GB2039900A - Octahydro-indolo[2,3- a]quinolisine derivative - Google Patents

Octahydro-indolo[2,3- a]quinolisine derivative Download PDF

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GB2039900A
GB2039900A GB7943199A GB7943199A GB2039900A GB 2039900 A GB2039900 A GB 2039900A GB 7943199 A GB7943199 A GB 7943199A GB 7943199 A GB7943199 A GB 7943199A GB 2039900 A GB2039900 A GB 2039900A
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Richter Gedeon Vegyeszeti Gyar Nyrt
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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
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine

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Abstract

The compound of formula (VII), <IMAGE> which compound is not only itself biologically active but also of use in the synthesis of 10-bromovincamines. Precursors of the formulae V, VI and VIII and by-product XI are also claimed. <IMAGE>

Description

SPECIFICATION Octahydro-indolo[2,3-a]quinolisine derivative This invention relates interalia to a new octahydro-indolo[2,3-a]quinolisine derivative of use in the synthesis of 10-bromovincamines.10-bromovincamine of formula (la)
and its epimer 1O-bromo-14-epivincamine of formula (lib)
as well as their acid addition salts are known compounds with valuable therapeutical effects. These compounds are psychostimulants and agents for increasing vigilance.
Published German patent application No. 2,458,164 describes vincamine derivatives having a halo, hydroxy, alkyl or methoxy substituent at any position of ring "A". Although the 1 0-bromo compound falls within this generic definition, no data are given in the specification about its preparation.
Belgian patent specification No. 862,019 describes a multistep process for the preparation of 10bromovincamine and its epimer by brominating vincadifformine. The resources of native vincadifformaine, utilized as starting substance in this process are, however, rather limited. A further disadvantage of the above process is that it yields mixtures of various compounds and isomers, which mixtures are difficult to separate.
We have now found that 1 0-bromovincamine and its epimer may readily be prepared from a new octahydro-indolo[2,3-a]quinolisine derivative which is itself readily obtained from easily available starting materials.
According to the present invention we provide the compound of formula VII,
The compounds of formula (VII) is not only useful as an intermediate but is itself also biologically active.
According to a further feature of the invention the compound of formula (VII) may be converted into the compound of formula (la) andior (Ib) or acid addition salts thereof by oxidation and subsequent separation of the desired compound of formula (la) and/or (Ib) followed, where required, by epimerization of a compound of formula (Ib) into a compound of formula (la) and/or by conversion of a compound of formula (la) and/or (Ib) into an acid addition salt thereof.
Oxidation is preferably effected by means of supported silver carbonate or manganese dioxide, e.g. silver carbonate or manganese dioxide precipitated on a celite support. Oxidation is carried out preferably in the presence of benzene or a homologue thereof as solvent. If xylene ortoluene is used as solvent, the compound of formula (la) is formed as the major product, whereas if oxidation is performed in a benzene medium, the product consists mainly of the isomer of formula (Ib).
The isomer of formula (Ib) can be epimerized into an isomer of formula (la) in a manner known per se, e.g.
by using an alkali metal alcoholate.
The compounds of formula (la) and (Ib) may be converted into their acid addition salts by conventional methods. The individual isomers may be seprated very easily e.g. by fractional crystallization.
According to one embodiment of the invention, the compound of formula (VII) may, if desired, be obtained, by deacylation of a compound of formula (Vl),
whereby the desired compound of formula (VII) is obtained. The compound of formula (VI) may itself be obtained if desired by reduction of a compound of formula (V),
followed by separation of the isomeric mixture thus obtained to give the desired compound of formula (VI).
According to an alternative embodiment, the above deacylation and reduction steps may be reversed.
Thus the compound of formula (VII) may be obtained, if desired, by reduction of a compound of formula (VIII),
followed by separation of the isomeric mixture thus obtained to give the desired compound of formula (VII).
The compound of formula (Vlil) may in turn be prepared, if desired, by deacylation of a compound of formula (V) as hereinbefore defined.
The compounds of formula (V), (VI) and (VII) are all novel compounds, the compound of formula (VI) being itself biologically active.
The deacylating step described above may be effected conveniently by means of a mineral acid, such as e.g. hydrochloric acid, or of an alkali metal alcoholate, such as e.g. sodium methyl ate. Deacylation is carried out preferably in the presence of an organic solvent especially a C1 5 alkanol.
In the reducing step, reduction is preferably effected by means of a complex metal hydride such as e.g.
sodium borohydride. Other reducing agents which may be used, however, include for example formic acid, triethylammonium formate and zinc and acetic acid.
The product of the reduction step is an isomeric mixture. If reduction is performed prior to deacylation, the cis isomer of formula (Vl) is the main product, which can be separated from the minor amount of the trans isomer e.g. by fractional crystallization or chromatography. The compound of formula (VI) may then be deacylated to obtain the cis isomer of formula (VII). If deacylation is performed first and then the deacylated compound of formula (VIII) is reduced, the cis isomer of the formula (VII) and its corresponding trans isomer are formed in approximately equal amounts in the reduction step. The isomers can be separated from each other by fractional crystallization or chromatography.The trans isomer corresponding to the compound of formula (VII) is preferably separated in the form of a salt of formula (IX),
from the compound of formula VII. The salt of formula (IX) is not only a novel compound but also, we have found, biologically active.
The compound of formula (V), used as the starting material in the above described processes and itself a novel compound, may for example be obtained by reacting the free base liberated from a salt of formula (III),
with an acrylate compound of formula (IV),
and treating the product thus obtained with perchloric acid. Preferably the compound of formula (IV) is reacted with the base liberated from the salt of formula (III) in the presence of a chlorinated hydrocarbon as solvent. The product of this reaction is treated with perchloric acid to yield the compound of formula (V) which may be separated e.g. by evaporation, and, if necessary, purified by trituration with an organic solvent and/or by crystallization.
The salt of formula (III) may be prepared, if desired by bromination of a salt of formula (it),
The salt of formula (II) may be prepared according to the method of E. Wenkert and B. Wickberg (J. Am.
Chem. Soc. 87, 1580 [19651). Its bromination to give the salt of formula (III) is exemplified in Example 1.
The invention is elucidated in detail by the aid of the following non-limiting Examples.
EXAMPLE 1 Preparation of 9-bromo- 1-ethyl- 1,23,46. 7-hexahydroindolo[2,3-a]quinolisin-5-ium perchlorate (compound of formula (III) 60.0 g (170 mmoles) of 1.ethyl-1,2,3,4,6,7-hexahydroindolo[2,3-a]quinolisin-5-ium perchlorate (compound of formula (II) are suspended in 600 ml of dichloromethane. 350 ml of water and 125 ml of a 2 N sodium hydroxide solution are added to the suspension obtained and the resultant mixture is shaken for 10 minutes.
The organic phase is separated and the aqueous phase is extracted with 125 ml of dichloromethane. The dichloromethane solutions are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated in v,acuo. The residue is dissolved in methanol, and the solution obtained is acidified to pH 4 with methanol saturated with dry hydrochloric acid at 0 C. The methanol is then evaporated off in vacuo.
The hydrochloride obtained as residue is dissolved in 350 ml of glacial acetic acid, the solution is diluted with 25 ml of methanol, and a solution of 11 ml (219 mmoles) of bromine in 150 ml of glacial acetic acid is added dropwise to the stirred mixture at room temperature. When addition is complete, the reaction mixture is stirred for further 0.5 hours, and then the glacial acetic acid solution is decanted. The residue is dissolved in 150 ml of hot methanol, and 14.64 ml of a 70% aqueous perchloric acid solution are added. The salt separated from the cooled solution is filtered off, washed with methanol and then with a small amount of ether, and dried. 45.1 g of a crystalline substance are obtained.
The glacial acetic acid solution decanted in the previous step is evaporated in vacuo, and the residue is crystallized together with the methanolic mother liquor obtained in the separation of the crystalline salt. 18.2 g of a yellow, crystalline substance are obtained as second crop. Since the physical properties of this substance are identical with those of the solid obtained in the first crystallization step, the two crops can be combined.
In this way a total amount of 63.3 g (86.2 %) of 9-bromo-1 -ethyl-1 ,2,3,4,6,7-hexahydro-indolo[2,3- a]quinolisin-5-ium perchlorate is obtained; m.p.: 218-220"C. After a repeated recrystallization from methanol the product melts at 239-240"C.
Analysis: calculated for C17H20N204CIBr(431 .72): C:47.30% H:4.67% N:6.49% found: C: 47.15 % H: 4.42 % N: 6.73 % IR spectrum (in KBr): 3270 (indole NH), 1630 (=C=N+) cm-1 EXAMPLE 2 Preparation of 9-bromo- 1-ethyl- 1-(2.acetoxy-2-methoxycarbonylethyl)- 1,2,3,4,6, 7-hexahydro- 12H- indolo[2,3-a]-quinolisin-5-ium perchlorate (compound of the formula /V/) 5.0 g (11.6 mmoles) of 9-bromo-1 -ethyl-i ,2,3,4,6,7-hexahydro-1 2H-indolo[2,3-a]quinolisin-5-ium perchlorate (compound of the formula /III/) are suspended in 50 ml of dichloromethane. 30 ml of water and 10 ml of 2 n sodium hydroxide solution are added to the suspension, and the mixture is shaken for 10 minutes. The organic phase is separated, and the aqueous phase is extracted with 10 ml of dichloromethane. The organic solutions are combined, dried over magnesium sulfate, and filtered. 10 ml of methyl (2-acetoxy)-acrylate (compound of the formula IIV/) are added to the filtrate, and the reaction mixture is allowed to stand at room temperature under argon atmosphere for 72 hours. The solvent is distilled off in vacuo, and the residue is triturated thrice with 50 ml of petroleum ether, each. Petroleum ether is decanted, the honey-like residue is dissolved in a small amount of hot methanol, and the solution is acidified to pH 6 with 70% aqueous perchloric acid solution. Ether is added then to the mixture, whereupon an oily phase separates.The oily phase is removed and triturated with dry ether. The resulting yellow crystals are filtered off and dried. 4.1 g (61.5%) of 9-bromo-1 -ethyl-l -(2-acetoxy-2-methoxycarbonylethyl)-1 ,2,3,4,6,7-hexahydro-1 2H-indolo[2,3- a]quinolisin-5-ium perchlorate are obtained; m.p.: 120-122 C. When recrystallized from isopropanol, the product melts at 198-200 C.
Analysis: calculated for C23H28N208CIBr(575.85) : C:47.97% H:4.90% N:4.86%.
found: C:47.85 % H: 4.66 % N: 5.00 % IR spectrm (KBr): 3320 (indole NH), 1770 (~C=O),1610 (~C=N±) cm-5 EXAMPLE 3 Preparation of 9-bromo- 1a-ethyl- 1.(2acetoxy-2-methoxycarbonylethyl) 1,2,3,4,6,7,12, 12ba-octahydro- indolo-[2,3-a]quinolisine (compound of the formula /VI/) 1.0 g (1.74 mmoles) of 9-bromo-1 -ethyl-l -(2-acetoxy-2-methoxycarbonylethyl)-l ,2,3,4,6,7-hexahydro-1 2H- indolo[2,3-a]quinolisin-5-ium perchlorate (compound of the formula /V/) is suspended in 25 ml of methanol.
The suspension is cooled to 0 C under constant stirring, and 0.7 g (18.6 mmoles) of sodium borohydride are added to the suspension in small portions. When addition is complete the mixture is stirred for additional one hour, and then it is acidified to pH 6 with glacial acetic acid. The reaction mixture is concentrated in vacuo, the residue is admixed with 30 ml of water, and the aqueous mixture is rendered alkaline (to pH = 10) with saturated aqueous sodium carbonate solution. The alkaline solution is extracted with 20 ml, 15 ml and 10 ml of dichloromethane. The organic solutions are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. The dry residue, which is a mixture of the title compound (cis isomer) and the respective trans isomer, is subjected to crystallization in order to separate the individual isomers.The cis isomer is crystallized from a mixture of methanol and water. The crystalline substance is washed and then dried 0.23 g (27.8%) of 9-bromo-1 aethyI-1 -(2-acetoxy-2-methoxycarbonyethyl)-1 ,2,3,4,6,7,1 2,1 2ba- octahydro- -indolo[2,3-a]quinolisine are obtained; m.p.: 159-160"C.
Analysis: calculatedforC23H29N204Br(477.41): C: 57.85% H:6.12% N: 5.87% found: C: 57.80 % H: 5.86 % N: 5.68 % IR spectrum (KBr): 3420 (indole NH), 1725 and 1745 (=C=O) cm-1.
NMR spectrum (in CDCI3:8 = 2.10 (s, 3H, CH3-O-CO-), 3.65(s, 3H, CH3-CO-), 7.22-7.58 (m, 3H, aromatic protons), 7.88 (s, 1 H, indole NH) ppm.
If desired, the trans isomer can be separated from the mother liquor and purified.
The ratio of the cis and trans isomers formed in the reaction is determined by preparative thin layer chromatography (adsorbent: silica gel PF254+366 plate, 20 cm x 20 cm x 1.5 mm in dimensions; solvent: a 10:1 mixture of chloroform and methanol). According to this measurement the ratio of cis and trans isomers amounts to 4:1.
EXAMPLE 4 Preparation of 9-brom o-1-ethyl-1- (2-h ydroxy-2-methoxycarbonylethyl)- 1,2,3,4,6, 7-hexahydro- 12H- indolo[2,3-a]-quinolisin-5-ium perchlorate (compound of the formula /Vl 11/) A mixture of 1.0 g (1.74 mmoles) of 9-bromo-1-ethyl-1-(2-acetoxy-2-methoxycarbonylethyl)-1 2,3,4,6,7- hexahydro-12H-indolo[2,3-a]quinolisin-5-ium perchlorate (compound of the formula /V/) and 30 ml of methanol, saturated at 0 C with dry gaseous hydrochloric acid, is refluxed for 3 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in hot methanol, and some drops of 70% aqueous perchloric acid are added to the solution. Crystallization is initiated by scraping.The mixture is allowed to crystallize in a refrigerator, thereafter the separated salt is filtered off, washed with a small amount of cold methanol, and dried. 0.5 g (53.9 %) of 9-bromo-l -ethyl-l -(2-hydroxy-2-methoxy-carbonylethyl)-1 ,2,3,4,6,7-hexahydro-1 2H- indolo[2,3-a]quinolisin-5-ium perchlorate are obtained; m.p.: 209-212"C. When recrystallized from methanol, the product melts at 225-226 C.
Analysis: calculated for C21H26N2O7ClBr(533.81): C: 47.25% H: 4.91 % N: 5.25% found: C: 47.51 % H: 4.95% N: 5.38% IR spectrum (KBr): 3400 (indole NH), 1725 ( > C=O), 1595( C=N±) cm-'.
EXAMPLE 5 Preparation of 9-bromo- ia-ethyl- 1-(2-h ydroxy-2-methoxycarbonylethyl)- 1,2,3,4,6,7,12, 12ba-octahydro indolo-[2,3-a1quinolisine compound of the formula /VI I/), and 9-bromo- 1a-ethyl- 1-r2-hydroxy-2- methoxycarbonyleth yl)- 1,2,3,4,6,7,12, 12b-octah ydro -indolo[2,3-a]quinolisin-5-ium perchlorate (compound of the formula /IX/) Method A: A mixture of 1.0 g (2.1 mmoles) of 9-brom-1 a-ethyl-i -(2-acetoxy-2-methoxycarbonylethyl)- 1,2,3,4,6,7,1 2,12ba-octahydro- -indolo[2,3-a]quinolisine (compound of the formmula IVII) and 30 ml of methanol saturated at 0 C with dry gaseous hydrochloric acid is refluxed for 3 hours.The reaction mixture is evaporated in vacuo. The residue is dissolved in 30 ml of a 1:1 mixture of acetone and water, and the pH of the solution is adjusted to 11 with saturated aqueous sodium carbonate solution. 30 ml of water are added to the alkaline solution, and the mixture is extracted with 30 ml, 25 ml and 20 ml of dichloromethane. The organic solutions are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. The residue is crystallized from methanol, the crystals are washed and then dried. 0.65 g (71.3 %) of 9-bromo-l a-ethyl-l -(2-hydroxy-2-methoxycarbonylethyl)-l ,2,3,4,6,7,12,1 2ba-octahydro -indolo-[2,3- a]quinolisine are obtained; m.p.: 222-225 C. When recrystallized from methanol, the product melts at 230-231 C.
Analysis: calculated for C2,H27N203Br (435.37): C: 57.94 % H: 6.25 % N: 6.43 % found: C: 57.98% H: 6.33% N: 6.38% IR spectrum (KBr): 3250 (indole NH), 1740 (=C=O) cm-1.
NMR spectrum (DMSO-d6): b = 0.98 (t, 3H, CH3-CH2-),3.44 3H, CH3-O-CO-), 6.86-7.56 (m, 3H, aromatic protons),9.91 1 H, indole NH) ppm.
Mass spectrum (M/e): 437, 436, 435,434, 375, 347, 345, 275, 250, 249, 154.
Method B: 6.8 g (12.7 mmoles) of 9-bromo-1 -ethyl-i -(2-hydroxy-2-methoxycarbonylethyl)-1 ,2,3,4,6,7- hexahydro-12H-indolo[2,3-a]quinolisin-5-ium perchlorate (compound of the formula /VIII/) are suspended in 300 ml of methanol. The suspension is cooled to 0 C under constant stirring, and 4.8 g (0.13 moles) of sodium borohydride are added to the mixture in small portions. When the addition is complete, the mixture is stirred for further one hour, and then it is acidified to pH 2 to 3 with 5 n hydrochloric acid. The acidic mixture is concentrated in vacuo, 350 ml of water are added to the residue, and the aqueous mixture is rendered alkaline (pH = 11) with 40% aqueous sodium hydroxide solution. The alkaline mixture is extracted with 100 ml, 80 ml and 60 ml of dichloromethane.The organic solutions are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. The dry residue, which is a mixture of 9-bromo-1 a-ethyl-1 -(2-hydroxy-2-methoxycarbonylethyl )-1,2,3,4,6,7,12,1 2ba-octahydro-indolo[2,3- a]quinolisine (cis isomer) and 9-bromo-1a-ethyl-1-(2-hydroxy-2-methoxy-carbonylethyl)-1,2,3,4,6,7,12,12b - octahydro-indolo[2,3-a]quinolisine (trans isomer), is subjected to fractional crystallization in order to separate the isomers from each other.
The cis isomer is crystallized from methanol, the crystals are washed and dried. 2.05 g (37 %) of 9-bromo-1 a-ethyl-1 -(2-hydroxy-2-methoxycarbonylethyl )-1,2,3,4,6,7,12,12ba-octahydro- -indolo[2,3- a]quinolisine are obtained. The physical properties of this substance are completely identical with those of the product obtained according to Method A.
The trans isomer, which remains in the mother liquor, can be separated and identified in the form of the perchlorate (compound of the formula /IXI).
The ratio of cis and trans isomers formed in the reaction is determined by preparative thin layer chromatography as described in Example 3. The isomers are present in a ratio of 1:1.
The physical constants of the trans isomer (compound of the formula /IX/) are as follows: Melting point: 248-251 C.
IR spectrum: 3300 (indole NH), 1742 (#C=O) cm-'.
EXAMPLE 6 Preparation of 10-bromovincamine (compound of the formula /la/) Method A: 1.0 g (2.3 mmoles) of 9-bromo-l a--ethyl-i -(2-hydroxy-2-methoxycarbonylethyl 1,2,3,4,6,7,1 2,12b&alpha;-octahydro- -indolo[2,3-a]quinolisine is dissolved in 50 ml of hot xylene, and .0 g of Fetison reagent (silver carbonate precipitated onto Celite support) are added to the solution. The reaction mixture is stirred and refluxed for 6 hours. The oxidizing agent is removed by filtration from the hot suspension, and the xylene filtrate is allowed to stand first at room temperature and then in refrigerator. The separated substance is filtered off, washed and dried. 0.5 g (50.2%) of 10-bromovincamine are obtained; m.p.: 210-213 C. When recrystallized from methanol, the product melts at 220-221 C.
Analysis: calculated for C21H25N2O3Br (433.35): C: 58.20% H: 5.81 % N: 6.460/0 found C: 58.15 % H: 5.76 % N: 6.35 % IR spectrum (KBr): 1750 ( C=O) cm-5.
NMR spectrum (CDCI3):o = 0.88 (t, 3H, CH3-CH2-), 3.77(s, 3H, CH3-O-CO-), 6.81-7.65 (m. 3H, aromatic protons) ppm.
Mass spectrum (mite: 434,432, 419, 417, 375, 373, 347,345, 332, 330, 317, 315, 266, 195, 180, 167, 115.
Method B: 1.0 g (2.3 mmoles) of 9-bromo-1 a-ethyl-1 -(2-hydroxy-2-methoxycarbonylethyl) 1,2,3,4,6,7,12,1 2ba-octahydro- -indolo[2,3-a]quinolisine is dissolved in 100 ml of hot, dry toluene, and 10.0 g of manganese (IV)-oxide precipitated onto Celite support and added to the solution. The reaction mixture is stirred and refluxed for 45 hours. The oxidizing agent is removed by filtration from the hot suspension, the toluene filtrate is concentrated in vacuo to about one-half of the original volume, and the concentrate is allowed to crystallize in refrigerator. The separated product is filtered off, washed and dried. 0.4 g (40.2 %) of 10-bromovincamine are obtained. The physical characteristics of the product are completely identical with those of the substance obtained according to Method A.
EXAMPLE 7 Preparation of 10-bromo- 14-epivincamine (compound of the formula /Ib/) 1.0 g (2.3 mmoles) of 9-bromo-i a-ethyl-1 -(2-hydroxy-2-methoxycarbonylethyl)-1 ,2,3,4,6,7,1 2,1 2b( octahydro-indolo[2,3-a]quinolisine is dissolved in 70 ml of dry, hot benzene, and 3.0 g of Fetison reagent are added to the solution. The reaction mixture is stirred and refluxed for 65 hours. The oxidizing agent is removed by filtration from the hot suspension, and the filtrate is allowed to crystallize in refrigerator. 0.3 g of non-reacted starting substance separate first. This substance is removed by filtration, the filtrate is concentrated, and the product is crystallized from the concentrate. 0.15 g (21.5%) of 10-bromo-14- epivincamine are obtained; m.p.: 193-195"C. When recrystallized from methanol, the product melts at 205-207"C.
IR spectrum (KBr): 1725 (~C=O) cm-1.
NMR-spectrum (in DMSO-d): o = 3.06 (s, 3H, CH3-OCO-), 6.88-7.58 (m, 3H, aromatic protons).
Mass spectrum (m/e): 434, 432, 388, 386, 375, 373, 347,345, 331, 329, 317, 315, 288, 286, 195, 180, 167, 115, 55.

Claims (36)

1. The compound of formula (VII),
2. A process for the preparation of 10-bromovincamine of formula (la)
and 10 bromo-14-epivincamine of formula (Ib),
and acid addition salts thereof which comprises oxidizing a compound of formula (VII) as defined in claim 1 and separating the desired compound of formula (la) and/or (Ib) followed, where required, by epimerization of a compound of formula (Ib) into a compound of formula (la) and/or by conversion of a compound of formula (la) and/or (Ib) into an acid addition salt thereof.
3. A process as claimed in claim 2 wherein oxidation is effected by means of supported silver carbonate or manganese dioxide.
4. A process as claimed in claim 2 or claim 3 wherein epimerization is effected by means of an alkali metal alcoholate.
5. A process for the preparation of compounds of formulae (la) and (Ib) and acid addition salts thereof substantially as herein described.
6. A process for the preparation of compounds of formulae (la) and (Ib) and acid addition salts thereof substantially as herein described with reference to the Examples.
7. Compounds of formulae (la) and (Ib) and acid addition salts thereof whenever prepared by a process as claimed in any one of claims 2 to 6.
8. A process for the preparation of a compound of formula (VII) as defined in claim 1 which comprises deacylating a compound of formula (VI),
whereby the desired compound of formula (VII) is obtained
9. A process as claimed in claim 8 wherein deacylation is effected by means of a mineral acid or of an alkali metal alcoholate.
10. A process as claimed in claim 8 or claim 9 wherein the compound of formula (VI) is obtained by reduction of a compound of formula (V),
followed by separation of the isomeric mixture thus obtained to give the desired compound of formula (Vl).
11. A process as claimed in claim 10 wherein reduction is effected by means of sodium borohydride, formic acid, triethylammonium formate or zinc and acetic acid.
12. A process as claimed in claim 10 or claim 11 wherein separation of the isomeric mixture is effected by fractional crystallisation or chromatography.
13. A process for the preparation of a compound of formula (VII) as defined in claim 1 which comprises reducing a compound of formula (Vlli),
followed by separation of the isomeric mixture thus obtained to give the desired compound of formula (VII).
14. A process as claimed in claim 13 wherein reduction is effected by means of sodium borohydride, formic acid, triethylammonium formate or zinc and acetic acid.
15. A process as claimed in claim 13 or claim 14 wherein separation of the isomeric mixture is effected by fractional crystallisation or chromatography.
16. A process as claimed in any one of claims 13 to 15wherein the isomer of the compound of formula (VII) is separated in the form of a salt of formula (IX),
17. A process as claimed in any one of claims 13 to 16 wherein the compound of formula (VIII) is obtained by deacylation of a compound of formula (V) as defined in claim 9.
18. A process as claimed in claim 17 wherein deacylation is effected by means of a mineral acid or of an alkali metal alcoholate.
19. A process as claimed in any one of claims 10 to 12, 17 and 18 wherein the compound of formula (V) is obtained by reacting the free base liberated from a salt of formula (III),
with an acrylate compound of formula (IV),
and treating the product thus obtained with perchloric acid.
20. A process as claimed in claim 19 wherein the reaction is effected in the presence of a chlorinated hydrocarbon as solvent.
21. A process for the preparation of a compound of formula (VII) as defined in claim 1 substantially as herein described.
22. A process for the preparation of a compound of formula (VII) as defined in claim 1 substantially as herein described with reference to the Examples.
23. A compound of formula (VII) as defined in claim 1 whenever prepared by a process as claimed in any one of claims 8 to 22.
24. A compound of formula (VI) as defined in claim 8.
25. A process for the preparation of a compound of formula (VI) as defined in claim 8 as defined in any one of claims 10 to 12.
26. A process for the preparation of a compound of formula (VI) as defined in claim 8 substantially as herein described.
27. A compound of formula (V) as defined in claim 10.
28. A process for the preparation of a compound of formula (V) as defined in claim 10 as defined in claim 19 or claim 20.
29. A process for the preparation of a compound of formula (V) as defined in claim 10 substantially as herein described.
30. A compound of formula (V) as defined in claim 10 whenever prepared by a process as claimed in claim 28 or claim 29.
31. A compound offormula (VIII) as defined in claim 13.
32. A process for the preparation of a compound of formula (VIII) as defined in claim 13 as defined in claim l7orclaim 18.
33. A process for the preparation of a compound of formula (VIII) as defined in claim 13 substantially as herein described.
34. A salt offormula (IX) as defined in claim 16.
35. A process for the preparation of a salt of formula (IX) as defined in claim 16 substantially as herein described.
36. Each and every novel method, process, compound and composition herein disclosed.
GB7943199A 1978-12-15 1979-12-14 Octahydro-indolo[2,3- a]quinolisine derivative Withdrawn GB2039900A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
HURI000692 HU177732B (en) 1978-12-15 1978-12-15 Process for producing 10-bromo-vincamine and acid additional salts thereof,and 10-bromo-14-epivincamine

Publications (1)

Publication Number Publication Date
GB2039900A true GB2039900A (en) 1980-08-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
GB7943199A Withdrawn GB2039900A (en) 1978-12-15 1979-12-14 Octahydro-indolo[2,3- a]quinolisine derivative

Country Status (7)

Country Link
JP (1) JPS5583784A (en)
CH (1) CH658059A5 (en)
DE (1) DE2950436A1 (en)
ES (1) ES486799A1 (en)
FR (1) FR2444037B1 (en)
GB (1) GB2039900A (en)
HU (1) HU177732B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4315011A (en) * 1978-07-12 1982-02-09 Richter Gedeon Vegyeszeti Gyar Rt. 1-Alkyl-9-bromohexahydroindolo quinolizium salts and use thereof to increase blood flow
HU181496B (en) * 1979-08-13 1983-07-28 Richter Gedeon Vegyeszet Process for preparing 10-bromo-15-hydroxy-e-homo-eburnanes
HU194220B (en) * 1985-04-19 1988-01-28 Richter Gedeon Vegyeszet Process for production of derivatives of 1,12 b disubstituated-octahydro-indolo /2,3-a/ quinolisine and medical compounds containing thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK139358B (en) * 1973-12-18 1979-02-05 Sandoz Ag Analogous process for the preparation of vincamine derivatives or acid addition salts thereof.
HU175527B (en) * 1977-03-28 1980-08-28 Richter Gedeon Vegyeszet Totalsynthesis of esters of apovincaminic acid and homologues
US4315011A (en) * 1978-07-12 1982-02-09 Richter Gedeon Vegyeszeti Gyar Rt. 1-Alkyl-9-bromohexahydroindolo quinolizium salts and use thereof to increase blood flow

Also Published As

Publication number Publication date
FR2444037B1 (en) 1985-09-20
FR2444037A1 (en) 1980-07-11
CH658059A5 (en) 1986-10-15
DE2950436A1 (en) 1980-07-10
ES486799A1 (en) 1980-10-01
JPS5583784A (en) 1980-06-24
HU177732B (en) 1981-12-28

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