Note: Descriptions are shown in the official language in which they were submitted.
Z9~5
This invention relates to 2-iminomethyl-3',4',5'-tri-
me-thoxycinnamic acid and esters thereof having the formula
CH O
~ COOR
~ I ,,
3 ~ ~ CH = C
\ CH = NH
wherein R is a hydrogen atom or an alkyl group having 1-4
carbon atoms, being useful as intermediates in the produc-
tion of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimi-
dine. The latter is a known compound, also called trimetho- i
prim, and has the formula
CH~O
3 ~ CH2 ~ ~ 2
CH30 NH2
Trimethoprim shows a useful antibacterial and sulphon-
amide-potentiating effect.
lo The inven-tion also relates to a process for the pro-
duction of the compounds of formula I.
It is known that the ethyl ester of 3,4,5-trimethoxy-
benzylidene-cyanoacetic acid having the formula
CH O
~ . COOC2H5
3 ~ CH = IC III
~ ..
CN
~ CH30
can be reduced in acid medium to form 3,4,5-trimethoxybenzyl-
cyanoacetic acid ethyl ester having the formula
CH O
,~ COOC2H5
; 3 ~~ CH2 - CH IV
.\ CN
-- 2 --
-
L04~
as a colourless oil, and that the said compound can be con-
densed with guanidine to form 2,4-diamino-6-hydroxy-5-(3',
; 4',5'-trimethoxybenzyl)-pyrimidine having the formula
CH30 H0
CH~0. ~ CH2 ~ ~ ~ 2
CH30 NH2
which again can be converted into trimethoprim by removal
of the 6-hydroxy group.
The said known method is disadvantageous in that re-
duction of the compound of formula III yields a compound,
formula IV 9 which owing to its physical properties is only
very difficultly recovered in an even tolerably pure s-tate.
lo This means that the compound of ~ormula V, which is produced
by condensation wi-th guanidine, and/or the trimethoprim pro-
duced therefrom, has to be subjected to further cost-adding
purifications in order to get a pharmaceutically acceptable
product
The object of the present invention is to overcome the
said disadvantage by providing an intermediate suitable ~or
the production o~ trimethoprim, which is easily recovered in
a pure state by crystallisation, instead of the compound of
formula IV.
It has surprisingly been found that this is possible,
when using, as an intermediate in the production of trime-
thoprim, hitherto unknown 2-iminomethyl-3',4',5'-trime-th-
oxycinnamic acid compounds which according to the inven-
tion are characterized in having the formula I, wherein R
is a hydrogen atom or an alkyl group having 1-4 c~rbon atoms.
According to the invention, the compounds of ~ormula I
can be produced under mild conditions, at room temperature,
. . . ......
~L~4Z9~5
by reduction in a neutral or alkaline medium of 3,4,5-trimethoxy-
benzylidene-cyanoacetic acid or an ester thereof of the formula
CH30 COOR
CH30 ~/ r CH =f II
CN
CH3O
wherein R is a hydrogen atom or an alkyl group having 1-4 carbon
atoms. The resulting compound of formula I can be isolated in
crystalline form, and it is recovered in quantitative yield. It
is thus extremely pure and will give extremely pure products when
used as an intermediate in the production of trimethoprim.
The reduction of the compound of formula II may be
carried out in any suitable solvent, such as ethanol, but according
to the invention particularly good results are obtained by using
pyridine bases, preferably picoline, as a solvent.
Trimethoprim can be produced from the present compounds
of formula I by first condensing with guanidine to obtain the
formerly mentioned 2.4-diamino-6-hydroxy-5-~3',4',5'-trimethoxy-
benzyl)-pyrimidine of formula V, which in known manner is converted
into trimethoprim by removing the 6-hydroxy group.
In the following the production and use of the present
intermediates is illustrated by some Examples.
Example 1
2-Iminomethyl-3',4',5'--trimethoxycinnamic acid ethyl ester
.
58.2 grams (0.2 mole) of 3,4,5-trimethoxy-benzylidene-
cyanoacetic acid ethyl ester and 1 gram of Pd/C ~10%) in
-" ~L0~29~s
380 ml of 2-picoline were s-tirred at room temperature under
a hydrogen pressure of 10 atmospheres, until no more hydro-
gen was consumed, when stirring was continued for further
two hours. The catalyst was filtered off, and the picoline
was evaporated in va uo. The residue was dissolved in 150
ml of hot ethanol. By cooling, 58.5 grams (100%) of 2-~ino-
methyl-3',4',5'-trimethoxycinnamic acid ethyl ester with
melting point 48-49C crystallized.
lo Example 2
2-Iminometh~1-3',4',5'-trimethoxycinnamic acid ethyl ester
8,73 grams (0.030 mole) of 3,4,5-trimethoxy-benzylidene-
cyanoacetic acid ethyl ester were dissolved in 130 ml o,f an-
hydrous e-thanol. There was added 0.1 gram palladium on car-
bon (10%), and the mixture was placed in a hydrogenation au-
toclave. Hydrogen was supplied to a pressure of 11 atmos-
pheres, and the reaction mixture was left with stirring, un-
til one equivalent of hydrogen had been consumed, when the
reaction stopped. Pouring out of the reaction mixture dis-
closed that a white subs-tance had crystallized. The mixture
was heated to 50C, resulting in the said white substance
dissolvin~; the catalyst was filtered off, and 6.31 grams of
the white product crystallized by cooling. Partial evapora-
tion of the paren-t lye yielded further 2.29 grams, making a
total yield of 8.60 grams, 97.0%. After recrystallization
from anhydrous eth~nol, the compound melted at 48-49C.
Use of the intermediate in the production of trimetho-
prim is illustra-ted by the following Examples.
Example 3
2,4-Diamino-6-hydrox~-5-(31,4',~5'-trimeth~ybenzyl)~ imidine
42~
To a mixture of 14.7 grams (0.050 mole) of the ethyl
ester of 2-iminome-thyl-3',4l,5'-trimethoxycinnamic acid and
4.78 grams (0.050 mole) of guanidine hydrochloride in 150
ml of toluene were added 5.4 grams (0.10 mole) o~ sodium
methoxide. The reaction mixture was refluxed for 11 hours.
The toluene was removed in vacuo by suction, and the resi-
due was dissolved in dilute aqueous sodium hydroxide. Acetic
acid was added to the solution to pH 4-6, resulting in the
precipitation of an almost white product. The produc-t was
lo removed by filtration, washed with water, and dried7 Yield r
13.2 grams, 86.3%.
r
Example 4
a) 6-Chloro-2 4-diamino-5-(3' L4~ ,5'-trimethox;ybenz~ pyri-
_idine
A mixture of 15.6 grams (0.051 mole) of 2,4-diamino-6-
hydroxy-5-(3',4',5'-trimethoxybenzyl)-pyrimidine and 75 mI
of phosphorus oxychloride was heated on a steam bath ~or
three hours. Excess of phosphorus oxychloride was removed
i
in vacuo by filtration with suction. Ice was added to the
residue, and potassium carbonate was added to pH 8. The pre- P
cipitated substance was filtered off, washed with water, and
dried. Yield 14.1 grams~ 85.2%.
After recrystallization from nitromethane, the compound
melted at 218.5-220.5C.
b) 2,4-Diamino-5-(3',4't5'-trimethoxybenzYl)-pyrimidine r
~ 8.11 grams (0.025 mole) of 6-chloro-2,4-diamino-5-(3', It
`~ 4',5'-trime-thoxybenzyl)-pyrimidine were suspended in 300 ml
of 96% ethanol, and 0.6 gram o~ palladium on carbon (5%) was
added. Hydrogen at atmospheric pressure was supplied to the
suspension. After consumption of one equivalent of hydrogen,
-- 6 --
~ Z~L5
the reaction stopped. The reaction mixture was evaporated
almost to dryness, and dilute acetic acid was added. The ca-
talyst was removed by filtration. Aqueous sodium hydroxide
was added to make the parent lye alkaline, whereby 2,4-dia- ;mino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine precipitated.
The compound was removed by filtration, washed with water,
and dried. Yield 6.59 grams, 90.9%.
After recrystallization from ethanol, the compound
melted at 200.5-202.0C.
lo f
Example 5
a) 6-Chloro-2,4-diamino-5-(3' 4' ~-trimethoxybe
midine
A mixture of 15.6 grams (0.051 mole) of 2,4-diamino-6-
hydroxy-5-(3t,4',5'-trimethoxybenzyl)-pyrimidine and 75 ml
of phosphorus oxychloride was heated on a steam bath for
I four hours. Excess of phosphorus oxychloride was removed
I in vacuo by suction. Ice was added to the residue, and po-
tassium carbonate was added to pH 8. The precipitated com-
pound was sucked off, washed with water, and dried. Yield
14.9 g, 90.0%. ~
b) 2,4-Diami~o-6-hydrazino-~-(3'~4' ~ l,
pyrimidine
16.2 grams (0.050 mole) of 6-chloro-2,4-diamino-5-(3'-
4',5'-trimethoxybenzyl)-pyrimidine were suspended in 85 ml
of hydrazine hydrate. The mixture was refluxed to dissolve
~' the chlorinated compound. After an hour and a half, the
reaction mixture was cooled in ice water and the hydrazino
derivative crystallized. The compound was filtered from the
parent lye and washed with cold methanol on the filter.
Yield 15.1 grams, 94~. Mel ing point 159-162C.
. . .
~Z~S
c) 2,4-Diam no-5-(3'~4'.5'-trimethox~benzyl)-pyrimidine s
8.0 grams (0.025 mole) of 2,4-diamino-6-hydrazino-5-
(3',4',5'-trimethoxybenzyl)-pyrimidine were suspended in
100 ml of water. The mixture was heated to 100C, at which
temperature 250 ml of a 0.40 M aqueous solution of CuS04 ~;
were added dropwise during 3/4 hour. After the said addition,
-the mixture was cooled, and free Cu, precipitated during the
reaction, was filtered off. Ammonia was added to make the
parent lye alkaline, resulting in the precipitation of a
lo greyish green substance, which was removed by filtration,
and aqueous sodium hydroxide was added to the parent lye,
whereby a further amount of the greyish green substance was
precipitated and also filtered off. The two fractions of
substance were recrystallized from H20 and activated carbon
to yield 6.2 grams, 85.5%, of 2,4-diamino-5-(3i,4~,5'-tri-
methoxybenzyl)-pyrimidine with melting point 199.5-201.5C.
~.
.
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