# US 4,399,069 A · Process for an enantioselective synthesis of optically active 14-oxo-E-homo-eburnane derivatives > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,399,069 A - Document ID: US4399069A - Status: Granted - Kind: A - Application number: 06/312,128 - Filed: 1981-10-16 - Granted: 1983-08-16 - Earliest claimed: 1980-10-12 - Assignees: Richter Gedeon Vegyeszeti Gyar Rt. - Inventors: Csaba Szantay; Lajos Szabo; Gyorgy Kalaus; Janos Sapi; Janos Kreidl; Maria Farkas nee Kirjak; Andras Nemes; Laszlo Cibula - Web page: https://patentgrep.com/patent/US4399069A ## CPC - C07D 471/14: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The invention relates to a new enantioselective synthesis for the preparation of optically active 14-oxo-E-homo-eburnane derivatives of the formula (Ia) ##STR1## wherein R.sup.1 is alkyl having from 1 to 4 carbon atom. In the synthesis optically active 6-alkoxycarbonylhexahydroindoloquinolizinium salts are employed as starting materials, which contain a center of chirality at the site of attachment of the carboxyl group. This center of chirality preserves the optical activity of the optically active tryptophan ester from which this compound has been prepared until a new center of chirality is formed in the molecule in a configuration corresponding to the desired end product. The carboxyl group, which is not needed in the end product and only serves to preserving the optical activity can then be eliminated. Compounds of the formula (Ia) are known in the art and may be used in the synthesis of (+)-vincamine and (+)-apovincaminic acid ethylester. ## Claims ### Claim 1 A process for an enantioselective synthesis of an optically active 14-oxo-E-homo-eburnane compound of the formula (Ia) ##STR11## wherein R.sup.1 is alkyl having from 1 to 4 carbon atoms, which comprises reacting an optically active 6-alkoxycarbonyl-hexahydroindoloquinolizinium salt of the formula (II) ##STR12## wherein R.sup.2 is alkyl having from 1 to 4 carbon atoms, X is perchlorate, with a methylenemalonic acid diester derivative of the formula (III) ##STR13## wherein R.sup.3 is alkyl having from 1 to 4 carbon atoms, in the presence of a basic catalyst, subjecting the resulting optically active 6-alkoxycarbonyl-hexahydroindoloquinolizinium-1-yl-methylene malonate of the formula (IV) ##STR14## to acid and a subsequent alkaline hydrolysis, then subjecting the resulting active hexahydroindoloquinoliziniumdicarboxylic acid compound of the formula (V) ##STR15## to selective decarboxylation, saturating the resulting optically active hexahydroindoloquinoliziniummonocarboxylic acid of the formula (VI), ##STR16## and cyclizing the resulting optically active octahydroindoloquinolizinemonocarboxylic acid of the formula (VII) ##STR17## with or without isolation, or subjecting it to esterification after isolation, or esterifying an optically active hexahydroindoloquinoliziniummonocarboxylic acid of the formula (VI) and then saturating same, and finally subjecting a compound of the formula (VIII) ##STR18## wherein R.sup.4 is alkyl having from 1 to 4 carbon atoms, obtained by esterification and a subsequent saturation or saturation and a subsequent esterification, to ring closure. ### Claim 2 (depends on 1) The process defined in claim 1, in which an optically active 6-alkoxycarbonyl-hexahydroindoloquinolizinium salt of the formula (II) is reacted with a methylenemalonic acid diester derivative of the formula (III) in the presence of an alkali metal tert.-alcoholate as a basic catalyst. ### Claim 3 (depends on 2) The process defined in claim 2, in which 3 to 7 mol.%, preferably 4 to 6 mol.% of the basic catalyst are used calculated for the amount of the 6-alkoxycarbonylhexahydroindoloquinolizinium salt of the formula (II). ### Claim 4 (depends on 1) The process defined in claim 1 in which a methylenemalonic acid diester derivative of the formula (II) is employed in a molar excess of 1.1 to 2 over a 6-alkoxycarbonyl-hexahydroindoloquinolizinium salt of the formula (II). ### Claim 5 (depends on 1) The process defined in claim 1 wherein reactions are carried out in an organic solvent inert under the reaction conditions, said solvent being an aliphatic or aromatic hydrocarbon which can be substituted by one or more halogens. ### Claim 6 (depends on 1) The process defined in claim 1 which comprises carrying out the reactions at a temperature between 0.degree. C. and 35.degree. C., ### Claim 7 (depends on 1) The process defined in claim 1, in which the acid hydrolysis of the optically active 6-alkoxycarbonylhexahydroindoloquinolizinium-1-yl-methylenemalonate salt of the formula (IV) is performed with a mineral acid, easily removable when evaporating the reaction mixture. ### Claim 8 (depends on 1) The process defined in claim 1 which comprises carrying out the acid hydrolysis at a temperature between 80.degree. C. and 120.degree. C. ### Claim 9 (depends on 1) The process defined in claim 1, in which the alkaline hydrolysis subsequent to an acid hydrolysis of the optically active 6-alkoxycarbonyl-hexahydroindoloquinolizinium-1-yl-methylene malonate of the formula (IV) is carried out with an aqueous solution of an alkali metal hydroxide, in the presence of an alkanol having from 1 to 4 carbon atoms, as a co-solvent. ### Claim 10 (depends on 10) The process defined in claim 10 wherein the latter reaction is carried out at a temperature between 10.degree. C. and 35.degree. C. ### Claim 11 (depends on 1) The process defined in claim 1 in which the selective decarboxylation of the optically active hexahydroindoloquinoliziniumcarboxylic acid of the formula (V) is performed thermically at a temperature between 150.degree. C. and 200.degree. C. ### Claim 12 (depends on 11) The process defined in claim 11 in which the selective decarboxylation is carried out in an inert organic solvent, having a boiling point between 150.degree. C. and 200.degree. C. ### Claim 13 (depends on 1) The process defined in claim 1 in which the saturation of the optically active hexahydroindoloquinoliziniummonocarboxylic acid of the formula (VI), is performed with catalytically activated hydrogen. ### Claim 14 (depends on 13) The process defined in claim 13 in which saturation is carried out by hydrogenation in the presence of a palladium-on-charcoal catalyst in a solvent, inert under the reaction conditions. ### Claim 15 (depends on 13) The process defined in claim 13 in which dimethyl formamide is used as an inert solvent for the hydrogenation. ### Claim 16 (depends on 1) The process defined in claim 1 in which the cyclization of the optically active octahydroindoloquinoliziniummonocarboxylic acid of the formula (VII) is carried out with a phosphorus oxyhalide. ### Claim 17 (depends on 16) The process of derfined in claim 16 in which cyclization is performed at a temperature between 10.degree. C. and 100.degree. C. ### Claim 18 (depends on 1) The process defined in claim 1 for the preparation of optically active 14-oxo-E-homo-eburnane compounds of the formula (Ia), which comprises subjecting the optically active hexahydroindoloquinoliziniummonocarboxylic acid of the formula (VI) to catalytic hydrogenation in the presence of a palladium-on-charcoal catalyst in dimethyl formamide, and subsequently cyclizing the resulting optically active octahydroindoloquinolizinemonocarboxylic acid of the formula (VII) without isolation from the reaction mixture, with phosphorus oxychloride, at a temperature between 10.degree. C. and 100.degree. C. ### Claim 19 (depends on 1) The process defined in claim 1 in which the esterification of the optically active octahydroindoloquinolizinemonocarboxylic acid of the formula (VII) is carried out with diazomethane. ### Claim 20 An optically active 6-alkoxycarbonyl-hexahydroindoloquinolizinium-1-yl-methylenemalonate of the formula (IV) ##STR19## wherein R.sup.1, R.sup.2 and R.sup.3 indpendently represent alkyl having from 1 to 4 carbon atoms and X stands for perchlorate. ### Claim 21 (depends on 20) (-)-1.alpha.-Ethyl-1.beta.-(2',2'-diethoxycarbonyle thyl)-6.beta.-methoxycarbonyl-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)-quino linium-5-ium perchlorate as defined in claim 20. ### Claim 22 An optically active hexahydroindoloquinolizinium-dicarboxylic acid of the formula (V), ##STR20## wherein R.sup.1 is alkyl having from 1 to 4 carbon atoms and X stands for perchlorate. ### Claim 23 (depends on 22) (+)-1.alp ha.-Ethyl-1.beta.-carboxyethyl-6-carboxy-1,2,3,4,6,7-hexahydro-12H-indolo(2 ,3-a)quinolizin-5-ium perchlorate as defined in claim 22. ### Claim 24 An optically active hexahydroindoloquinoliziniummonocarboxylic acid of the formula (VI) ##STR21## wherein R.sup.1 is alkyl having from 1 to 4 carbon atoms and X stands for perchlorate. ### Claim 25 (depends on 24) (-)-1.alp ha.-Ethyl-1.beta.-carboxyethyl-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quino lizin-5-ium perchlorate as defined in claim 24.