Note: Descriptions are shown in the official language in which they were submitted.
` 1~)6~96
This i.nvention relates to new indolo-quinoli%idine
derivati~es doubly substituted in the l-position and to a
process for the preparation thereof.
. The new hexahydro-indolo-quinolizidine derivatives
of the present invention contain a cyanoethyl group and an
alkyl group in the l-position, and correspond to the general
formula
A
NC CH2 CH2
wherein
R represents an alkyl group of 1 to 6 carbon atoms,
A is a hydrogen atom and B is the anion X of an acid, or
A is a pair of electrons and B is H20.
According to the above definition of A and B, the
new compounds of the general formula I are either acid addition
salts of the general formula
~ N ~ X(~~ (Ia~
~1
NC--CH2--CH2
wherein R represents an alkyl group of 1 to 6 carbon atoms and
X represents the anion of an acid, or bases of the general
formula
,
~.1 -2-
67~6
W(~ (Ib)
R
NC-CH2-CH2
wherein R represents an alk~l ~roup of 1 to 6 carbon atoms -
both being particular cases o~ th.e compounds. o~ the general
formula I.
~ Numerous compounds are found amongst indoloquinolizi-
: dines disubstituted in the l-position ~hich are important from
a medical viewpoint, such as vincamine and:i.ts derivatives.
Disubstituted derivatives of this type have been
prepared already by synthesis ~E. ~enk.ert et al.: J.A.C.S.
8:, 1580/1965~, Szantay, Sza~o, Kalaus: Tetxahedron Letters
: 1975, 191.
Disubstituted hexahydro-indolo-~u;`nolizidenes contain-
; ing a cyanoethyl group next to the alkyl group in the l-position
have, h~o~ever, not yet been prepared.
In the new compounds o~ general ~ormula I prepared
according to the present invention, the alk~yl group R may have
a straigh.t or a branched carbon ch.àin. 5uch alkyl groups may
be for instance the methyl, ethyl, n-pxopyl, isopropyl, n-butyl,
isobutyl, terbutyl, amyl, isoamyl, hexyl etc. groups, X may be
the anion of any or~anic or inorganic acid, e.g. a halide, such
as fluoride, ch.lori.de, bromide and iodide, s.ulphate, phosphate,
perhalide, such as perchIorate, perbromate etc. acetate
propionate, oxalate, citra-te~ 'enzoate, naph.toate, maleinate,
riOI~
` 1~674~6
succinate, salîcylate, p-toluenesulphonate etc anion.
In the new compounds of the general formula I, R represents
preferably an eth~l or an n-butyl group and X represents preferably a
perchlorate ion~
The new compounds of the general formula I can be prepared
according to the present invention br reacting a compound of general
formula II
`: R
wherein R has the same meaning as given above, with acrylonitrile. If
required, the thus obtained compound of the general formula /Ib/, wherein
R has the same meaning as given above, is reacted with an acid, or if
required, the obtained compound of general formula Ia, wherein R has same
meaning as given above and X represents the anion of an acid, is reacted
with a base.
The starting materials of the~general formula II~ may be prepared
by the method described by E. Wenkert et al., J.A.C.S. 87 1580 /1965/. In
- ~ this method ethyl-~-bromo-propyl-malonic acid diethyl ester is prepared
from malonic ester and is then hydrolysed by~boiling with hydrogen bromide
and decarbo~ylated; subsequently, it is esterified with diazomethane to
yield 2-eth~1-5-bromo-valeric acid~methyl e~ter, the latter is condensed
with triptamine to produce 1-/3-indolyl-ethyl/-3-ethyl-piperidine-2-one,
which in turn is treated with phosphorus oxychlor1de. Alternatively, the
compounds of the general formula may be prepared by reacting an ~-alkyl-~-
hydroxy-pentaroyl-triptamide vith phosphorous oxrchloride.
In the process of this invention the starting compounds of the
general formula II are used in the form of their salts, preferably in the
form of their acid addition salts. Preferred representatives of the acid
addition salts are for example perhalides, such as perchlorate~ perbromate
etc. Before the reaction with acr~lonitrile the starting materials of
1~67~96
general formula II are set free from their acid addition salts in the
reaction mixture itself, b~ treating with a base. The compounds of the
general formula II thus obtained are then reacted with acr~lonitrile. The
dilute aqu~ous solution of an inorganic base ma~ be used for this purpose.
Examples of bases preferably used are the hydroxides of the alkali metals,
such as sodium hydroxide, potassium hydroxide etc. The amount of base
used may exceed the necessar~ equivalent amount b~ about 2Q-40%. The
liberation of the bases of the general formula ~I from~theIr salts ma~ be
carried out suitably in an inert organic solvent which is immiscible with
~ater. Such solvents may be for example halogenated hydrocarbons such as
chloroform, carbon tetrachlorid, dichloromethane~ 1,2-dichloroethane, tri-
chloroeth~lene etc. The liberation of the base is suitably carried out in
an inert atmosphere, preferably in nitrogen or argon. In view of the two-
phase reaction mixture, it is advantageous to use continuous stirring. The
base is liberated in a short time, after s-2a minutes of stirring. The
temperature employed may var~ in a wide range, though room temperature is
p~eferred. The organic phase is then separated and dried,
AcrrlQn~trIle ~s added ta this d~ed organl~solut~on. It is
suitable to use acr~lonitrile in excess In the range of ~-8, preferably 5
moles for e~ery mole of the starting materlal of the general formula II,
The reaction time and temperature are not o deeisive importance for the
reaction, but it i5 preferred generally to work at room temperature and to
leave the reaction mixture to stand for 1-4 days at that temperature. In
carrying out the process of this invention the use of freshl~ distilled
acrylonitrile is recommended.
The reaction mixture may be processed in the usual wa~. If or
instance a solution is obtained at the end of the reaction, then the solvent
can be evaporated preferably in vacuo.
If the reaction of acrylonitrile with the compounds of the general
formula II yields compounds of the general formula Ib, these ma~ be con-
verted, if required, into the corresponding acid addition salts of the
general formula Ia, by heating the base with an acid, e.g. with an inorganic
~Lo~;7~96
acid such as hydrochlorid acid~ h~drobromic acid, phosphoric acid, or an
organic carbox~lic acid, as acetic acid, proplan~c aeid~ glycolic acid,
maleic acid, succinic acid, tartaric acid, citric acid, salic~clic acid,
benzoic acid, an alk~l sulphonic acidJ such a5 meth~le sulph~nic acid or an
ar~l sulphonic acid, such as p-toluenesulphQn~c ac~d ~tc
The formation of the salt is usually carried out in an inert
solvent, preferabl~ in an aliphatic alcohol. The base of general formula
Ib is dissolved in the above solvent and then the appropriate acid ls
added until the pH-valueofthe mixture becomes slightly acidic /about pH=6
The precipitated salt of the general formula Ia is then separated from the
reaction mixture.
The compounds of the general formula Ib ma~ be liberated from the
acid addltion salts of the general formula Ia b~ heating th~, salt ~ith a
base. An inorganic base ma~ be used preferabl~, for example the aqueous
solution of an alkali metal hydroxide such as sodlum hydroxide. The preferred
procedure is to suspend a salt of general formula Ia~m water, then to add
an inert organic solvent - for example a halogenated hydrocarbon such as
dichloromethane. Then the said inorgam c bàse is added to the mixture
under cooling and stirring in an inert gas atmosphere. The base of the
general formula Ib usually separates in the form of an oil consisting of
the corresponding compound of the general formula Ic
NC-CH2-CH2
R
This oil may easily be crystallised for lns~ance fr~m an aliphatic alcohol,
such as methanol, and so a base of the general f~rmula ~b ls obtain~d in a
crystalline form.
The compounds of general formula I contain asymmetric carbon atoms.
In the process of this invention racemic compounds of general formula I are
obtained. The process of this invention includes also the separation of
~674~6
the optical antipodes. The resolution of the racemic compounds may be
performed ~y kno~n methods such as by the formation and separation of
diastereomeric salts.
T~ m~ound~ o~ th~ genqral ~Q~mula I ~tained b~ the pracess o
the pre~ent invention may be further purified lf re~uired, e,g. ~r recry-
stallisation. Suitable solvents for the recrystalllsatiQn are for example
aliphatic alcohols, such as methanolJ ketones, such as acetone, aliphatic
esters, especially the alkyl esters of fatt~ acids3 such as ethyl acetateJ
further acetonitrile J as well as mixtures of the said solvents, such as the
mixture of ethyl acetate and ether etc.
The compounds of general formula I are obtained by the process of
this invention in high rields and in well identifiable form. The analytical
results showed good agreement with the calculated valuesJ and the positions
of the infrared bands of the characteristic groups proved unequivocally the
structure shown by the general formula I.
The compounds of miaeral formula I prepared by the process of this
invention are valuable intermediate products for the preparation of thera-
peuticall~ active indolo-quinolisidines disubstituted in the l-position.
Further particulars of the process of the invention are shown by
the following examples.
Example 1 :
Cl-Ethyl-1,2J3J4,6J7-hexah~o-indQlo_~,3- ~
quinalizln-l-rl~-propionitrile (betain-s~tru~ture~.
10.0 g.~28.5 mmoles) of 1-ethyl-2,3J4,GJ7J12-hexahydro-indolo
/2J3-aT quinolizinium perchlorate are dissolved in 100 ml of dichloro-
methane. 75 ml. of distilled water and 20 ml. of 2 n sodium hydroxide
solution are added in an argon atmosphere under stirring. The reaction
mixture is stirred for further lQ minutesJ then the Qrganic phase is separa-
ted and dried with anhydrous potassium carbanate. The drying agent is
filtered off and then 10 ml. (142 mmoles)of freshly distilled acrylonitrile
are added. The system is ~lushed with argon and left standing at room
temperature. After two days of standing ~during which time the colour of
106749G
the solution deepens) the solution is evaporated to dryness in vacuo and in
an argon atmosphere ~using a water bath of at maximum 40-50 C). The resi-
dual dark red oil is triturated with 5 ml. o~ methanol. It disintegrates
in~ediately into orange-yellow crystals which are sucked off. The weight of
the obtained crystals is 8,10 g. The crystals are recrystallised using
fifteen times their volume of methanol. In this way 7.30 g. (79.4%) of cry-
stalline (l-ethyl-1,2,3,4,6,7-hexahydro-indolo[2,3-à]quinolizin-1-yl)-
propionitrile are obtained, having a melting point of 122-123 C.
Analysis: calculated for C20H23N3H20 ~
C: 74,27%, H: 7.79 %. N: 12.99 %.
found: C: 74.05%. H: 7.87 %. N: 12.92 %.
I.R. spectrum ~KBrj: 2280 cm 1 ~ -CN)9
1662 cm 1 and
1608 cm 1 (` C=N ~).
U.V. spectrum (in methanol):
Amax: 242 nm (log ~ = 4.0026).
254 nm Clog ~ = 3.9777),
362 nm (log ~ = 4.3944).
Example 2:
~1-Ethyl-1-~2-cyano-ethyl)-1,2,3,4,6,7-hexa-
hydro-12H-indolo~2,3-a]quinolizinium perchlorate.
1 g. of (1-ethyl-1,2,3~4,6,7-hexahydro-indolor2,3-a]quinolizin-1-
yl~-propionitrile is dissolved in 20 ml of hot methanol and the solution is
acidified to pH=6 using 70 % perchloric acid. The precipitated yellow
crystals are filtered off and dried. 1,05 g. of 1-ethyl-1-(2-cyano~ethyl)-
1,2?3,4,6,7-hexahydro-12H-indoloE2J3-a]quinolizinium perchlorate are ob-
tained, mel~ing point 209-211 C. After recrystallisation from methanol
the ~elting point of the above product is raised to 211-212 C.
Analysis:
calculated for C20H24N3C104 QM = 405,86):
C: 59.18 %, H: 5,96 %, N: 10.35 %
found: C: 59.23 %, H: 6.02 %J N: 10.49 %
~L86~6
I.R. spectrum ~KBr): 3290 cm 1 ~indole ~ NH)
2360 cm~l ~ -CN~
1620 cm~l ~ C ~ N~ ~ }.
Example 3.
l-n-Butyl~ 2-cya~o-eth 1~-1,2~3,4,~,7-hexa-
hydro-12H-indolo/2,3-a~quinolizinium perchlorate.
5,0 g (13 3 mmoles) 1-n-butyl-1,2,3,4,6,7-hexahydro-indolo~2,3-a7
quinolizinium perchlorate are suspended in 5Q ml. a dichloromethane and then
50 ml, of distilled ~ater and 10 ml. of 2n aodIum hydroxide solution are
added to it in an argon~atmosphere, under stirring. After 10 minutes of
stirring the organic layer is separated and dried ~ith anhydrous potassium
carbonate. The desiccant is filtered of-f, then S.0 ml ~71 mmoles) of
freshly distilled acrylonitrile are added to the solution which is subse-
quently flushed ~ith argon and left standing at room temperature. After
three days of standing the reaction mixture is e~aporated in vacuo. The
residual red oil is evaporated in vacuo. The residual red oil is dissolved
in 5 ml of methanol and made slightly acidic ~pH=6) by the addition of
70% perchlQric acid solution. Scraping the ~alls of the reaction vessel
induces crystal formation. The amount of crystals obtained may be increased
by placing the reaction mixture into a refrigerator. The yellow crystals
which separate are sucked off and ~ashed~in cold methanol. 4.20 gm of
crystalline l-n-butyl-1-~2-cyano-ethyl)-1,2,3,4,6,7-hexahydro-12H-indolo
/2,3-a/quinolizinium-perchlorate are obtained, melting point; 215-220 C.
The product is recrystallised from fivefold volume of methanol 3.70 g.
~64.1 %) of the pure product are obtained as yello~ needle crystals having
a melting point of 224-226C.
Analy~is:
calculated fQr C~2H28N3C104 ~M = 433.91):
C: 60.87 %, H: 6.50 %, N: 9.68 %
found: C: 60.60 %~ H: 6.29 %, N: 9.82 %
I.R. spectrum ~BKBr): 3328 cm 1 (indole ~ NH~
~L~)67496
2304 cm 1 (-CN)
1625 cm~l and
16Q5 cm~l C ~ C ~ N ~ ~.
Exam~le ~
l-n-Butyl-1,2,3,4,6,7-hexahydro-12H-indolo
/2,3-_1quinolizine perchlorate ~starting material)
42.65 g. (1355 mmoles) of ~-n-butyl-~-hydroxy-pentanayl-triptamide
are dissolved in 250 ml. of freshly distilled phosphoryl chloride. The
solution is refluxed for 8 hours. After cooling the solution is evaporated
in vacuo and the residual dark brown oil is dissolved in 300 ml. of dichloro-
methane. 300 ml. of distilled ~ater are added to the solut~on~ The
solution is cooled ~ith ice water and then made alkaline to pH=14 using
sodium hydroxide solution. The mixture is shaken well, then the organic
layer is separated. The aqueous layer is extracted ~wice with 100 mL of
dichloromethane. The organic solutions are com~ined and dried ~ith magneslum
sulphate. The sol~ent is distilled off in ~acuo. The resldual red oil is
dissol~ed in a small ~olume o~ methanol and acidified to pH=6, using 70%
aqueous perchloricacid. Yello~ crystals separate immediat~ly. The amount
of crystals obtained may he increased by putting the reaction mixture into a
refrigerator. 29.90 g. (61.7%) of crystalline 1-n-butyl-1,2,3,4,6,7-hexa-
hydro-12H-indolo/2,3-~ quinolizine perchlorate are obtained, melting point:
198-200 C. The product is recrystallised from methanol, whereby the
melting point of the product is raised to 201-202 C.
Analysis:
calculated ~r Cl~H25N2C104 (M = 380.86):
C: 59.91 %, H: 6.61 %, N: 7.35 %,
found C: 60.26 %, H: 6.67 %, N: 7.03 %.
I.R. spectrum ~KBr~: 3240 cm 1 (indole NH)
1629 cm 1 ~ ~ C = N ~ )
U.V. spectr~m ~in methanol):
max: 359 nm, ~log ~= 4.3598?
lQ
I~6749G
Exam~le 5
~l-Ethyl-1,2,3,4,6,7-hexahydro-indolo/2,3-a/-
quinolizin-l-yl)-prop_onitrile (betain-structure)
1.00 g. of 1-ethyl-1-~2-cyano-ethyl)-1,2,3,4,6,7-hexahydro-12H-
indolol2,3-alquinolizinium perchlorate is suspended in 100 ml. o distilled
water then 40 ml. of dichloromethane are added to it. The mixture is made
alkaline to pH 10-11 with 40% sodium hydroxide solution in an argon atmos-
phere under stirring and external water cooling. After stirring for further
fex minutes, the red coloured organic phase is separated. The aqueous
solution is shaken out with another 20 ml. of dichloromethane. The
organic solutions are combined and dried with magnesium~sulphate. The sol-
vent is removed in vacuo and a red oil ~o,75 g) is obtained as residue
The oil is triturated with 1 ml of methanol, whereupon it forms
red crystals. The crystals are sucked off to yield 0.72 gm. of crystalline
~l-eth~1-1,2,3,4,6,7-hexahydro-indoloL2,3-a/quinolizi~l-yl)propionitrile,
melting point: 122-123 C -
