Патент USA US2558071

Patented June 26, 1951
2,558,068
UNITED STATES ‘PATENT OFFICE
2,558,068
PROCESS OF PRODUCING 3,4-DIMETHYL-5
PHENYL-Z-IMINOTHIAZOLIDINES
Anton Wolf, Heidelberg, Germany
1
N0 Drawing. Application August 23, 1949,
Serial No. 111,979
10 Claims. (Cl. 260—306.7)
.
The present invention relates to organic com
2
an organic solvent, e. g. methanol, ethanol, vdi
pounds being useful for therapeutic application.
butyl ether, the chlorine-substitution products of
More speci?cally the invention relates to a new
‘hydrocarbons, such as chlorofrom or ethylene di
chloride, furthermore'benzene or pyridine, can be
process of producing substituted 2-iminothiazoli
dines, exactly speaking 3,4-dimethyl-5-phenyl-2
used apart from water.
In the above described process the reaction
products are produced as salts of the thiocyanic
acid. The thiocyanates can be transformed into
iminothiazolidines these compounds representing
chemotherapeutic substances of high value.
3,4-dimethyl-5-phenyl-2-iminothiazolidines are
produced by causing a thiocyanic acid salt to act
upon l-phenyl-l-chloro-2-methylamino-propane
hydrochloride in the presence of a solvent or sus
'a salt of any other acid according to known
10
methods.
>
The following examples are inserted in order to
pension medium. The reaction takes place in two
illustrate the above describedinvention.
,
well distinguishable stages the ?rst one compris
(1.) 1.5 kg. of racemic l-phenyl-1-chloro—2
ing heating both reaction components in an acid
methylamino-propane hydrochloride I are sus
reactive medium having a pH of 1—2.5 this stage 15 pended in 6 liters of ethyl alcohol together with
leading to the formation of l-phenyl-l-thiocyan
1.15 kg. of ammonium thiocyanate and 25- g. of
_2-methylamino-propane, the second one compris
dry caustic potash or caustic soda and the reac
ing the further heating of the reaction product
tion mixture is heated at a re?ux condenser for
of the ?rst stage in an alkaline reactive medium
two hours. The reaction product having cooled
having a pH of 5.4-8.5 this stage leading to 3,4 20 down the precipitate which has formed and is
dimethyl-5-phenyl-2-iminothiazolidine_ a nucleus
having been formed. Advantageously both phases
composed of 3,4-dimethyl-5-phenyl-2-iminothi
azolidine thiocyanate and ammonium chloride is
of the reaction are combined into one single stage
extracted with water in order to remove the am
monium chloride. The remaining vsalt of the
itial products in an alkaline reactive medium from 25 thiazolidine is recrystallized from hot water. The
the combination being realized by heating the in
the beginning of the reaction; 3,4-dimethyl-5
pheny1-2-iminothiazolidine is the immediate re
action product.
l-phenyl-1-thiocyan-2-methyl
thiocyanate of the'base melts in the pure'state
at 190-192“ C. The yield amounts toabout 80%
of the theoretical yield.
-
amino-propane, however, can also be used as in
itial material and can be converted into 3,4-di
The free base is precipitated by adding an al
30 kali to the aqueous solution of the ‘dimethyl
methyl-5-phenyl-2-iminothiazolidine by being
phenyl-iminothiazolidine thiocyanate. The free
heated in an alkaline reactive medium.
base is an oil which can be converted into its
If the above named two reaction components
hydrochloride by dissolving the oil in ‘ethyl alco
are caused to react with each other in a neutral
hol, drying the solution and treating it with hy
organic solvent, heating at a re?ux condenser for 35 drochloric acid dissolved-in ethyl alcohol; the hy
8 hours is necessary. But if an alkaline agent,
drochloride has the melting point of 222°-224° C.
e. g. a caustic alkali, ammonia, methylamine,
aniline, ephedrin, pyridine or quinoline, are added
to the organic solvent, the reaction is ?nished
after a short time.
Instead of l-phenyl-1-chloro-2-methylamino
propane hydrochloride the analogously consti
tuted l-phenyl-1-bromo-2-methylamino-propane
hydrobromide can be used as starting material.
If the levorotatory l-phenyl-l-chloro-Z-meth
ylamino-propane hydrochloride is used as start
ing material, the above described method results
40 in the formation of the thiocyanic acid salt of
d-3,4-dimethyl-5-phenyl-2-iminothiaz0lidine, the
thiocyanate having the melting point of 1'70'-171°
C., and a 5% methanol solution of this thiocya
nate shows the speci?c rotationof [a]D2°°=—|-124=°.
If the optically active 3,4-dimethyl-5-phenyl-2
By dlSSOlVillg the resulting thiocyanate in Water
iminothiazolidines are intended to be produced,
and adding an alkali to the aqueous solution the
the levorotatory - l - phenyl - l-chloro-Z-methyl
free base is precipitated as an oil which is con
amino-propane hydrochloride is used as starting
verted into the hydrochloride of the base by treat
material for producing the dextrorotatory com
ing. the oil with hydrochloric acid dissolved in
pound from which by being acted upon with a 50 ethyl alcohol. The hydrochloride melts at
thiocyanic acid salt the thiocyanic acid salt of
235-238° C. It is likewise dextrorotatory the
d-3,4-dimethyl-5-phenyl-2-iminothiazolidine can
speci?c rotation of . a 5% aqueous solution,
be produced.
In an analogous manner d-l
phenyl-1-chloro-2-methylamino~propane hydro
chloride leads to the thiocyanate of 1-3,4—di
methyl-5-phenyl-2-iminothiazolidine.
Preferably the alkali salts of thiocyanic acid
are used in the process of the present invention,
e. g. the sodium salt, the potassium salt or the
ammonium salt. As solvent or suspension medium
amounting to [a]D2°°=+l56.4°.
In an analogous manner the hydrochloric acid
salt‘ of l-3,4-dimethyl-5-phenyl-2-iminothiazoli
dine is formed, if the dextrorotatory l-phenyl-l
chloro-2-methylamino-propane hydrochloride is
used as-starting material in the above ‘described
process. The l-3,4-dimethyl-5-phenyl-2-imino
thiazolidine hydrochloride has the melting point
2,558,068
4
3.
2. The process of producing 3,4-dimethy1-5
of 235-238° C. and shows in a 5% aqueous solu
tion the speci?c rotation of .
. phenyl-Z-iminothiazolidine which process com
prises causing a salt of thiocyanic acid to act upon
1-phenyl-1-chloro-2-methylamino-propane hy
(2.) 26.6 g. of the thiocyanic acid salt of 1-.
phenyl-l-thiocyan-Z-methylamino-propane are
dissolved in 150 com. of water while heating and
drochloride suspended in a diluent vehicle in
which the reactive materials are at least partly
soluble while making alkaline the pH of the
5 com. of concentrated caustic soda solution are
reaction mixture.
-
3. The process of producing 3,4-dimethyl-5
added to the solution. Crystals of the thiocyanic
acid salt of dimethyl-phenyl-iminothiazolidine 10 phenyl-Z-iminothiazolidine which process com
begin to separate very soon. The yield amounts
prises causing the ammonium salt of thiocyanic
to 23.5 g., that are 88% of the theoretical yield.
acid to act upon 1-phenyl-l-halogen-Z-methyl
(3.) 18.75 g. of racemic 1-phenyl-1-chloro-2
amino-propane hydrohalide suspended in a dil
methylamino~propane hydrochloride and 14.5 g.
uent vehicle in which the reactive materials are
of ammonium thiocyanate are suspended in a 15 at least partly soluble while making alkaline the
.mixture being composed of 450 ccm. of ethylene
pH of the reaction mixture.
dichloride and 50 ccm. of pyridine and heated at
4. The process of producing 3A-dimethyl-5
' a reflux condenser on the water bath for 1/2 hour.
phenyl-2-iminothiazo1idine which process com
The reaction product is further treated as has
prises causing the ammonium salt of thiocyanic
been described in Example 1. The yield amounts 20 acid to act upon 1-phenyl-l-chloro-2-methyl
to 12.8 g. corresponding to 61.2% of the theoretical
amino-propane hydrochloride suspended in a dil
yield.
'
uent vehicle in which the reactive materials are
(4.) 18.75 g. of racemic l-phenyl-l-chloro-Z
at least partly soluble while making alkaline the
methylamino-propane hydrochloride, 14.5 g. of
pH of the reaction mixture.
~
ammonium thiocyanate and 10 g. of l-ephedrin 25
5. The process of producing 3,4-dimethyl-5
are suspended in 500 com. ethylene dichloride
phenyl-2-iminothiazolidine which process com
and heated at a re?ux condenser on the water
prises causing a salt of thiocyanic acid to act upon
bath for 2 hours. The reaction product is cooled
l-phenyl-1-halogen-2-methylamino-propane hy
down to 0° C., the separating mass of crystals is
drohalide in an aqueous alkaline medium having
?ltered with suction and then carefully washed
a pH of 5.4-8.5.
out with ethylene dichloride and subsequently
6. The process of producing 3,4-dimethyl-5
with water. The yield amounts to 17.9 g. corre
phenyl-2-iminothiazolidine which process com
sponding to 85.5% of the theoretical yield.
prises causing a salt of thiocyanic acid to act upon
(5.) 37.5 g. of raceznic 1-phenyl-1-chloro-2
1-phenyl-1-halogen-2-methylamino-propane hy
methylamino-propane hydrochloride are sus
drohalide suspended in a diluent vehicle in which
pended in 200 com. of water, 29 g. of the am
the reactive materials are at least partly soluble
monium salt of thiocyanic acid are added to the
containing an alkaline reactive agent.
suspension and the mixture is heated to about
'7. The process of producing 3,4-dimethyl-5
80° C. on the water bath for one hour a pH of
phenyl-2-iminothiazolidine which process com
1-2.5 being maintained. The reaction product
prises the steps consisting in heating l-phenyl
after having cooled down separates as a mass of
1-halogen-2-methylamino-propane hydrohalide
crystals and 33 g. of the thiocyanic acid salt of
and a salt of thiocyanic acid suspended in a dile
l-phenyl-1-thiocyan-2-methylamino-propane of
uent vehicle in which the reactive materials are
the melting point of 135-139“ C. are obtained;
at least partly soluble while maintaining a pH
this yield amounts to 81.2% of the theoretical
of 1-2.5 in the reaction mixture and subsequent
yield. The corresponding free base melts at
ly heating the previously formed l-phenyl-l
'75-'78° C., the hydrochloride of the base melts at
thiocyan-Z-methylamino-propane in an alkaline
208-210° C.
reactive medium having a pH of 5.4-8.5.
26.6 g. of the thiocyanic acid salt of l-phenyl
8. The process of producing 3,4-dimethyl-5
1-thiocyan-2-methylamino-propane are dissolved 50 phenyl-2-iminothiazolidine which process com
in 150 com. of water while heating and 5 com. of
prises the step consisting in heating the thiocyanic
concentrated caustic soda solution are added to
acid salt of l-phenyl-1-thiocyan-2-methylamino—
the solution. Crystals of the thiocyanic acid salt
propane suspended in a diluent vehicle in which
of dimethyl-phenyl-iminothiazolidine begin to
the reactive materials are at least partly soluble.
separate very soon. The yield amounts to 23.5 g., i ~
9. The process of producing 3,4-dimethyl-5
that are 88% of the theoretical yield.
phenyl-2-iminothiazolidine which process com
After having fully described and disclosed the
prises the step consisting in heating the thiocyanic
present invention, what I claim is:
acid salt of l-phenyl-l-thiocyan-2-methylamino
1. The process of producing substituted 2
iminothiazolidines, chosen from the group con
sisting of the racemic, the levorotatory and the
propane suspended in a diluent vehicle in which
the reactive materials are at least partly soluble
while making alkaline the pH of the reaction
dextrorotatory 3,4 - dimethyl-5-phenyl—2-imino
mixture.
thiazolidine which process comprises causing a
salt of thiocyanic acid to act upon a compound
chosen from the group consisting of the racemic,
‘
10. The process according to claim 8 in which
the heating of the thiocyanic acid salt of l-phen
' yl-1-thiocyan-2-methylamino-propane is carried
the levorotatory and the dextrorotatory l-phen
out in a diluent vehicle which also contains an
yl-l-halogen-2-methylamino-propane hydrohal
alkaline agent chosen from the group consisting
ide, whilst the reactive materials are suspended in
a diluent vehicle in which'they are at least partly
of caustic alkali, ammonia, methylamine, aniline,
ephedrine, pyridine and quinoline.
soluble, said vehicle being chosen from the group 70
consisting of methanol, ethanol, di-butyl ether, a
ANTON WOLF.
chlorine-substitution product of a lower aliphatic
hydrocarbon, benzene, pyridine and water.
No references cited.