CH675724A5 - - Google Patents

Description

CH 675 724 A5

description

The present invention relates to a new and improved process for the preparation of dimer alkaloid compounds, especially the Catharanthus (Vinca) alkaloid group, and it provides an improved process for the preparation of the antivirus, antileukemia (antineoplastic) compounds, vincristine and vinblastine of formula XXI.

The invention is set out in claim 1.

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Indole unit (Catharanthin)

Dihydroindole unit (Vindolin)

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The above compound is when R = COOCH3 Ri = CH3 and R13 = OCH3, vinblastine (NSC 49 432) and when R = COOCH3 and R13 = OCH3 and Ri = CHO (N-formyl), vincristine (NSC 67 574).

The present series of dimeric alkaloids, including important anti-tumor agents (anti-tumor agents), are derived from an indole such as catharanthine (Formula II, R = COOCH3) and a dihydroindole unit, e.g. Vindolin (formula III) is formed, the halves being connected via a carbon-carbon bond which contains an aliphatic central member C18 in the indole unit and an aromatic carbon member C15 in the vindoline section.

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The coupling reaction conditions as described in the present invention relate to an important modification of the method developed in these laboratories (U.S. Patent No. 4,279,817; Helv. Chim. Acta, 59, 2858 (1976)) (Scheme 1). In particular, the present modification permits the preparation and isolation of the highly unstable dihydropyridium intermediate VI (R = COOCH3), which is formed on the coupling of catharanthine N-oxide (formula IIa) with vindoline (formula III).

In general, the Nb oxide derivative of the indole unit (formula IIa) or related analogues (formula IV, where Ri = R2 = R3 = R4 = H or R2 = R3 = R4 = H and Ri = alkyl group of the structure (CH2 ) nCH3 with n = O to 10), which are prepared with a peracid such as m-chloroperbenzoic acid or p-nitroperbenzoic acid in an inert organic solvent such as methylene chloride or other polyhalogen-organic solvents, at different temperatures, for example -77 ° C, 0 ° C, room temperature and above. The N-oxide intermediate thus formed is used for the next step without isolation. The fragmentation reaction, which fragments the Cs-Cis bond of the indole-Nb-oxide intermediate, is carried out in the presence of a reactant such as trifluoroacetic anhydride. In order to maximize the subsequent coupling reaction, which

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CH 675 724 A5

With natural dimers bound to cis (indole unit) and C15 (dihydroindole unit) accelerated, the dihydroindole unit can be added to the reaction mixture before the fragmentation reaction. As alternative reaction components for the trifluoroacetic anhydride component used in the fragmentation and coupling, trichloroacetic anhydride, acetic anhydride, acetyl halides and tosyl anhydride can be used. These reaction components cause a fragmentation of the Polonovski type of the Cs-Cis bond in the compounds indicated in the formulas IIa and IV.

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CH 675 724 A5

SCHEME I

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R = COOCH3

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CH 675 724 A5

The reaction conditions for temperature, time and pressure are generally similar to those used in the Polonovski reaction, which in its original application contained the deacidification of tertiary and heterocyclic amines by acylation of the corresponding N-oxides with acetic anhydride or acetyl chloride ( see Merck Index, 8th edition, 1968, page 1203). The temperature of the fragmentation and coupling reaction can vary from -70 ° C to 40 ° C and is preferably in the low temperature range. The portions of the reaction that relate to the formation of the N-oxide compound can be carried out in an open or under an inert gas atmosphere such as under argon or another inert group zero gas of the periodic table such as under helium, nitrogen, neon, etc. . The same inert atmosphere conditions are applied in the fragmentation and coupling sections of the reaction and under positive temperature control, preferably in the range of -40 ° C to -60 ° C.

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Due to the low temperature required for the reactions of the later stages, the reaction time can vary from a few hours to a few days.

The first indole-dihydroindole dimer intermediate formed after the (stereospecific) coupling reaction has an iminium salt function on the Nb atom of the indole half, as represented by the formulas V or VI. Reduction of this iminium intermediate by reaction with alkali metal borohydride (NaBH4, KBH4, LÌBH4) produces the dimeric alkaloid (s) as described in US Pat. No. 4,279,817.

As such, in the present invention, the iminium intermediate (Formula VI) can be isolated by careful manipulation. After the coupling reaction is complete, the reaction mixture is directly transferred to a suitable chromatographic system such as e.g. applied for column, thin-layer or high-performance liquid chromatography, preferably for alternating phase and / or size exclusion separation processes. The temperature of operation can range from 4 ° C to

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CH 675 724 A5

Vary room temperature. Alternatively, volatile reaction components and solvents, which are present in the reaction mixture together with the iminium intermediate, can be removed under reduced pressure and at a reduced temperature, preferably below -10 ° C. The resulting solid (formula 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 can vary from 2 to 10. The solution of the iminium intermediate (formula VI) can then be purified by the chromatographic methods described above before further characterizations. Alternatively, the iminium intermediate solution can be used directly for subsequent reactions. The use of inert atmosphere conditions may or may not be necessary.

If the starting indole moiety has a C3-C4 double bond (e.g. catharanthine (II)), the resulting coupling intermediate contains an a, β-unsaturated iminium functional group as represented by Formula VI. Reduction of VI with alkali metal borohydride (NaBH4, KBH4, LÌBH4) yields 3 ', 4'-dehydrovinbIastin compounds (formula VII). In the present process, a new reduction process is used in which conversion of the iminium intermediate (formula VI) to the enamine (formula VIII) can be achieved. Reaction components used for this reaction include 1,4-dihydropyridine compounds (the so-called NADH models) as represented by Formula IX,

wherein R 1, R 2, R 3, R 4, Rs and R 6 can be any member from the group consisting of H, alkyl, substituted alkyl, aryl and substituted aryl. Two series of such compounds are readily available (Chem. Rev. 82, 232 (1982); Chem. Rev. 72.1 (1972)). The former are known as Hantzch esters, in which R3 and R5 in formula IX are carboxylic acid esters, e.g. Are carbethoxy (COOC2H5). The second row are the N-substituted 1,4-dihydronicotinamides (Formula IX) in which Ri is a substituted alkyl or substituted aryl functional group, e.g. Is benzyl, and R3 is CONR7R8, where R7 and Re can be any member of the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl functional groups.

The above reducing agents can be used alone or in combination. If 1,4-dihydropyridines are used to reduce iminium VI, organic solvents such as alcohols, acetonitrile or higher members of these series, dimethyl sulfoxide, dimethylformamide, various ethers such as dioxane, tetrahydrofuran etc., chlorinated hydrocarbons etc., usually without an aqueous buffer can be used as a co-solvent. The progress of the reduction is monitored by direct analysis of the reaction mixture on a suitable chromatographic system, preferably with alternating-phase high-performance liquid chromatography. This procedure is used to optimize the reaction temperature, time, pressure and concentration of the reaction components. The reaction temperature can vary from -60 ° C to 60 ° C, and preferably from 4 ° C to room temperature. The response time can vary from a few minutes to several days depending on other parameters. The reduction is carried out under protection with inert conditions such as argon or an inert group zero gas of the periodic table (nitrogen, helium, neon, etc.).

The enamine (formula VIII) formed in the reduction described above can be used directly for subsequent reactions or isolated by careful treatment or manipulation. The reaction mixture is applied directly to a suitable chromatographic system such as column, thin-film or high-performance liquid chromatography system, preferably in alternating phase and / or gel permeation separation processes. The operating temperature can vary from 4 ° C to room temperature. Alternatively, volatile reaction constituents and solvents which are present in the reaction mixture are removed under reduced pressure and at a reduced temperature, preferably below -10 ° C. The resulting residue can be purified by the chromatographic methods described above before further characterization or transformation.

Treatment of enamine VIII with alkali metal borohydride (NaBH4, KBH4, UBH4) produces the 4-deoxovinblastine compounds (formula X, R = COOCH3) and 4'-deoxo-4'-epivinblastine compounds (formula XI, R = COOCH3). On the other hand, under oxidizing conditions, the enamine VIII can be converted into the vinblastine / vincristine series via the iminium intermediate (formula XVI).

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CH 675 724 A5

XI '

Oxidizing conditions that can be used to convert enamine (Formula VIII) to an iminium intermediate (Formula XVI) include:

(1) controlled aeration / oxidation;

(2) addition of flavin coenzymes (riboflavin, formula XII, R = H; flavin mononucleotide (FMN), formula XII, R = PO32 "; flavin adenine dinucieotide (FAD), formula XII, R = (PC> 3) 22 ~ adenosine), followed by controlled aeration / oxidation;

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XII

(3) addition of the reduced form of the flavin coenzymes (dihydroriboflavin, formula XIII, R = H; dihydrofinin mononucleotide (FMNH2), formula XIII, R = PO32 "; dihydroflavin adenine dinucleotide (FADH2), formula XIII, R = (P03) 2 ~ adenosine), followed by controlled aeration / oxidation;

(4) addition of flavin-coenzyme analogs with the isoalloxazine structure, as represented by the formula XIV, where R 1, R 2 and R 3 can each be a member from the group consisting of alkyl, substituted alkyl, aryl - and substituted aryl functional groups, and subsequent controlled aeration / oxidation;

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CH 675 724 A5

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XIV

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(5) Add the reduced form (1,5-dihydro) of the above Fiavin coenzyme analogs as represented by Formula XV, where Ri, R2 and R3 can each be a member from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl functional groups, and subsequent controlled aeration / oxidation;

(6) addition of hydrogen peroxide and / or hydroperoxides as represented by the formula R-OOH, where R can be an alkyl, substituted alkyl, aryl or substituted aryl functional group;

(7) addition of peracids as represented by the formula R-CO3H, where R can be an alkyl, substituted alkyl, aryl or substituted aryl functional group;

(8) addition of hyperoxides;

(9) adding a hydroxyl residue (OH) which can be generated in a variety of ways, e.g. by using hydrogen peroxide in the presence of iron (II) -lon;

(10) adding a metal ion that is a good electron acceptor, e.g. Iron (III) -lon (Fe + 3); Copper (II) ion (Cu + 2); Copper (I) -lon (Gu + 1); Mercury (ll) ion (Hg2 + 2) and silver ion (Ag + 1), with subsequent controlled aeration / oxidation.

The oxidation processes, the controlled aeration / oxidation (condition (1)), the Fiavin-coenzyme analogs (conditions (4), (5)), peroxides (condition (6)), peracids (condition (7)), hyperoxides ( Condition (8)), hydroxyl group (OH) (condition (9)) and metal ions capable of electron transfer (condition (10)) can include in organic solvents such as alcohols, acetonitrile or higher members of these series, dimethyl sulfoxide, dimethyiformamide , various ethers such as dioxane, tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, etc. can be carried out.

The oxidation processes involving flavin coenzymes (conditions (2), (3)) require an aqueous buffer (eg phosphate, Tris-HCl, MES buffer) at pH 5-9, but preferably in the range of 6 -8, as a solvent. An organic co-solvent, e.g. Alcohols, acetonitrile or higher members of this series, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethyiformamide can be used.

The progress of the oxidation process is monitored by direct analysis of the reaction mixture on a suitable chromatographic system, preferably alternating-phase high-performance liquid chromatography. This process is used to optimize the reaction temperature, time, pressure and the concentration of the reaction components. The reaction temperature can vary from -60 ° C to 60 ° C and preferably from 4 ° C to room temperature. The response time can vary from a few minutes to a few days depending on other parameters. The reaction is carried out at atmospheric pressure.

The conversion of the intermediate (formula XVI) into vinblastine (formula I) can be carried out by reacting XVI with alkali metal borohydride (NaBH4, KBH4, LÌBH4) in suitable solvents (organic or aqueous), as used in the oxidizing process (conditions (1) - ( 10)) used to be achieved.

For practical purposes, the isolation of intermediates (formulas VI, Vili, 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) can preferably be carried out in a single-container operation.

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CH 675 724 A5

ÇO, Me OÖH

XVI

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H ^ '18 'vindolin

H COgMe

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In summary, the present process is applicable to the preparation of dimer products of catharanthine and dihydrocatharanthine with vindoline as starting materials and phenyl, alkyl and amide derivatives, which are encompassed by the following formulas:

where R

XXI

XXIÏ

can be.

hz

XXIII

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CH 675 724 A5

Formula XXI is as shown and in this formula alk represents a lower alkyl group with Ci-Ce and preferably C1-C3; Aryl is monoaryl such as Benzyl, styryl and xylyl; Ri is a member of the group consisting of hydrogen, alk, CHO and COR5, where R5 is alkyl or aryl; R2 and R3 are members of the group consisting of hydrogen and -CO-alk; R4 is a member of the group consisting of COO-alk, CONH-NH2, CONH2, CONHRs and CON (R6) 2, where R6 is alkyl; Z is a member from the group consisting of -CH2-CH2- and -CH = CH-, and R is a member from the indole family represented by Formula XXII, wherein R7 is a member from the group consisting of Is hydrogen or COO-alk; Rs is a member of the group consisting of hydrogen, OH, O-alk, OCO-alk or alkyl; Rg is a member from 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 or OCO-alk; or by the formula XXIII, in which Rh is a member from the group consisting of hydrogen or COO-alk and R12 is a member consisting of alkyl.

The present invention differs from the prior art (U.S. Patent No. 4,279,817) in several important stages, specifically the isolation and characterization of unstable intermediates VI, VIII and XVI, and their subsequent conversion to the clinical drugs vinblastine and Vincristine. The prior art describes a process for the preparation of dimer alkaloids which are analogs of clinical drugs, e.g. 3 ', 4'-dehydrovinblastine according to formula VII.

Intermediate VI is prepared by contacting vindoline or a vindoline derivative (formula XXI if R is H) with an indole derivative which is formed by a compound of formula XXIV in which R13 is a member from the group consisting of hydrogen or COO-alk, or by a compound of formula XXV, in which R14 is a member from the group consisting of H or COO-alk, and R15 is a member from the group consisting of hydrogen or alkyl, is shown.

In addition to catharanthine, any indole unit represented by Formula XXVI can be used. In formula XXVI, R, Ri, R2 and R3 are members of the group consisting of hydrogen, OH, O-alk, OCO-alk, alkyl or aryl. In formula XXVI, as already indicated above, alk are lower alkyl ChC6 and preferably C1-C3, and aryl monoaryl such as benzyl, xylyl etc.

In formulas XXI to XXVI and generally in this application and in the claims, alk and alkyl denote lower alkyl as defined in formula XXI and aryl denotes monoaryl as similarly defined in formula XXI.

Intermediate VI thus obtained is used in a highly specific and new process involving 1,4-reduction to provide the next important intermediate VIII. Intermediate VIII is further converted to the new intermediate XVI by a new process and the latter is used in another new reducing process to provide the compounds of general structure XXI when R is a compound of formula XXII.

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

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CH 675 724 A5

Another highly significant and novel feature of this invention is that the isolation of intermediates VI, VIII and XVI is not essential and the whole process, if carefully monitored for VI, VIII and XVI by HPLC, is dimeric Products of the formula XXi from the starting indole (formulas II, XXII and XXIII) and dihydroindoi- (formula XXI, R = H) units can be carried out in a single-container operation.

Experimental part - examples

Preparation of the iminium intermediate (formula VI) via modified Polonovski reaction

The reaction was carried out under anhydrous conditions. All glassware was oven dried at 120 ° C. The solvent, methylene chloride, and the coupling reaction ingredient, tri-fluoroacetic anhydride, were distilled before using P2O5.

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, m-chloroperbenzoic acid (132 mg, 0.8 mmol) was added, and the mixture was stirred for 5 minutes. To the catharanthine N-oxide (IIa) thus formed, a solution of vindolin (III, 270 mg, 0.6 mmol) in methylene chloride (1 ml) was added and the mixture was cooled to 60 ° C. Trifluoroacetic anhydride (0.2 ml, 1.5 mmol) was added to the stirred reaction mixture, which was kept at -60 ° G for 2 hours. After this time, the solvent and excess reaction components were removed in vacuo at -20 ° C, leaving a reddish-brown residue which contained the iminium intermediate. The latter was characterized by alternating phase high performance liquid chromatography (HPLC) (Waters Ra-dial-Pak C18 or CN cartridge, methanol H20-Et3N as solvent system). It was found that the yield of VI in this reaction exceeded 80% by reducing VI (NaBH4, methanol, 0 ° C.) to the known 3 ', 4'-dehydrovinblastine (formula VII).

Reduction of iminium intermediate (formula VH with 1-benzvl-1,4-dihvdronicotinamide (formula IX: Ri = benzvl. R? = Ra = R * = Rr = H: Ra = CONHpì - synthesis of enamine (formula Villi - (method A )

To a stirred solution of iminium intermediate (VI, 100 mg) in degassed acetonitrile (5 ml) was added 1-benzyl-1,4-dihydronicotinamide (135 mg, 0.63 mmol, 6 equivalents) under a positive atmosphere of argon Room temperature (20 ° C) was added over a period of 5 hours. After this time, the reaction mixture, monitored and controlled by alternating phase HPLC (Waters Radial-Pak C18 or CN cartridge, methanol / H20 / Et3N solvent system), showed complete conversion of VI to a mixture of enamine VIII and 3 ', 4' -Dehydrovinblastine (VII) in a ratio of 1: 1 (75% yield).

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

In one experiment, the mixture of enamine (VIII) and 3 ', 4'-dehydrovinbiastine (VII) obtained as described above was treated with an excess of sodium borohydride (500 mg) at 0 ° C. The reaction mixture was then basified with NH4OH and extracted with ethyl acetate (3 x 200 ml). The combined organic phase was dried over magnesium sulfate. The product obtained was subjected to preparative thin-layer chromatography on silica gel (methanol / ethyl acetate as elution system) after removal of organic solvent. The product was shown to be a mixture of unreacted 3 ', 4'-dehydrovinblastine (VII) and the known compounds 4'-deoxovinblastine (X, R = COOCH3) and 4'-deoxo-4'-epivinblastin (XI, R = COOCH3). The presence of the latter compounds provided unambiguous evidence for the structure of enamine VIII.

Reduction of iminium intermediate (formula VD with 3.5-diethoxvcarbonvl-2.6-dimethvl-4-phenvl-1.4-dihvdropvridin (Hantzch ester analog. Formula IX. Ri = H: Ra = Rs = COOCHpCHa: R? = Rr = CHa: Rd = Phenvfl - alternative synthesis of enamine (formula Villi - (method B1

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-dihydropyridine (264 mg, 8 equivalents) placed in ethanol (12 ml) under a positive atmosphere of argon. The reaction mixture was heated under reflux for 3 hours. After this time, alternating phase HPLC analysis (as described above) among other products showed the formation of enamine VIII and 3 ', 4'-dehydrovinblastine (VII) in a 1: 1 ratio (60% yield).

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CH 675 724 A5

Synthesis of vinblastine (formula I) by oxidation of enamine (formula Villi to iminium intermediate) (formula XVIi with flavin mononucleotide (FMN. Formula XII. R = POa2-] - Method 1.

To a stirred reaction mixture containing the enamine (VIII) obtained as described above (Method A) from Iminium VI (100 mg) ", FMN (80 mg, 1 equivalent) was dissolved in Tris-HCl buffer (2 ml) under a positive atmosphere of argon was added and the solution was kept in the dark at room temperature (20 ° C.) for 16 hours, after which time the inert atmosphere of argon was replaced by air and the reaction mixture was stirred for a further 2.5 hours Analyzes showed conversion of enamine VIII to the iminium intermediate XVI and also to other products (see below). Sodium borohydride (500 mg) was added at 0 ° C and the reaction mixture was made basic with NH4OH and with ethyl acetate (3 x 200 ml), the combined organic extract was dried over magnesium sulfate and the solvent was 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%), catharin (Formula XVIII, 7 mg, 7.5%); Vinamidine (Formula XIX, 5 mg, 5.6%) and the reduction product of Vinamidine (Formula XX, 19 mg, 20%).

Synthesis of vinblastine (Formula Ii by oxidation of the enamine (Formula Villi with hydrogen peroxide to give the iminium intermediate (Formula XVIi - Method 2.

To a solution containing the enamine (VIII) obtained from iminium intermediate VI (100 mg, method 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 alternating phase HPLC analyzes showed complete conversion of enamine VIII. Sodium borohydride (500 mg) was added at 0 ° C 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) and gave the following dimeric alkaloids: vinblastine (I, 4 mg, 4%), 3 ', 4'-dehydrovinbiastine (VII, 5 mg, 4 , 8%), leurosine (XVII, 13 mg, 12.5%), catharin (XVIII, 5 mg, 4.8%) the reduced form of vinamidine (XX, 30 mg, 27.6%).

Synthesis of Vinblastine (Ii by Oxidation of the Enamine (Villi with Air to the Iminium Intermediate Product (Formula XVIi - Method 3

A solution containing the enamine (VIII) obtained from the iminium intermediate (VI, 100 mg) by Method A was stirred in the open air at room temperature for 3 hours. At the end of this time, sodium borohydride (500 mg) was added at 0 ° C, and the reaction mixture was 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 removed by preparative thick layer chromatography (silica gel, methanol / ethyl acetate) and gave vinblastine (I), 4 mg, 4%).

Synthesis of vinblastine (Ii by oxidation of the enamine (formula Villi with air in the presence of egg sendlli chloride to the iminium intermediate (XVIi - Method 4

To a stirred solution containing the enamine (VIII) obtained from the iminium intermediate (VI, 100 mg, method A), iron (! Ll) chloride (1 equivalent) was added and air through the solution at 0 ° C bubbled over a period of 0.5 hours. Sodium borohydride (500 mg) was added at 0 ° C and the reaction mixture was basified with NH4OH before extraction with ethyl acetate (3 x 100 ml). The combined organic extract was dried over Na2SÛ4 and the solvent was removed in vacuo. The crude product was purified by thick layer chromatography (silica gel, methanol / ethyl acetate) to provide vinblastine (I, 37 mg). Based on the enamine (50 mg) present in the mixture, the yield in this step was 70%.

Claims (7)

Claims 1. Process for the preparation of compounds of formula XXI 12 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 675 724 A5 where R XXI XXII or XXIII can be, where in formula XXI alk = CH3 or (CH2) nCH3 with n = 1-5 Ri = CHs or CHO R2 = H or CO-alk Rs = H R4 = COO-alk or CONR13 R14, where R13 and R14 can be any member from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or benzyl group, Z = -CH = CH- or -CH2-CH2- and in the formulas XXII and XXIII the substituents have the following meaning: R7 = H or COO-alk Ra = H, OH, O-alk, OCO-alk or alkyl Rg = H, OH, O-alk, OCO-alk or alkyl R10 = H, OH, O-alk, OCO-alk R11 = H or COO-alk R12 = H or alkyl, the method being used for the synthesis of a dimer consisting of an indole unit of the natural ibogaalkaloid family, which contains an aza-bicyclo-octane section, and a dihydroindole unit of the natural aspidosperma and vinca Alkaloid families is derived, the stereochemistry of the carbon-carbon bond between these two units being identical to that of vinblastine, characterized in that (a) an N-oxide intermediate of formula IIa IIa is formed at a temperature of -70 ° C to + 40 ° C by the indole unit by oxidizing the bridge nitrogen and without isolating the intermediate product; (b) treating the N-oxide-indole intermediate in the presence of a member from the group consisting of acetic anhydride, halogenated acetic anhydride and acetyl chloride to cause fragmentation of the Cs-Cis bond of the indole-Nb-oxide intermediate ; 13 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 675 724 A5 (c) without isolating the product from step (b) the reaction product is coupled to a dihydroindole unit in the presence of acetic anhydride, halogenated acetic anhydride and acetyl chloride at a low temperature of -70 ° C to + 40 ° C under inert conditions; (d) isolating the product from step (c) by solvent evaporation at -20 ° C to 0 ° C; (e) the product of step (d) is reduced by 1,4-dihydropyridine compounds represented by Formula IX, Are group consisting of H, alkyl, aryl or N-substituted 1,4-dihydronicotinamides, where Ri can be a substituted alkyl or benzyl group, this reduction under an inert atmosphere at -60 ° C to + 60 ° C below Using solvents selected from a member of the group consisting of lower alkylalkanols, acetonitrile, dimethyl sulfoxide, dimethyiformamide, dioxane, tetrahydrofuran and chlorinated lower hydrocarbons; (f) the product of step (e), an enamine of Formula VIII isolated by solvent evaporation at a temperature of from -20 ° C to 0 ° C; (g) the enamine obtained in step (f) is used to produce an iminium intermediate of the formula XVI by an oxidation process, the oxidation process (a) controlled ventilation / oxidation in open air; (b) controlled aeration / oxidation plus a metal ion; (c) controlled aeration / oxidation plus a flavin coenzyme and (d) Controlled aeration / oxidation plus a treatment agent selected from hydrogen peroxide and hydroperoxides, with a wide range of organic solvents 14 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 675 724 A5 is applied at pH 5 to 9 and a reaction temperature of -60 ° C to + 60 ° C; (h) isolating the product, an iminium intermediate obtained in step (g) by solvent evaporation, at -20 ° C to 0 ° C and (i) the product obtained in step (h) is converted into the target compound of the formula XXI by reduction with alkali metal borohydride. 2. The method according to claim 1, characterized in that a 1,4-dihydropyridine compound is used in process section (e), in which Ri is a substituted alkyl or benzyl group and R3 CONR7R8, where R7 and Rs can be any member of the group , which consists of hydrogen, alkyl or benzyl groups. 3. The method according to claim 1, characterized in that it, including the end product of formula XXI, is carried out in a one-container operation. 4. The method according to claim 1, characterized by the step of isolating an enamine and oxidizing this enamine to an iminium intermediate, formula XVI, by an oxidation process, namely by (a) controlled ventilation / oxidation in open air; (b) controlled aeration / oxidation plus a metal ion; (c) controlled aeration / oxidation plus a Falvin coenzyme. 5. The method according to claim 4, characterized by the step in which in the oxidation process step (a) a treatment agent is added, which is selected from hydrogen peroxide and hydroperoxides. 6. The method according to claim 1, characterized in that the iminium intermediate isolated by solvent evaporation at a low temperature in the range from -20 ° C to 0 ° C to a vinca alkaloid selected from vinblastine and vincristine by reduction with alkali metal borohydride is reduced. 7. Compound according to formula VIII vmdoHn as an intermediate in the process according to claim 1. 15