CA1067496A - 1-(2-cyano-ethyl)-1,2,3,4,6,7-hexahydro-12h-indolo(2,3-a) quinolizino compounds - Google Patents
1-(2-cyano-ethyl)-1,2,3,4,6,7-hexahydro-12h-indolo(2,3-a) quinolizino compoundsInfo
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- CA1067496A CA1067496A CA236,327A CA236327A CA1067496A CA 1067496 A CA1067496 A CA 1067496A CA 236327 A CA236327 A CA 236327A CA 1067496 A CA1067496 A CA 1067496A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
A B S T R A C T
A compound of the general formula I
(I)
A compound of the general formula I
(I)
Description
` 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
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 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
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 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 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 -
. 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
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 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
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 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 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 -
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of the general formula I
(I) wherein R represents an alkyl group of 1 to 6 carbon atoms, A is a hydrogen atom and B is the pharmaceutically acceptable anion X? of an acid, or A is a pair of electrons and B is H2O, which comprises reacting a corresponding compound of the general formula (II) with acrylonitrile, and where required converting the obtained base of the general formula (Ib) wherein the meaning of R is the same as given above, by reaction with an acid, into the corresponding acid addition salt of the general formula (Ia) wherein X? is the pharmaceutically acceptable anion of an acid.
(I) wherein R represents an alkyl group of 1 to 6 carbon atoms, A is a hydrogen atom and B is the pharmaceutically acceptable anion X? of an acid, or A is a pair of electrons and B is H2O, which comprises reacting a corresponding compound of the general formula (II) with acrylonitrile, and where required converting the obtained base of the general formula (Ib) wherein the meaning of R is the same as given above, by reaction with an acid, into the corresponding acid addition salt of the general formula (Ia) wherein X? is the pharmaceutically acceptable anion of an acid.
2. A process as claimed in claim 1, characterized in that a salt of the compound of the general formula (II) is employed, and is first reacted with a base and then the obtained base of the general formula (II) is reacted in the same reaction mixture with acrylonitrile.
3. A process as claimed in claim 2, characterized in that perchlorate is employed as the salt of a compound of the general formula (II).
4. A process as claimed in claim 1, 2 or 3 characterized in that the reaction is carried out in an inert organic solvent.
5. A process as claimed in claim 1, 2 or 3 characterized in that the acrylonitrile is used in excess related to the compound of the general formula (II).
6. A compound of the general formula (I) defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
7. A process as claimed in claim 1, 2 or 3 wherein in the starting material of formula (II) R is ethyl.
8. A process as claimed in claim 1, 2 or 3 wherein in the starting material of formula (II) R is n-butyl.
9. A process as claimed in claim 1 which comprises reacting 1-ethyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizinium perchlorate in the presence of water and a water-immiscible organic solvent with an alkali to liberate the free base into the organic solvent, reacting the organic solvent solution of the base with acrylonitrile to produce (1-ethyl-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinazolin-1-yl)-propionitrile, and reacting the latter with perchloric acid.
10. A process as claimed in claim 1 which comprises reacting n-butyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizinium perchlorate in the presence of water and a water-immiscible organic solvent with an alkali to liberate the free base into the organic solvent, reacting the organic solvent solution of the base with acrylonitrile to produce (1-n-butyl-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinazolin-1-yl)-propionitrile, and reactlng the latter with perchloric acid.
11. 1-Ethyl-1-(2-cyano-ethyl)-1,2,3,4,5,6,7-hexahydro-12H-indolo[2,3-a]quinolizinium perchlorate, when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
12. 1-n-Butyl-1-(2-cyano-ethyl)-1,2,3,4,5,6,7-hexahydro-12H-indolo[2,3-a]quinolizinium perchlorate, when prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HURI544A HU170205B (en) | 1974-09-27 | 1974-09-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1067496A true CA1067496A (en) | 1979-12-04 |
Family
ID=11000955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA236,327A Expired CA1067496A (en) | 1974-09-27 | 1975-09-25 | 1-(2-cyano-ethyl)-1,2,3,4,6,7-hexahydro-12h-indolo(2,3-a) quinolizino compounds |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS5159897A (en) |
| AT (1) | AT345994B (en) |
| AU (1) | AU497150B2 (en) |
| BE (1) | BE833894A (en) |
| BG (1) | BG30777A3 (en) |
| CA (1) | CA1067496A (en) |
| CH (1) | CH623585A5 (en) |
| CS (1) | CS186720B2 (en) |
| DD (1) | DD122820A5 (en) |
| DE (1) | DE2541485C3 (en) |
| DK (1) | DK138328B (en) |
| FR (1) | FR2286139A1 (en) |
| GB (1) | GB1473484A (en) |
| HU (1) | HU170205B (en) |
| IL (1) | IL48144A (en) |
| NL (1) | NL7511284A (en) |
| PL (1) | PL96854B1 (en) |
| SE (1) | SE421207B (en) |
| SU (1) | SU619106A3 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU174502B (en) * | 1976-12-30 | 1980-01-28 | Richter Gedeon Vegyeszet | Process for preparing new octahydro-indolo/2,3-a/quinolizine derivatives |
-
1974
- 1974-09-27 HU HURI544A patent/HU170205B/hu unknown
-
1975
- 1975-09-12 CH CH1208475A patent/CH623585A5/en not_active IP Right Cessation
- 1975-09-17 DE DE2541485A patent/DE2541485C3/en not_active Expired
- 1975-09-17 AT AT711275A patent/AT345994B/en not_active IP Right Cessation
- 1975-09-19 IL IL48144A patent/IL48144A/en unknown
- 1975-09-19 AU AU85018/75A patent/AU497150B2/en not_active Expired
- 1975-09-23 FR FR7529073A patent/FR2286139A1/en active Granted
- 1975-09-23 CS CS7500006410A patent/CS186720B2/en unknown
- 1975-09-25 BG BG031071A patent/BG30777A3/en unknown
- 1975-09-25 DD DD188550A patent/DD122820A5/xx unknown
- 1975-09-25 NL NL7511284A patent/NL7511284A/en not_active Application Discontinuation
- 1975-09-25 SE SE7510784A patent/SE421207B/en not_active IP Right Cessation
- 1975-09-25 CA CA236,327A patent/CA1067496A/en not_active Expired
- 1975-09-25 GB GB3931375A patent/GB1473484A/en not_active Expired
- 1975-09-26 PL PL1975183604A patent/PL96854B1/en unknown
- 1975-09-26 DK DK433175AA patent/DK138328B/en not_active IP Right Cessation
- 1975-09-26 BE BE160438A patent/BE833894A/en not_active IP Right Cessation
- 1975-09-26 SU SU752176207A patent/SU619106A3/en active
- 1975-09-26 JP JP50117084A patent/JPS5159897A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IL48144A (en) | 1979-07-25 |
| NL7511284A (en) | 1976-03-30 |
| DE2541485C3 (en) | 1982-05-13 |
| BE833894A (en) | 1976-01-16 |
| CS186720B2 (en) | 1978-12-29 |
| AT345994B (en) | 1978-10-10 |
| DD122820A5 (en) | 1976-11-05 |
| AU497150B2 (en) | 1978-12-07 |
| JPS5159897A (en) | 1976-05-25 |
| PL96854B1 (en) | 1978-01-31 |
| FR2286139B3 (en) | 1978-05-05 |
| DK433175A (en) | 1976-03-28 |
| AU8501875A (en) | 1977-03-24 |
| FR2286139A1 (en) | 1976-04-23 |
| BG30777A3 (en) | 1981-08-14 |
| ATA711275A (en) | 1978-02-15 |
| GB1473484A (en) | 1977-05-11 |
| SE7510784L (en) | 1976-03-29 |
| HU170205B (en) | 1977-04-28 |
| IL48144A0 (en) | 1975-11-25 |
| DK138328B (en) | 1978-08-14 |
| SE421207B (en) | 1981-12-07 |
| DE2541485B2 (en) | 1981-08-06 |
| DK138328C (en) | 1979-01-22 |
| SU619106A3 (en) | 1978-08-05 |
| DE2541485A1 (en) | 1976-04-15 |
| CH623585A5 (en) | 1981-06-15 |
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