# US 4,400,249 A · Partial synthesis process for preparing (+) -vincamine and related indolic alkaloids > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,400,249 A - Document ID: US4400249A - Status: Granted - Kind: A - Application number: 06/272,383 - Filed: 1981-06-10 - Granted: 1983-08-23 - Earliest claimed: 1980-09-30 - Assignees: Linnea SA - Inventors: Giovanni Benardelli - Web page: https://patentgrep.com/patent/US4400249A ## CPC - C07D 461/00: Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine (dimeric indolo alkaloids C07D519/04) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract A process of partial synthesis of vincamine and related indolic alkaloids for use as the active principal ingredient in drugs for treatment of diseases of the circulatory system and the central nervous system. The process includes the technique of activating oxygen in the elementary state in situ into an excited singlet state for chemical reaction by subjecting a reaction mixture to gaseous oxygen blowing under substantially ambient temperature and pressure conditions while effecting irradiation of the mixture by a light source. Operating conditions of the partial synthesis process are simplified, treatment times are reduced, and conversion yields are high. ## Claims ### Claim 1 A process for preparing vincamine and other related indolic alkaloids represented by the general formula (I): ##STR4## wherein: (a) when X=Y=H, R'=--OH, R=--COOCH.sub.3, formula (I) represents vincamine, (b) when X=Y=H, R'=--COOCH.sub.3, R=--OH, formula (I) represents 16-epivincamine, (c) when X+Y=a double bond, R'=--OH, R=--COOCH.sub.3, formula (I) represents .DELTA..sup.14 -vincamine, (d) when X+Y=a double bond, R'=--COOCH.sub.3, R=--OH, formula (I) represents .DELTA..sup.14 -16-epivincamine, comprising the steps of: a compound of the general formula (II): ##STR5## wherein: (e) when X=Y=H, formula (II) represents vincadifformine, and (f) when X+Y=a double bond, formula (II) represents tabersonine, is used as a starting substrate; a reaction medium, comprising a low molecular weight alcohol, a trialkyl phosphite as a reducing agent, and a photosensitizer, is prepared; said substrate is added to said reaction medium, said trialkyl phosphite being present in a stoichiometrical excess with respect to said substrate; the thus formed reaction mixture is subjected to gaseous oxygen blowing under substantially ambient temperature and pressure conditions and at the same time said mixture is subjected to irradiation from a light source in order to activate oxygen in situ, for a time not exceeding 150 minutes, to obtain oxidation of said substrate and a resulting reduction; the treated reaction mixture is acidified, alkalized and extracted; and finally the extraction residue is subjected to fractional crystallization and/or column chromatography in order to separate distinct products represented by said general formula (I) in the pure state. ### Claim 2 (depends on 1) A process according to claim 1 for the preparation of said vincamine (I: X=Y=H, R=--COOCH.sub.3, R'=--OH) as a principal product and of said 16-epivincamine (I: X=Y=H, R=--OH, R'=--COOCH.sub.3) as a secondary product, wherein: said vincadifformine (II: X=Y=H) is used as said starting substrate. ### Claim 3 (depends on 1) A process according to claim 1 for the preparation of said .DELTA..sup.14 -vincamine (I: X+Y=a double bond, R=--COOCH.sub.3, R'=--OH) and of said .DELTA..sup.14 -16-epivincamine (I: X+Y=a double bond, R=--OH, R'=--COOCH.sub.3), wherein: said tabersonine (II: X+Y=a double bond) is used as said starting substrate. ### Claim 4 (depends on 3) A process according to claim 3, wherein: said low molecular weight alcohol comprises methanol which is used as a solvent. ### Claim 5 (depends on 4) A process according to claim 4, wherein: said trialkyl phosphite is used as a reducing agent in a 1.1 to 1.5 stoichiometrical excess with respect to said substrate. ### Claim 6 (depends on 5) A process according to claim 5, wherein: said photosensitizer is present in said reaction medium in an amount between 0.006% and 0.1% (by weight/volume) with respect to said reaction medium. ### Claim 7 (depends on 6) A process according to claim 6, wherein: said photosensitizer is a compound selected from the group consisting of: the disodium salt of 2', 4', 5', 7'-tetrabromofluoresceine (eosine-yellowish); the 7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-diprop anoic acid (hematoporphyrin; and the disodium salt of 3',6'-dichloro-2,4,5,7-tetraiodofluoresceine (Rose Bengal). ### Claim 8 (depends on 7) A process according to claim 7, wherein: said photosensitizer is stabilized in said reaction medium by addition of a base, such as sodium hydroxide or sodium carbonate. ### Claim 9 (depends on 8) A process according to claim 8, wherein: said reaction mixture is subjected to oxygen blowing equal to 5-10 liters/hour under substantially ambient conditions of temperature and pressure for a period of 30 to 90 minutes, while said mixture is subjected to light irradiation from an incandescent lamp. ### Claim 10 (depends on 8) A process according to claim 8, wherein: said reaction mixture is subjected to oxygen blowing equal to 5-10 liters/hour for a period of 60-150 minutes under substantially ambient conditions of temperature and pressure, while said mixture is subjected to light irradiation from an incandescent lamp. ### Claim 11 (depends on 1) A process according to claim 1, wherein: said low molecular alcohol comprises methanol which is used as a solvent. ### Claim 12 (depends on 1) A process according to claim 1, wherein: said trialkyl phosphite is used as a reducing agent in a 1.1 to 1.5 stoichiometrical excess with respect to said substrate. ### Claim 13 (depends on 1) A process according to claim 1, wherein: said photosensitizer is present in said reaction medium in an amount between 0.006% and 0.1% (by weight/volume) with respect to said reaction medium. ### Claim 14 (depends on 13) A process according to claim 13, wherein: said photosensitizer is a compound selected from the group consisting of: the disodium salt of 2',4',5',7'-tetrabromofluoresceine (eosine-yellowish); the 7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-diprop anoic acid (hematoporphyrin); and the disodium salt of 3',6'-dichloro-2,4,5,7-tetraiodofluoresceine (Rose Bengal). ### Claim 15 (depends on 1) A process according to claim 1, wherein: said photosensitizer is stabilized in said reaction medium by addition of a base, such as sodium hydroxide or sodium carbonate. ### Claim 16 (depends on 1) A process according to claim 1, wherein: said reaction mixture is subjected to oxygen blowing equal to 5-10 liters/hour under substantially ambient conditions of temperature and pressure for a period of 30 to 90 minutes, while said mixture is subjected to light irradiation from an incandescent lamp. ### Claim 17 (depends on 1) A process according to claim 1, wherein: said reaction mixture is subjected to oxygen blowing equal to 5-10 liters/hour for a period of 60-150 minutes under substantially ambient conditions of temperature and pressure, while said mixture is subjected to light irradiation from an incandescent lamp.