Classifications

• • 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

Definitions

• This invention has as an object a process for preparing pentacyclic alkaloids of the eburnamonine-vincamine group and in particular, racemic and optically active Vincamine.
• the compound of general Formula I for which the junction of the cycles D and E is cis, that is to say where hydrogen at position 3 and the ethyl radical at position 16 are cis with respect to one another, corresponds to dl- Vincamine.
• the compound of general Formula I, where the junction of the cycles D and E is trans, corresponds to dl-iso-vincamine.
• Vincamine has been isolated from several species of the vinca kind, particularly Vinca minor L. As for dl-vincamine, it would have been found in the Tabernaemontalna rigida species.
• Vincamine possesses very interesting therapeutic properties thanks to a double action.
• Vincamine is used especially in vascular cerebral complaints, in cerebrosclerosis, loss of conscience due to cranial traumatisms or due to the after-effects of acute cerebral insufficiency.
• This invention has principally as object to allow one to obtain a pure Vincamine by a synthetic route which does not necessitate a starting material of vegetable origin, the provision of which is often expensive and risky.
• the process of the present invention is essentially characterized in that one treats the tetracyclic compound of HrCOzC HaCOa (II) with a basic agent to obtain the lactamic compound of general Formula III:
• indole- (2,3-a) quinolizine whose substituents 12b-H and 'l-ethyl are at cis position with respect to one another, are called cis indolo-(2,3-a) quinolizine.
• trans indolo-(2,3-a) quinolizine the derivatives of indolo-(2,3-a) quinolizine, whose substituents 12b-H and l-ethyl are at trans position with respect to one another, are called trans indolo-(2,3-a) quinolizine.
• cis-eburnane The derivatives of eburnane or E-homo-e-burnane at junction D/E cis are called cis-eburnane or cis E-homoeburnane.
• the conversion of the tetracyclic compound, II, into lactam, III, is effected in the presence of a basic agent, specifically a strong alkaline base.
• a basic agent specifically a strong alkaline base.
• This can for example be an alkali-metal hydride, amide or alcoh'olate.
• an alkali-metal tertiary alcoholate such as sodium t-amylate to convert the compound, Ila, into the corresponding lactam, 14-oxo E-homo-eburnane, of the D/E' cis series.
• nitrite one can use n-propyl nitrite, butyl nitrite, such as t-butyl nitrite or isoamyl nitrite.
• basic agent one generally uses a strong alkaline base, such as an alkali-metal hydride or tertiary alcoholate, such as sodium hydride, sodium t-butylate or t-amylate.
• Passage of the hydroxyimino derivative, IV, to the corresponding dioxo compound, V, is accomplished by the classic methods for regenerating a ketone function starting from an oxime.
• an aldehydic or ketonic reagent such as benzaldehyde, formaldehyde, pyruvic acid, glyoxylic acid or levulic acid, the reaction preferably being carried out in the presence of an acid, for example hydrochloric acid or sulphuric acid.
• the present invention has as object a process for preparing an optically active vincamine, characterized in that one treats an enantiomer of cis 1,2,3,4,6,7,12,l2b octahydro l-ethyl l-carbomethoxyethyl indo (2,3-a) quinolizine with a basic agent to obtain the corresponding enantiomer of cis 14-oxo E-homo-eburnane (D/E cis junction), causes a nitrosation reagent to react on this latter to form the corresponding enantiomer of cis l4-oxo IS-hydroxy-imino E-homo-eburnane, treats this with a reagent for regeneration of ketones starting from oximes, to obtain the corresponding enantiomer of cis 14,15-dioxo E-homo eburnane which one subjects to the action of an alkali-metal methylate, and obtains,
• the process of the invention for the preparation of vincamine, is characterized in that one treats 1,2,3, 4,6,7,l2,l2b-octahydro lot-ethyl IB-carbomethoxyethyl l2ba-indolo (2,3-a) quinolizine with a basic agent to obtain 14-oxo 3a,16a(20)-E-h0m0 eburnane, causes this latter to react with a nitrosation reagent to form 14-oxo 15-hydroxyimino 3a,16cc(20)E-h0m0 eburnane, treats this with a reagent for regenerating a ketone starting from oxime, to obtain 14,15-dioxo 30t,16OL(20)-EhOITlO eburnane which one subjects to the action of an alkalimetal methylate.
• This process is carried out in a manner identical to that specified above for the use of a basic agent of the nitrosation reagent and of the reagent for regenerating a ketone starting from the corresponding oxime.
• the present application has likewise as object a variant of the above process, in which the final reaction is effected in two stages.
• This variant is characterized in that one treats one of the enantiomers of cis 14,15-dioxo E-homo eburnane with an acid agent or with a basic agent giving rise to hydroxyl ions, obtains the corresponding enantiomer of cis 14-hydroxy 14-carboxy-eburnane, and causes this latter to react with a reagent for forming methyl esters to obtain an optically active vincamine.
• vincamine In particular, to obtain according to this variant vincamine, one treats 14,15-dioxo 3a,16x(20)-E-hOm0 eburnane with an acid agent or with a basic agent giving rise to hydroxyl ions to form vincaminic acid, and causes this latter to react with a reagent for forming methyl esters.
• the basic agent giving rise to hydroxyl ions is preferably an alkali-metal or alkaline-earth hydroxide, for example caustic potash or baryte.
• Conversion of the acid obtained into methyl ester is eifected according to the usual methods, such as for example by the action of diazomethane.
• the cis and trans epimers of 1,2,3,4,6,7,12,12b-octahydro l-ethyl l-carboxyethyl 4-oxo indolo (2,3-a) quinolizine are obtained by saponification of the mixture of epimers of 1,2,3,4,6,7,12,12b-octahydro l-ethyl l-carbomethoxyethyl 4-oxo indolo (2,3-a) quinolizine and can be separated by physical methods, and particularly by simple fractionated crystallization.
• the other enantiomer, dextrorotatory in dimethylformamide, is the corresponding lfi-ethyl 12b/3-H derivative, and leads, during the syntheses, to vincamine.
• the application has likewise as object a process for preparing vincamine or vincamine according to the process or variant above, and in which the starting product is obtained by saponification of 1,2,3,4,6,7,12,12boctahydro l-ethyl 1 carbomethoxyethyl 4-oxo indolo (2,3-a) quinolizine, separation of the cis and trans isomers of 1,2,3,4,6,7,12,12b-octahydro l-ethyl l-carboxyethyl 4- 0x0 indolo (2,3-a) quinolizine, resolution of cis 1,2,3,4, 6,7,12,12b-octahydro l-ethyl l-carboxyethyl 4-oxo indolo (2,3-a) quinolizine into its optical antipodes by means of an optically active base, esterification of an enantiomer of cis 1,2,3,4,6,
• 1,2,3,4,6,7,12,12b-octahydro let-ethyl lfl-carbomethoxyethyl 12bu-indolo (2,3-a) quinolizine used as starting product for preparing vincamine is obtained by saponification of 1,2,3,4,6,7,12,12b-octahydro l-ethyl 1-carbomethoxyethyl4-oxo indolo (2,3-a) quinolizine, separation of the cis and trans isomers of 1,2,3,4,6, 7,12,12b-octahydro l-ethyl l-carboxyethyl 4-oxo indolo (2,3-a) quinolizine, resolution of the cis isomer into its optical antipodes by means of an optically active base, isolation of the enantiometer 1,2,3,4,6,7,12,12b-octahydro lot-ethyl
• the epimeric sodium salts obtained can be separated by crystallization of one of the epimers in ethanol or in a mixture of ethanol and water, such as 95% ethanol.
• the optically active base is for example l-ephedrine, d-ephidrine, quinine, (d) u-phenyl ethylamine, cinchonine, D(-) or L(+) threo l-p-nitrophenyl 2-N,N-dimethylamino propane 1,3-diol, L(+) threo l-p-nitrophenylamino propane-1,3-diol or L() threo S-amino 6- phenyl 1,3-dioxan.
• This esterification can likewise be effected with diazomethane.
• PREPARATION I 1,2,3,4,6,7,12,12B-OCTAHY DRO l-ETHYL 1 CARBOMETHOXYETHYLINDOLO (2,3-A) QUINOLIZINE Stage A: l,2,3,4,6,7,12,12b-octahydro l-ethyl l-carbomethoxyethyl 4-oxo indolo (2,3-a) quinolizine One takes to reflux a mixture of 231.5 g. of tryptamine, 371 g. of dimethyl 4-ethyl 4-forrnyl pimelate obtained according to the process described in [J Am. Chem. Soc. 86 (1964), 2946] and 1160 cc.
• Stage B 1,2,3,4,6,7,12,12b-octahydro l-ethyl l-carbomethoxyethylindolo (2,3-a) quinolizine
• quinolizine One puts in suspensions, under agitation and under nitrogen, 250 g. of 1,2,3,4,6,7,12,12b-octahydro l-ethyl l-carbomethoxyethyl 4-oxo indolo (2,3-a) quinolizine in 2500 cc. of tetrahydrofuran, adds 172.5 g. of phosphorus pentasulphide and continues agitation for four hours at 25-27 C.; one filters, rinses the filter with tetrahydrofuran. One thus obtains solution A.
• trans derivative of 1,2,3,4,6,7,12,12b-octahydro lethyl l-carbomethoxyethylindolo (2,3-a) quinolizine is in the form of a solid colourless product, melting at 149 C.
• the solution obtained is cooled to 20 C.
• Stage B Resolution of cis 1,2,3,4,6,7,l2,l2b-octahydro 1- ethyl 1-carboxyethyl4-oxoindolo (2,3-a) quinolizine
• One prepares a solution containing 263 g. of l-ephedrine in 1.45 litres of dichlorethane.
• One adds 525 g. of the cis isomer obtained in the preceding stage, then 380 cc. of dichlorethane.
• One takes to reflux while agitating and distills about 380 cc. of dichlorethane.
• the precipitate obtained is separated by filtration.
• the mother liquors of filtration of the levorotatory isomer are evaporated to dryness.
• the residue recrystallized in ethanol is constituted of 159 g. of starting racemic acid which one can again resolve.
• the rotatory power of the l-ephedrine salt of 1,2,3,4,6, 7,12,12b-octahydro 1OL-thy1 lfi-carboxyethyl 4-oxo 12aindolo (2,3-a) quinolizine is characterized by:
• Stage C 1,2,3,4,6,7,12,12b-octahydro lot-ethyl lp-carbomethoxyethyl 4-oxo 12ba-indolo (2,3-a) quinolizine
• One cools to 25 C. and neutralizes by the addition of 1.2 cc. of pyridine.
• Stage D 1,2,3,4,6,7,12,12boctahydro let-ethyl lfl-carbomethoxyethyl IZboc-itldOlO (2,3-a) quinolizine 200 g. of the product obtained in the preceding stage are put in suspension in 2 litres of tetrahydrofuran. One adds 138 g. of phosphorus pentasulphide. One agitates for 4 hours under an atmosphere of nitrogen, while keeping the temperature in the region of 25 C.
• the filtrate is added slowly to 1 kg. of Raney nickel (previously washed with tetrahydrofuran), while agitating under an atmosphere of nitrogen, at about 25 C. One leaves in contact for one and a half hours after the end of the addition of the filtrate. One separates the nickel by filtration. The filtrate is evaporated to dryness in vacuo. One obtains 173 g. of 1,2,3,4,6,7,12b-octahydro lot-ethyl l B-carbomethoxyethyl 12ba-indolo (2,3-a) quinolizine.
• PREPARATION III l,2,3,4,6,7,12,12B-OCTAHYDRO l fl-ETHYL lot-CARBO'METHOXYETHYL 12B/8-IN- DOLO (2,3-A) QUINOLIZINE Starting with 1,2,3,4,6,7,12,12b-octahydro lfi-ethyl 1acarboxyethyl 4-oxo 12b 3-indolo (2,3-a) quinolizine (obtained in stage B of Preparation II), by applying the process described in stages C and D of Preparation II, one obtains successively:
• 1,2,3,4,6,7,12,12b-octahydro 1 3-ethyl lu-carbomethoxyethyl 4-oxo l2b 8-indolo (2,3-a) quinolizine 1,2,3,4,6,7,12,12b-octahydro 1,B-ethyl lu-carbomethyethyl 4-thioxo 12bp-indolo (2,3-a) quinolizine 1,2,3,4,6,7,12,12b-octahydro 1 fl-ethyl lot-carbomethoxyethyl 12bp-indolo (2,3-a) quinolizine.
• Stage B 14-oxo IS-hydroximino E-homo-eburnane, dl, cis isomer
• This compound is in the form of a solid colourless product, melting at 260 C.
• Stage C 14,15-dioxo E-homo-eburnane, dl, cis isomer
• 14-oxo 15-hydroximino E- homo-eburnane dl, cis isomer dissolves 6.78 g. of 14-oxo 15-hydroximino E- homo-eburnane dl, cis isomer, in 34 cc. of 40% formic aldehyde, 17 cc. of water and 17 cc. of hydrochloric acid, heats the solution at 75 C. for fifteen minutes and cools; one alkalizes by the addition of ammonia, extracts with methylene chloride, washes the organic phases with water, dries on sodium sulphate and distills to dryness; one purifies by chromatography and recrystallization in ether; one obtains 1.38 g. of 14,15-dioxo E-homo-eburnane, dl, cis isomer, in the form
• Stage D dl-vincamine
• dl-vincamine One dissolves 0.25 g. of sodium in 50 cc. of methanol, brings the solution back to 25 C. and adds 0.50 g. of 14,15 dioxo E-homo-eburnane, dl, cis isomer, under nitrogen; one leaves in contact for one hour at ambient temperature, neutralizes by the addition of 0.65 cc. of acetic acid, distills the methanol in vacuo and takes up the residue with water; one suction-filters, washes with water and dries at 60 C.; one obtains 0.471 g. of dlvincamine in the form of a solid colourless product, melting at 265 (Koffler block) and at 239.5 C. by differential thermal analysis.
• EXAMPLE II DL-ISO-VINCAM-INE Stage A: 14-oxo E-homo-eburnane, dl, trans isomer One puts in suspension in 200 cc. of tetrahydrofuran 4.2 g. of sodium hydride (50%) in mineral oil and agitates for ten minutes at ambient temperature; one adds 20 g. of trans derivative of l,2,3,4,6,7,12,12b-octahydro 1- ethyl l-carbomethoxyethylindolo (2,3-a) quinolizine obtained according to the process described in Stage B of Preparation I, and 400 cc. of tetrahydrofuran and agitates for fifteen minutes at 25 0; one obtains a solution of 14-oxo E-homo-eburnane, trans isomer, which one uses it is in the following stage.
• Stage B 14-oxo 15-hydroximino E-homo-eburnane, dl, trans isomer
• 14-oxo E-homoeburnane, dl, trans isomer obtained in Stage A, one adds 60 cc. of t-butyl nitrite and leaves in contact for one hour fifteen minutes, under nitrogen and at 25 0.; one pours the reaction mixture in a solution of 40 g. of ammonium chloride in 1500 cc.
• the compound is in the form of a solid yellow product, melting at 226 C.
• Stage C 14,15-dioxo E-homo-eburnane, dl, trans isomer
• One heats to 85 C. a mixture of 2 g. of l4-oxo l5-hydroximino E-homo-eburnane, dl, trans isomer, 10 cc. of 5 N hydrochloric acid and 10 cc.
• Stage D d1 3-iso vincaminic acid
• Stage E dl-iso vincamine To 2 cc. of a solution of diazomethane in methylene chloride one adds 3 mg. of dl 3-iso vincaminic acid and leaves in contact for fifteen minutes at ambient temperature; one destroys the excess diazomethane by the addition of acetic acid, evaporates to dryness in vacuo and obtains dl 3-iso vincamine in the form of a solid colourless product.
• Stage B 14-oxo 15-hydroxyimino 3a,16a(20)-E-l10m0- eburnane
• 14oxo 3a,16a(20)-E-homo-eburnane 660 cc. of toluene
• 440 cc. of t-butyl nitrite One adds to the suspension obtained 670 cc. of a solution of sodium t-amylate in toluene titrating 19 g. of sodium per litre.
• Stage C 14,15-dioxo 3a,16u(20)-E-homo-eburnane
• 600 cc. of 40% formol 300 cc. of water and 300 cc. of hydrochloric acid.
• the solution is then poured onto 2 kg. of ice.
• Stage D vincamine
• the product obtained in the preceding stage is put in suspension in 100 cc. of methanol, and the mixture is poured into a solution of 15 g. of sodium in 2.5 litres of methanol.
• the precipitate thus formed is filtered, washed and dried.
• the crude vincamine obtained is purified by the formation of acetate then decomposition of acetate with triethylamine.
• Vincamine can also be obtained in the following way:
• EXAMPLE IV () VINCAMINE Starting with 1,2,3,4,6,7,12,12b-octahydro lfi-ethyl 1acarbomethoxyethyl 12bp3-indolo (2,3 -a) quinolizine (obtained in Preparation III), by applying the process described in Stages AB--C-D of Example III, one obtains successively:
• a nitrosation reagent selected from the group consisting of an alkyl nitrite containing from 1 to 5 carbon atoms to react on the lactamic compound of general Formula 111:
• an optically active cis 1,2,3,4,6,7,12,12b-0cta hydro 1 ethyl 1 carboxyethyl 4 oxo indolo (2,3-a) quinolizine is obtained by saponification of 1,2,3,4,6,7, 12,12b-octahydro l ethyl 1 carbomethoxyethyl 4-oxo indolo (2,3-a) quinolizine, separation of the cis and trans isomers of 1,2,3,4,6,7,12,12b'- octahydro 1- ethyl 1 carboxyethyl 4 oxo indolo (2,3 a) quinolizine, resolution of cis 1,2,3,4,6,7,12,12b-octa- 19 q-oxo indolo (2,3-a) quinolizine, reaction
• An E-homo-eburnane selected from the group consisting of 14-oxo E-homo-eburnane, 14-oxo 15-hydroxyimino E-homo-eburnane and 14,15-dix0 E-homoeburnane.

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• 1971
  • 1971-03-22 US US00126929A patent/US3770724A/en not_active Expired - Lifetime
  • 1971-03-23 IL IL36474A patent/IL36474A/xx unknown
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  • 1971-03-31 AT ATA2739/71A patent/AT309699B/de not_active IP Right Cessation
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• 1975
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• 1980
  • 1980-02-28 IT IT8048032A patent/IT8048032A0/it unknown

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