Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
11~86~
The present invention relates to new 2,4-diamino-
5-benzylpyrimidines of the general formula
' 1~' ~NH2
wherein R1 denotes hydrogen or Cl 6-alkyl; R2 denotes
hydrogen; R denotes mercapto, Cl 6-alkylthio,
carbXY~Cl_6~alkylthio, Cl-6-alkoxy-cl 6-alkyl-
thio, dimethylcarbamoylthio, -S(O)R' or -S02R'
and R4 denotes Cl_6-alkylthio, -S(O)R or S02R , or
R denotes hydrogen; R and R denote Cl 6-
alkylthio, -S(O)R' or -S02R', and R3 denotes
Cl 6-alkoxy, mercapto, Cl 6-alkylthio, carboxy-
Cl 6-alkylthio, dimethylcarbamoylthio, -S(O)R',
-S02R' or -NR"R"', or
R denotes hydrogen; R denotes Cl 6-alkoxy;
: R denotes mercapto, Cl 6-alkylthio, carboxy-
Cl 6-alkylthiO, cl_6-alkoXY-Cl_6-alkYlthi~
dimethylcarbamoylthio, -S(O)R' or -S02R', and
R4 denotes Cl 6-alkylthio, -S(O)P~' or -S02R', or
X~ ~
:- ' -.
~L~8611
-2-
Rl denotes hydrogen; R2 denotes halogen; R3
d4enotes Cl_6-alkylthio, -S(.O~R' or -S02R', and
R denotes Cl_6-alkylthio, -S(O)R' or -S02R', or
R denotes hydrogen; R2 denotes halogen or
Cl-6-alkoxy;
R3 denotes mercapto, Cl 6-alkylthio, carboxy-
Cl 6-alkylthio, carbalkoxy-Cl 6-alkylthio, cyano-
Cl 6-alkylthiO, cl_6-alkoxY-Cl_6~alkYlthi~
Cl_6 alkoxy-Cl_6-alkoxy-Cl_6-alkylthio, dimethyl-
carbamoylthio, -S(O)R' or -S02R', and R4 denotes
halogen or Cl 6-alkoxy;
R' denotes Cl 6-alkyl; R" and R"' independently
of one another denote hydrogen or Cl 6-alkyl or
together denote C2 6-alkylene (possibly with :;
1-3 double bonds),
and their physiologically compatible salts, a process for
their preparation, as well as pharmaceutical preparations
based on these compounds and the production of said phar-
maceutical preparations.
The general formula I comprises the groups of
compounds of the formulae I-l to I-5:
R 1 a NH2
--O N
R4a
` iL1~363L1
-- 3 --
.
01 I 2
R4a
3 ~ NH2
l H2
H f NH2
R4a
NH2
,J ~NlN H2
R4b
,. ~ ~ . , ..... . ~.; . .. . .
. .
. . .
_ 4 _ ~ ~ 8 6
In the for~ulae I-1 to I-5:
R1a denotes hydrogen or C1 6-alkyl;
R2a denotes C1 6-alkylthio, -S(O)R' or S02R';
R denotes C -alkoxy;
2c 1-6
R denotes halogen;
R2d denotes halogen or C1 6-alkoxy;
R3a denotes mercapto, C1 6-alkylthio, carboxy_
C1 6-alkylthio, C1 6-alkoxy-C1 6-alkylthio,
dimethylcarbamoylthio, -S(O)R' or -S02~';
R3b denotes C1 6-alkoxy, mercapto, C1 6-alkylthio,
carboxy-C1 6-alkylthio, dimethylcarbamoylthio,
-S(O)R', -S02R' or -NR"R"';
C R3c denotes C1 6-alkylthio, -S(O)R' or -S02R';
R3d denotes mercapto, C1 6-alkylthio, carboxy-
C1 6-alkylthio, carbalkoxy-C1 6-alkylthio,
cyano-C1 6-alkylthio, C1 6-alkoxy-C1 6-alkyl-
thio C 6-alkXY-c1 6-alkoxy-c1-6 y
dimethylcarbamoylthio, -S(O)R' or -S02R';
R4a denotes C1 6-alkylthio, -S(O)R' or -S02R';
R denotes halogen or C1 6-alkoxy.
The substituents R', R" and R"' have the meanin~s
already specified above.
Examples of C1 6-alkyl radicals are methyl, ethyl,
propyl, isopropyl, butyl, ~ec.-butyl, isobutyl, tert.-
butyl, pentyl and hexyl, methyl and ethyl being prefer-
red. Examples of C2 6-alkylene radicals are ethylene,
trimethylene, tetramethylene and pentamethylene. Exam-
ples of radicals derived therefrom having 1-3 double
bonds are vinylene, propylene, 2-butenylene, 1,3-buta-
dienylene, 1,4-pentadienylene or 1,3,5-hexatrienylene.
Halogen subsSituents are in particular chlorine,
bro~ine and iodine, chlorine and bromine being preferred.
The process for the preparation of the compounds
according to the invention is characterised in that
~863 1
--5--
(a) a compound of the formula
F~1
R~ $~CH2--Z
R3
R4
wherein Rl, R2, R3 and R4 have the afore-mentioned
meanings, Z denotes a -C(CN) = CH-Y or
-CH(C )CH(oR5)2' group, Y denotes a leaving group,
and R denotes Cl 6-alkyl, 2-Cl_6-alkoxyethyl,
2-phenoxyethyl or 2-benzyloxyethyl, or both R
radicals together denote Cl 6-alkylene,
is condensed with guanidine or a guanidine salt, or
(b) in a compound of the formula
R ~ ~NH2 III
R4
wherein X denotes halogen and Rl, R2, R3 and R4 have the
afore-mentioned meanings,
the substituent X is reductively eliminated, or
(c) to prepare a compound of the formula I-l, a
substituted benzylpyrimidine of the formula
,~
.
. . .
.
:,, -. : ., :
- . , .. : :
-6-
NH2
, .
NH2
wherein R6 denotes Cl 6-alkoxy (.preferably methoxy),
benzyloxy, hydroxy or halogen, is reacted with
a compound of the formula
R 1 a
R~
a
R4a
wherein Rla, R3a and R4a have the afore-mentioned meanings,
or
(d) a compound of the formula I is modified at the sub-
stituents R2, R3 and/or R4 by generally known methods,
: and the compound obtained is converted if desired into
a physiologically compatible salt.
According to variant (a) of the process according
to the invention, a compound II is reacted with guani-
dine or a guanidine salt. The reaction can be carried
out in a manner known per se, e.g. in an organic sol-
vent such as an alkanol (methanol, ethanol), in di-
methylformamide, dimethylsulphoxide or N-methylpyr-
azolone, at a temperature between 25 and 200, preferably
~8611
-- 7 --
between 50 and 170. The carbonate and hydrochloride
may for example be used as guanidine salts. Typical
examples of~ea~n~ groups represented by the symbol Y
in the formula II are for example alkoxy groups, such
as methoxy, ethoxy, propoxy, etc., 2-(C1 6-alkoxy)-ethoxy
groups such as 2-methoxyethoxy and 2-ethoxyethoxy, 2-
phenoxyethoxy, 2-benzyloxyethoxy, alkylthio groups, the
amino group and amino groups substituted by aliphatic,
aromatic or heterocyclic groups, such as alkylamino,
benzylamino, arylamino te.g. optionally substituted
anilino or naphthylamino), dialkylamino, 1-imidazolyl,
pyrrolidino, piperidino~ piperazino or morpholino. Par-
ticularly preferred as a 1eaV1n~G group is the anilino ra-
dical,whose phenyl ring may be mono or poly-substituted
by halogen, alkyl or alkoxy.
The starting compounds II may, as shown in the re-
action scheme I, be prepared from compounds of the formu-
la VIII, and the individual reaction steps can be car-
ried out in analogy to known conversions.
Thus, an aldehyde of the formula VIII may for ex-
ample be reacted with a ~-alkoxypropionitrile of the form-
ula NC-CH2-CH2-oR5 to form a compound of the formula VI,
and may be reacted in the presence of an alkali metal
alkoxide such as sodium methoxide or potassium tert.-
butylate and an alcohol such as methanol, ethanol or pro-
panol, to form a compound of the formula II-a. The ~
un~aturated compound VI is in equilibrium with the cor-
responding ~,~-un~aturated compound II-e, which can be
converted with guanidine to form a compound I.
If an aldehyde of the formula VIII is firstly reac-
ted with malodinitrile under the conditions of a Knoeven-
agel condensation (optionally in the presence of a basic
catalyst3, then a dinitrile of the formula VII is obtained
that can be converted by selective hydrogenation, e.g.
with half a mole of sodium borohydride, into the compound
II-b.
An aldehyde of the formula VIII can be converted by
condensation with ~-morpholinopropionitrile into a com-
.
- 8 ~
pound of the formula II-c, which can either be used dir-
ectly as a starting material for the conversion accord-
ing to the invention or, and in fact preferably, first
o~ all converted,by replacing the morpholino group by
the anilino group,into a compound of the formula II-d.
- :. .
- -: . : , . :. ......... .
.. . . , :
~ 86~1
-9- ~
,
o U ~~ H ~ ~/ H
U a~
o 3
o
o
. o /
H I ~ =I/ H
_ ~0
N c~ 1~ \ cC
Z U~
C:
~=I 5
Z u~ \ . ( H
n~ ~¢
.~ N ~\
c~ + I z ,~
,
- . . ..
~ 8~
-- 1 o
The conversion of VIII to II-d can also be carried
out directly with ~-anilinopropionitrile, though the
morpholino-anilino variant represents the most expedient
way for preparing the benzylpyrimidines I since in this
way better yields may be achieved under milder conditions.
The methods for preparing the sulphur-containing
benzylpyrimidines of the invention from aldehydes of
the formula I are in principle analogous to the known
methods for preparing the corresponding, sulphur-free
benzylpyrimidines. -
C The aldehydes of the formula VIII are, with the ex-
ception o~ 3,4-bis-(methylthio)-benzaldehyde ~i.e. com- - -
pound VIII-1 with R a = hydrogen and R3a = R4a = methyl-
thio), new compounds and are likewise the subject of the
present invention. By analogy with the subdivision of
the compounds I, the aldehydes VIII may be divided in
the following sub-groups VIII-1 to VIII-5:
R1 a
R~/C HO R 2 d VI I I - 2
. a`r VIII-l R4a
R4a
. .
R.b CHO R~ ,~CHO ~ R~CHO
R4 a R4 a I R4 b
VIII-3 VIII-4 I VIII-S
.
.:
~ 86~
In the formulae VIII-1 to VIII-5, the ~ubstituents
have the meanings already defined above.
The aldehydes of the formula VIII may be prepared
from known compounds according to methods kno~n per se,
e.g. such as described in detail in Examples 9-18 and
as diagrammatically illustrated in the following reac-
tion summaries II-V, or in an analogous manner.
A reaction for which there is up to now no parallel
in the literature and which i~ therefore new is the
thermolysis of a compound XXIII to form a compound VIII-5d
(cf. reaction scheme V). The reaction is preferably car-
ried out in dimethylformamide at a temperature of approxi-
mately 50C up to the reflux temperature of the reaction
mixture. The reaction is catalysed by traces of alkali
metal x~nthogenates, for example potassium xanthogenate.
The reductive elimination of the halogen atom X,
which is preferably a chlorine or bromine atom, in a com-
pound of the formula III according to process variant
(b) can be carried out in a manner known per se by treat-
ing a compound III with suitable reducing agents such as
zinc in glacial acetic acid, amalgamated zinc in caustic
soda, or by catalytic hydrogenation, for example in the
presence of a noble metal catalyst such as palladium,
and in an inert solvent such as ethanol.
The compounds of the formula III are new and are
likewise the object of the present invention. They can
be prépared by methods similar to the known methods,
which are summarised in the following reaction scheme VI.
- .~ : .:
~: :
. ': ~' :
.
86~1
1~ --
~eact~or s~ e TT
Rla R1a
HO~ ~3 S--A I kyl HO~ ~--7
5--Alkyl
H3C--N ~Cl
C~3 Rta
H3C--~ ~ 2III-l
CH3 5--Alhyl
R 1a
~CHO 1l $ ~II-le
HOOC--alkyl--S H3C--I ~S
S--Alkyl CH3 5--Alkyl
VIII-ld
'nyd~ol~ys~s
(. ' R1a \ R1a
-- ~[~CHO ,L~' VIII-la
Alkyl--O--alkyl--S --~ HS ~
S--Alkyl S--Alhyl
VIII-lc
Al`~ Ltion ~ .
~ ~CHO
,[OJ VII -lb
A l kyl--S ~
S--A I kyl
~8611
-- 13 --
Reac ~ion scre~e III
S--AlhYI ~CHO
X''rII ~I~H C~
Alkyl--S~CHO CH3
Alkyl--O~ Alhyl--S ~CHO
~ S--Alhyl ~C ~ OJ x I T--2
VI I I--2c H3C--N ~ ~
9r COOEt CH3 S--Alhyl
5r
¦ 1. (3S--Alhyl Alhyl--S~CHO
~ 2. Red. ll I O J VIII-2e
A I kyl--S ~CHO H3C--Nl ~C S~
Alkyl--S ~4 7
S--Alkyl ~ ~yd--Ol'J9~5
C ~III-2b
Alkyl--S~CHO Alkyl--S~ VILI--2a
HOOC--alkyl--S~ HS~
S--A I ky I S--A I ky I
'iII, -2d
A l k y l--5~CI-10 R" ~ N~Ç o A l k y I--S~C O O E t _-
S--Alhyl S--Alhyl S--Alkyl
'~ { - ilIII-2~ XI:{
. :- ... :
- ~ :. . : ,- . .
-: '.'. .. : ,, -
..
36~1
-- 14 --
Re~ t on scl s~e rr
1~10~ 0~
S~
H3C--N~CI
CH3
C .A I hYI--0~ 3
CH3 S -Alhyl
~1
Alkyl--O~CHOAjyl--0~ VIII-3b
HOOC--alhyl--SH3C--I ~S
S--Alkyl CH3 5--Alkyl
- VIII-3e
~drol~rsis
\
Alkyl--O~CHO All<yl--0~/ CHO
Alkyl--O--alkyl--S~HS~ VIII-3a
S--Alkyl S--Alkyl
VIII-3d
Al~c~,lati o n
S--All.V~
.. . ..
.- . ....
~86~1
~ a~ ... .
r ! ( --~,
. ~ C ~: C
g~ D _
-->I ~ oo ~ E ~
~J X
-- 0=~ ~,) U T X
_~ ~ _ T
~ . ~ Q
X X X
:.
- :
~1~8611
-- 16
Reac ~,lon sC:ne~re -~JI
~R4 / \ R ~
R4 CN
}32/?d c r
~ , NaBH4
R~ /CN R1
~CI H2 I R~o/
R4 j~ R4 X I
Ho/~NlNH2
/ Guanidine
R 1NH2
N PO X 3 ~ II I
- 17 ~ 6~ 1
The conversion of a compound IV with a compound V
according to process variant (c) can be carried out in
the presence of an inorganic acid, for example orthophos-
phoric acid, polyphosphoric acid, a hydrohalic acid such
as hydrochloric acid or hydrobromic acid, or an organic
acid, for example a trihalogenated acetic acid such as
trifluoroacetic acid.
The reaction is preferably carried out in a temper-
ature range from about 50 to about 100C. In general,
the inorganic or organic acid used for the reaction may
serve as solvent, but if de~ired an inert organic sol-
vent may also be used. The acid addition salt of a com-
pound of the formula I-1 thus obtained is separated in
the usual way at the end of the reaction and is t~n puri-
fied by conventional purification methods, such as crys-
; tallisation or filtration. The free base can be obtain-
ed by neutralising the acid addition salt, for example
with an alkali metal hydroxide.
Whereas the starting compounds of the formula IV
are known, some of the compounds of the formula V are
new compounds. The new compounds can be prepared in a
manner known per se from known compounds, e.g. 1,2-
dimercaptobenzene, 2-methylmercaptobenzene, 3,4-dimer-
captotoluene or 3,4-bis-~methylthio)-toluene, or by
analogy to the preparation of these known compounds,
for example by alkylating a mercapto group and/or oxi-
dising an alkylthio group to an alkylsulphinyl or
alkylsulphonyl group. A carboxyalkylthio compound may
be prepared by for example reacting a mercapto compound
with an ~-halogenated carboxylic acid derivative, such
as an ester or amide, followed by hydrolysis.
Specific compounds of the formula I according to
the invention can also be modified within the framework
of generally known methods at the substituents R2, R3
and/or R4, i.e. can be converted into one another (pro-
cess variant d). Thus, for example, a mercapto group
in a compound I can be converted with an alkylating agent
- ~i - . .
.. , . . . .
- ,. . . .
. : . ,.,: .,, ~, ::, , :
-- .
8~
- 18 _
into an alkylthio group, an alkoxyalkylthio group or
a carboxyalkylthio group. Alkylthio groups can be oxi-
dised to alkylsulphinyl and/or alkylsulphonyl groups,
or these can be reduced in a method known per se to
alkylthio groups. The dimethylcarbamoylthio group can
be converted by hydrolysis into the mercapto ~roup.
Salts of the co~pcun~ ~ formula I include salts with
acids (so-called acid addition salts), and also, depend-
ing on the substituent on the benzyl radical, salts with
bases.
For the preparation of acid addition salts, in par-
ticular of salts that can be used in pharmaceutical pre-
parations, i.e. that are physiologically compatible, there
may be used the inorganic and organic salts conventionally
employed for this purpose, such as hydrochloric acid,
sulphu.ic acid, phosphoric acid, formic acid, acetic acid,
oxalic acid, tartaric acid, maleic acid, benzoic acid,
succinic acid, fumaric acid, levulinic acid, salicylic
acid, citric acid, isocitric acid, adipic acid, lactic
acid, d-ketoglutaric acid, malic acid, malonic acid,
glyceric acid, mevalonic acid, glucuronic acid, neuraminic
acid, glutaric acid, glucaric acid, aspartic acid, glu-
conic acid, mandelic acid, ascorbic acid, lactobionic
acid, glucoheptonic acld, glutamic acid, nicotinic acid,
pantothenic acid, folic acid, adenylic acid, geranylic
acid, cytidilic acid, inosinic acid and methanesulphonic
acid.
Examples of salts with bases are the sodium and po-
tassium salt.
The compounds oP the formula I and their salts have
an antibacterial action. They inhibit bacterial dihydro-
folic acid reductase (DHFR) and moreover potentiate the
action of sulphonamides and other dihydrofolic acid syn-
thetase inhibitors.
Examples of sulphonamides that are potentiated by
the compounds according to the invention are members of
:: ,: . . r
'' ' ~
36~1
_
the pyrimidine, isoxazole,oxazole,and pyrazine series
such as sulphadiazine, sulphadimethoxine, sulphadoxine,
sulphamerazine, sulphameter, sulphamethazine, 6-methoxy-
4-sulphanilamidopyrimidine, sulphamethoxazole, sulphis-
oxazole, 3-sulphanilamido-4,5-dimethylisoxazole, sulpha-
moxole and sulphalene. The compounds according to the
invention are quantitatively differentiated from known
compound~ by lower 50% inhibition concentration~ of bac-
; terial DHFR, for example in the case of E. coli, and by
basically higher Q-values (50% inhibition of DH~R in
( rats/50% inhibition of DHFR in E. coli), which repre-
sents a measure o~ the selectivity of inhibition of
bacterial DHFR, as well as by a lower toxicity.
Data illustrating the antibacterial action of some
typical compounds according to the invention are summar-
ised in Table 1.
Table 1
Compound I Activity in vitro 50% inhibition8
(MIC) of DHFR (Mx10
~' Rl R R3 R4 E. col1 S aureus E. coli .
H OCH3 SCH3 OCH3 0,02 0,4 0,35
H OCH3 2H5 OCH3 0,04 0,4 0,l8
H OCH3 SC2H40CH3 OCH3 l,O 9,7
H SCH3 N ~ SCH3 > l 4,0 0,52
H SCH3 OCH3 Br 0,2 l,O l,l
H SCH3 OCH3 OCH3 O,l 0,78 0,5
H SCH3 OCH3 SCH3 0,7 0,2 0,72
H SCH3 SCl~3 SCH3 0,2 0,2 0,45
H H SCH3 SCll3 0,7 l,6
CH3 H SCH3 SCH3 0,7 0,7 l,5 I
- - .
J ~8~
- 20 -
The benzylpyrimidines according to the invention
can thus be used as pharmaceutical preparations with a
direct or delayed release of the active substance, in
admixture with an organic or inorganic inert carrier ma-
terial suitable for oral, rectal or parenteral application,
e.g. water, gelatin, gum arabic, lactose, starch, magnes-
ium stearate, talc, vegetable oils, polyalkylene glycols,
Vaseline, etc. The pharmaceutical preparations may be
formulated in solid ~orm, e.g. as tablets, pills, sup-
positories or cap ules; in semi-solid form, e.g. as
ointments; or in liquid form, e.g. as solutions, suspen-
sions or emulsions. They may optionally be sterilised
and/or contain further adjuvants such as preservatives,
stabilisers, wetting agents or emulsifying agents, taste im-
provement agents, salts for altering the osmotic pressure,
or buffer substances. The pharmaceutical preparations
may be formulated in a manner generally known to those in
the art.
In preparations in which the compounds according to
the invention are applied in combination with sulphonamides,
the weight ratio of the two components with respect to one
another may vary within wide limits. The ratio may be be-
tween 1:40 and 10:1, and is pre~erably 1:5 to 5:1. A ta-
.. blet may for example contain 80 to 400 mg of a compound
I and 400-80 mg of a sulphonamlde. In preparations con-
taining a compound I as the single active component,
100-1000 mg serves as a guideline for an individual dose
which, depending on requirements, can be administered one
or more times per day.
Example 1
A solution of 36 g of 3,5-dimethoxy-4-methylthiobenz-
- aldehyde and 28 g of ~-morpholinopropionitrile in 300 ml
of dimethylsulphoxide was heated to 60C and 3.9 g of
solid sodium methylate was added thereto. A slightly
exothermic reaction was observed and the solution immed-
iately became dark. The solution was stirred for one hour .-
in an oil bath (60C), cooled, and poured into iced water.
'' ,. ~ . :
36~1
- 21 -
The product was then extracted with ethyl acetate,
washed with sodium chloride solution, and dried over
sodium sulphate. After removing the solvent, 56 g --
(99%) of 3,5-dimethoxy- ~-(morpholinomethylene)-4-
~methylthio)-hydrocinnamic acid nitrile was obtained in
the form of a bright yellow oil (M.P. 110-113C, in ethyl
acetate/pentane), which was processed further in this form.
56 g of 3,5-dimethoxy-a-(morpholinomethylene)-4-
(methylthio)-hydrocinnamic acid nitrile dissolved in
250 ml of isopropanol were added to a mixture of 18.6 g
of aniline and 11.5 g of acetic acid prepared while cool-
( ing with ice. The mixture was heated for 2 hours under
reflux, 100 ml of isopropanol were distilled off towards
the end of the reaction, the reaction mixture was then
cooled to 0C, 300 ml of water were added, and the pro-
duct was extracted with ethyl acetate. The organic phase
was washed with sodium chloride solution, dried over so-
dium sulphate, and concentrated by evaporation. 50 g of
crude ~-anilinomethylene-3,5-dimethoxy-4-(methylthio~-
hydrocinnamic acid nitrile crystallised from the residue.
Recrystallisation from ethyl acetate/pentane provided 40 g
(72%) of the compound having a melting point of 206-210C.
A solution of 10.2 g of ~-anilinomethylene-3,5-dime-
thoxy-4-~methylthio)-hydrocinnamic acid nitrile and 16.6 g
of guanidine carbonate in 200 ml of ethanol, containing
2.15 g of sodium, was heated for 20 hours under reflux.
The solvent was removed, the residue was suspended in iced
water, and the crystals were suction filtered, exhaustive-
ly washed with iced water, and recrystallised from hot
ethanol. 7.1 g (77.5~) of 2,4-diamino-5-/ 3,5-dimethoxy-
4-(methylthio)-benzyl/-pyrimidine, having a melting point
of 231-232C, were obtained.
Example 2
By analogy to the method described in Example 1, fur-
ther aldehydes of the formula VIII were converted via com-
pounds II-c and II-d into compounds of the formula I. The
j
.. , . ,,. : ,. ~ ,. . .
~ 36~1 -
- 22 -
results are given in Table 1.
6~1
. . ,;
- 23 - 1~ , ; I ~ .,
~ h ;~
a~ ~ 5 E
Y ~ H 11
h h ~ . H i .
_, ~ ; .
X ^ ~r! ~ ~ '
N _I --I N r-l Nr~ N N N N N .
. ~U .--i O Cl ~ ~) N N Ul N N U~ N
.. H E; l_ N ~1 a~ N ~9 NO ~ NO N N NO N
'
~: C~ ~`I O a~ I O N
~--~ n ' Lll .,
I~ o u~
o ~ ~ o
~ ~ O N O ~ !
3 H ~-- 0 ~I C~a~, 1~ ~ U~ ~i ~ ~r O ~D .
J~ . _ ~ ~
C~ O N a~ 0 ~7 g ~ No
' ~ _l . ~1 ~1 _I _I _I ~ r-l ~I r~~ N
~a .40~ I I~D ~ O u~
H ~
H - _
.C~ ~ ~ 1` 0
D
s tl)
O rl~~ ~ O O O 1~ ~
-_~ ~
I ~ N, U ) ~ ~ 1` Ul ' '
H ~ Ul ~ 0 0 ~'7 ~ (' _t ~ ~ ~)
~1 ,_.____ _ _ l
~I . r~ Gi U-) ~ CO --I '~ N ,
P~ ~ , ,! -' , ' Q~ ~, , ~r , I
U;l U~~0N ~r ~0 O 0 0 _ I 1~CO
C IE ~ N ~U~ ~ ~ o ~9
_~ ~
~ ,_~ ~ _
~ c'P 1~ r~ ~ _I N O _I N ~ r~
rO ~1_ _ . `
O ~_ ~rl N t~ ~D
U') ~D I ~N _I r~ ~ ~ r~ ~ ~,~ ~,
_ _._ - _ _
H ~1 ~) ~
O 1-~ ~ ~ ~ 1` N ~ C~l O N (~t N ~ .
r;;) ._ . ~ :
'1t`'l '1 ~ ~I r~l 1'~ ~
~r rn ~ ~ r $ _ r rn
Ou u u u ro alu ~C U ~ O
1~ 1 :
O ' \ \
,.7 N ~ r~ r~(~ r~ r~ rr)
~; u 1~ u ' ~ ~ ~ o ~ o=
J~ O O U~ r,l~ r~
~ ~ ~ ~ 7
N 50 o U 2 X ~ u m J s u u
U) ~Jl r~ ~n O O r
~ . ~.__ ~
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8~1
- 24 _
I
Example 3
A solution of 1.4 g of 3-bromo-4,5-bis-~methylthio)-
- benzaldehyde, 0.85 g of ~-methoxypropionitrile and 0.14 g
of sodium methylate in 15 ml of absolute methanol was hea-
ted for 13 hours under reflux. The solvent was removed,
the residue was taken up in 10 ml of methylene chloride,
and the solution was washed with water, dried, and con-
centrated by evaporation. The crude 3-bromo-4, 5-bis-
(methylthio)-~-(methoxymethylene)-hydrocinnamic acid ni-
trile (1.5 g) obtained was heated for 18 hours under re-
flux with 0.6 g of guanidine hydrochloride and 0.35 g of
sodium methylate in 5 ml of ethanol. After distilling
off the solvent, the residue was purified by column chro-
matography on silica gel using ethyl acetate/methanol
(3:1, v/v) as eluting agent, and recrystallised from me-
thanol. 2,4-diamino-5-/ 3-bromo-4,5-bis-(methylthio)-
benzyl~-pyrimidine was obtained, having a M.P. of 240-243C.
Example 4
A mixture of 10.6 g of 3,5-dimethoxy-4-methylthio-
benzaldehyde, 6 2 g of ethyl cyanoacetate and 2 drops of
piperidine was heated in an open flask for 90 minutes at
120C while stirring, and wa~ then cooled and recrystal-
lised from ether/n-heptane. The yield of ethyl ~-cyano-
3,5-dimethoxy-4-methylthiocinnamate, M.P. 98-100C tfrom
ethanol), was 12.0 g (80%).
0.23 g of sodium borohydride was added while stirring
to a suspension of 6.0 g of ethyl ~-cyano-3,5-dimethoxy-
4-methylthiocinnamate in 130 ml of ethanol and 2 drops of
lN caustic soda, a solution thereupon being formed. After
30 minutes, the ethanol was evaporated off at 40C under
a water jet vacuum, the residue was taken up in ether,
and the solution was washed with water and filtered through
silica gel. 5.0 g (79.1%) of ethyl ~-cyano-3,5-dimethoxy-
4-methylthiohydrocinnamate was obtained as a colourless oil.
In another experiment a solution of 3 g of ethyl ~-
cyano-3,5-dimethoxy-4-methylthiocinnamate in 250 ml of
: ,.
, ~ ~ -:: : : ;
:: ,
~1~86~1
methanol and 500 mg of 5% Pd/C was hydrogenated for 24
hours under normal pressure and at room temperature.
After conventional working up, 3.0 g ~ 100%) of ethyl
~-cyano-3,5-dimethoxy-4-methylthiohydrocinnamate were
isolated.
2.7 g of guanidine hydrochloride were added to a
solution of 0.7 g of sodium in 60 ml of absolute ethanol.
After 30 ~inutes the suspension was filtered and 4.5 g
of ethyl ~cyano-3,5-dimethoxy-4~methylthiohydrocinnamate
were added to the filtrate. The reaction mixture was
boiled under reflux for 18 hours, evaporated to dryness,
r and the residue was suspended in water and extracted
three times with 200 ml of ethyl acetate. The extract
was concentrated by evaporation and the residue wa~ crys-
tallised from methanol. 1.8 g (38.~%) of 2,6-diamino-5-
~3,5-dimethoxy-4-methylthiobenzyl)-4-pyrimidinol having
a M.P. of 2l3-215C was obtained.
0.73 g of dimethylaniline was added dropwise while
stirring to a suspension of 0.96 g of 2,6-diamino-5-(3,5-
dimethoxy-4-methylthiobenzyl)-4-pyrimidinol in 7.6 g of
phosphorus oxychloride. The mixture was boiled for 4 hours
while stirring and approximately half the excess phosphoru~
oxychloride wa~ distilled off under reduced pressure. Ap-
- proximately 10 g of ice was added to the remainder. The
suspension was then allowed to stand for 36 hours at room
temperature and adju~ted to a pH of 10 with concentrated
ammonia solution. The ~uspension formed was freed from
dimethylaniline by steam distillation. After cooling the
aqueou~ suspension, the solid crude product was suction
filtered, dissolved in benzene/methanol (4:1, v/v), and
filtered through silica gel. After evaporating off the
solver.t, the 2,6-diamino-4-chlo~-5-t3,5-dimethoxy-4-
methylthiobenzyl)-pyrimidine was recrystallised from me-
thanol; M.P. 218-221C.
150 mg of zinc powder was added to a solution of
167.7 mg of 2,6-diamino-4-chlor3~-(3,5-dimethoxy-4-methyl-
,. .
: : ; : . :. :: :
. .
. -
36~
- 26 -
thiobenzyl)-pyrimidine in 1.6 ml of glacial acetic acid
and 10 mg of mercuric chloride in 0.2 ml of water. The
mixture was boiled under reflux overnight while stirring.
The solution obtained was filtered hot, and unreacted
zinc was washed out with 0.5 ml of glacial acetic acid.
The filtrate was diluted with 2 ml of water and made al-
kaline with concentrated ammonia solution while cooling.
The suspension was extracted three times with 5 ml of ethyl
acetate, the extract was dried and concentrated by evapor-
ation, and the residue was recrystallised from methanol.
148 mg of 2,4-diamino-5-(3,5-dimethoxy-4-methylthio-
r benzyl)-pyrimidine having a M.P. of 231-232C were obtained.
Example 5
A mixture of 3.03 g of 3,4-bis-(methylthio)-toluene,
2.8 g of 2,4-diamino-5-methoxymethylpyrimidine and 15 ml
of orthopho~phoric acid was stirred for 6 hours at 100.
After cooling and diluting with 5 ml of water, 45 ml of
a 50% potas~ium hydroxide solution was dripped in at 0.
The solid product was suction filtered, stirred twice with
water, dis~olved in methanol, and the solvent was then
evaporated. The residue (2.5 g) was purified by column
chromatography on silica gel using ethyl acetate~methanol
(; ~3:1, v/v) as eluting agent. The 2,4-diamino-5-/ 2-methyl-
4,5-bi~(methylthio)-benzyl/-pyrimidine isolated was recrys- .:
talli~ed from methanol; M.P. 217-222C.
Example 6
3.9 g of 2,4-diamino-5-/ 3,5-dimethoxy-4-(methylthio)-
benzyl/-pyrimidine were dissolved in 90 ml of acetic acid,
1.3 g of 30% hydrogen peroxide wa~ added, and the mixture
was stirred for 3 hour~ at room temperature. The ~olution
was then poured onto iced water and made alkaline with
concentrated ammonia solution. The crystalline precipitate
was suction filtered and recrystallised from methanol/methy-
lene chloride. 2.8 g (70g) of 2,4-diamino-5-/ 3,5-dimethoxy-
4-(methylsulphinyl)-benzyl/-pyrimidine was obtained in the
form of bright yellow crystals having a M.P. of 288-289C.
. ~ ~
- : : ' ' . . ' ' -
~ - 27 _ ~ 6~
Example 7
610 mg of 2,4-diamino-5-/ 3,5-dimethoxy-4-~methyl-
sulphinyl)-benzyl/-pyrimidine, dissolved in 15 ml of
glacial acetic acid and 1 ml of 30~ hydrogen peroxide,
were stirred for 24 hours at room temperature. The mix-
ture was then poured onto ice, made alkaline with concen-
trated ammonia solution, and the crystalline precipitate
was suction filtered, washed well with water and dried;
yield: 580 mg ~85%) of 2,4-diamino-5-J 3,5-dimethoxy-4-
(methylsulphonyl)-benzyl~-pyrimidine, M.P. 297-298C
(with decomposition).
Example 8
9 g of 2,4-diamino-5-~3,5-dimethoxy-4-mercaptobenzyl)-
pyrimidine-hydrochloride~ 4.1 g of potassium carbonate
and 2.5 g of dimethylsulphate were heated in 80 ml of
acetone for 16 hours under reflux. The reaction solu-
tion was filtered, the solvent was removed, and the re-
sidue was taken up in ethyl acetate and washed with water.
On concentrating the dried solution by evaporation, 2.7 g
~88~) of colourless 2,4-diamino-5-/ 3,5-dimethoxy-4-
(methylthio)-benzyl/-pyrimidine having a M.P. of 230-232C
cryatallised out.
(' Example 9
A solution of 23 g of sodium nitrite in 60 ml of
water was added dropwise to a suspension, kept at 0-5C,of63.3g
of methyl 4-amino-3,5-dimethoxybenzoate in 300 ml of water
and 75 ml of concentrated hydrochloric acid. The now
clear,orange-coloured solution was dripped into an ice-
cold, vigorously stirred solution of 80 ~ of potassium
methyl xanthogenate in 300 ml of water, whereupon a vigor-
ous evolution of gas was observed. After stirring for 4
hours at room temperature the product was extracted with
ethyl acetate, and the extract was washed with sodium
chloride solution and dried over sodium sulphate. 54 g
(60%) of crude S-/ 4-(methoxycarbonyl)-2,6-dimethoxy-
phenyl~-O-methyldithiocarbonate, having a M.P. of 113-115C,
~re obtained from the residue remaining after evaporation.
:
- : ~ :
.. . ..
- ~8 _ ~ ~ S~ ~ ~
A mixture of 29 g of S-/ 4-(methoxycarbonyl)-2,6-
dimethoxyphenyl/-0-methyldithiocarbonate and 2 g of pot-
assium methyl xanthogenate was stirred in 450 ml of di-
methylformamide for one hour at 100C. The ~olvent was
then removed under reduced pressure and the residue was
taken up in ethyl acetate. After washing with water and
saturated sodium chloride solution, the residue was dried
over sodium sulphate and the solvent was removed. The
residue provided, after recryqtallisation from cyclohex-
ane, 18.8 g ~81%) of methyl 3,5-dimethoxy-4-(methylthio)-
benzoate in the for~ of colourless crystals having a
M.P. of 86-88C.
50 g of morpholine in 200 ml of toluene was added
dropwise to a solution, cooled to 0C, of 150 g of sodium
dimethoxyethoxy alanate t70% in toluene) in 150 ml of
toluene. The clear solution was then stirred at 0C and
added dropwi~e while Qtirring to a solution, cooled to
-20C, of 30 g of methyl 3,5-dimethoxy-4-(methylthio)-
benzoate in 700 ml of toluene. The mixture was stirred
for a further 5 hours and then 100 ml of water wa~ slow-
ly added dropwise, 100 ml of 3N hydrochloric acid was
added, and finally the pha~es were separated in a separa-
ting funnel. The aqueous phase was extracted twice with
ethyl acetate while the organic phases were washed with
sodium chloride solution and dried over sodium sulphate.
Concentration of the solution resulted in 26 g of a yel-
low oil that crystallised completely and, after recry-
stalli~ation from ethyl acetate/pentane, yielded 21 g
~78%) of 3,5-dimethoxy-4-~methylthio)-benzaldehyde hav-
ing a M.P. of 54-56C.
Example 10
.
In a manner analogous to that described in Example 9,
21 1 g of methyl 4-amino-3,s-dimethoxybenzoate were con-
verted into 19 g ~68%) of S-/ 4-methoxycarbonyl)-2,6-
dimethoxyphenylJ-0-ethyldithio carbonate having a M.P. of
84_86C, and the latter wa~ further converted in 90%
, . - .~ . ,-
.~ . ~ . ,
6~1
yield into methyl 3,5-dimethoxy-4-ethylthiobenzoate hav-
ing a M.P. of 50-52C.
120 ml of a 20% diisobutyl aluminium hydride solu-
tion in hexane were added dropwise within 10 minutes to a
solution of 10.8 ~ of methyl 3,5-dimethoxy-4-(ethylt~o)-
benzoate in 100 ml of absolute ether stirred at 0C. The
resulting mixture was stirred for a further 2 hours at
0_5C, 100 ml of water was slowly added dropwise ~ollowed
by 150 ml of 3N hydrochloric acid, and the product was
taken up in ether-and washed till neutral. The solution
was dried over sodium sulphate, the solvent was removed,
and the remaining yellow oil (11.2 g) was ta~en up in
100 ml of methylene chloride and the solution was stirred
at room temperature in the presence of 15 g of manganese
dioxide. After 3 hours a further 15 g o~ manganese dioxi-
de was added. The resulting mixture was then stirred for
3 hours, filtered through a filter aid based on diatomace-
OU9 earths, and the filtrate was then concentrated by
evaporation. The residue, when crystalli~ed from ether/
pentane, yielded 9.2 g t96.5%) of 3,5-dimethoxy-4-
(ethylthio)-benzaldehyde in the form of colourless crys-
tals havin& a M.P~ of 38-39C.
Example 11
In a manner similar to that described in Example 9,
21.1 g of methyl 4-amino-3,5-dimethoxybenzoate were con-
verted into 23 g (66%) of S-/ 4-(methoxycarbonyl)-2,6-
dimethoxyphenyl/-0-(2-methoxyethyl)-dithiocarbonate of
M.P. 86-88C, the latter was further converted in a 42%
yield into methyl 3,5-dimethoxy-4-(2-methoxyethylthio)-
benzoate of M.P. 56-58C, and finally reduced to 3,5-
dimethoxy-4-(2_methoxyethylthio)_benzaldehyde (yield 88%).
Example 12
48 g of ethyl 3,5-dibromo-4-nitrobenzoate were added
in portions at 15-30C under a nitrogen atmosphere and
~ : , . . ~- :
, , . ~ . . : : ; : ~:
1~8611
- 30 -
while stirring and cooling with iced water, to a sus-
pension of sodium mercaptide prepared from 35.5 g of a
55% sodium hydride dispersion in mineral oil and 270 ml
of dimethylPormamide and 39.6 g of methyl mercaptan in
190 ml of dimethylformamide. The mixture was stirred for
4 hours at room temperature, poured into 4 l of water,
the precipitated crystals were combined with the ether
extracts from the filtrate, and the solvent was removed.
Recrystallisation of the residue from ether/petroleum
ether yielded 10.2 g of ethyl 3,4,5-tris-(methylthioJ-
benzoate. The aqueous filtrate obtained during the work-
ing up was cooled and adjusted to pH 2 with concentrated
hydrochloric acid, and the solid material was suction
filtered and dried. After esterification with ethanol/
HCl, 28 g of a mixture of ethyl 3-bromo-4,5-bis-~methyl-
thioJ-benzoate and ethyI 3,4,5-tris-~methylthio)-benzoate
(weight ratio approx. 1:1) was obtained, which was separ- .
ated by column chromatography on silica gel using methy-
lene chloride as eluting agent. 13.8 ~ (32%) of ethyl
3-bromo-4,5-bis-(methylthio)-benzoate of M.P. 69-71C and r
12.8 g (in all 23 g, i.e. 60%3 of ethyl 3,4,5-tris-(methyl-
thio)-benzoate o~ M.P. 89-93C were obtained.
On esterifying the mixture with methanol/HCl and work-
ing up in an analogous manner, methyl 3-bromo-4,5-bis-
(methylthio)-benzoate of M.P. 105-106C and methyl 3,4,5-
tris-~methylthio)-benzoate of M.P. 122-124C were obtained.
In a manner similar to that described in Example 10,
35.9 g of methyl 3-bromo-4,5-bis-(methylthio)-benzoate
were then reduced in 62% yield to 3-bromo-4,5-bis-(methyl-
thio)-benzaldehyde, and 24.1 e of methyl 3,4,5-tris-
(methylthio)-benzoate were reduced in 58~ yield to 3,4,5-
-tris-(methylthio)-benzaldehyde of M.P. 160-161C.
In another embodiment methyl 3-bromo-4,5-bis-(methyl-
thio)-benzoate and methyl 3,4,5-tris-(methylthio)-benzoate
were prepared as follows:
(a) 1.76 g of ethyl 4-nitro-3,5-dibromobenzoate was added
in portions at 15-25C under a nitrogen atmosphere and
~ 36~1
- 31 _
while stirring and cooling with iced water,to a suspen-
sion of sodium mercaptide prepared from 0.55 g of 55~
sodium hydride dispersion (in mineral oil) in 10 ml of
dimethylformamide and 1 ml of methyl mercaptan in 6 ml
of dimethylformamide. The reaction mixture was then
stirred for 20 minutes at room temperature, evaporated
to dryness under a high vacuum at 45C, 30 ml of water
was added to the residue, and the latter was then extrac-
ted with ether. The ether extract was dried, filtered,
and concentrated by evaporation. 1.5 g t94%) of ethyl
3-bromo-4,5-bis-~methylthio)-benzoate of M.P. 72-73C
were obtained from the residue after recrystallisation
from hot n-heptane.
~b) 28 g of ethyl 4-nitro-3,5-dibromobenzoate was added
in portions at 15-25C under a nitrogen atmosphere and
while stirring and cooling with iced water to a suspen-
sion of sodium mercaptide prepared from 20.7 g of 55~
sodium hydride dispersion (in mineral oil) in 160 ml of
dimethylformamide and 27 ml of methyl mercaptan in 110 ml
of dimethylformamide. The reaction mixture was then
stirred for 4 hours at room temperature, evaporated to
dryness under a high vacuum at 45C, 750 ml of water
was added to the residue, and the latter was extracted
5 times with ether, each time with 150 ml of ether. The
ether extract wa~ dried, filtered,and concentrated by
evaporation. 16.5 g ~75%) of ethyl 3,4,5-tris-~methyl-
thio)-benzoate of M.P. 90-92C were obtained from the
residue after recrystallisation from hot n-heptane.
Exa_ple 13
20 ml of methyl mercaptan was added to a suspension,
cooled to 0C, of 10.8 g of sodium methylate in 150 ml
of methanol. The mixture was stirred for 30 minutes at OC
and 13.6 g of ethyl 3,5-dibromo-4-nitrobenzoate were
added, resulting in a thick suspension. ~.fter 5 minutes
the reaction mixture was concentrated by evaporation,
.. ... .. ~
3611
- 32 -
the residue was extracted with ether, and the extract
was washed with water. After recrystallisation from me-
thanol, 13 g (92%) of methyl 3,5-dibromo-4-(methylthio)-
benzoate of M.P. 101-102C were obtained
In a manner analogous to that described in Example
10, 14.7 g of methyl 3,5-dibromo-4-(methylthio~-benzoate
were reduced in 83% yield to 3,5-dibromo-4-~methylthio)-
benzaldehyde of M.P. 87-89C.
Example 14
A mixture of 22 g of ethyl 4-amino-3,5-dibromoben-
zoate, 100 ml of acetic acid, and 14.4 g of 2,5-diethoxy-
tetrahydrofuran was kept for one hour at 100C and then
concentrated by evaporation under reduced pre~sure. The
dark residue was taken up in ethyl acetate, the solution
was first washed with sodium bicarbonate solution and then
with ~odium chloride solution, and was finally dried over
~odium sulphate and evaporated to dryness. 20 g (60%) of
ethyl 3,5-dibromo-4-pyrrolo-benzoate of M.P. 106-107C
were obtained from ether/petroleum ether. 18.5 g of this
compound in 40 ml of warm dimethylformamide was added
dropwi~e to a solution, stirred at room temperature, of
methyl mercaptide ~prepared from 6 g of sodium hydride and
approx. 15 g of methyl mercaptan in dimethylformamide)
in 100 ml of dimethylformamide. The resulting solution
was stirred for a further 16 hours at room temperature,
concentrated by evaporation, taken up in ethyl acetate,
adjusted to pH of 2 with hydrochloric acid, washed with
saturated Aodium chloride Aolution, dried over sodium
sulphate, and reconcentrated by evaporation. The resi-
due was esterified in ethanol/HCl and the solution was
then concentrated by evaporation. 8.8 g (57%) of crystal-
line ethyl 3,5-bi~-~methylthio)-4-pyrrolo-benzoate of
M.P. 108-109C were obtained from the residue dissolved
in ether, after addition of hexane.
.- . , . . ~ ~ .
.
- .;
.
11~86~1
- 33 -
In a manner similar to that described in Example 10,
21 g of ethyl 3,5-bis-~methylthio)-4-pyrrolo-benzoate
were then reduced in 67% yield to 3,5-bis-~methylthio)-
4-pyrrolo-benzaldehyde of M.P. 146-148C.
Example 15
6.2 ml (5.0 g) of methyl mercaptan was added dropwise
to a suspension, stirred at 0C, of 4.7 g of sodium hy-
dride t50~), freed from oil by washing twice with pentane,
in 100 ml of dimethylformamide. After 15 minutes, 12.25 g
of 3,5-dimethoxy-4-bromobenzaldehyde in 50 ml of dimethyl-
formamide wa~ added dropwise. The brown solution, which
became lighter in colour, was stirred for half an hour
at room temperature, poured onto iced water, and the mix-
ture was then extracted with ethyl acetate. The extract r
was washed with water, cold 1N hydrochloric acid and
saturated sodium chloride solution, dried over sodium sul-
phate, and the yellow oil remaining after removal of
the solvent wa~ crystallised from methanol. Yield 8.9 g
(84%) of 3,5-dimethoxy-4-(methylthio)-benzaldehyde of
M.P. 55-56C.
Example 16
A solution of 18 g of methyl mercaptan in 70 ml of
dimethylformamide was added dropwiqe while stirring and at O-5C
under a nitrogen atmosphere to a suspension of 1~.5 g of
sodium hydride (55%) in 200 ml of dimethylformamide. Af-
ter 30 minutes' stirring at room temperature, 1.5 g of
cuprous chloride followed by 21 g of 3,5-dibromo-4-hy-
droxybenzaldehyde were added. The reaction mixture was
stirred for 68 hours at 120C, a further 1.5 g of cuprous
chloride wa~ added, and the reaction mixture was then
stirred a further 20 hours at 150C. The mixture was
then concentrated by evaporation in a high vacuum, the
residue was taken up in 10% NaCl solution, and the solu-
tion was then filtered through diatomaceous earth. The
aqueou phase was extracted with ether, acidified with
.... . :-
. . . .: .: , ~
~: . ... . .
. , ~: .. ~ :.
- 34 _
concentrated hydrochloric acid, while cooling, and ex-
tracted with ethyl acetate. The ethyl acetate extract~
washed with water were dried and concentrated by evapor-
ation, 9 g of the mixture obtained (in all 14 g) were
dissolved in 90 ml of acetone, and 10.7 g of potassium
carbonate were added. 7.5 ml of dimethyl
sulphate were added to the resultant suspension. The
reaction mixture was stirred for 18 hours at 5QC and
then suction filtered, and the inorganic salts were -;
washed with acetone and the filtrate was concentrated
by evaporation. The evaporation residue was dissolved
in ethyl acetate, washed in succession with concentrated
ammonia and water, and ~eparated using heptane/acetone
t7:1, v/v). 3-bromo-5-methylthio-anisaldehyde of M.P.
54-56C, yield 3.5 g, was first eluted, followed by
3,5-bis-(methylthio)-anisaldehyde of M.P. 84-86C ~from
n-heptane), yield 2.6 g.
Example 17
27.3 g of 1-methyl-3,4-dithiophenol (prepared from
4-methylanthranilic acid according to Synthesis 1976,
471) in 110 ml of ethanol were added dropwise within
20 minutes to a solution of 23 g of 85a potaqsium hy-
droxide in 1gO ml of ethanol. 49.6 g of methyl
iodide in 70 ml of ethanol was added after 45 minutes
to the solution, the KI that had precipitated out after
30 minutes' stirring was filtered off, the ethanol was
evaporated off, and the 3,4-bis-~methylthio)-toluene obtained
was distilled at 95-98C/1 mm Hg. Yield 30.0g (93%),
M.P. 38-39C (heptane).
21.6 6 of phosphorus oxychloride was added drop-
wise at 15-20C to a solution of 27 g of 3,4-bis-(methyl-
thio)-toluene in 20 g of N-methylformanilide, and the
solution was stirred for 24 hours at 55C. A suspension
of 9.6 g o~ N-methylformanilide and 10.8 g of phosphorus
oxychloride wa~ then added to the reaction solution,
which was stirred for a further 24 hours at 55C. Water
.
; .
8~1
-35-
was added to the cooled mixture, the latter was extrac-
ted with ether, the combined extracts were dried and
evaporated to dryness, and the residue was chromatographed
on silica gel using benzene. 14.7 g of 3,4-bis-(methyl-
thio~-6-methylbenzaldehyde of M.P. 51-52C (heptane)
were obtained.
In an analogous manner, 1,2-bis-(methylthio)-benzene
was obtained in an 83% yield from 1,2-dithiophenol, and was
converted in 39~ yield into 3,4-bis-(methylthio)-benzaldehyde
of M.P. 50C.
Example 18
18 g of syringaldehyde followed by 15 g of dimethyl-
thiocarbamoyl chloride were added in portions to a sus-
pension, stirred at 0C, of 2.64 g of sodium hydride in
150 ml of dimethylformamide in such a way that the inter-
nal temperature did not exceed 10C. The reaction mixture
was then stirred for 4 hours at room temperature, taken
up in ethyl acetate, washed in succession with cold
3N hydrochloric acid, lN caustic soda and saturated so-
dium chloride solution, and dried. 16.2 g (60%) of 0-
(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethyl-thiocarbamate
of M.P. 173-176C crystallised, after addition of hexane
from the solution concentrated by evaporation.
14.5 g of 0-(4-formyl-2,6-dimethoxyphenyl)-N,N-
dimethyl-thiocarbamate were heated for 2 hours at 220C,
cooled, and crystallised from ethyl acetate/hexane. 12.1 g
(83%) of S-(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethyl-
thiocarbamate of M.P. 183-186C were obtained.
This compound was converted by basic hydrolysis
into 3,5~ethoxy-4-mercapto-benzaldehyde.
0-(4-formyl-2-methoxyphenyl)-N,N-dimethyl-thiocar-
bamate of M.P. 114-115C was prepared in 78.5% yield in
a similar manner from ~anillin, and was then converted
in 83% yield into S-(4-formyl-2-methoxyphenyl)-N,N-di
methyl-thiocarbamate of M.P. 109-110C and finally
hydrolysed to 4-mercapto-3-methoxybenzaldehyde.
~. ,
.. . : .. ' !
," . :: '' '
.. ': ~ . , :
36~1
- 36 -
Example 19
A suspension of 1.6 g of 2,4-diamino-5-/ 4-(N,N-
dimethyl-carbamoylthio)-3,5-dimethoxybenzyl7-pyrimidine
in 25 ml of methanol and 25 ml of 3N caustic soda was
heated for 16 hours under reflux and under an argon at-
mosphere, whereupon 2 clear solution was formed. The
crystalline precipitate that separated out on cooling
was suction filtered and dissolved in 20 ml of water and r
10 ml of methanol. 500 mg of sodium borohydride was
added to the solution, the latter was allowed to st~nd
for one hour and then acidified to pH 3 with 3N hydro-
chloric acid, and the crystals formed were suction fil-
tered and dried under a high vacuum. 0.8 g ~62%) o~
2,4-diamino-5-~4-mercapto-3,5-dimethoxybenzyl)-pyrimidine-
hydrochloride of M.P. 275-277C was obtained.
Example 20
86 g of guanidine hydrochloride were added to a 901u-
tion of 20.7 g of sodium in 250 ml of methanol. After
filtration, the solution was added dropwise at 95C within
30 minutes to a solution of 98 g of freshly prepared
3,5-dimethoxy-4-(methylthio)- ~ -(2-methoxyethoxymethylene)-
hydrocinnamic acid nitrile in 250 ml of ethylene ~lycol
monomethyl ether, the methanol being continuously distil-
led off. The temperature was raised for one hour to
120C and during this time 200 ml of solvent were dis-
tilled off under reduced pressure. The reaction mixture
was then cooled to 0C and 400 ml of water were added.
The cr-Jstalline precipitate was suction filtered and
then washed in succession with water, ethanol and ether.
Yield: 59 g of colourless 2,4-diamino-5-/ 3,5-dimethoxy-
4-~methylthio)-benzyl7-pyrimidine of M.P. 219-223C.
The starting material was prepared as follows:
71 g of ~-methoxy-ethoxypropionitrile was added
dropwise to a solution of 3.5 g Qf Yodium in 500 ml of
anhydrous ethylene glycol monomethyl ether. The solu-
tion was heated to 90C and 106 g of 3,5-dimethoxy-4-
. , :
.
,
., ; :.
.~ :
_ 37 _ ~ 6~
(methylthio)-benzaldehyde was added in portions while
stirring. The reaction mixture was heated to 125C,
50 ml of solvent distilling off. Residual solvent was
remo~ed under reduced pressure at 65C and the residue
was taken up in ethylene chloride and washed 3 times,
each time with 300 ml of water. The aqueous pha~es were
extracted twice with 300 ml of ethylene chloride, and
the combined organic phases were dried over sodium sul-
phate and evaporated to dryness. The dark oil ~155 g)
obtained was distilled under a high vacuum at 200C and
yielded 98 g (60~) of 3,5-dimethoxy-4-~methylthio)_~-
(2-methoxy-ethoxymethylene)-hydrocinnamic acid nitrile
in the form of a vi~cous yellow oil, which was immed-
iately processed further.
Example 21
1.35 g of sodium methylate was added to a solution
of 5.3 g of 3,5-dimethoxy-4-~methylthio)-benzaldehyde
and 3.1 g of ~-imidazolyl propionitrile in 50 ml of
ethanol, and then heated for 5 hours under reflux. To the
brown solution was added a suspension of 4.8 g of
guanidine hydrochloride and 2.7 ~ of sodium methylate
in 50 ml of ethanol. The ethanol was distilled off and
the residue was then ~tirred for 90 minutes at 100C.
The reaction mixture was suspended in water and filtered,
and the filtrate was concentrated by evaporation and the
re~idue was recrystallised from ethanol/ether. 3.6 g
~48%) of 2,4-diamino-5-/ 3,5-dimethoxy-4-(methylthio)-
benzyl/-pyrimidine of M.P. 224-227C were obtained in the
form of bright yellow crystals.
Example 22
0.6 g of hydrogen peroxide (30%) was added to a solu-
tion of 1.6 g of 2,4-diamino-5-/ 4-~ethylthio)-3,5-
dimethoxybenzyl~-pyrimidine in 30 ml of acetic acid and
the mixture was stirred for 4 hours at room temperature.
The mixture was then poured onto ice, adjusted to a pH of
- 38 -
10 with concentrated ammonia solution, and the precipi-
tated crystals were suction filtered. APter recrystalli-
sation from methanol~ether, 1.45 g (86%) oP 2,4-diamino-
5-/ 4-ethylsulphinyl)-3,5-dimethoxybenzylJ-pyrimidine
were obtained in the Porm of colourless needles, M.P.
256-258C (with decomposition).
Example 23
2.1 ml oP 30% hydro~en peroxide was added to a solu-
tion of 5.82 g oP 2,4-diamino-5-/ 3,5-dimethoxy-4 (methyl-
thio)-benzyl~-pyrimidine in 130 ml of glacial acetic acid.
(~ The mixture was stirred Por 7 hours at room temperature.
70 ml oP this solution were poured onto approx. 70 g
oP ice, the mixture was made alkaline with concentrated
ammonia while cooling, suction filtered, the residue was
suspended in a small amount of concentrated ammonia and
then, after decanting, triturated with ethyl acetate,
suction filtered and dried. 1.25 g oP crude 2,4-diamino-
5-~ 4-methoxy-3-methylsulphinyl-5-methylthiobenzyl/-
pyrimidine was obtained, while 0.4 g oP pure product of
M.P. 215-217C was obtained from the ammoniacal filtrate
by extraction with ethyl acetate and evaporation to dry-
ness .
( A further 0.6 ml of 30% hydrogen peroxide was added
to the other part oP the reaction mixture, and stirred
overnight at room temperature. After working up in a
similar manner and recrystallisation from ethanol, 300 mg
oP 2,4-diamino-5-/ 4-methoxy-3,5-bis-(methylsulphinyl)-
benzyl/-pyrimidine of M.P. 178-180C was obtained.
Example 24
36 g of 2,4-diamino-5-~ 3,5-dimethoxy-4-(dimethyl-
carbamoylthio)-benzyl7-pyrimidine was added at room tem-
perature under a nitrogen atmosphere to a suspension of
sodium mercaptide prepared from 10 g oP 55% sodium hy-
dride dispersion (in mineral oil) in 200 ml of dimethyl
formamide and 11 g of methyl mercaptan in 50 ml of di-
.
~. :: ~ . : . :
::
~86~
- 39 -
.
methylformamide. The mixture was stirred ~or 3 hours
at 55C, ethyl bromoacetate (24.5 ml) was then added
dropwise at 15-25C, and the mixture was stirred for a
further hour at room temperature. The solution was con- -
centrated by evaporation in a high vacuum, the residue
was taken up in 1N HCl, the solution was washed with
ether, adjusted to pH 8 by adding 1N NaOH while cooling
with ice, was then suction filtered, and the residue was
washed well with water and dried. Yield: 32 g (84~6p)
of 2,4-diamino-5-~ 4-(carbethoxymethylthio)-3,5-dimethoxy-
benzyl7-pyrimidine of M.P. 156-161C.
C
Example 25
A mixture of 9.5 g of 2,4-diamino-5-/ 4-carbethoxy-
methylthio)-3,5-dimethoxybenzyl~-pyrimidine, 75 ml of
ethanol, 50 ml of water and 27.5 ml of 1N NaOH was stir-
red for 2 hours. After filtration, the ethanol was re-
moved under reduced pressure, and the residue was neutra-
lised by adding 27.5 ml of 1N HCl, suction filtered, wash-
ed with water and dried. 7 g of 2,4-diamino-5-~ 4-~ar-
boxymethylthio)-3,5-dimethoxybenzyl~-pyrimidine of M.P.
280C (with deccap~sition) was obtained.
Example 26
3.6 g of 2,4-diamino-5-~ 3,5-dimethoxy-4-(dimethylcar-
bamoylthio)-benzyl~-pyrimidine was added at room tempera-
ture and under a nitrogen atmosphere to a solution of so-
dium mercaptide prepared from 1 g of 55% sodium hydride
dispersion ~in mineral oil) in 20 ml o~ dimethylformamide
and 1.1 g of methyl mercaptan in 5 ml of dimethylformamide.
The mixture was stirred for 2 hours at 55C and 5-bromoval-
eronitrile (2.5 ml~ was then added dropwise at 15-25C and
the mixture was stirred for a further hour at room temp-
erature. The solution was concentrated by evaporation in
a high vacuum, and the residue was triturated with ether,
suction filtered, suspended in water, and again suction fil-
tered. 1.9 g Or 2,4-diamino-5-~ 4-(4-cyanobutylthio)-
,. . "- ~ . . :: , . -
,,, , ., ~ ~ : -:, : :" . :,
- 40 -
3,5-dimethoxybenzyl~-pyrimidine of M.P. 186-188C was ob-
tained after double recrystallisation from methanol.
Example 27
5.45 g of 2,4-diamino-5-/ 3,5-dimethoxy-4-(dimethyl-
carbamoylthio)-benzyl/-pyrimidine was added to a suspension
of sodium mercaptan prepared from 1.44 g of 55 sodium hy-
dride dispersion (in mineral oil) in 30 ml of dimethylform-
amide and 1.94 ml (1.58 g) of methyl mercaptan in 7.5 ml
of dimethylformamide. The mixture was stirred for one
hour at 55C and then 4.57 g of 1-(2-chlorethoxy)-2-methoxy-
ethane was then added at 20C. APter 10 minutes at room
temperature, the reaction mixture was worked up in the us-
ual manner and, after recrystallisation from methanol, 2,4-
diamino-5-~ 3,5-dimethoxy-4-~2-(2-methoxyethoxy)-ethylthio~ -
benzyl/-pyrimidine of M.P. 161-162C was obtained, which
was shown by thin layer chromatography to be of uniform
composition.
Example 28
A mixture of 3.6 g of 2-(2-chlorethoxy)-2'-methoxy-
diethyl ether, 3.1 g of sodium-4-/T2,4-diamino-5-pyrimi-
dinyl)-methyl/-2,6-dimethoxyphenyl thiolate and 30 ml of
dimethylformamide was stirred for 2 hours at 80C, suction
filtered, and the filtrate was evaporated to dryness.
The residue was triturated with ether, suction filtered,
washed with water and dried. The crude product obtained
(3.5 g) was purified by column chromatography on silica
gel using methanol/propanol/NH40H (5:5:0.5; v/v/v) and
yielded 1.8 g of pure 2,4-diamino-5- ~3,5-dimethoxy-4-/2-~-
(2-methoxyethoxy)-ethox~ ethylthio/-benzyl~-pyrimidine of
M.P. 130-131C.
Example 29
Tablets of the following composition were prepared:
- . ~ -
8Ç~1
- 41 -
mg/tablet
2,4-diamino-5-/ 3,5-dimethoxy-4-
(methylthio)-benzyl7-pyrimidine 50.00
Cold swelling starch 12.50
Sodium carboxymethyl ~tarch12.50
Powdered lactose 143.75
Magnesium stearate 1.25
220.00
The mixture was granulated wet with addition of
water and pressed into tablets.
(. ~
. , . ~ ~;
