GB2204036A - Synthesis of vinblastine and vincristine - Google Patents

Description

PROCESS FOK TBE SYNTHESIS OF VINBLASTINE AND VINCRISTINE The present invention relates to a new and improved method particularly for producing dimer alkaloid compounds especially of the Catharanthus (Vinca) alkaloid group and, in particular, is an improved method for producing the antiviral, antileukemic (antineoplastic) compounds, vincristine and vinblastine, of Formula I.

OH 7 Indole Unit RTr (Catharanthine) H 's 'H 1' X Y ) Dihfdroinn Unit H OH (\'indotine) H3O 17 N H OL H3C WRí The above compound, when R is COUCH3, and K1 is OCH3, is vinblastine (NSC 49432) and when K is COOCH3, and s1 is OCH3 and N1 is N-CHO (N-formyl), vincristine (NSC 67574).

The present series of dimeric alkaloids, including important antitumor agents, are formed from an indole, such as catharanthine (Formula II, K - COOCH3), and a dihydroindole unit, e.g. vindoline (Formula III), in which the halves are linked via a carbon-carbon bond involving an aliphatic centre C18 in the indole unit and an aromatic carbon C15 in the vindoline portion.

The conditions for the coupling reaction as described in the present invention, relate to an important modification of the method developed in these laboratories [U.S. Pat. No. 4,279,817; Helv. Chim. Acta, 59, 2858 (1976)] (Scheme 1). In particular, the present modification allows the preparation and isolation of the highly unstable dihydropyridinium intermediate VI (K CUOCH3), being formed in the coupling of catharanthine N-oxide (Formula Ila) with vindoline (Formula III).

In general, the Nb-oxide derivative of the indole unit (Formula IIa) or related analogues (Formula IV, where R1 = R2 = R3 = R4 H or R2 = R3 = R4 = H and R1 = alkyl group of structure, (CH2)nCH3 where n = 0-10) prepared with a peracid such as m-chloroperbenzoic acid or p-nitroperbenzoic acid in an inert organic solvent such as methylene chloride or other polyhalo organic solvents, is achieved at various temperatures; for example, -77 OC, OOC, room temperature and above. The N-oxide intermediate thus formed is used for the next step without isolation. The fragmentation reaction which fragments the C5-C18 bond of the indole N1 Nb-oxide intermediate is carried out in the presence of a reagent such as trifluoroacetic anhydride.To maximize the subsequent coupling reaction which promotes the formation of a natural dimer bonded at C18 (indole unit) and C15 (dihydroindole unit), the dihydroindole unit may be added to the reaction mixture prior to the fragmentation reaction. As alternative reagents for the trifluoroacetic anhydride component used in fragmentation and coupling, there may be utilised trichloroacetic anhydride, acetic anhydride, acetyl halides and tosyl anhydride. These reagents bring about a Polonovski-type fragmentation of the C5-C18 bond in the compounds shown in Formulas Ila and IV.

Scheme 1

The reaction temperature, time and pressure conditions in general are similar to those employed in the Polonovski reaction which, in its original application, involved the dealkylation of tertiary and heterocyclic amines by acylation of the corresponding N-oxides with acetic anhydride or acetyl chloride (cf.

Merck Index, 8th ed., 1968, page 1203). The temperature of the fragmentation and coupling reaction may vary from -700C to 400C and preferably at the low temperature range. The portions of the reaction relating to the formation of the N-oxide compound may be conducted in the open or under inert gas atmosphere such as argon or other inert gas of Group Zero of the Periodic Table such as helium, nitrogen, neon, etc. The same inert atmosphere conditions are employed in the fragmentation and coupling portions of the reaction and under a positive temperature control preferably in the range of -40 0C to 6000.

t vR3 < K R, H C02CH3 2 H \lint ne n2 R1 IV V 2Ke N 0 r I) J3 vr vII VI

W2Me I 3 Dozing VIII Due to the low temperature necessary for the later stage reactions, the reaction time may vary from several hours to several days.

The first formed indole-dihydroindole dimer intermediate, after the (stereospecific) coupling reaction, possesses an iminlu salt function at then atom of the indole moiety as represented by Formulas V or VI. Reduction of this iminium intermediate by reacting with alkali metal borohydride (NaBH4, KBS4, Lib4) produces the dimeric alkaloid(s) as described in U.S.

Pat. No. 4,279,817.

In the present invention, the iminium intermediate (Formula V or VI) ) may be isolated as such by careful manipulation. After the coupling reaction is completed, the reaction mixture is applied directly on an appropriate chromatographic system such as column, thin layer or high performance liquid chromatography, preferably reverse phase and/or size-exclusion separation methods. The temperature of the operation may vary from 40C to room temperature.Alternatively, volatile reagents and solvents which are present together with the iminium intermediate in the reaction mixture may be removed under reduced pressure and temperature, preferably below -100C. The resulting solid (Formula V or VI) is then dissolved in various organic solvents, such as halogenated hydrocarbons, ethers, alcohols, acetonitrile, etc., and/or various aqueous buffers. The pH of the buffer may vary from 2 to 10. The solution of iminium intermediate (Formula V or VI) can then be purified by the chromatographic methods described above before further characterisations. Alternatively, the iminium intermediate solution can be used directly for subsequent reactions. The use of inert atmosphere conditions may or may not be necessary.

When the starting indole unit has a C3-C4 double bond (e.g. catharanthine (II)), the resultant coupling intermediate contains an ar S-unsaturated iminium functional group as represented by Formula VI. reduction of VI with alkali metal borohydride (NaBH4, KBH4, LiBH4), gives 3',4'-dehydrovinblastine compounds (Formula VII).

Ihe present process utilises a novel reduction method in which conversion of the iminium intermediate (Formula VI) to the enamine (Formula VIII) can be achieved. Keagents used for this reduction include 1,4-dihydropyridine compounds (the so-called NADH models) as represented by Formula IX,

where R1, R2, K3, K4, K and K6 can be any member of the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl. Two series of such compounds are readily available [Chem. Hev. 82, 232 (1982); Chem. Rev.

72, 1 (1972)]. The first is known as Hantzch esters where K3 and R5 in Formula IX are carboxylic esters, e.g.

caboethoxy (COOC2H5). The second series is the N-substituted 1,4-dihydronicotinamides (Formula IX) in which R1 is a substituted alkyl or substituted aryl function, e.g. benzyl, and R3 is CONS7R8 where K7 and can be any member of the group consisting of hydrogen, alkyl, substituted alky, aryl and substituted aryl functions.

The above reductants can be used singly or in combination. When 1,4-dihydropyridines are used to reduce iminium VI, organic solvents, such as alcohols, acetonitrile or higher members of this series, dimethyl sulfoxide, dimethylformamide, various ethers such as dioxane, tetrahydrofuran, etc., chlorinated hydrocarbons, etc. are employed, normally without an aqueous buffer as co-solvent. The progress of the reduction is monitored by direct analysis of the reaction mixture on an appropriate chromatographic system, preferably reverse phase high performance liquid chromatography. This method is used to optimise the reaction temperature, time, pressure and concentration of reactants. The reaction temperature may vary from -60 C to 60 C, and preferably from 4 C to room temperature.The reaction time may vary from several minutes to several days depending on other parameters. The reduction is conducted under cover with inert conditions such as argon or an inert gas of Group Zero of the Periodic Table (nitrogen, helium, neon, etc.).

The enamine (Formula VIII) formed in the above reduction may be used directly for subsequent reaction or isolated by careful manipulation. The reaction mixture is applied directly on an appropriate chromatographic system such as column, thin layer or high performance liquid chromatography, preferably reverse phase and/or gel-permeation separation methods. The temperature of the operation may vary from 4 C to room temperature.

Alternatively, volatile reagents and solvents present in the reaction mixture are removed under reduced pressure and temperature, preferably below -10OC. The resultant residue can be purified by the chromatographic methods described above before further characterisation or transformation.

Treatment of the enamine VIII with alkali metal borohydride (NaBH4, KBH4, LiBH4) produces the 4'-deoxovinblastine compounds (Formula X, R-COOCH3) and 4'-deoxo-4'-epi-vinblastine compounds (Formula XI, R COOCH3). Whereas, under oxidative conditions, the enamine VIII can be transformed to the vinblastine/ vincristine series via the iminium intermediate (Formula XVI).

Oxidative conditions that are used for converting enamine (Formula VIII) to an iminium intermediate (Formula XVI) include: (1) controlled aeration/oxygenation; (2) addition of flavin coenzymes [riboflavin, Formula XII, R - H; flavin mononucleotide (FMN), Formula XII, R - PO32-; flavin adenine dinucleotide (FAD), Formula XII, R - (Po 2- adenosine] followed by 32 controlled aeration/oxygenation;

(3) addition of the reduced form of the flavin coenzymes [dihydroriboflavin, Formula XIII, R - H; dihydroflavin mononucleotide (FMNH2), Formula XIII, K PO32-; dihydroflavin adenine dinucleotide (FADH2); Formula XIII, R - (PO3)2-adenosine@ followed by controlled aeration/oxygenation;

(4) addition of flavin coenzyme analogues having the isoalloxazine structure as represented by Formula XIV, where K1, R2 and R3 can be a member of the group consisting of alkyl, substituted alkyl, aryl and substituted aryl functions, and followed by controlled aeration/oxygenation;

(5) addition of the reduced form (1,5-dihydro) of the above flavin coenzyme analogues as represented by Formula XV, where R1, R2 and K3 can be a member of the group consisting of alkyl, substituted alkyl, aryl and substituted aryl functions, and followed by controlled aeration/xygenation;;

(6) addition of hydrogen peroxide and/or hydroperoxides as represented by the Formula K-UOH, where r car be an alkyl, substituted alkyl, ary' cr Sjbstituted aryl function; (7) addition of peracids as represented by the Formula K-C(93H, where K can be an alkyl, substituted alkyl aryl or substituted aryl functions; (8) addition of superoxides; (9) addition of a hydroxyl radical (OH) generated in a variety of ways, for example, by the use of hydrogen peroxide in the presence of ferrous ion.

(10) addition of a metal ion which is a good electron acceptor, for example, ferric ion (Fe+3); cupric ion (Cu+2); cuprous ion Cu+1), mercuric ion (Hg2+2) and silver ion (Ag+1) followed by controlled aeration/oxygenation.

The oxidative processes involving controlled aeration/oxygenation (condition (1)), the flavin coenzyme analogues (conditions (4), (5), peroxides (condition (6)), peracids (condition (7)), superoxides (condition (8)), hydroxyl radical (OH) (condition (9)) and metal ions capable of electron transfer (condition (10)) can be carried out in organic solvents such as alcohols, acetonitrile or higher members of this series, dimethyl sulfoxide, dimethylformamide, various ethers such as dioxane, tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, etc.

The oxidative processes involving flavin coenzymes (conditions (2), (3)), require an aqueous buffer (for example, phosphate, Tris HC1, MES buffers) at pH 5-9, but preferably in the range 6-8, as solvent. An organic co-solvent, e.g. alcohols, acetonitrile or higher member of this series, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, can be used.

The progress of the oxidative process is monitored by direct analysis of the reaction mixture on an appropriate chromatographic system, preferably reverse phase high performance liquid chromatography. This method is used to optimise the reaction temperature, time, pressure and concentration of reactants. The reaction temperature may vary from -600C to 60 0C and preferably from 40 to room temperature. The reaction time may vary from several minutes to several days depending on other parameters. The reaction is conducted at atmospheric pressure.

The conversion of intermediate (Formula XVI) to vinblastine (Formula I) may be achieved by reaction XVI with alkali metal borohydride (NaBH4, KBS4, LiBS4) in suitable solvents (organic or aqueous) as used in the oxidative process (conditions (1)-(10)).

For practical purposes, isolation of intermediates (Formulas V, VI, VIII, XVI) ) is not required and the entire process from the indole unit (Formula II) and the dihydroindole unit (Formula III) to the end product vinblastine (Formula I).may be preferably conducted in an one-pot operation.

C02Me HO 18 H .

XVI

XVLI XVIII

In summary, the present method is applicable to the production of dimer products from catharanthine and dihydrocatharanthine with vindoline as starting materials and phenyl, alkyl and amide derivatives embraced by the following formulas:

Formula XXI is as pictured and in that formula alk represents a lower alkyl group of C1-C6 and preferably C1-C3; aryl is mono-aryl such as benzyl, styryl, and xylyl; R1 is a member of the group consisting of hydrogen, alk, CHO and COR5 where R5 is alkyl or aryl; R2 and K3 are members of the group consisting of hydrogen and -CO-alk; R4 is a member of the group consisting of COO-alkyl, CONH-NH2, CONH2, CONHR6, and CON(R6)2 where R6 is alkyl;Z is a member of the group consisting of -CH2-CH2 - and -CH-CH- and K is a member of the indole family represented by Formula XXII where R7 is a member of the group consisting of hydrogen, or COO-alk; R 8 is a member of the group consisting of hydrogen, OH, .O-alk, OCO-alk or alkyl; Kg is a member of the group consisting of hydrogen, OH, O-alk, OCO-alk, or alk; R10 is a member of the group consisting of hydrogen, OH, O-alk, OCO-alk, or Formula XXIII where R11 is a member of the group consisting of hydrogen or COO-alk; R12 is a member consisting of alkyl.

The present invention differs from the prior art [U.S. Pat. No. 4,279,817] in several important stages specifically the isolation and characterisation of unstable intermediates V, VI, VIII and XVI, and their subsequent conversion to the clinical drugs vinblastine and vincristine. The prior art describes a method for producing dimer alkaloids which are analogues of the clinical drugs, for example, 3',4'-dehydrovinblastine of Formula VII.

Intermediates V and VI are prepared by contacting vindoline or a vindoline derivative, [Formula XXI when K is H] with an indole derivative represented by a compound of Formula XXIV where R13 is a member of the group consisting of hydrogen or COO-alk or by a compound of Formula XXV where K14 is a member of the group consisting of H or COO-alk and R15 is a member of the group consisting of hydrogen or alkyl.

In addition to catharanthine, any indole unit represented by Formula XXVI -may be employed. In the Formula XXVI, K, K1, K2 and K3 are members of the group consisting of hydrogen, OH, O-alk, OCO-alk, alkyl or aryl. In the Formula XXVI, as previously stated, alk is lower alkyl C1-C6 and preferably C1-C3, and aryl is mono-aryl such as benzyl, xylyl, etc.

In Formulas XXI - XXVI and generally in this application and claims, alk and alkyl mean lower alkyl as defined in Formula XXI and aryl means monoaryl as similarly defined in Formula XXI.

The intermediate VI, thus obtained, is utilised in a highly specific and novel process involving 1,4-reduction, to afford the next important intermediate VIII. Intermediate VIII is further converted by a novel process to the novel intermediate XVI and the latter is utilised in another new reductive process to afford the compounds of general structure XXI, when K is a compound of Formula XXII.

In a similar series of reactions, intermediate V, leads to compounds of general structure XXI when K is a compound of Formula XXIII.

Another highly significant and novel feature of this invention is that the isolation of intermediates V1, VIII and XVI is not essential and the entire process, monitored carefully for VI, VIII and XVI by HPLC, can be conducted to the dimeric products of Formula XXI from the starting indole (Formulas II, XXI1 and XXIII) and dihydroindole (Formula XXI, K - H) units in a one-pot operation.

The following Examples illustrate the invention.

EXAMPLE 1 Preparation of the Iminium Intermediate (Formula VI) via Modified Polonovski Keaction The reaction was performed under anhydrous conditions. All glassware was oven-dried at 120 0C. The solvent, methylene chloride, and coupling reagent, trifluoroacetic anhydride, were distilled from P205 prior to use.

To a solution of catharanthine (II, 200 mg, 0.6 mmol) in dry methylene chloride (2 ml) at -20 C under a positive atmosphere of argon was added m-chloroperbenzoic acid (132 mg. 0.8 mmol), and the mixture stirred for 5 min. To the catharanthine N-oxide (Ila), thus formed, was added a solution of vindoline (III), 270 mg, 0.6 mmol) in methylene chloride (1 ml) and the mixture cooled to -600C. Trifluoroacetic anhydride (0.2 ml, 1.5 mmol) was added to the stirred reaction mixture maintained at -60 C for 2 hours. After this time, the solvent and excess reagents were removed in vacuo at -20 C to leave a reddish-brown residue containing the iminium intermediate. The latter was characterised by reverse phase high performance liquid chromatography (HPLC) (Waters Radial-Pak C18 or CN cartridge, methanol-H2O-Et3N as solvent system).It was shown that the yield of VI in this reaction exceeded 80% by reduction of VI (NaBH4, methanol, 0 C) to the known 3',4'-dehydrovinblastine (Formula VII).

EXAMPLE 2 Keduction of Iminium Intermediate (Formula VI) with l-Benzyl-1,4-dihydronicotinamide (Formula IX, benzyl, K2 = K = KG = H; K3 = CONH2 - Synthesis of Enamine (Formula VIII) - (Procedure A) To a stirred solution of iminium intermediate (V1, 100 mg) in degassed acetonitrile (5 ml) was added l-benzyl-l,4-dihydronicotinamide (135 mg, 0.63 mmol, 6 equivalents) under a positive atmosphere of argon at room temperature (20 C) over a period of 5 hours. After this time, the reaction mixture, as monitored by reverse phase HPLC (Waters Radial-Pak C18 or CN cartridge, methanol H2O ET3N solvent system), indicated complete conversion of VI to a mixture of enamine VIII and 3',4'-dehydrovinblastine (VII) ) in a ratio of 1:1 (75% yield).

Alternatively, to a stirred solution of iminium intermediate (VI, 100 mg) in methanol (5 ml) kept initially at 0 C for 0.5 hours was added dropwise or in portions, a solution of l-benzyl-1,4-dihydronicotinamide (56 mg, 0.26 mmol, 2.5 equivalents) in methanol (2 ml) under a positive atmosphere of argon over a period of 5 hours. During this time the solution was allowed to warm up to room temperature. HPLC monitoring, as above; indicated complete conversion of VI to a mixture of enamine VIII and 3',4'-dehydrovinblastine (VII) in a ratio of 1:1 (75% yield).

In one experiment, the mixture of enamine (VIII) and 3',4'-dehydrovinblastine (VII) obtained as described above, was treated with excess sodium borohydride (500 mg) at OOC. The reaction mixture was then made basic with NH4OH and extracted with ethyl acetate (3 x 200 ml).

The combined organic phase was dried over magnesium sulphate. The product obtained, after removal of organic solvent, was subjected to preparative thin layer chromatography on silica gel (methanol/ethyl acetate as eluting system). The product was shown to be a mixture of unreacted 3',4'-dehydrovinblastine (VII), and the known compounds 4'-deoxovinblastine (X, K - COOCH3) and 4'-deoxo-4'-epivinblastine (XI, K - COOCH3). The presence of the latter compounds provided unambiguous evidence for the structure of enamine VIII.

EXAMPLE 3 Reduction of Iminium Intermediate (Formula V1) with 3,5-Diethoxycarbonyl-2,6-Dimethyl-4-PhenYl-1,4- Dihydropyridine (Hantzch ester analogue, Formula IX, R1 = H; R3 = R5 = COOCH2CH3; R2 = R6 = CH3; R4 = phenyl Alternative Synthesis of Enamine (Formula VIII) (Procedure B) To a stirred solution of iminium intermediate (VI, 100 mg) in degassed acetonitrile (3 ml) was added 3,5-diethOxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydro- pyridine (264 mg, 8 equivalents) in ethanol (12 ml) under a positive atmosphere of argon. The reaction mixture was refluxed for 3 hours. After this time, reverse phase HPLC analysis (as described above) indicated, among other products, formation of enamine VIII and 3',4'-dehydrovinblastine (VII) in a ratio of 1:1 (60% yield).

EXAMPLE 4 Synthesis of Vinbiastine (Formula I) by Oxidation of Enamine (Formula VIII) to Iminium Intermediate (Formula (XVI) with Flavin Mononucleotide (FMN, Formula XII, R = PO32-) - Method 1 To a stirred reaction mixture containing the enamine (VIII) obtained as described above (Procedure A) from iminium VI (100 mg) was added FMN (80 mg, 1 equivalent) dissolved in Tris HC1 buffer (2 ml) under a positive atmosphere of argon. The solution was kept in the dark at room temperature (200C) for 16 hours. After this time, the inert atmosphere of argon was replaced by air and the reaction mixture stirred for another 2.5 hours.Reverse phase HPLC analyses indicated Xransform.aticn oa enamine VIII to the iminnut intermediate XVI as well as to other products (see later) Sodium borohydride (500 mg) was added at 0 0C and the reaction mixture made basic with NH4OH and extracted with ethyl acetate (3 x 200 ml). The combined organic extract was dried over magnesium sulphate and the solvent removed in vacuo to provide a crude product (85 mg).

Purification of the latter by thick layer chromatography (silica gel, methanol:ethyl acetate 1:5) allowed the separation of the following dimeric products: vinblastine (Formula I, 22 mg, 23%); 3',4'-dehydrovinblastine (Formula VII, 16 mg, 17%), leurosine (Formula XVII), 8 mg, 9%) catharine (Formula XVIII, 7 mg, 7.5%); vinamidine (Formula XIX, 5 mg, 5.6%) and the reduction product of vinamidine (Formula XX, 19 mg, 20%).

EXAMPLE 5 Synthesis of Vinblastine (Formula I) by Oxidation of the Enamine (Formula VIII) with Hydrogen Peroxide to the Iminium Intermediate (Formula XVI) - Method 2 To a solution containing the enamine (VIII) obtained from iminium intermediate VI (100 mg, Procedure A) was added hydrogen peroxide (30%, 1.2 ml, 95 equivalents) under an inert atmosphere of argon. The reaction mixture was stirred at room temperature for 5.5 hours when reverse phase HPLC analyses indicated complete conversion of enamine VIII. Sodium borohydride (500 mg) was added at OOC and extracted with ethyl acetate (3 x 200 ml). The combined organic extract was dried over magnesium sulfate and removed in vacuo.The resulting product mixture was separated by thick layer chromatography (silica gel, methanol/ethyl acetate) to give the following dimeric alkaloids: vinblastine (I, 4 mg, 4%), 3',4'-dehydrovinblastine (Vll, 5 mg, 4.8%), leurosine (XVII, 13 mg, 12.5%), catharine (XVIII, 5 mg, 4.8%), the reduced form of vinamidine (XX, 30 mg, 27.6%).

EXAMPLE 6 Synthesis of Vinblastine (I) by Oxidation of the Enamine (VIII) with Air to-the Iminium Intermediate (Formula XVI) - Method3 A solution containing the enamine (VIII) obtained from the iminium intermediate (VI, 100 mg) by Procedure A was stirred in open air at room temperature for 3 h.

After this time, sodium borohydride (500 mg) was added at 0 C and the reaction mixture made basic with NH4OH and extracted with ethyl acetate (3 x 200 ml). The combined organic extract was dried over MgSO4 and removed in vacuo. The resulting crude product was separated by preparative thick layer chromatography (silica gel, methanol/ethyl acetate) to give vinblastine (I, 4 mg, 4%).

EXAMPLE 7 Synthesis of Vinblastine (I) by Oxidation of the Enamine (Formula VIII) with Air in the Presence of Ferric Chloride, to the Iminium Intermediate (XVI) - Method 4 To a stirred solution containing the enamine (VIII) obtained from the iminium intermediate (VI, 100 mg, Procedure A) was added ferric chloride (1 equivalent) and air bubbled through the solution at 0 0C for a period of 0.5 hour. Sodium borohydride (500 mg) was added at 0 0C and the reaction mixture made basic with NH4OH before extraction with ethyl acetate (3 x 100 ml). The combined organic extract was dried over Na2 SO4 and the solvent removed in vacuo. The crude product was purified by thick layer chromatography (silica gel, methanol/ethyl acetate) to give vinblastine (I, 37 mg). Based on enamine (50 mg) present in the mixture, the yield in this step is 70%.

Claims (8)

Claims:

1. A process for the production of dimeric compounds represented by the following formula

wherein in formula XXI Alkyl = CH3 or (CH 2)nCH3 where n = 1-5 R1 = CH3 or CHO K2 = H or CO-alk R3 = H R4 = COO-alk or CONR13 R14 where R13 and R14 can be any member of the group consisting of hydrogen, alkyl, substituted alkyl, aryl or substituted aryl functions Z = -CH-CH- or -CH2-CH2 K = One of formulae XXII or XXIII

joined at the carbon atom of the latter carrying R7 or K11 respectively and wherein K7 = H or COO-alk R8 = H, OH, O-alk, OCO-alk or alkyl K9 = H, OH, O-alk, OCO-alk or alkyl K10 = H, OH, O-alk, OCO-alk R11 = H or COO-alk R12 = H or alkyl from an indole unit of the natural Iboga alkaloid family containing an aza bicyclo-octane portion and a dihydroindole unit of the natural Aspidosperma and Vinca alkaloid families, the stereochemistry of the carbon-carbon linkage between these two units being identical with that of vinblastine which consists of (a) forming an b-oxide intermediate at a temperature of -700 to +400C from said indole unit by oxidizing the bridge nitrogen and without isoiating said intermediate; (b) treating said N-oxide indole intermediate in the presence of one member of the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride to effect a Polonovski-type fragmentation reaction; (c) without isolating the product of step (b); coupling said reaction product with a dihydroindole unit in the presence of acetic anhydride, halogenated acetic anhydride, and acetyl chloride at a low temperature of from -700C to +400C under inert conditions; (d) the product of step (c) is isolated by solvent evaporation preferably at low temperature in the range of -20 0C to 0 0C;; (e) the product of step (d) is reduced by 1,4-dihydropyridine compounds represented by formula IX

where R' and R'5 in formula IX are carboxylic esters (COO-alk) and K'1, R'2, '4 and R' 6 are members of the group consisting of H, alkyl, aryl (Hantzch ester series) or N-substituted 1,4-dihydronicotinamides where R'1 is a substituted alkyl or substituted aryl function, example, benzyl and K' 3 is CONK7K8 where K7 and R8 can be any member of the-group consisting of hydrogen, alkyl or aryl functions;; wherein said reduction is conducted under an inert atmosphere at -600 to +60 C and preferably in the @emperature range 4 0C to 20 0C and utilizing solvents selected from the group consisting of lower alkyl alkanols, acetonitrile, dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran, and chlorinated lower hydrocarbons; (f) the enamine product of step (e) is isolated by solvent evaporation, preferably at low temperature in the range of -200C to 0 C; (g) the enamine obtained in step (f) is used -to prepare a corresponding iminium intermediate by an oxidative process including: (1) controlled aeration/oxygenation in the ambient atmosphere; or (2) controlled aeration/oxygenation in presence of a metal ion; or (3) controlled aeration/oxygenation in presence of a flavin coenzyme; or (4) controlled aeration/oxygenation in presence of a treating agent selected from hydrogen peroxide and hydroperoxides; utilizing an organic solvent at pH 5-9 and a reaction temperature of -600C to + 60 C; (h) the product, an iminium intermediate, obtained in step (g) is isolated by solvent evaporation, preferably at low temperature in the range of -20 0C to OOC; (i) the product obtained in step (h) is converted to the target compound of formula XXI, by reduction with alkali metal borohydride.

2. The process according to claim 1 wherein the process including the formation of the final product of formula XXI is conducted in a one-pot operation.

3. The process according to claim 1 or 2 wherein a said N-oxide indole intermediate is utilized as starting material and is coupled with the dihydroindole unit and is reduced by a 1,4-dihydropyridine compound by the procedure of step (c) of claim 1.

4. The process of any preceding claim, wherein said enamine, previously isolated is used as starting material, the enamine being oxidized to an iminium intermediate by an oxidative process including: (1) controlled aeration/oxygenation in the ambient atmosphere; or (2) controlled aeration/oxygenation in presence of a metal ion; or (3) controlled aeration/oxygenation in presence of a flavin coenzyme, after which steps (h) and (i) of claim 1 are carried out.

5. The process of claim 4, wherein, in controlled aeration/oxygenation step (1), hydrogen peroxide or a hydroperoxide is added.

6. The process according to any preceding claim, wherein in controlled aeration/oxygenation step (1), the product iminium intermediate isolated by solvent evaporation at a low temperature in the range of -20 0C to 0 0C is reduced by an additional step to a Vinca alkaloid selected from vinblastine and vincristine by reduction with alkali metal borohydride.

7. A process for the production of a compound represented by the formula XXI set out in claim 1, substantially as described in the Examples.

8. The compound represented by one of the formula XXI as set out in claim 1, whenever produced by the process claimed in any one of the preceding claims.