CA1261336A - Racemic trans hydroxyiminooctahydroindolo¬2,3-a|-quinolizine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to a process for preparing a racemic cis or trans hydroxyiminooctahydroindolo (2,3-a) quinolizine derivative of formula II or an optically active form thereof (II) wherein R1 and R2 are identical or different alkyl groups having from 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof, which process comprises treating a racemic cis or trans compound of formula IV

Description

3~

This divisional application is divided out of parent application Serial No. 405,030 filed on June 11, 1982.
The parent application related to compounds of formula I (hereinafter defined), processes for their preparation and pharmaceutical compositions containing them.
The present divisional application relates to compounds of formula II (hereinafter defined), processes for their prepara-tion and pharmaceutical compositions containing them.
The invention of the parent application relates to a new process for the preparation of apovincaminic acid esters.
More particularly, the inventlon concerns a new process for preparing racemic cis and/or trans apovincaminic acid esters of the formula (I) ~ (I) Rloo~

9,~

-2~ 336 23305-842D

and the corresponding optically active derivatives of -the formulae (Ia) ~ I N (Ia) RlooC ,~ 1 ~
and/or (Ib) \\ I ~ ~- N (Ib) R OOC
and/or (Ic) ~ n~ (Ic) R OOC
and/or (Id) ~ N ~ N (Id) R OOC R ~

In the above formulae R and R2 are identical or different alkyl groups having from 1 to 6 carbon atoms.

_3_ 1~6~33~ 23305-842D

Racemic cis and/or trans compounds of the formula ~I) and the corresponding optically active compounds of the formulae (Ia) and/or (Ib) and/or (Ic) and/or (Id) are prepared by a synthesis in which if desired, racemic hexhydroindolo / 2,3-a 7 quinolizinium derivatives of the formula (V) X~ (V) wherein R2 and R3 are identical or different alkyl groups having -- . .
~6133 from one to 6 carbon atoma, and X stand~ for an acid reaidue or ~ al~anolate hav~lg from one to 6 carbon atom~, are resolved with optically ~ctive dibenzoyltartaric acid, 5 the optically actlve hexahydroindolol 2,3-a 7quinolizlnium derlvative~ of the formula (Va) I,~ X~ (V~) R300C~ ~H2 ~2 and/or (Vb) 15 ~ (Vb) R300C-CH~-CH2 ~J\

obtained or the racemic compoun~s OI ~he formula (V), wherein R2, R3 and X have the aame meanlng ae defined above, a) are reduced with an alkali metal hydride, if deolred racemic trans octahydroindolo~ 2,3-a_7quinolizinee of the formula (IV) ~ ~ (IV) R300C--CH~CH_ ~) ~ 5- ~26133~ ~

wherein R2 and R3 have the same meani~g as defined above, are reeolved with D-tartaric acid and from the opt~cally active taxtarates ob~ained the corre~po~din~ optically ac~ive base~ are set free, a~d the optlcally actlve ootahydrolndolo-5 ~ 2,~-a 7quinolizine derivatives of the ~ormulae (IVa) ~ ~ ~ (IVa) R~OO~-CH2-cH~ - 2 and/or (IVb) ~5 ~ ~ (IVb) ~ CH2-CH2~

or the racemlc trans octahydrolndolo¦ 2,~-a_7quinolizlnes of 20 the formula (IV), whereln R2 and R3 have the seme meaning as defined above, if desired, are subJected to alkaline hydrolysls, and the racemic trans octahydroindolo~ 2,3-a 7-quinolizinecerboxylic acids of the formula (III) ~2 ~X6133~

or the corresponding optically active derivatives of the formulae (IIIa) (IIIa) and/or (IIIb) ~ ` (IIIb) HOOC-CH2-CH2 ~

wherein R2 has the same meaning as defined above, if desired after resolving racemic trans compounds of the formula (III), are esterified, and the optically active octahydroindolo- ~2,3-a~ quinolizine derivatives of the formulae (VIa) (VIa) R400C-CH2-CH ~

and/or (VIb) ,~

~ 33U6 ~ (VIb) ~ 0 0 C- ~ ~`H2 obtained or the corresponding racemic trans compounds of the formula (VI) ~ v ~

~ ~ 0 C - C H2 C H2~ ~
wherein R2 has the same me~ning a~ defined above and R4 i~ en alkyl group having from one to 6 carbon atoms, which may be identical with or dlfferent from R3, are treated with tert.-butyl nitrlte in ~n aromatio hydro-20 carbon ~olvent, subsequently with ~n alkali metal tert.--alcoholate and optlonally with an aprotlo dipolar solvent and if desired, with an alkanol of the formula R5-oH, wherein R5 i8 an alkyl group having from one to 6 carbon atom~, which may be identical with or dlfferent from R4, the 25 racemic tr~ns hydroxylminooctahydroindolo~ 2,3-a_7-quinolizlne derivative~ of the formula (II) `

~133fi ~' ~ ~ (II) RlOOC--C--CH2 ~
11 ~2 - _j N-OH
or the corresponding optically active derlvatives of the formulae (IIa) 10 ~

~ ¦ ~ (IIa) R~ C-C~

15 and/or (IIb) ~ (IIb) N-OH

wherein ~ has the same meaning as derined above and Rl i8 identical with R4 or R5, if desired after coverting them into their acid addition salts and/or resolving the 25 racemic trans compo-mds o~ the i'ormula (II), are treated with a concentrated, not volatile acid, in an inert organic ~olvent, to yield racemic trane compounds of the formula (I) or the optically active compounds of the formulae (Ia) and~or (Ib); or b) are ~ub~cted to catalytic hydrogenatlon, if de~lred the racemic Ci9 octahydroindolo~ 2,3-a_7qulnollzines of the formula (IV) (IV) F~)oc-c~J~cH;~
wherein R2 and R3 have the eame meaning a~ deflned above, are re~olved with D-t~rtaric acid and from the optically active tartarates obtained the corre~pondln~ optically active ba~e~ are ~et free, and the optlcally active octa-hydrolndolo~ 2,3-a 7quinolizine derivatlves of the formulae (IVc) 1 ~ ~ (IVc) R~C-C~2-CH2 ~2 ~nd/or (IVd) ~ ~ ~IVd) f~OOC-CH2C:H2~ ~

- lo ~26133~; ~

or the racemio Ci9 octahydroindolo~ 2,3-a 7quinolizines of the formul~ (IV), wherein R2 and n~ have the ~ame meaning as defined above, if desired, are sub~ected to alkaline hydroly~is, and the racemic ci~ octshydroinaolo~ 2,3-a 7quinolizlne-5 oarboxylic ac1ds of the formula (III) (III) 0 HO(~C-CH;~ CH2 ~,2 or the oorrespondlng optically aotive derlvativeo of the formulae (IIIc) ~ (IIIo) HOO C- CH~CH~

20 and/or (IIId) ~ (IIId) ~O~)C-C~~CH2 R~

~6~3fi ~ 23305-842D

wherein R2 has the same meaning as defined above, if desired after resolving racemic cis compounds of the formula (III), are esteri-fied, and the optically active octahydroindolo-[2,3-a]quinolizine derivatives of the formulae (VIc) ~ (VIc) R ooc-CH2~cH2 R2 and/or (VId) ~ I ~ (VId) R

obtained or the corresponding racemic cis compounds of the formula (VI) ~ ~VI) wherein R2 has the same meaning as defined above and R4 is an alkyl group having from one to 6 carbon atoms, which may be identical with or different from R3, are treated with tert.-butyl nitrite in an aromatic hydrocarbon solvent, subse-quently with an alkali metal tert.-alcoholate and optionally with an aprotic dipolar solvent and if desired, with an alkanol of the formula R5-oH, wherein ~.

33~i R5 is an alkyl group having from one to 6 carbon atoms, which may be identical with or different from R4, the racemic cis hydroxyiminooctahydroindolo[2,3-a]quinolizine derivatives of the formula (II) (II) R OOC-C-CH
N-OH

or the corresponding optically active derivatives of the formulae (IIc) ~ ~1 ~ (IIc) R OOC-C-CH~-N-OH

and/or (IId) ~2~133Ç;

~ (IId) R~0 0 C~ C~ C H~2 ~ ~
I~OH

wherein R has the same meanillg a~ defined above and Rl 18 identical with n4 or R5, lf deeired a~ter converting lG them into th~ir acid addition salt~ and/or re~olvlng the raoemic cie compounds of the formula (II), sre treated with a concentrated, not volatile acid, in an inert organic ~olvent~
to yield racemic Ci9 COmI)OUnd8 0~ the formula (I) o.r the optically actlve compound~ of the rormulae (Ioj and/or (Id) and lf ~e~ired, racemic CiB or trans compound~ of the formula (I) or the optically active trans compound~ oi~ thc formulae (Ia) and/or (Ib) or the optically aotive cis compounds of the formulae (Ic) and/or (Id) are tr~nsesterlfied in a manner l~own ~
It is well lcnowll that racemio cis apovincaminic acid esters of the formula (I) and the optically actlve oi~
compounds of the for~lula (Ic) poY~ess valuable pharmaceutical properties, and in particular (+)~cis-apovincaminic acid ethyl e~ter show~ excellent vasodilating activity.
~ccording to the ~ungarian Patent Specification No. 163,143 racemlc, Ci9 compound~ of the formula (I) and optically activeJ ci~ compound o~ the formula tIc) were prepared by hydrolyzing the pharmaceutically actlve vincamine

3~i;

and converting the vincaminic acid obtained into a desired ester from which the corresponding apovincaminic acid ester was obtained by splitting off water; or alternatively, vinoamine was first converted into apovincamine by splitting off water which was then subjected to hydrolysis and the apovincaminic acid obtained was converted into a desired ester. Thls process is disadvantageous in that at first vincamine should be prepared by a multi-step syn-thesis from which the corresponding apovincaminic acid esters can be prepared with a yield of at most 60 % only.

Racemic, trans compounds of the formula (I) were described in the European Patent Application No. 13315.
The optically active trans compounds of the formulae (Ia) and (Ib) are new and show valuable antiinflammatory, anticon-vulsive, CNS, anticholinergic, antiparkinsonism and anti-athero-sclerotic activities. The last intermediates of the formulae (II), (IIa), (IIb), (IIc) and (IId) are also new and may be utilized in treating cardiovascular diseases. The optically active inter-mediates of the formulae (IIIa), (IIIb), (IIIc) and (IIId), have antihypoxic and anticonvulsive activities, and the optically active intermediates of the formulae (IVa), (IVb), (IVc), (IVd) and (VIa), (VIb), (VIc), (VId), respectively show antiallergic, antibradyquinine, CNS, antiarrhytmic, antihypoxic, anticonvulsive, antidepressive, sedative, hypnotic, cholesterine, antiallergic and antiulcer activities and decrease the lipoproteine level. These compounds have first been described in the Hungarian Patent -15~ 3~ 23305-842D

Application No. 171 660 and some of them are patent vasodilators.
Moreover, all intermediates in the above process are valuable starting compounds for other pharmaceutically active compounds having an indoloquinolizine or eburnane skeleton, e.g. vincamine, vincamone, et cetera.
The process includes all processes for the preparation of compounds of the formulae (I), (Ia), (Ib), (Ic~ and (Id), starting from compounds of the formulae (V), (Va), (Vb) or (IV), (IVa), (IVb), (IVc) or (IVd) or (VI), (VIa), (VIb), (VIc) or (VId) or (III), (IIIa), (IIIb), (IIIc), (IIId) or (II), (IIa), (IIb), (IIc) or (IId).
The process further relates to the preparation of all new intermediates, i.e. compounds of the formulae (II), ~IIa), (IIb), (IIc) and (IId).
In other words, the process may be interrupted at any stage of the synthesis, i.e. at any intermediate or may be accomplished starting from any intermediate.

In the formulae in the symbols Rl, R , R , R4 and R5 the alkyl groups having from 1 to 6 carbon atoms may be straight or branched chained alkyls having from 1 to 6 carbon atoms, i.e.
methyl, ethyl, _-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, _-pentyl, isopentyl, _-hexyl or isohexyl groups.
X as an acid residue may represent a residue of any organic or inorganic acid and preferably is a perhalogenate, e.g. perchlorate; and as an alkanolate stands for an alkanolate corresponding to any of the alkyls referred to in connection 126133~
- 16 - i23305-842D

with Rl, R2, R3, R4 and R5, preferably methanolate Resolution of the racemic cis and racemic trans com-pounds of the formulae (IV~ and (V) is carried out in any organic solvent or solvent mixture inert under the reaction conditions.
Suitable solvents include e.g. aliphatic or aromatic hydrocarbons optionally substituted by one or more halogens, such as dichloro-methane; or alkanols having from one to 6 carbon atoms, such as methanol, ethanol or mixtures thereof.
For catalytic hydrogenation of the compounds of formulae (V), (Va) and (Vb) as a catalyst preferably palladium-on-charcoal is employed but the reaction may be successfully performed in the presence of any conventional hydrogenation metal catalyst, optionally precipitated on a carrier, as well. Catalytic hydro-genation is carried out in the presence of an organic solvent or solvent mixture inert under the reaction conditions. Suitable solvents include aprotic dipolar solvents, such as dimethyl forma-mide; or protic solvents, such as alkanols having from one to 6 carbon atoms, such as methanol, ethanol, etc. or mixtures there-of.
The reduction of the compounds of the formulae (V), (Va) and (Vb) is preferably carried out in the presence of sodium boro-hydride but for example lithiumaluminium hydride may also be employed. The reduction is carried out in an alkanol having from one to 6 carbon atoms, such as methanol, ethanol, etc.
The alkaline hydrolysis of the compounds of the formulae (IV), (IVa), (IVb) and (IVc), (IVd) is performed in a mixture of an inorganic base, e.g. alkali metal hydride, such as sodium 1~61~

- 17 - ~23305-842D

hydride, an alkanol having from one to 6 carbon atoms and water.
I'he acids of the formuale (III), (IIIa), (IIIb), (IIIc) and (IIId) obtained by alkaline hydrolysis may be converted into a corresponding salt by a suitable base, or into other functional derivatives, e.g. acid halides, acid amides, nitriles, acid anhydrides, acid azides, etc.
Esterification of the compounds of the formulae (III), (IIIa), (IIIb), (IIIc) and (IIId) may be carried out by any of the known methods.
When converting compounds of the formulae (VI), (VIa), (VIb), (VIc), and (VId) into compounds of the formulae (II), (IIa), (IIb), (IIc), and (IId), respectively, as an aromatic hydrocarbon solvent for example benzene, toluene, xylene, etc. may be employed. Suitable alkali metal tertiary alcoholates include potassium or sodium alcoholates having 4 to 8 carbon atoms, e.g.
potassium tert.-butylate, sodium-tert.-butylate, potassium tert.-amylate, sodium tert.-amylate. Optionally an aprotic dipolar solvent, e.g. dimethyl formamide, dimethyl acetamide, etc.
may also be added to the reaction mixture just as an alkanol of the formula R5-oH.
Compounds of the formulae (II), (IIa), (IIb), (IIc) and (IId) are then treated with a concentrated not volatile acid, for example a concentrated mineral acid e.g. concentrated sulfuric acid; or an organic aliphatic or aromatic sulfonic acid, such as methanesulfonic acid, ethanesulfonic acid, dodecylsulfonic acid, benzenesulfonic acid, p-toluene -18 ~ ~ 6 1 3~5 23305-842D

sulfonic acid, ~-naphthylsulfonic acid, ~-naphthylsulfonic acid, et cetera. The acid treatment may be accomplished in an inert organic solvent, e.g. an alkanol having from 1 to 6 carbon atoms, such as methanol, ethanol, et cetera; or in an aprotic organic solvent, e.g. an aromatic hydrocarbon optically substituted with one or more halogene, such as benzene, toluene, xylene, chloro-benzene; or in cyclic ethers, such as dioxane.
The inventions of the parent and divisional applications will now be illustrated in greater detail in the following Examples, which are given for illustration and not limitation of our invention.
Example Resolution of l-(methoxycarbonylethyl)-l-ethyl-1,2,3,-

4,6,7-hexahydro-12H-indolo~ 2,3-a 7quinolizinium methanolate 100.0 g. (0.2699 moles) of 1-(2'-methoxycarbonyl-ethyl)-l-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo~ 2,3-a 7quinolizi-nium methanolate are dissolved in 200.0 ml. of dichloromethane at room temperature, whereupon a solution of 100.0 g. of dibenzoyl-l-tartaric acid monohydrate (0.2673 moles) in 400.0 ml. of dichloromethane is added with stirring. The mixture is stirred at room temperature for one hour, whereupon the precipitated substance is filtered off, washed with dichloromethane and dried.
91.84 g. (0.1322 moles ) of l~-(2'-methoxycarbonyl-ethyl)-~-ethyl--1,2,3,4,6,7-hexahydro-12H-indolo/ 2,3-a 7quinolizinium-dibenzoyl tartarate are obtained. Yield: 98.0 % (calculated for the ~-ethyl form).

lX6~336 -- 19 -- ~

~ D = -68.6 (c = 1, in DMF) Baee con-tent: 48.49 % (theoretlcal: 48.73 %) Melting point: 139.5 to 140 C
Erom the salt obtained the corresponding base iY set

5 free, whlch i9 then converted into the corresponding methano-late ~ld perchlorate, re~pectively.
1~(2~-methoxycarbonylethyl)-1 ~-ethyl-1,2,~,4,6,7-hexahydro--12H-indolo~ 2,3-~ 7quinolizinium methanolata: melting point:
151 to 152 C;
10 ~ ~20 -Z7.6 (o ~ MF)-1 ~(2'-methoxycarbonylethyl)-1 ~-ethyl-1,2,3,4,6,7-hexahydro--12~-indolo~ 2,~-a 7quinolizinlum HC104: melting polnt: 178 to 180 C;
L~ 7= -23.S (c ~ 1, DMF) From the mother liquor of the re~olution the oorres-~ondlng ~alt~ of the ~-ethyl antipode may be prepared, after ~etting free the ba~e.

~xamPle ?
The re~olution of l-(methoxycarbonylethyl)-l-ethyl--1,2,3,4,6,7-hexahydro-12~1-lndolo~ 2,3-a 7qulnolizinium methanolate 100.~ g. (0.2699 mole~) of 1-(2'-methoxycarbongl-ethyl)-l-ethyl-1,2,3,~,6,7-he~hydro-12H-lndolo~ 2,3-a 7 25 quinollziniu~ methanolate are dis~olved in 200.0 ml. of dichlorometh~le at room temperature, whereupon a ~olution o~
100.0 g. (0.2673 moles) of dibenzoyl-d-tartaric acid in ~00.0 ml. of dichloromethane i8 added. After ~tirring at ~X613;~6 - 20 - i23305-842D

room temperature for one hour the reaction mixture is filtered, washed with dichloromethane and dried.
91.7 9. (0.1320 moles) of l-~x(methoxycarbonylethyl)~
ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizinium di-benzoyl tartarate are obtained. Yie:Ld: 97.8~ (calculated for the 13-ethyl antipode).
[~DO] = +68.8 (c = 1, DMF) Base content: 48.5% (theoretical: 48.73~) Melting point: 139 to 140C
From the crude compound obtained the corresponding methanolate and perchlorate salts can be prepared, after setting free the corresponding base.
l~-(methoxycarbonylethyl)-1~-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizinium methanolate: melting point: 150 to 152C;
[~ ~ = +27.8 (c =1, DMF) l~-(methoxycarbonylethyl)l~-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a]quinolizinium perchlorate: melting point: 178.5 to 180C;
[~~ = +24 (c = 1, DMF).
From the mother liquor of the resolution the correspond-ing salts of the ~-ethyl antipode can also be prepared, after setting free the base.
Example 3 (-)-13-(2'-Methoxycarbonylethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octa hydro-indolo[2,3-a]quinolizine 34.7 9. (0.05 moles) of (-)-1~-(2'-methoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quino-lizine-5-ium (-)-dibenzoyltartarate in 70 ml. of dimethyl forma-mide, in the presence of 0.25 g. of a 10~ palladium-on-charcoal catalyst are hydrogenated for 2.5 hours, at 40C, under atmos-pheric pressure. Catalyst is filtered off and is then washed with altogether 10 ml. of dimethyl formamide in two portions. To the filtrate 200 ml. of a 5~ aqueous methanol solution is poured under vigorous stirring. The (-)-dibenzoyl tartarate of the title compound is precipitated. The product is washed with altogether 10 ml. of cold methyl alcohol in two portions and dried. Yield:
26 g. (75%).
Melting point: 150-152C
[~2D0] = -120.1 (c =2, DMF) Example 4 (+)-1~-(2'-Methoxycarbonylethyl)-l~-ethyl-1,2,3,4,6,7, 12,12b~-octahydro-indolo~2,3-a]quinolizine Following the procedure described in Example 3 but starting from 34.7 g. (0.05 moles) of (+)-1~-(2'-methoxycarbonyl-ethyl)-1~-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quinolizine-5-ium (+)-dibenzoyltartarate, the title compound is obtained, weigh-ing 25.5 g. (73.5%).
Melting point: 150 to 151C
[~2D0] = +119.8 (c = 2, DMF) Example 5 (+)-13-(2'-Methoxycarbonylethyl)-1 -ethyl-1,2,3,4,6,7, 12,12b~-octahydro-indolo[2,3-a]quinolizine 4.39 g. (0.01 moles) of (-)-1~-(2'-methoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quinoli-zine-5-ium perchlorate are suspended in 100 ml. of methyl alcohol i~6133t~
- 22 - ~23305-842D

at 60C, and at the same temperature 1.2 9. of sodium borohydride are added in one hour, in more portions, whereupon the mixture is stirred for a further one hour. 70 ml. of methyl alcohol are distilled of~ from the reaction mixture, the residue i6 stirred at 0C, washed by covering with cold methyl alcohol and washed to neutral with distilled water. 1.7 9. (50%) of the title compound are obtained, melting at 108 to lO9~C.
[~20] = +69.7 (c = 1, CHC13) Example 6 (-)-1 (2'-Methoxycarbonylethyl)-l~-ethyl-1,2,3,4,6,7,12, 12b~-octahydro-indolo[2,3-a]quinolizine Following the procedure described in Example 5 but starting from 4.39.g. (0.01 moles) of (+)-1~-(2'-methoxycarbonyl-ethyl~ -ethyl-1,2,3,4,6,7-hexahydro-12H-indolo-[2,3-a]quino-lizine-5-ium perchlorate, 1,73 9. (51%) of the title compound are obtained, melting at 108 to 109C.
[~20] = -68.9 (c=l, CHC13) lX6~33~

Example 7 Resolution of racemic trane 1-(2'-metho~yoarbonyl-ethyl)-l-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo-~ 2,3-a 7qulnoli~ine 34 g. (0.1 moles) of the tltle oo~pound are suepended in 400 ml. of methyl alcohol at 55 C and a solu-tion of 15 g. (0.1 mole~) of D-tartarlo acid ln 40 ml. of methyl alcohol of 55 C i8 added at the sa~e temperature.
The homogeneou~ ~olution i~ cooled to 15 C. The pre-10 cipitated (~ -(2'-methoxycarbonylethyl)-1 ~-ethyl--1,2,3,4,6,7,12,12b~-octahydro-indolo~ 2,3-a 7quinollzln--5-ium D-tartarate is filtered and wa~hed with altogether 50 ~1 of cold methanol in two portion~. 24,1 g. (98.3 0 of the above compound are obtained, melting at 213 to 215 C~
15 ~ ~ 20_7 ~ ~44.a (c ~ 1, DMF) The corre~ponding base i8 set free a~ follows:
The product is dis~olved in 200 ml. of water, the pH is ad~usted to 9 with aqueous ammonla and the mixture is extracted with altogether 120 ml. o~ dlchlorometh~ne, in 20 three portions. ~fter drying the solution le evaporated and the obtained oily re~idue i8 boiled with 30 ml. oi methanol.
15~5 8. (91.5 0 of (+)-13-(2'-methoxycarbonylethyl)~
-ethyl-1,2,3,4,6,7912,12b~ octahydro-indolo~ 2,3-a 7-quinoli~ine are obtained, melting at 108.5 to 109 C.
25 ~ ~ 20 7 ~ ~70 1 (c 3 1~ CHC13) From the meth~nolic mother liquor o~ the resolution the other optically active l~omer i8 i~olated. It is evapora-ted to 100 ~1., diluted with 200 ml of water and after lX~ 3~;

- 24 - ~23305-842D

adjusting the pH to 9 by aqueous ammonia and is extracted with altogether 120 ml. of dichloromethane in three portions. The mixture is dried, evaporated and the oily residue is boiled with 30 ml. of methanol. lS.l g. (89~) of (-)-1~-(2'-methoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quino-lizine are obtained, melting at 109C.
[~2D0] = -69.4 (c = 1, CHC13) Example 8 (+)-1~-(2'-Carboxyethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3,-a]quinolizine

6.8 g. (0.02 moles) of (+)-1~-(2'-methoxycarbonylethyl-ld-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]-quinolizine, 80 ml. of methanol, 4 ml. of water and 2 9. of sodium hydroxide are refluxed for one hour, whereupon 50 ml. of the mixture are distilled off under reduced pressure, 80 ml. of water are added and the pH is adjusted to 6.5 with a 1 M aqueous citric acid solu-tion, at 60C. The title compound is filtered off at 20C and is then washed with altogether 50 ml. of distilled water in two portions. 6.34 g. (99%) of the title compound are obtained, melt-ing at 144C with decomposition.
[~20] = +52.4 (c = 1, ethanol) Example 9 (-)-h~-(2'-Carboxyethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolizine Following the procedure described in Example 8 but 5 starting from 6.8 g. (0.02 moles) of (-)-1~-(2'-methoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3a]quino-3~i lizine, 6.39 g. (98%) of the title compound are obtained, melting at 144C with decomposition.
~X2DO] = -48.6 (c=l, ethanol) Example 10 (-)-13-[(2'-Methoxycarbonyl-2'-hydroxyimino)-ethyl~-~X-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo-[2,3a]quino-lizine and its hydrochloride To 34 g. (0.1 moles) of (-)-1~-(2'-methoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7,12,12bx-octahydro-indolot2,3-a]-quinolizine 20 ml. of absolute toluene, a 55 to 60% toluene solu-tion of 30 ml. of tert.-butyl nitrite and then 17 g. (0.15 moles) of potassium tert.-butylate are added. The mixture is stirred at 25 to 30C for 20 minutes, 150 ml. of absolute methanol are slowly added and the mixture is stirred at 40C for 3 hours. The reac-tion mixture is then cooled to 20C, is acidified up to pH = 1 with concentrated hydrochloric acid, 50 ml. of water are added and the mixture is stirred at +5C for 2 hours. The precipitate is filtered off, the KCl is washed out with water and the precipi-tate is dried. 32.5 g. (80%) of hydrochloride of the title com-pound are obtained, melting at 265 to 272C with decomposition.

- ~6~:336 -- 26 ~

~-~ 20 7= _57 (c = 1, DMF) ~ rom the hydrochloride obtailled the ~ree ba~e is prepared by suspending the salt in 80 ml. of methanol and adding a mixture of 25 ml. of 25 ~ aqueous ammonium hydroxide 5 ~olution and 40 ml. of water dropwlse, with etirring. A~ter one hour stirring it i9 oooled to 10 C, flltered, washed with water hnd dried. 24 to 25 g. of the title compound are obtained, melting at 208 to 210 C.
~-~ 20 7 ~ -62 (o o 1, ~MF) Example 11 ~ (2'-Methoxycarbonyl-2'-hydroxyimlno)-ethyl 7--1 ~-ethyl-1,2,3,4,6,7,12,12b ~-ootahydro-indolo-~ 2,3-a 7quinollzine a) Following the procedure described ln Example 10 but replaclng K-tert~-butylQte by 15 g. of Na-tert.-butylate 24 g. (60 0 of the title compound are obta1ned.
b) Following the procedure under point a) but adding also 7 ml. o~ dLmethyl ~ormamide to the reaction 20 mlxture, 32.5 g (ao o 0~ the tltle compound are obtained.

Example 12 (-)-1 ~12'-Ethoxycarbonyl-2'-hydroxyimlno)-ethyl 7--1 ~-ethyl-1,2,~,4,6,7,12,12b ~-oct~hydro-indolo-~ 2,3-a_7quinolizine and ite hydrochlorlde ~ollowing the procedure described in Ex~mple 10 but replacing methanol by 150 ml. of abaolute ethanol, 25 g.
of the HCl ~alt of the title compound (60 ~ are obtained, - 27- ~L2 melting at 257 to 260 C.
t D _7 ~ -55 (c ~ 1, rMF) The corre~ponding base i~ set rree in aqueou~ ethanol wlth a 25 % ammonlum hydroxide ~olutlon, according to 5 E~cample 10. 21 g. o~ the title compound are obtained, melting ~t 172 to 173 C.
0c D0 7, -118 (c ~c 1, ~C

~xamPle 13 (+)-1 oc-~ (2'-Ethoxy¢arbonyl-2'-h;rdro2cyimlno)-et}url 7--l~-ethyl-1,2,3,4,6,7,12,12b~-ootahydro-lndolo~ 2,3-a 7-quinolizine a~d its hydrochloride Following the prooedure descrlbed ln E~cample 10 but etarting from 34 g. of (+)-1 oC-(2'-methoxycarbo~ylethyl)--lF~-ethyl-1,2,3,4,6,7,12,12b~octahydro-lndolo~ 2,3-a 7-qulnolizine and u~lng 150 ml. of ab~olute ethanol Q~l an alcohol, 25.2 g. (60 %) of the hydrochlorlde Or the tltle co~pound are obtained, meltln~ at 258 to 260 C.
~ ~ D _7 ~ +55 (c ~ 1, ~IF) The oorreeponding baae i8 ~et free in aqueous ethanol with a 25 % ammonium hydroxlde solutlon, according to Example 10, 21.3 e. of the title compound are obtained, meltlng at 171 to 172 C.
~ oC 20 7 ~ +118 (o, 1, CHC13) ~6~336 Example 14 (-)-1~-[(2'-Methoxycarbonyl-2'-hydroxyimino)-ethyl]-1~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]-quinolizine and its hydrochloride Following the procedure described in Example 10 but starting from 34 g. (0.1 moles) of (~ x-(2'-methoxy-carbonyl-ethyl)-13-ethyl-1,2,3,4,6,12,12b~-octahydro-indolo[2,3-a]quino-lizine, 24.3 g. (60%) of the hydrochloride of the title compound are obtained, melting at 214 to 215C.
~X20~ = -46 (c = 1, DMF) The hydrochloride obtained is suspended in 50 ml. of water, 100 ml. of chloroform are added, whereupon the pH is adjus-ted to 9 with 25% aqueous ammonium hydroxide solution. The chloroform phase is separated, the aqueous phase is extracted with 20 ml. of chloroform. The combined organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is recrystal-lized from 30 ml. of dichloroethane. 16 g. of the title compound are obtained, melting at 166 to 168C.
[~20] = _54 (c = 1, DMF
Example lS
(+)-1~-[(2'-Methoxycarbonyl-2'-hydroxyimino)-ethyl]-1~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo-[2,3-a]quino-lizine and its hydrochloride Following the procedure described in Example 10 but starting from 34 9. (0.1 moles) of (+)-1~-(2'-methoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quino-lizine, 25 9. (61,5%) of the hydrochloride of the title compound ~X~ 336 .

are obtained, melting at 214 to 215C.
[~D20] = +46 (c = 1, DMF) From the hydrochloride the corresponding free base is obtained, as described in Example 14. 19.2 9. of the title com-pound are obtained, melting at 166 to 168C.
[~D20] = +53.2 (c = 1, DMF) Example 16 (-)-1~-[(2'-Ethoxycarbonyl-2'~hydroxyimino)-ethyl]~
ethyl-1,2,3,4,6,7,12,12bx-octahydro-indolo[2,3-a]-quino-lizine hydrochloride Following the procedure described in Example 10 butstarting from 35.4 9. (0.1 moles) of (-)-1~-(2'-ethoxycarbonyl-ethyl)-l~-ethyl-1,2,3,4,6,7,12,12b~-octahydroindolo[2,3-a]quino-lizine and using 150 ml. of absolute ethanol as an alcohol, 23 9.
(55%) Of the title compound are obtained, melting at 247 to 249C.
[~20] = -44 (c = 1, DMF
Example 17 (+)-13-[(2'-Ethoxycarbonyl-2'-hydroxyimino)-ethyl]-(1~-ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo-[2,3- a]quinolizine hydrochloride Following the procedure described in Example 10 but starting from 35.4 9. (0.1 moles) of (+)-1~-(2'-ethoxycarbonyl-ethyl)-~x-ethyl-1,2,3,4,6,7,12,12b~-octahydroindolo[2,3-a]quino-lizine and using 150 ml. of absolute ethanol as an alcohol, 23.2 9. of the title compound are obtained, melting at 248 to 249C.
~X20] = +45 (c = 1, DMF
Example 18 Racemic trans 1-[2'-Ethoxycarbonyl-2'-hydroxyimino)-3~

ethyl]-l-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo-[2,3-a]quinolizine hydrochloride Followiny the procedure described in Example 10 but starting from 35.4 g. (0.1 moles) of racemic trans l-(ethoxy-carbonylethyl)-l-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a]quinolizine and using 150 ml. of absolute ethanol as an alcohol, 25.1 g. (60%) of the title compound are obtained, melting at 226 to 228C (decomp.).
[~20] = + 0 (c = 1, DMF) Example 19 (+)-Trans-apovincaminic acid ethylester 4.75 g. (0.025 moles) _-toluenesulfonic acid monohydrate are refluxed in a flask equipped with a Marcusson water condenser, under atmospheric pressure, whereupon the toluene is made up to 70 ml. and 4.2 g. (0.01 moles) of (-)-1~-[(2'-ethoxycarbonyl-2'-hydroxyimino)-ethyl]-l~-ethyl-1,2,3, 4,6,7,1Z,12b~-octahydro-indolo[2,3-a]-quinolizine hydrochloride are added. The reaction mixture is refluxed for 1.5 hours and 30 ml. of water are added at room temperature. The mixture is adjusted to pH 9 with an aqueous ammonia solution. After separation the toluene phase is evapor-ated under reduced pressure, the oily residue is boiled with 5 ml.
of ethanol and filtered at 0C. 3.14 g. (90~) of the title com-pound are obtained, melting at 120 to 122C.
GY20] = +144.4 (c = 1, CHC13) Example 20 (-)-Trans-apovincaminic acid ethylester Following the procedure according to Example 19 but ~61~fi - 31 - ~3305-842D

starting from 4.2 9. (0.01 moles) of (+)-13-t(2'-ethoxycarbonyl-2'-hydroxyimino)-ethyl]-lo~ethyl-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolizine hydrochloride, 3.18 g. (91~) of the title compound are obtained, melting at 121 to 122C.
[~20] = -147.6 (c = 1, C~C13) Example 21 Racemic trans-apovincaminic acid ethylester Following the procedure according to Example 19 but starting from 4.2 g. (0.01 moles) of racemic trans 1-~(2'-ethoxy-carbonyl-2'-hydroxyimino)-ethyl]-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine hydrochloride (Example 21), 3.22 g. (92~) of the title compound are obtained, melting at 106 to 108C.
[~20] = + 0 (c = 1, C~C13) _ ~2 ~ 33 6 Example 22 Racemic cls-apovlncaminio acid ethyleeter Following the prooedure deucribed in Exa~ple 19 DU~
starting from 4.2 g. (0.01 mole3) of racemic Ci8 ~ ( 2~ -5 ethoxycarbonyl-2'-hydroxyimLno)-ethyl 7-1-ethyl-1,2,3,4,6,-

-7,12,12b-ootahydro-indolo~ 2~3-u 7quinslizine hydroohloride~
3. 22 g. (92 0 0~ the title compound are obtained, melting at 122 C.
~~X 20 7 G + 0 ( C ~ 1 ~ CHC13) Examvle 23 (+)-ci~~apovincaminic acid ethyleeter Following the procedure de~cribed in Example 19 but starting from 4.2 g. (0.01 mole~) of (~ ~(2'-ethoxy-15 carbonyl-2'-hydroxyimino)-ethyl 7-1~ -ethyl-1,2,3,4,6,7,12,--12b ~-octahydro-indolol 2,3-a_7quinolizlne hydrochloride, 3.14 g. (90 %) of the title compound are obtained, melting at 148 to 151 C.
~-~ 20 7 _ +147 (c = 1, CHC13) Example 24 (-)-oi~-apovincaminic acld ethyleoter Following the procedure deecribed in ~xample 19 but ~tarting from 4.2 g. (0,01 moles) o~ (+)-1~-~ (2'-ethoxy-25 carbonyl-2'-hydroxyimino)-ethyl 7-l~ethyl-1,2,3,4,6,7,12,--12b~-octahydro-indolo~ 2,3-a 7quinolizine hydrochloride, 25.2 g. (60 0 of the $itle compound are obtained, meltlng at 148 to 151 C.

d 20 7 ~ -145.8 (c - 1, CHCl~)

Claims (25)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a racemic cis or trans hydroxy-iminooctahydroindolo (2,3-a) quinolizine derivative of formula II
or an optically active form thereof (II) wherein R1 and R2 are identical or different alkyl groups having from 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof, which process comprises treating a racemic cis or trans compound of formula IV

(IV) or an optically active form thereof, wherein R2 is as defined above and R3 is an alkyl group of from 1 to 6 carbon atoms, with t-butyl nitrite in an aromatic hydrocarbon solvent followed by treatment with an alkali metal tertiary alcoholate and where required forming a pharmaceutically acceptable acid addition salt thereof.

2. A process according to claim 1 wherein the compound of formula IV is obtained by reducing a compound of formula V

(V) wherein R2 is as defined above and R3 is C(1-6)alkyl, and X is an acid residue or an alkanolate having from 1 to 6 carbon atoms.

3. A process according to claim 1 wherein a compound of formula II, as defined in claim 1, so obtained is converted into another compound of formula II by transesterification.

4. A process according to claim 1 further comprising the step of resolving and separating an isomer from a mixture of isomers so obtained.

5. A process according to claim 1 wherein the alkali metal tertiary alcoholate is in contact with an aprotic dipolar solvent.

6. A process according to claim 1 wherein the alkali metal tertiary alcoholate is a potassium or sodium alcoholate having from 4 to 8 carbon atoms.

7. A process according to claim 1 wherein the aromatic hydro-carbon solvent is benzene, toluene or xylene.

8. A process according to claim 5 wherein the aprotic dipolar solvent is dimethyl formamide or dimethyl acetamide.

9. A process according to claim 2 wherein X is perhalogenate.

10. A process according to claim 2 wherein X is perchlorate or methanolate.

11. A process according to claim 1, 2 or 3 wherein R1 and R2 are both ethyl.

12. A compound of formula II as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.

13. A compound of the formula IIa (IIa) wherein R1 and R2 are each an alkyl group of from 1 to 6 carbon atoms.

14. A compound of the formula IIb (IIb) wherein R1 and R2 are each an alkyl group of from 1 to 6 carbon atoms.

15. A compound of the formula IIc (IIc) wherein R1 and R2 are each an alkyl group of from 1 to 6 carbon atoms.

16. A compound of the formula IId (IId) wherein R1 and R2 are each an alkyl group of from 1 to 6 carbon atoms.

17. A compound according to claim 12, 13 or 14 wherein R1 and R2 are each ethyl.

18. A compound according to claim 15 or 16 wherein R1 and R2 are each ethyl.

19. A racemic cis hydroxyiminooctahydroindolo (2,3-a) quino-lizine of the formula (II), as defined in claim 1 or a pharmaceuti-cally acceptable acid addition salt thereof.

20. A racemic trans hydroxyiminooctahydro (2,3-a) quinolizine derivative of the formula (II), as defined in claim 1 or a pharma-ceutically acceptable acid addition salt thereof.

21. A pharmaceutical composition comprising an active ingre-dient in admixture with a pharmaceutically acceptable diluent or carrier wherein the active ingredient is a compound according to claim 12, 13 or 14.

22. A pharmaceutical composition comprising an active ingre-dient in admixture with a pharmaceutically acceptable diluent or carrier wherein the active ingredient is a compound according to claim 15 or 16.

23. A pharmaceutical composition comprising an active ingre-dient in admixture with a pharmaceutically acceptable diluent or carrier wherein the active ingredient is a compound according to claim 12, 13 or 14 wherein R1 and R2 are each ethyl.

24. A pharmaceutical composition comprising an active ingre-dient in admixture with a pharmaceutically acceptable diluent or carrier wherein the active ingredient is a compound according to claim 15 or 16 wherein R1 and R2 are each ethyl.

25. A pharmaceutical composition comprising an active ingre-dient in admixture with a pharmaceutically acceptable diluent or carrier wherein the active ingredient is a compound according to claim 19 or 20.