6,8-tetra
(ethylthio)~pyrimidmpyrimidine and pyrollidine.
pure product was obtained in the form of ivory-colored,
microcrystalline' prisms having a melting" point of
95-97“
C;
,
(b) 2,6 - ‘di - (ph'enylthio)-4,8-di-(N'-methyl-pipera
‘
zyl)-pyrimido-pyrimidine, melting point 204-206" C.,
from 2,4,6,8-tetra-phenylthio=)hpyrimido-pyrimidine and
Analysis.—C17H29N7O3S; molecular weight‘: I 411.5.
Calculated: 49.62% C; 7.10% H. Found: 49.10% C;
N-rnethyl-piperazine.
7.02% H.
-
_
(0) 2,6 - di - (benzylthio) - 4,8-di-(N'-methyl-pipera
EXAMPLE 38v
Preparation of Various 2,4,8-Triaiiiino-6-Phenyl
Pyrirhidol-Pyrimidines
(a) Preparation of 2,4,8-trirnorpholyl-6-phenylepyrimi
zyl)-pyrimido-pyriniidine, melting" point 155-156” C.,
10
from 2,4,6,8-tetra-(benzylthio)pyrimido-pyrimidine' and
N-methyl-piperazine.
(d) 2,6 - dithio - 4,8-dipipei‘idino-pyrimido;pyrimidine,
do-pyrimidine: 3.9 gm. (0.01 mol)_ 2-rnorph'olyl-4,8-di
melting point 175-180" C. (decomposition) vfrom"2,4,6-,8
tetrathio-pylimid0~pyrimidine and piperidine.
(ethylthio) - 6 - phenyl - pyriniido-pyrimidine were heated
with 80 cc. morpholine‘for three'lio'urs at‘abo'ut' 200° C. 15
(e) 2,6‘- 'di‘ - (phenylthio) - 4,8-di(methyl'-et'hano>l
in a sealed tube. The solution obtained thereby was'ex
amino)-pyrimido-pyrimidine, melting'point 147-148° C.,
tensively concentrated by evaporation. Theresidue was
from 2,4,6,8-tetra- (phenylthio) -pyrimido=pyrimidine' and
taken up in about 100' cc. WaterQWhereby- the" reaction
product separated out as an orange-coloredprecipitate.
methyl-ethanol-amine.
(f) 2,6 - di - (benzylthio)- - 4,8-di-(methyl-ethanol
It was separated by vacuum filtration‘, washed‘ and dried. 20 amine)-pyrimidoapyrimidine, melting point 115-117° C.
The yield of raw product was 3.2 gm.- (70% of theory).
from 2,4,6,'8-t'etra'-('benzylthio)epyrimido-pyrimidine and
For analysis, the raw‘ product’ was recrystallized twice
methyl-ethanol-amine.
1
_
from'isopropan'ol, yielding orange'microcrystalline needles
(g) 2,6 - di - (phenylthio) - 4,S-dihydrazino-pyrimido
having a melting point of 236-237° C.
Analysis.—C24H30NqO3; molecular weight: 464.6. _ Cal
culated: 62.06% C; 6.51% H.
6.63%
H.
V
25
pyrimidine, melting point, 150-152“ C., ‘from 2,4,6,8
tetra- (phenyl-thio) ~pyrimido-pyrimidine and hydrazine.
Found: 62.40% C;
p
EXAMPLE 41
_
(b) Preparation" of 2 - morpholy1#4,8-di-(B-hydroxy~
ethyl -amino) -6-phenyl~pyrimido#pyrimidine:
3.9‘ gm.
(0.01 mol) 2-morpholy'l-4',8-‘di-('ethylthio)-6iphenyl-py
_
Preparation of Various 7 2,4;6-Triizmin0-8-ThiolPyriinido
Pyrimidines
30
rimido-pyrimidine were re?uxed‘ with 20 cc. ?-hydroxy
Thev following.- compounds were prepared‘ using‘ a pro
ethyl-amine :for about one hour. The' mixture thus ob
cedure analogous of that described in vExample 31' but
tained was taken up in about‘ 100cc. water, whereupon
without using pressure,-Vfr0m thecorresponding 2,6-bis
the reaction product‘ separated out in the form of a light
(diethanolamino)'-4,8-dithio-pyrimido-pyrimidines> by re
yellow precipitate. The yield was 3.1 gm. (75% of theo 35 ?uxing with the corresponding amines.
ry). Recrystalized from ethanol, the pure product was
(a) 2,6 - ‘bis - (diethanolamino) - 4 - morpholyl-8é
obtained in the form of a light yellow microcrystalline
benzylthio-pyrimido4pyrimidine, melting point 121-124”
powder (small needles‘) having a melting point‘ of.224
C., from 2,6-bis-(diethanolamino)-4,8-di-(benzylthio)-py
246° C.
rimidoapyrimidine and morpholine.
EXAMPLE‘ 39
40
Preparation of Various 2,6-Di-(Eihylihi0)4,8-Diumino
PyrimidohPyrimidine's
'
(11) 2,6 - bis - (diethanolamino) - 4 - (.l’,2',5',6'
t‘etrahydro - pyridyl) - 8 - ethylthio-pyrimido-pyrimidine,
melting point ISO-152° C., from 2,6-bis-(diethanol
amino)-4,8rdi-(ethylthio)-pyrimido-pyrimidine and 1,2,5,
'
(a) Preparation of 2,6 - di - (ethylthio)-4,8-di-(N’
G-tetrahydro-pyridine.
methyll- piperazyl)~pyrimido-pyrimidine: -3.7 gm. (0.01
( c) 2,6~bis ( diethanolamino) -4- ( 3 '-n1ethyl-piperidyl ) -8
45
mol) 2,4,6,8-tetra—(ethyl-thio)-pyrimido-pyrimidine were
‘ethylthio - pyrimido - pyrimidine-hydrochloride, melting
re?uxed with 15 cc. N-m-ethyl-piperazine for 5 hours.
point 124-126° C., from 2,6-bis-(diethanolamino)-4,8-di
The reaction mixture thus obtained was taken up in 150
(ethylthio)-pyrimido-pyrimidine and 3-methyl-piperidine.
cc. water and the aqueous mixture was allowed to stand
(d) 2,6 - bis(diethanolamino) -.4 - (3>'-hydroxy-piper—
for several hours. The substituted pyrimido-pyrimidine
idyl) - 8 - ethylthio-pyrimido-pyrimidine, melting point
reaction product separated out as an orange crystalline‘ 50
l70-173° C., from 2,6 - bis - (diethanolamino)-4,8-di
precipitate, which was isolated by vacuum ?ltration,
, washed and dried.
(ethylthio)-pyrimido-pyrimidine and 3-hydroxy-piperi
For puri?cation, the raw product was
dine.
recrystallized once from a mixture of methanol and water
.
'
(e) 2,6 - bis - (diethanolamino) -, 4 - pyrrolidyl-S
(3:1), yielding 2.6 gm. (58% of theory) of the analyti
athylthio-pyrimido~pyrimidine,
melting point 175-177°
55
cally pure substance consisting of very small lightiorange ' C., from; 2,6-bis-(diethanolamino)-4,8-di-(ethylthio)-py
prisms having a melting point of 119-121 ‘’ C.
rimido-pyrimidine andpyrrolidine.
Analysis.-—C20H32N8S2; molecular weight: 448.6. Cal
-
(1‘) 2,6 - bis(diethanolamino') - 4 - piperidyl - 8 - benzyl
cuiated: 53.45% C; 7.20% H; 14.20% S. Found:
thio-pyrimido-pyrimidine,
from 2,6-‘bis-(diethanolamino)
53.54% C; 7.60% H; 14.10% S.
Using a procedure analogous to that described under 60 4,8-di- (benzylthio) ~pyrimido-pyrimidine and piperidine.
(a) above, the following 2,6-di-(ethylthio)-4,8-diamino
EXAMPLE 42
pyrimido-pyrimzidines were prepared from the starting ma
Preparation of Various 2,4,6-Tris-(Diethanolamino)-8
terials indicated in each case:
(b) 2,6 - di - (ethylthio)-4,S-dimorpholyhpyrimido
pyrimidine, melting point 184-185° C., from 2,4,6,8~tetra
Thio-Pyrimido-Pyrimidines
65
(ethylthio) -pyrimido-pyrimidine and morpholine.
(6) 2,6 - di(ethy1thio)-4,8-dipiperidyl-pyrimido-pyrim
(a) 2,4,6 - tris - (diethanol-amino) -8-phenylthio-pyrimr
idine, melting point 132-133° C., from 2,4,6,8-tetra
(ethylthio)-pyrimido~pyrimidine and piperidine.
,
EXAMPLE 40
Preparation of Various ‘2,6-Di-Thio-4,8-Diamino-Pyrim
id0~Pyrirnidines
The following compounds were‘ prepared using a pro
cedure analogous to that described in Example 39.
‘ '
The following compounds were prepared by using a
procedure analogous to that described in Example 31.
ido-pyrimidine, melting point 182-184° C., from 2,6-bis
70
(diethanolamino) - 4,8-di-(phenylthio)-pyrimido-pyrimi
dine or 2,6-dichloro-4,8-di-(phenylthio)-pyrimido~pyrimi
dine and diethanolamine.
(b) 2,4,6 - tris - (diethanolamino)-8-benzylthio-py
rimido-pyrir'nidine, melting point 174-175 ° C., from 2,6
75 bis - (diethanolamino) - 4,8-di-(b'enzy1thio)-pyrimido-py
3,031,450
32
31
rimidine or 2,6-dichloro-4,8-di-(benzylthio) -pyrimido-py
rimidine and diethanolamine.
2,6 - dimorpholyl - 4,8. - bis - (diethanolamino) - pyrimido
[5,4-d1-pyrimidine;
2,6 - bis - (diisopropanolamino) - 4,8-dipiperidyl-pyrimido—
[5,4-d1-pyrimidine;
EXAMPLE 43
Preparation of Various 2,6-Dim0rp'h0lyl-4,~8-Di(Alkoxy)
'
5 2,6 - di-(methyl-ethanol-amino)-4,8-dipiperidyl-pyrimido
[5,4-d]-pyn'midine;
2,6-dimorpholyl-4, 8-di- (methyl-ethanol-amino) -pyrimido
[5,4-d]-pyrimidine;
Pyrimid'oaPyrimidines‘
The following compounds were prepared by using a
procedure analogous to that described in Example 23, but
2,4,6,8 - tetra - (methyl - ethanol - amino) - pyrimido
[5,4-d1-pyrimidiné;
4, 6, S-trimorpholyl-pyrimido- [5,4-d] -pyrimidine;
without pressure.
(a) 2,6 - dimorpholyl - 4,8 - di - '(ethoxy)-pyrimido
pyrimidine, melting point 242—244° C., from 2,6-dichloro
6 - diethanolamino - 4,8-dimorpholyl-pyrimido- [5,4-d]~py
4,8-di-(ethoxy)-pyrimido-pyrimidine and morpholine un
der re?ux.
rimidine;
4,6,8-tri-(methylamino) ~pyrimido- [5,4-d1-pyrimidine;
.
(b) 2,6-dimorpholyl-4,8-di-(methoxy-ethoxy-pyrimido
pyrimidine, melting point 212-215 ° C., from 2,6—dichloro
4,8-di-(methoxy-ethoxy)-pyrimido-pyrimidine and mor
6 - morpholyl - 4,8 - bis - (ethylamino) - pyrimidolSA-d}
15
pyrimidine;
6-morpholyl-4,8-diamino-pyrimido-[5,4-d]-pyrimidine;
pholine under re?ux.
4,87 bis - (methylamino) - pyrimido - [5,4-d] ~pyrimidine;
and
EXAMPLE 44
‘
I4,8-bis-(dimethylyamino) -pyrimido- [5,4-d] -pyrimidine.
'
2,6-Dimorph01yl-4,8-Dithio-Pyrimido-Pyrimidine
In addition to the above-described cardiovascular activi
ty, the compounds of the invention also exhibit a high
spasmolytic activity which approaches and even surpasses
This compound was obtained by reacting 2,6-dich1oro
4,8-dithio-pyrimido-pyrimidine with morpholine.
2.7 gm. (0.01 mol) 2,6-diehloro-4,S-dithio-pyrimido 25 the spasmolytic activity of papaverine. Especially e?ective
‘spasmolytic agent of the generic group are, for instance,
the following compounds:
pyrimidine were refluxed for thirty minutes with 7.0 gm.
(0.08 mol) morpholine in 50 cc. dioxane. After the re
action mixture was taken up in 200 cc. water the raw
2,6 - di - (ethyl - ethanol - amino) - 4,8 - dimorpholyl
product precipitated out as a brown residue after several
hours. The residue was ?ltered otf, washed with water and
2,6 - dimorpholyl - 4,8 - di - (propyl - ethanol - amino)
then dried. The dry residue was dissolved in cold benzene,
?ltered, and the ?ltrate then evaporated to dryness in
6 - morpholyl - 4,8 - di - (ethyl - ethanol-amino) -pyrimido
pyrimido-[5,4-d] -pyrimidine;
pyrimido- [5,4-d1-pyrimidihe;
vacuum. The remaining residue was dissolved in a small
[5,4-d] -pyrirnidine; ‘
amount of hot dioxane and after cooling and the addition
6 - morpholyl - 4,8 - bis - (ethylamino - pyrimido-[5,4-id]
pyrimidine.
of methanol the reaction product, separated out as an
orange-brown amorphous precipitate, M.P. 187-190“.
All these compounds are considerably more eifective
and also exhibit a more prolonged activity than theophyl
line. The most active compounds of this group of com
EXAMPLE 45
pounds are many times as effective as papaverine.
2,4,8 - Tris - (Methyl - Ethanolamino)-6-Phenylthi0-Py
4,6,8 - tri - (methylamino) -pyrimido-[5,4-d]-pyrimidine
rimido-Pyrimidine, Melting Point 55-58 ° C.
This compound was prepared using a procedure analo
_ exhibits not only a cardiovascular activity but has ‘also di
uretic properties corresponding to those of theophylline,
but of considerably more prolonged duration.
gous Example 37, from» 2,4,6,8 - tetra(phenylthio) - py
rimido-pyrimidine and methyl-ethanol-a'rnine.
6 ~. (p-diethylamino-ethoxy)-4,8-dimorpholyl-pyrimido
All of the basic substituted pyrimido-pyrimidines em
[5,4-d] -pyrimidine has a markedly better dilating e?ect
braced by Formula I above, as well as their non-toxic 45 upon the coronary arteries than theophylline and lowers
alkali metal salts and non-toxic acid addition salts exhibit
the blood pressure only slightly.
;
' cardiovascular activity. Very low doses produce excellent
2,6 - dimorpholyl - 4,8 - bis-(propyl-ethanol-amino)-py
vasodilation of the coronary arteries without substantially
rimido- [5,4-d]-pyrimidine has a cardiovascular as well as
affecting the blood pressure. Higher doses, beginning with
activity.
about‘0.5 to 1.0 mgm./ kg. body weight, produce a hypo 50 a diuretic
While we have disclosed various speci?c embodiments
tensive effect which is the result of general vasodilation
of our invention, it will be obvious to persons skilled in
and decrease in peripheral resistance; not only the coronary
the art that various changes and modi?cations may be made
arteries but also the blood vessels of the brain are dilated,
therein without departing from the spirit of the invention
causing a marked and comparatively prolonged increase
or the scope of the appended claims.
55
in the blood ?ow through the brain.
We claim:
The above-described effects of the compounds em
1. A compound selected from the group consisting of
braced by Formula I are not accompanied by any adverse
basic substituted pyrimido~[5,4-d] -pyrimidines having the
effects upon the heart. This is proven by the fact that,
formula
for instance, 2,6 - bis - (diethanolamino)-4,8-dipiperidyl
pyrimido-pyrimidine markedly increases the cardiac out 60
put. The range of therapeutic ‘application of the new
compounds is quite remarkable.
.
Speci?c compounds of the generic group which are
especially effective as vasodilators and produce the above
described advantageous effects are, for instance, the follow 65
ing:
R:
2,6 - bis - (diethanolamino) - 4,8 - dipyrrolidyl-pyrimido
[5 ,4-d] -pyrimidine;
2,6 - bis - (diethanolamino) - 4,8 - bis-(diethy-lamino) -py
rimido-[5,4-d] -pyrimidine;
2,6 - bis - (diethanolamino) ~ 4,8 - dimorpholyl-pyrimido
[5,4-d]-pyrimidine;
2,6 - dimorpholyl - 4,8 - di - (propyl - ethanol - amino) -py
rimido-[5,4-d]-pyrimidine;
'
wherein from two to four, inclusive, of the substituents
R1, R2, R3 and R4 are basic moieties selected from the
70 group consisting of amino, lower alkylamino, dialkyl
amino wherein the alkyl moieties have from 1 to 12 car
bon atoms, mono-(hydroxy-lower a1kyl)amino, di-(hy
droxy-lower alkyl)-amino, (hydroxy—lower alkyl)-alkyl
amino wherein the alkyl moiety has from 1 to 12 carbon
75 atoms, (lower alkoxy-lower aIkyD-amino, lower alkenyl
3,031,450
34
33
amino, cyclohexyl-amino, phenyl-amino, ha'lophenyl
amino, nitrophenyl-amino, (lower alkoxy-phenyD-amino,
[(di-lower alkyl-amino)-phenyl]pamino, benzylamino,
2. 2,6 - bis - (diethanol - amino) - 4,8 - dipiperidyl- '
pyrimido- [ 5 ,4-d] -pyrimidine.
3. 2,6 - bis - (diisopropanol - amino) - 4,8 - dimorphol
semicarbazidyl, hydrazinyl, guanidyl, ethyleneimino, pi- -
yl-pyrimido-[5,4-d1-pyrirnidine.
peridyl, lower alkyl-piperidyl, lower alkoxy-piperidyl, hy
droxy-piperidyl, pyrrolidyl, lower alkyl-pyrrolidyl, lowerv
ethyl-thio-pyrimido— [5,4-d] ~pyrirnidine.
alkoxy-pyrrolidyl, hydroxy-pyrrolidyl, morpholyl, lower
4. 2,6 - bis - (diethanol - amino) - 4 - piperidyl - 8
5. 2,6 - bis - (diethanol - amino) - 4,8 - bis - (3’ - meth
alkyl-morpholyl, lower alkoxy-morpholyl, hydroxy-mor
pholyl, tetrahydropyridyl, lower alkyl-tetrahydropyridyl,
lower alkoxy-tetrahydropyridyl, hydroxyptetrahydropyri
dyl, hexarnethyleneimino, lower alkyl-hexamethylene
imino, lower alkoxy-hexamethyleneimino, hydroXy-hexa
methyleneimino, tetrahydroquinolyl, lower alkyl-tetrahy
droquinolyl, lower alkoxy-tetrahydroquinolyl, hydroxy
tetrahydroquinolyl, piperazyl, lower alkylpiperazyl, lower
alkoxy-piperazyl, hydroxy-piperazyl and N'-lower alkyl
yleneimino) -pyrimido- [5 ,4-d] -pyrimidine.
piperazyl, and the remaining substituents R1 to‘ R4 are
selected from the group consisting of hydrogen, halogen,
[5,4-d] -pyrimidine.
hydroxyl, mercapto, lower alkyl, phenyl, lower alkoxy,
vdi-lower-alkyl-amino-lower alkoxy and lower alkyl-thio,
phenyl-thio, benzyl-thio, lower alkoXy-lower alkoxy, their
non-toxic alkali metal salts and their non-toxic acid addi
tion salts.
yl-piperidyl) -pyrimido- [5 ,4-d] -pyrimidine.
.
6. 2 - (diisopropanol - amino) - 6 - (diethanol - amino)
4, S-dipip eridyl-pyrimido- [5 ,4-d] -pyrirnidine.
7. 2,6 - bis - (diethanol F amino) - 4,8 - bis - (1’,2’,S',
6'-tetrahydro-pyridy1) -pyrimido- [ 5,4-d] -pyrimidine.
8. 2,6 - bis - (diethanol - amino) - 4,8 - di - (3' - hy
droxy-piperidyl) -pyrimido— [ 5,4-d] -pyrirnidine.
9. 2,6 - bis - (diethanol - amino) - 4,8 - di — (hexameth
10. 6 - chloro - 4,8 - di - (ethyleneimino) - pyrimidop
References Cited in the ?le of this patent
FOREIGN PATENTS
807,826
Great Britain ________ __ Jan. 21, 1959
UNITED STATES PATENT. OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,031,450
April 24, 1962
Franz Gottwalt Fischer et a1,
It is hereby certified that error appears in the above numbered pat
ent requiring correction and that the said Letters Patent should read as
corrected below.
Column 5, line 47, for "hydroge" read —— hydrogen ——;
column 7, line 62, for "4.29%" read —- 4.92% --; column 9,
line 52, strike out "pyrimido-"; column 10, lines 35 and 36,
for "(diisopropanol-amino)" read —— (diisopropanol-amine) ——;
column 11, line 41, for "theroetical" read —— theoretical ——;
same column, line 54, for "Dipieridyl" read -— Dipiperidyl ——;
column 13, line 62, for "pyrimiden" read —- pyrimidine ——;
column 16, line 33, for "4l—l43° C." read —— l4l-l43° C. -—;
line 51, for "18-1 0° C. " read -— l58—l60° C. —-; same column,
line 55, for "92-1 3° C. " read —— l92-l93° C. ——; column 17,
lines 48 and 49, after "corresponding" insert —— sodium -—;
same column, line 61, for "analyltical" read —— analytical ——;
column 18, line 73, for "(3’ —methyl—piyeridyl)—" read -- (3' —
methyl-piperidyl)- --; column 19, line 35, for "2,6—d-" read
-— 2,6-di- --; - column 20,
line 33,
for "(diethyanolamino)"
read -—~ (diethanolamino) —-; column 22, line 9, for "81% of
theory)." read -— (81% of theory). ——; same column, line 11,
for "chlorinde" read —- chloride —-; column 24, line 29, for
"2,o-(diethanol-amino)"read —- 2,6—bis~(diethanol—amin0) ——;
same column, line 52, for "—ethylthio)—" read -- -(ethylthio)—
——; column 25,
line 50, for "-e!:hanol—" read —— -(ethanol- —-;
column 26, line 9, for "—(henzylthio-" read —- —(benzylthio)
—-; line 43, strike out "a"; same column, lines 60 and 61, for
"—phenylthio)-" read —— —(phenylthio\)- -—; column 27, lines 44
and 45, strike out ": 0.01 mol 2,6—di—(f5-hydroxyethyl-amino)—
4,8-diamino-pyrimido-pyrimidine"; column 28, line 1, strike out
2,6-dianilino-4,8-di-(benzyl0xy)—pyrimido—pyrimidine" and
insert instead —— 2,6-dianilino-4,8-dihydroxy-pyrimido—pyrimi
dine or 5.3 gm (0.01 mol) 2,6-dianilino-4,8—di—(benzyloxy)—
pyrimido-pyrimidine -—; column 29, line 38, for "224-" read
—— 244- ——;
column 30,
line 6,
for "—phenylthio)—" read ~
-(phenylthio)— ——; column 31, line 14, for "-ethoxy" read
—— -ethoxy) ——; column 32, line 34, for "—(ethylamino-" read
——
—(ethylamino)-
-—.
Signed and 'sealed this llth day of September 1962.
(SEAL)
Attest:
ERNEST W. SWIDER
Attesting Officer
DAVID L. LADD
Commissioner of Patents
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