Note: Descriptions are shown in the official language in which they were submitted.
77~
The present inverltion rela-tes to nove~ hasic ace-
tani.li.des, to a process for their preparation and to a phar-
maceutica1 composition con-taining these novel acetanilides.
The present invention provides novel compounds which
e.g. may be used as local anaesthesia and antiarrhythmic
active agents, and which show a lower toxicity and an improved
effectiveness over the compounds known in the ar-t.
The presen-t invention also provides processes for
preparing the novel compounds, which are easy to carry out
and which are economical.
According to the present invention there are pro-
vided basic acetanilides having the formula III
/ Rl
/j ~ I]:I
/ ----Nll-C~-C112-~5
o
R~
"~
~214776
WhC`I-eill 1~1 is l~ydrogerl or a lower allcyl ~1roup, a1~d 1~4 is
1~alo9e1l, a lower alkoxy, a nitro, amino, propiony1 or trl-
halomethyl, particularly a trifluoromethyl group and R5 is
a basic group selected from di lower alkyl amino, lower cyclo
alkyl amino, or a 6-membered heterocyclic group having at
least one nitrogen atom in the ring and their pharmacologi-
cally useful salts.
The process of the present invention Eor preparing
thc 1~ovel basic acetanilides of the formula III
~_
- ~214776
Nl-l -C -C~ R5 :[ I I
~
wherein R~ 4 and R5 are defined above, and their pharma-
cologically useful salts, is characterized in that an
lQ aniline of the formula I
_~ 1
/~ \ ~ I
N1~2
1~ ~'~< ' ,.
R4
wherein Rl and R4 are defined above, is reacted under cool-
ing or at room temperature in a solvent and in the presence
of a base with a halogen compound of formula II
X-CO-CH2-Hal II
wherein X is a hydroxyl group, an ester group, a halide, an
amide group or an anhydride group, and Hal is a halogen atom
to yield a compound of formula IV
--/ 1
~ l-l-co-c~l2-llal IV
wherein Rl, R4 and Hal are defined above, and that then
these compounds are reacted in an inert solvent at elevated
temperature with an amine delivering the group R5, and that
the obtained compounds may be transformed into their phar-
g - 3 -
77~
macoloqically ~Iseful salts.
The interrnediates of formula IV are prepared in
such a way that halogen fatty acids or other suitable
derivatives, such as esters, halides (e.g. acid chloride or
bromide), amides or anhydrides, are contacted with an
aniline under cooling or at room temperature in a solvent,
e.~. acetone, acetic acid, acetic acid ethylester, chloro-
form, in the presence of a base, such as sodiu~ carbonate,
lo potassium carbonate, sodium bicarbonate or potassium bi-
carbonate, sodium acetate, or in an aqueous sodium acetate
buffer. The halogen acetanilides of the general formula IV
are reacted with an amine in an inert solvent, preferably
benzene, at an elevated temperature.
The acetanilides of the general formula III may
also be prepared without isolation of the intermediate of
the formula IV, in that after the halogen alkanoylization
the corresponding amine is added to the reaction mixture in
a higher boiling inert solvent, e.g. toluene or xylene,
followed by heating this mixture.
The compounds of the general formula III, wherein
R4 is amino, may be prepared from the corresponding ace-
tanilides of the formula III, wherein R4 is nitro, by reduc-
tion.
The acetanilides of formula III, wherein R4 is
halogen, may be prepared either from the corresponding
anilines, as described above, or from the acetanilides,
wherein R4 is amino, with the Sandmeyer reaction.
The process of this invention may also be effected
in the presence of catalysts. A person skilled in the art
may easily determine the suitable reaction tempe~ratules and
reaction times~ Usually one works at standard pressur.,
- 4 -
776
whereby also excess pressure and under pressure (vacuum) are
not excluded.
The administration of the novel compounds of
formula III according to this invention is realized in a
conventional way, as this is known in the prior art for the
known compounds.
The preferred embodiments are illustrated in the
set of Examples, wherein also some nove~ starting materials
and intermediates are described and where the temperatures
are in C
A. With isolation of the intermediate of the
~ormula ~V
Example 1
To a mixture of 53 g (0.35 mol) 2-ethoxy-6-
methyl-aniline in 525 ml absolute acetone and 70 g sodium
bicarbonate are added drop by drop under cooling with ice
during one hour 46 g (0.4 mol) chloroacetyl chloride, and
then this mixture is stirred for one hour at room tempera-
ture. The inorganic salt is filtered with suction and
washed with acetone. The filtrate is evaporated in the
vacuum of a water jet pump, to the residue water is added,
and the precipitated crystals of 2-chloro-2'-ethoxy-6'-
methyl-acetanilides, mp. 148-149, are filtered with
suction.
Example 2
As described in Example 1, 2-chloro-2'-methyl-6'-
nitro-acetanilide is obtained, mp 140-141.5 when 2-methyl-
6-nitro-aniline is used instead of 2-ethoxy-6-methyl-ani-
line.
776
Alnillat.io
.Ex am~ :1. e
_ _
To 10.25 ~ (0.0~5 mol) 2-chloro-2'-ethoxy-6'-
methyl-acetarlilide in 10 ml benzene are added to 10 g (0.136
mol) diethylamine and this mixture is refluxed for 6 hours.
After cooling the precipitated die-thylamine hydrochloride is
filtered with suction, washed with benzene! and the filtrate
is evaporated in the vacuum of the water jet pump. To the
residue is added water and ether, the base is extracted from
the ether layer with 5% hydrochloric acid, the aqueous aci-
dic solution is rendered alkaline,and extracted with ether.
After drying and evaporation the ether the resiude is dis-
solved in ethanol, and under cooling, ethereal hydrochloricacid is added drop by drop, and the hydrochloride of 2-
diethyl amino-2'-ethoxy-6'-methyl-acetanilide, mp. 107-109 ,
is obtained.
Example 2
As described in Example 1, 2-piperidino-2~-ethoxy-
6'-methyl-acetanilide, mp. 79-80, is obtained, and the base
is reacted to the hydrochloride, mp. 192-193, when piperi-
dine is used instead of diethylamine.
Example 3
When pyrrolidine is used instead of diethylamine,
as described in Example 1, 2-pvrro]idino-2'-ethoxy-6'-
methyl-acetanilide, mp. 60.5-62 is obtained, which is
reacted to the hydrochloride, mp~. 180~181.5.
xample
As described in Example 1, 2-diethyla~ o-2'-
.~ \ 6 ~
776
methyl-6'-llitro-acetanilide, mp. 60~-61, is obtained from
2-chloro-2'-methyl-6'-nitro-acetanilide and diethylamine, as
well as its hydrochloride, mp. 166-168 .
Example 5
When piperidine is used instead of diethylamine~
as described in Example 4, 2-piperidino-2'-methyl-6'-nitro-
acetanilide, mp. 72-73, and its hydrochloride, mp. 192-
194, is obtained.
Example 6
As described in Example 1, the hydrochloride of
2-diethylamino-2'-trifluoromethyl-acetanilide, mp. 160.1,
is prepared, when 2-chloro-2'-trifluoromethyl-acetanilide
and diethylamine is used.
Example 7
When pyrrolidine is used instead of diethylamine,
as described in Example 6, the hydrochloride of 2-pyrroli-
dino-2'-trifluoromethyl-acetanilide, mp. 229.4, is obtai-
ned.
Example 8
As described in Example 1, the hydrochloride of
2-pyrrolidino-2'-propionyl-acetanilide is prepared, when
2-chloro-2'-propionyl-acetanilide and pyrrolidine are used.
Example 9
As described in Example 1, the hydrocllloride of 2-
35 pyrrolidino-2'-methyl-6'-propionyl-acetanilide, mp. 192.6,
is prepared when 2-chloro-2'-methyl-6'-propionyl-acetallilide
~r
f~ - 7 -
1~:14776
and pyrrolidine are used.
Tlle 2-methyl-6-propionyl-aniline, which is used as
startin~ material, is prepared as follows from 2-amino-3-
methyl-benzonitrile:
From 6.3 g (0.26 mol) magnesium and 25.5 g ethyl-
bromide in 130 ml absolute ether the ethyl magnesium-bromide
is prepared which is heated for 30 minutes on the water
bath. A solution of 6.65 (0.05 mol) 2-amino-3-methyl-
benzonitrile in 100 ml absolute ether is then added slowly
drop by drop, and the mixture is refluxed under stirring for
15 hours. After cooling the mixture is poured on 110 g ice
and the solution of 15.6 g ammonium-chloride in 67 ml water
is added. The ether layer is separated, and the aqueous
layer is extracted wi-th ether. From the combined ether
layer the ether is distilled off, and the residue is re-
fluxed with 9.5 ml water and 11.2 m] concentrated hydro-
chloric acid for 30 minutes. After cooling the mixture is
extracted with ether, the aqueous layer is rendered alkaline
and extra~cted with ether. After drying and evaporating the
ether the 2-methyl-6-propionyl-aniline is obtained, which
was characterized as hydrochloride, mp. 191.2.
Example 10
.
To 10.9 g (0~.05 mol) 2-chloro-2'-chloro-6'-
methyl-ace-tanilide in 30 ml absolute toluene are added 12.75
g (0.15~mol) cyclopentylamine in 50 ml toluene, and this
mixture is refluxed for 6 hours. After cooling the pre-
cipitated cyclopentylamine-hydrochloride is filtered with
suction, the filtrate is evaporated and to the residue is
added water and ether. The ether is e~tracted with 5~
hydrochloric acid solution, wherefrom the hydrochloride of
2-cyclopentylamine-2'-chloro-6'-methyl-acetanilide crys-
tallizes, mp. 20~.7.
-- 8
\
` ~214776
From 1 g of the hydrochloride the base was pre-
pared, mp. 76.8 .
Example 11
When cyclopropylamine in benzene is added to 2-
chloro-2'-chloro-6'-methyl-acetanilide and when this mixture
is heated in an autoclave having a glass insertion for 10
hours at a temperature of 100, and when after cooling the
prescription of Example 1 is followed, then the hydrochlo-
ride of 2-cyclopropylamine-2'-chloro-6'-methyl-acetanilide,
mp. 257, is obtainéd.
B. Without isolation of the intermediate of
formula IV
Example 1
To 18.6 g (0.1 mol) 2-bromo-6-methyl-aniline in
150 ml absolute acetone and 20 g sodium bicarbonate are
added drop by drop under cooling with ice during one hour 12
g (0.11 mol) chloroacetyl chloride and then this mixture is
stirred at room temperature for 30 minutes. To the mixture
are added 22 g (0.3 mol) diethylamine in 50 ml toluene, and
this mixture is refluxed for 6 hours. The further treatment
is the same as described in section A in Example 1.
The hydrochloride of the 2-diethylamino-2'-bromo-
6'-methyl-acetanilide, mp. 172-174, is obtained.
a) The same 2-diethylamino-2'-bromo-6'-methyl-
acetanilide can be prepared according to the Sandmeyer
reaction from 2-diethylamino-2'-amino-6'-methyl-acetanilide
as follows:
11.75 g (0.05 mol) 2-diethylamino-2'-amino-6`-
~'
~214776
methyl-acetanilide in 30 ml 48go hydrobromic acid are cooled
in an ice bath, and at a temperature of -5 this mixture is
diazotized with 3.45 g sodium nitrite in 20 ml water during
30 minu~es (iodo-starch paper test) and then this mixture is
stirred for 40 minutes at a temperature of -5. This sus-
pension is added slowly to a mixture having a temperature of
70 of 4 g CuBr in 20 ml 48% hydrobromic acid, and this
mixture is stirred for 2 hours at this temperature. After
cooling this mixture is extracted with ether, the acidic
solution is rendered alkaline and ex-tracted with ether.
After drying and evaporating the ether the residue is dis-
solved in ethanol and transformed into the hydrochloride
with ethereal hydrochloric acid, which is identical with the
product, mp. 172-174, described in Example 1.
Reduction of the 2-diethylamino- and 2-piperidino-
2'-methyl-6'nitro-acetanilide.
Example 1
a) To 25 g (0.094 mol) 2-diethylamino-2'-methyl-
6'-nitro-acetanilide in 500 ml concentrated hydrochloric
acid are added under stirring during one hour 100 g tin
(II)-chl~oride. The mixture is heated for 30 minutes on a
boiling water bath, after cooling with ice this mixture is
rendered alkaline with 35% sodium hydroxide solution,
followed by an extraction with ether. After washing, drying
and evaporating the ether the 2-diethylamino-2'-amino-6'-
methyl-acetanilide, mp. 105-106.5, is obtained, which is
transformed into its dihydrochloride, mp. 182-184, with
ethereal hydr,ochloric acid.
b) The same 2-diethylamino-2'-amino-6'-methyl-
acetanilide is also obtained as follows:
To a mixture of 300 ml Pd/C in 60 ml water under
~-- 10 --
1~14776
nitrogen are added 4.8 c; sodium borohydride in 90 ml water.
Thell the solutioll of 15.9 g~(0.06 mol) 2-diethylamirlo-2'-
methyl-6'-llitro-acetallilide in 150 ml Methanol is added drop
by drop during 30 minutes, and this mixture is filtra-ted,
the filtrate is evaporated in -the vacuum of a water jet
pump, water is added and the precipitated crystals are
filtered with suction. Mp. 105-106.5 .
Example 2
1~
As described in Example l b), 2-piperidino-2'-
amino-6'-methylacetanilide, mp. 169-170, is prepared with
-the difference, that the mixture is heated before the
filtration, because -the product is lit-tle soluble in cold
methanol. The base is dissolved in ethanol and transfor-
med with an etheric hydrochloric acid into -the dihydro-
chloride. MP. 25g-260C.
~ -- 11 --
