Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1068Z~9
The present invention relates to a process for pre-
paring derivatives of 2-aminoindane of the following general
formula:
R~
-N 2 n ~ R
~ ~ ~ - R
in which n = 2, 3 or 4, the (CH2)n group having a straight or
branched chain, Rl represents a hydrogen atom, an alkyl or hy-
droxyalkyl group having 1 to 3 carbon atoms or an alkenyl or
alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl
or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or
alkynyl group having 2 or 3 carbon atoms, whereby Rl and R2 may
be identical or different and may form together with the con-
tiguous nitrogen atom a nitrogenous heterocyclic group, R3 rep-
resents a hydrogen atom or a substituent, such as a hydroxy,
chloro, trifluormethyl or lower alkyl radical, which may be in
the ortho, meta or para position of the phenyl group and R4 re-
~ presents a hydrogen atom, an alkoxy radical having 1 to 3 carbon
; atoms or a dialkylamino group, as well as the acid addition salt~
of the 2-aminoindane derivatives of formula (I).
More specifically, the invention relates to a process
20~ for preparing derivatives of 2-aminoindane of formula
,~ :
R4 ( ) / 1
N~ R2~
~ ~ l ~ R3 (I)
,
C
. J ~
1068Z89
in which n = 2, 3 or 4, the (CH2)n group having a straight or
branched chain, Rl represents a hydrogen atom, an alkyl or
hydroxyalkyl group having 1 to 3 carbon atoms or an al~enyl or
alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl
or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl
or alkynyl group having 2 or 3 carbon atoms, whereby Rl and R2
may be identical or different and ma~ form together with the
contiguous nitrogen atom a six-membered nitrogenous heterocyclic
group, R3 represents a hydrogen atom, a hydroxy, chloro, tri-
fluormethyl or lower alkyl radical, which may be in the ortho,meta or para position of the phenyl group and R4 represents a
hydrogen atom, an alkoxy radical having 1 to 3 carbon atoms or
a dialkylamino group, as well as the acid addition salts of the 2-
.
aminoindane derivatives of formula (I), in which process a N-
phenyl-2-aminoindane of formula
.,
~ _N / (II)
, ~ .
~ in which R3 and R4 have the meanings given above, is reacted
.~ w~h sodamide (NaNH2) and a halogenated amine of formula
~,` ~1 " .
Hal - (CH2)n _ R2 ~' (III)
~ 20 in which n, Rl and R2 have the meanings given above, by
heating the reactive mass to boiling temperature in a medium
consisting of an inert organic solvent, characterized in that
for the purpose of simplifying the procedure, a mixture of soda-
~ mide and an organic solvent is heated to reflux temperature,
:. the mixture is reached with N-p~enyl-2-aminoindane of formula
~ (II) which is used in its free form, or in the form of its hydro-
.i'
chloride, and after the emission of ammonia, always keeping the
. mixture at reflux temperature, a halogenated amine of formula
- la -
1068Z89
(III1 is added in the form of its hydrochloride, with a molar
amount of sodamide equal to the sum of the molar amount of hydro-
chloride of halogenated amine of formula (III) and of the molar
amount of the N-phenyl-2-aminoindane of formula (III), in its
free form, or with a double molar amount of the hydrochloride of
the N-phenyl-2-aminoindane of formula (II), followed by separa-
tion of the entire product of formula I, in its free form or
as an acid salt thereof.
It i`Q known that the compounds of formula I have inter-
esting cardiac anti-arrhythmic properties.
There is known a process for preparing the compounds
of formula (I), in which process a N-phenyl-2-aminoindane of
formula:
,
, . . .
,~
:j:
., .
, ~
:
. .
'R
':;
..
,
J-~23~ - lb -
1068Z~9
R4 H
~b-~
~ 3 (II)
; in which R3 and R4 have the meanings given abo~e, is reacted
with sodamide (NaNM2) and an halogenated amine of formula:
R
Hal - (CH2)n - N \
R2 ~ (III)
in which n, Rl and R2 have the meaning~ given above.
`~ In this known process it is necessary, before reac~
.i~ ting the N-phenyl-2-aminoindane of formula (II) with sodamide
,,~ . , ~.
and the halogenated amine of formula (III), to effect at least ~-
~15 one preliminary reaction which consists in releasing the free
.base of the hydrochloride of the halogenated amine of formula . :~
while this halogenated amine of formula (III) must be in .
the form of a hydrochloride because it is unstable in its free -
base form.
20~ In the same manner the N-phenyl-2-aminoindane of for-
mula (II? is initially al~o in the hydrochlorlde form, so that
in the:known process this compound is also first converted into
i:ts free~base berore it is reacted with sodamide and the haloge-
nated~a~ne~of formula (III~. ~
:It ~haa now been found that the known process may con-
siderably~be;simpli~ied, on an industrial scale~ when the pre-
;l^~minary can~ersi:on o~anyone of the hydrochlorides of the
reagents~of~fQrmulae~ and (III) is omitted~ provided that
. ~ an exces~s~of~sodamide is us~ ~ith respect to the amount of sod-
. ~ 30~ :amide which~iæ~necessary for the conversion of the reagent of
. ~ formula~ into its~;`sodium~salt.
In~accordance wîth the present invention, a mixture
` 106~2l~9
of sodamide and an organic solvent~ such as benzene or toluene,
heated to reflux tempera~ure, is reacted with N-phenyl-2-ami-
noindane of formula (II), p~ sibly in the form of its hydro-
chloride, and, after the emission of ammoniac has ended, al-
ways keeping the mixture at reflux temperature, ~he halogenated
amine of formula. (III) is added in the form of its hydrochlo-
ride, the amount of sodamide (NaNH2) being sufficient not only
for the formation of the sodium salt of the N-phenyl-2-aminoin-
dane of formula (II), as an intermediate compound but also to
- 10 release the free base from the hydrochloride of the N-phenyl-2- :
aminoindane of formula (II) and/or the hydrochloride of the ha-
logenated amine of formula (III).
In a first embodiment of the process according to the
invention, the reactions represented schematically hereafter
15 are involved:
'. Schemes 1 ' `
:
. 1) AH + NaNH2 ~ ANa + NH3
... li.~ 2) ANa + BCl.HCl ~ AH + NaCl ~ BCl
~- 3) AH + NaNH2 ~~~~~~~ ANa + NH3
~, 20 ~3 ANa + BCl -~ I + NaC1
. 1 _ . .
.. Balance: AH + BCl.HCl+2 NaNH2 ~ I+2NaC1~2 NH3
ll: In these reaction schemes:
A = ~ -N /
BCl ~ chlorinated amine of formula (III )
. I _ compound of formula (I)
,.
As can be observed from the reaction schemes 1, in
, ~
_ J _
1068Z89
which are used as starting materials a N-ph~nyl-~-a~inoindane
of formula (II) represented by AH, a h-rdrochloride of a chlori-
nated amine of formula (III) represented by BCl.HCl and sodamide
(NaMH2), the amount of sodamide used is equal to at least two
moles for one mole of AH and one mole of BCl.HCl~ This sodamide
~erves not onl~ for the formation of the sodium salt of the N-
phenyl-2-aminoindane Or formula (II) (ANa), but also to release
the chlorinated amine of formula (III~ ~rom its hydrochloride.
In a second embodiment of the procèss according to the
invention, one also uses the N-phenyl-2-aminoindane of formula
(III) in its hydrochloride form.
In this case~ the reactions represented schematically
hereafter are involved:
Schemes 2:
1) AH.HCl + NaNH2 ~~~~~ AH ~ NaCl + NH
~ 3
2) AH + NaNH2 ~ ANa + NH3
- 3) ANa + BCl.HCl ~ AH + NaCl I BCl
4) AH + NaNH2 ~~~~~ A.Na ~ NH3
5) ANa + BCl ~ I + NaCl
~, . . . .. . . _
; 20 Balance: AH.HCl + BCl~HCl + 3NaNH2 ~ I + 3NaCl + 3NH3
As can be observed from the reaction schemes 2, in
`~ which are used, as starting materials, the hydrochloride of a
N-phenyl-2-aminoindane of formula (II) represented by AH.HCl,
the hydrochloride of a halogenated amine of formula (III) re-
~25 presented by BCl.HCl and sodamide (NaNH2), the amount of soda-
mide u~ed is equal to at least three moles for one mole of
AH.HCl and one mole of BCl.HCl.
This sodamide serves no~ only for the formation of
ii the sodium salt of N-phenyl-2-aminoindane of formula II tANa),
~ut also to relea~e the N-phenyl-2-aminoindane of formula II
(AH) from its hydrochloride and the chlorinated amine of formula
III (BCl) from its hydroc~loride (3Cl.HCl)~
-` ~06~289
When the reagents of formula II and of formula III
are used in their hydrochloride form, they are added ~o the
reaction medium containing the sodamine as solutions in an orga-
nic solvent such as benzene or toluene.
The reactions take place at reflux temperature under
a nitrogen blanket and when the reactions are ended, the reac-
tion mixture is cooled and treated with water to extract the
sodium chloride, whereafter an acid addition salt, such as hy-
drochloride, is prepared from the obtained compound of formula I.
Accordin~ to a particular feature of the invention,
an exces-q of about 15/~o of the hydrochloride of the halogenated
amine of formula III is used with respect to the amount of N- f
; phenyl-2-aminoindane. ~ -
Other characteristics and details of the in~ention
will appear from the following illustrative examples:
; EX~PLE 1
,."~ . ........................................ I
~l~ Preparation of the hydrochloride of N-phenyl-N-diethylamino-
'd ' ' ' 1:
propyl-2-amino1ndane (formula I: n - 3; R1 = R2 = -C2H5 ; R3 =
H; R4 = H )
In a reaction tank are charged i~s2~5 kilograms (~36
;i~ mo~es) of hydrochloride of N-phenyl-2-a~inoindane, 75 liters
of concentrated ammonia, 75 liters of water and 120 liters of
toluene. The mixture is stirred and one observes that the N- `
phenyl-2-aminoindane gradually passes to the toluene phase. Af-
~2~5 ~ ter extraction by means of two fractions of 50 liters of toluene,
the toluene fractions are joined together, dried over magnesium
sulph~and fiItered. Thus a toluene solution of the free base
(N-phenyl-2-aminoindane) is obtained.
Further, an enamelled steel reaction tank is charged
$ ~
~ 30 with 39 kilograms (100~ moles) of powdered sodamide and this
.,,s ~ .
j load is covered with 100 liters of toluene.
,i~
~ 5 -
,, .
- 1068289
The content of the tank is stirred by means of a
mechanic stirrer and heated to reflux temperature under a ni-
trogen stream and secured from moisture. Then the toluene solu-
tion of N-phenyl-Naminoindane is slowl7 poured into the tank.
~ith each addition of a fraction of this latter solution an
emission of ammonia takes place which can be easily controlled
by using, for instance, a paraffin bu~bler.
When the whole solution of N-phenyl-2-aminoindane
~las been introduced into the tank, 72 kilograms t3~6.~ mole ;
- 10 excess of 15~o) of hydrochloride of y-chloroprop~ldiethylamine
(formula III, n = 3; R1 = R2 = C2H5) are poured by portions
into said tank, thereby securing the reagent from moisture.
The reaction mixture is further refluxed during 3
to 4 hours, and the reactions are followed on thin layers to
determine the exact duration of the reactions.
; When the reactions are ended, the reac~ion mixture
,;,
i5 cooled and 200 liters of water are added. After stirring the
aqueous wa~hing fraction is removed and 125 liters of concentra_
ted hydrochloric acid and 275 liters of water are added.
` 20 The reaction mixture is extracted twice again with
50 liters of 1N hydrochloric acid, and then the toluene phase
is removed. When the pH value is zero, th9 acidic aqueous phase
is extracted by means of small fractions of dichloromethans
until n ~ oloration of this solvent, which removes many impuri- ;
.~!
ties, is observed an~more.
The pH is then adjusted to a value of exactly 6, by
adding a concentrated sodium hydroxide solution. ~hen the pH is
stabilized at this value the aqueous phase is extracted by means
~;~ of chloroform ( 1 fraction of 250 liters and 2 fractions of 100
liters). The joined chloroformic solutions are then washed with
~ater, dried, filtered and evaporated to dryness.
The residue is taken up with ace~one (using about 10
6 -
,
`-` 10682~9
liters of this solvent per kilogram of compound to be obtained).
The acetonic phase is then heated to re~lux tempera-
ture until dissolution of the solid matter, treated with carbon
black (5%), filtered and concentrated to about half its volume.
Upon cooling by means of brine, the monohydrochloride
of the desired N-phenyl-N-diethylaminopropyl-2-aminoindane crys-
tallizes.
The obtained crystals are separated in a centrifugal
dryer or on a buchner filter and recrystallized from acetone
(without carbon black).
One thus obtains, with a yield of about 70~0, ~hite -~
crystals melting at 127 - 130C (i~Iettler).
EX~PLE_2
Preparation of the hydrochloride of N-phenyl-N-diethylamino-
proP~ 2-aminoindane (Pormula I: n = 3; Rl = R2 = -C2H5; R~ _
H; R4 = H).
?i
Into a dry enamelled steel tank, 52 kilograms (1.344
moles) of powdered sodamide are charged and this load is covered
with 575 liters of dry toluene.
To the stirred mixture, heated to reflux temperature
under nitrogen, ~2.5 kilograms (336 moles) of dry hydrochloride
of N-phenyl-2 aminoindane are added by portions. ~lith each addi-
tion of this reagent an emission of ammonia takes place which
can easily be controlled.
~25 Then 72 kilograms (3~6.~, moles) of hydrochloride of
y-chloropropyl diethylamine are added by portions whereby the
stirring is maintained and the reaction mixture is kept at re-
flux temperature under nitrogen.
Aftér 3 to 4 hours the reactions are ended and one
~,
proceeds in the manner described in example 1.
,~
c`l One obtains white crystals of N-phenyl-N-diethyl-
aminopropyl-2-aminoindane melting at 127 - 130C.
'
- 7 -
~ . ' . . . . . . '
-` 1068Z89
EX~iPLES 3_to ~2,
Proceeding in the manner described in example 1 or
example 2, one can prepare by using the compounds of formula II
and formula III in the form of their hydrochlorides, the com-
polmds Or rormula I indicated in the following table I:
" ,,
... .
", . .
~`i i
','~'t ` '
~,..;,
;;'
'.~
.~i, . .
i~
.'. 1
.~,
,t - ~ _
:, _ . . . . . .
` :1068Z89
: :
U~ ~ ~ ~ o ~ ~ ~ ~o o ~ ;~ U~
: ~ ~ ~~ ~ ~ , -' ~ ~ ~ ~ ~ ~ ~ o
O tr~ ~ ~ o~ ~y ~ t~ o~ ~ u~
U~ ~ ~ ~ ~ ~ U~ ~ ~ o ~ .~ t.~
.. .
a~
O ~h ~ ~ ~) ~ ~ ~ ~ h ~C)
~ h ~ h
~1 OS O O O O O O O S O O O O
., . ~ ~ 5~ ~ S 5: ~ h .S S~ ,S' ,s: ~
o~ o o o o o o o h ~n o O O O h
V~ h ,s: ~c~ ~ ~5 ~ h h h g ~ h h ~h h
1 h h ~ h ~ ~ -
. ¢ S~ S ~ .s:: S S ~ S C t ~ .~: S ,s:: .C ~ ` '
,',., . .,
~1 ' . ', ......
. . .
C~ N
O
o
O : .
O ~ ~ X ~ S h ~: N
~ ' 0 0 0 ~ V C~ O
~' ~: ~ h 5~
, ~ ~ ~ ~ h ~ S h.
:~ ~ ~ : :
~068289
t` o ~ ~ ~ CO ~ C~ U~ ~ o
~o ~ o ~ ~ ~ ~ ~ ~ o
~ o ~ ~ ~ o .~ ~o
', . ~ ~ O ~ ~ ~ ~ ~ ~ O ~ C~
~,
rl ~ ~ h
O O o o .~: o o o o
o~ ~ S S J~ ~ o 5~ C ~ s
S: O O O S~ ~ 0 0 ~d ~ O a O ~ O
~,1 o h S~ h ~ H h H ,1 :~ h h ~ -1 h
Cl ~ P~ X ~ X ~ X P~
,'~',' S 5:: S ~ O S O ~ S S S O S
,,~
~, :2
æ æ
U~
' :! ~ ::C ~ t~ ~ ~ ~
~ ~ a ~:~ ~ ¢ O o o " " " ~ ~ o
~: I
H
i . I -
1~ ~ C 1 W ~
o .'
,~ '
~1 0 ~
8 ~ ~ C~ u~ u~ ~ ~ ~ ~ ~ ~ ~ W
0 ,1 ::C ~ C O ~ C X a V
~ C:~ ~ H ~ t~ 1 N S~
.`~ ~ ~ V C~ V C~ C~ V V C~
. ;
~ Q~ `
N N CN X
` ~:::
`~ ~ ;~
. ~ ~: ~ ~ ~ t~ ~ N
~:
:
X ,~: O~ O ~ N ~ ~ ~ ~ O ~~
,~ ~ N N t~l t~ ~ (~I
'1
~d
i ` .. .- ` ` .. . . . :
