FR2472571A1 - PROCESS FOR THE PREPARATION OF HALOGENO-VINCAMINIC AND HALOGENO-APOVINCAMINIC ESTERS DERIVATIVES - Google Patents

Abstract

Halovincaminic acid and haloapovincaminic acid ester derivatives of the formulae and in which R<1> and R<2> denote alkyl having 1-6 carbon atoms, and X denotes halogen, are prepared in accordance with the processes defined in the patent claims.

Description

dans lesquelles R1 et -R2 représentent des groupes alkyles de 1 à 6 atomes de carbone et X représente un halogène, leurs sels formés par addition avec des acides acceptables pour l'usage pharmaceutique et leurs antipodes optiques, ce procédé étant caractérisé en ce que l'on traite un dérivé halogéné d'hydroxy-oxo-E-homo-éburnane répondant à la formule générale

dans laquelle R2 et X ont les sgnimications indiquées ci-dessus, ou ses épimères, antipodes optiques ou sels formés par addition avec des acides, par un agent oxydant et on fait réagir le dérivé hélogéné de dioxo-ehomo-ébur- nane ainsi obtenu, qui répond à la formule générale

dans laquelle R2 et X ont les significations indiquées cidessus, ou le cas échéant le dérivé d1hydroxyimino-oxo-é- burnane formé après réaction avec l'hydroxylamine ou un sel d'hydroxylamine, qui répond à la formule générale

dans laquelle R2 et X ont les significations indiquées ci-dessus, ou ses sels formés par addition avec des acides, le cas échéant après résolution, avec un alcanol répondant à la formule générale R1-OH dans laquelle R1 a les significations indiquées ci-dessus, en présence d'un agent alcalin, après quoi, si on le désire, on traite le dérivé d'ester halogéno-vincaminique formé, qui répond à la formule générale Ia dans laquelle R1, R2 et X ont les signification! indiquées ci-dessus, par un acide approprié à la formation de sels acceptables pour l'usage pharmaceutique, et/ou le résout ou on l'hydrolyse, et on fait réagir le dérivé d'acide halogéno-vincaminique obtenu, qui répond à la formule générale

dans laquelle R2 et X ont les significations indiquées cidessus, ou le dérivé dthydroxyimino-oxo-E-éburnane de formule générale IV dans laquelle R2 et X ont les significations indiquées ci-dessus, ou un sel de ce composé formé par addition avec un acide, si on le désire après résolution, avec un alcool de formule générale R1 -OH - dans laquelle R1, R2 et X ont les significations indiquées cidessus - en présence d'un acide concentré déshydratant, et, si on le désire, on traite le dérivé d'ester halogénoapovincaminique obtenu, qui répond à la formule générale Ib dans laquelle R1, R2 et X ont les significations indiquées ci-dessus, par un acide approprié à la formation de sels acceptables pour l'usage pharmaceutique, et/ou on le résout.The present invention relates to a new process for preparing the halogeno-vincaminic and halogeno-apovincaminic ester derivatives corresponding to the general formulas.

in which R1 and -R2 represent alkyl groups of 1 to 6 carbon atoms and X represents halogen, their salts formed by addition with acids acceptable for pharmaceutical use and their optical antipodes, this process being characterized in that 'treating a halogenated derivative of hydroxy-oxo-E-homo-eburnan corresponding to the general formula

in which R2 and X have the meanings indicated above, or its epimers, optical antipodes or salts formed by addition with acids, by an oxidizing agent and the helogenic derivative of dioxo-ehomo-eburan thus obtained is reacted, which responds to the general formula

in which R2 and X have the meanings indicated above, or where appropriate the hydroxyimino-oxo-e-burnane derivative formed after reaction with hydroxylamine or a hydroxylamine salt, which corresponds to the general formula

in which R2 and X have the meanings indicated above, or its salts formed by addition with acids, optionally after resolution, with an alkanol corresponding to the general formula R1-OH in which R1 has the meanings indicated above , in the presence of an alkaline agent, after which, if desired, the halogen-vincaminic ester derivative formed is treated, which corresponds to the general formula Ia in which R1, R2 and X have the meanings! indicated above, with an acid suitable for the formation of pharmaceutically acceptable salts, and / or it is resolved or hydrolyzed, and the resulting halo-vincaminic acid derivative is reacted, which corresponds to the general formula

in which R2 and X have the meanings indicated above, or the hydroxyimino-oxo-E-eburnan derivative of general formula IV in which R2 and X have the meanings indicated above, or a salt of this compound formed by addition with an acid , if desired after resolution, with an alcohol of the general formula R1 -OH - in which R1, R2 and X have the meanings indicated above - in the presence of a dehydrating concentrated acid, and, if desired, the halogenoapovincaminic ester derivative obtained, which corresponds to the general formula Ib in which R1, R2 and X have the meanings indicated above, by an acid suitable for the formation of salts acceptable for pharmaceutical use, and / or it is solves.

In formulas Ia and Ib, R1 and R2 represent straight or branched chain alkyl groups of 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, npentyl, iso-pentyl, n'hexyl or iso-hexyl.

The halogen referred to in formulas Ia and Ib can consist of a fluorine, chlorine, bromine or iodine atom.

The X substituent of formulas Ia and Ib can be attached to any carbon atom of the ben zene ring, but the process according to the invention is preferably used to prepare 9, 10- and il-ha-logeno-ester derivatives. vincamines.

The compounds corresponding to the general formula Ia, which are known, exhibit interesting pharmacological activity; they are suitable for use in the treatment of abnormal behaviors resulting, with age, from the degradation and calcification of the vessels of the brain, for the treatment of disturbances of consciousness caused by head trauma, and for the stimulation of mental capacity and freshness of mind.

Some of the compounds of general formula Ia have been previously described in FRG patent No. 2,458,164. According to this patent, a mixture of 17-halo-vincamine and 11-halo-apovincamine is prepared by acid cleavage of the ester. 3- (1-ethyl-1 0-halo-octahydro-indolo-quinolizine-i -yl) -2-methoxy-propenoSque acid methyl. After the reaction, the 11-halogenovincamine must still be isolated from the mixture. The starting material is prepared from the corresponding halotryptamine and the diacetal of the ethyl ester of the acid -aldehyde (pt oluene-sulfonyloxy) - propa-1 -y7- malonic by a synthesis in five stages of operation, passing through complicated intermediates. According to the same patent, for example 11-bromovincamine is obtained by bromination of vincamine which also has pharmacological interest but no yield is indicated; according to the applicant's tests, this yield is not sufficient: it is 35%.

The compounds corresponding to the general formula Ib also exhibit an interesting pharmacological activity: anti-hypoxemic and protective activity of the brain.

The compounds corresponding to the general formula Ib in which R2 represents the ethyl group, X a bromine atom, those for which X is a bromine atom fixed in position 10 or i1 of the ring, R1 representing an ethyl or n-butyl group and those for which X represents a bromine atom fixed in position 9 of the ring, R1 representing the n-butyl group, are known; all the other compounds corresponding to the general formula Ib are new.

The preparation of the known compounds is described in European Patent Application No. 1940. According to the description of this patent application, the corresponding vincaminic ester is brominated, giving a mixture of esters 9-, 10- and 71-. bromo-vincamines. The individual isomers are then isolated from the mixture and the water is removed with formic acid. No indication of performance is given. From an industrial point of view, the process has significant drawbacks. On bromination, we do not obtain a single product but a mixture of isomers. This mixture must still be subjected to all the separation operations. As a result, the yield of the individual isomers is obviously much lower than if a single isomer were formed. And upon dehydration with formic acid, the separation of the product from the reaction mixture still presents difficulties.

In accordance with the invention, the compounds corresponding to the general formulas Ia and Ib can be obtained from starting products which are themselves easy to prepare, passing through simple intermediates and in two stages of synthesis of an implementation simple, with good yields and in good states of purity.

The compounds corresponding to the general formula II also have pharmacological activity: they have vasodilator activity and can be prepared in a simple manner with good yields.

The starting compounds corresponding to the general formula II in which X is fixed in position 9 or II of the ring system can be obtained by direct halogenation of the corresponding unsubstituted 14-oxo-15-hydroxy-E-homo-eburnan derivative (application Hungarian Patent Publication No. RI-721).

The starting compounds corresponding to the general formula II in which X is fixed in position 10 of the ring system can be obtained by alkali treatment of 9-halo-1 - (2-hydroxy-2-alkoxycarbonyl-ethyl) -octahydro -indolo, 3-a7 quinolizine corresponding (Hungarian patent application published under No. RI - 723).

Compounds of general formula II can be oxidized using any oxidizing agent capable of converting the hydroxy group at position 15 to an oxo group without undesirable modification elsewhere in the molecule. Among the oxidizing agents which are suitable, mention may be made of manganese dioxide, silver carbonate deposited on Celite, chromium trioxide and others.

Preferably, for the oxidation of the compounds of general formula II, an active oxidizing agent deposited on a support with a large surface area, itself inactive in the reaction, for example Celite, is used and the oxidizing agent is preferably active manganese dioxide (Tetrahedron 33, 1803 (1979)).

The manganese dioxide is preferably used in an amount of 8 to 10 times and more particularly 10 times the amount of the starting material.

The oxidation of the compounds of general formula II is carried out in an inert apolar aprotonic organic solvent which does not participate in the reaction. Among these solvents, there will be mentioned optionally halogenated aliphatic hydrocarbons such as chloroform, dichloromethane, etc., aromatic hydrocarbons such as toluene, xylene, etc., cyclic ethers such as dioxane, tetrahydrofuran, etc.

The oxidation is carried out at a temperature of 20 to 500C and preferably at room temperature.

For the reaction of the compounds of general formula III formed by oxidation with hydroxylamine, the latter is preferably used in the form of a salt, for example as a hydrohalide, inter alia the hydrochloride.

The reaction is advantageously carried out in a 3 to 5-fold excess of hydroxylamine.

The formation of oxime using hydroxylamine is carried out in an inert organic solvent. Since in the course of the reaction there is not only the formation of water but also the release of an acid, it is recommended to add an acid-binding agent to the reaction mixture. For example, trialkylamines such as triethylamine can be used. It is also possible to use a solvent which, because of its basic properties, is capable of fixing the acid released. Pyridine, for example, constitutes such a solvent.

The reaction with hydroxylamine is carried out hot, at a temperature of 80 to 1100C.

Compounds corresponding to the general formula
III or IV are reacted with an alcohol of general formula R1 -OH in which R1 corresponds to the ester group to be introduced into the molecule, in the presence of an alkali agent, preferably an alkali metal tert-alcoholate such as tert -Lithium, potassium or sodium butoxide.

The compounds corresponding to the general formula Ia are hydrolyzed with the aid of an inorganic base, for example an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, in a solution of a C1-C6 alkanol.

The compounds of general formula IV or V are reacted with an alcohol of general formula R1 -OH in which R1 corresponds to the ester group to be introduced into the molecule, in the presence of a dehydrating concentrated mineral acid, for example sulfuric acid concentrate, polyphosphoric acid, etc., or anhydrous oxalic acid, etc.

The treatments of the reaction mixture in any phase of the operations and the isolation of the final product can be carried out according to known techniques and which depend on the nature of the starting components, of the final product, of the solvent, etc .; thus, for example, when, at the end of the reaction, the product precipitates. The precipitate can be separated by filtration, if, on the other hand, the product remains in solution, it can be isolated advantageously by concentrating in vacuo.

The dry residue is then crystallized from a suitable inert organic solvent. The solvent is chosen as a function of the dissolution and crystallization properties with respect to the substance to be crystallized.

To isolate the reaction product from the reaction mixture, one can also operate by extracting the product with an inert organic solvent such as dichloromethane, dichloroethane, etc., followed by drying and evaporation of the organic solution and, where appropriate, crystallization of the residue. The desired product can also be precipitated from the reaction mixture by adding an inert organic solvent such as ether, the substance then being isolated by filtration.

The compounds of formulas Ia and Ib can be reacted with acids which give salts formed by addition and which are acceptable for pharmaceutical use.

For the formation of the salts, the following acids can be used, for example: mineral acids such as halogenated hydracids, in particular hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perhalogenated acids such as perchloric acid, etc .; organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric, succinic, tartaric, ascorbic, citric, malic, salicylic acids, lactic, cinnamic, benzoic, phenylacetic, p-aminobenzolque, p-hydroxybenzolque, p-aminosalicylic etc., alkanesulphonic acids like methanesulphonic acid, ethanesulphonic acid, etc., cycloaliphatic sulphonic acids and for example cyclohexylsulfonic acid, arylsulfonic acids and for example p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, etc., amino acids and for example aspartic acid, l glutamic acid, N-acetyl-aspartic acid, N-acetyl-glutaric acid, etc.

The formation of the salt is carried out in an inert organic solvent, for example an aliphatic alcohol containing from 1 to 6 carbon atoms, by dissolving the racemic or enantiomeric compounds of formula Ta or Ib in this solvent and adding the acid, as it is. or in the same solvent, until moderate acidity of the mixture, (up to pH 5 to 6). The salt formed by the addition and which precipitates can be separated from the mixture by a simple technique, for example by filtration.

The racemic compounds corresponding to the general formulas Ia and Ib are resolved by known techniques, but it is also possible to use as starting components optical isomers of the compounds of general formula II.

The optical isomers and racemates of the compounds corresponding to the general formulas Ia and Ib and their salts formed by addition with acids can, when desired, be subjected to other purification operations, for example to recrystallization. The nature of the solvent to be used for the recrystallization depends on the possibilities of dissolution and crystallization of the substance to be crystallized. Aliphatic alkanols containing 1 to 6 carbon atoms, acetonitrile, etc. can be used.

The process according to the invention makes it possible to prepare the compounds corresponding to the general formulas Ia and Ib in an identifiable form. Infra-red spectra and mass spectrum values unequivocally confirm the structure of compounds.

The examples which follow illustrate the invention without, however, limiting its scope; in these examples, the indications of parts and percentages are understood to be by weight unless otherwise specified.

Example 1
9-bromo-14.75-dioxo-E-homo-eburnan (3 alpha, 17 alpha)
To a solution of 0.25 g (0.62 mmol) of 9 bromo-14-oxo-15-hydroxy-4-homo-eburnan (3 alpha, 17 alpha) in 10 ml of anhydrous dichloromethane is added 2.0 g of active manganese dioxide (Merck) and the reaction mixture is stirred at room temperature for 3 h. The solid part of the suspension is filtered and washed three times with 3 ml of anhydrous dichloromethane. The filtrate is combined with the washing liquid and concentrated in vacuo. The oily residue is crystallized from 3 ml of ether. 0.13 g of the desired product is obtained in crystallized form from 3 ml of ether.

0.13 g of the desired product is obtained in the crystalline state and melting at 135 ° -1370 ° C., which corresponds to a yield of 52.3%.

empirical formula: C20H21N2o2Br (mol weight
cular: 401.31) IR spectrum (KBR): [# max 1730 cm-

1695 cm- (amide CO)] mass spectrum: (m / e): (402, 401, 400, 399,
387, 385, 375, 373, 371, 359,
357, 346, 344, 331, 329, 317,
315, 277, 275, 180, 167, 153,
140.)
Example 2
9-bromo-vincamine
0.12 g (0.3 mmol) of 9-bromo-1,4, 15-dioxo-E-homo-eburnan (3 alpha, 17 alpha) is dissolved at 400C in 5 ml of anhydrous methanol, it is added to the mixture. solution of 10 mg of potassium tert-butoxide and the mixture is left to stand for 2 h at room temperature. The mixture is then neutralized to pH 7 with glacial acetic acid and concentrated in vacuo. 15 ml of a 5% aqueous sodium bicarbonate solution is added to the residue and the mixture is extracted three times with 10 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo. The oily residue is crystallized from 2 ml of methanol.

0.074 g of the desired compound is obtained in the state of white crystals, melting at 210-2110C, which corresponds to a yield of 57.1%.

Empirical formula: C21H25N203Br (mol weight
cular: 433.35)
RR spectrum (KBR): s max 1740 cm

Mass spectrum: (m / e): 434, 432, 419, 417,
375, 373, 345, 332, 330, 317,
315, 266, 195, 180, 167, 175.)
Example 3
(+) - 9-bromo-1 4,1 5-dioxo-E-homo-eburnan (3 alpha, 17 alpha)
To a solution of 0.65 g (1.36 mmoles) of (+) 9-bromo-14-oxo-13-hydroxy-E-homo-eburnan (3 alpha, 17 alpha) in 40 ml of absolute dichloromethane, one 4.9 g of active manganese dioxide (Merck) is added and the reaction mixture is stirred at room temperature for 1 hour 30 minutes. The solid part of the suspension is filtered, washed three times with 5 ml of anhydrous dichloromethane and the combined filtrates are concentrated in vacuo. The oily residue is crystallized from 5 ml of ether.

0.324 g of crystalline product is obtained, melting at 64-650C, ie a yield of 59.1%.

Empirical formula: C20H21BrN20 (molecular weight
401.31)
IR spectrum (KBR): [# max 1725 cm 1

1965 cm- (C = P of amide)] Optical rotation: [&alpha;]## = + 71.4 (c = 1 in the
dichloromethane)
Example 4
(+) - 9-bromo-vincamine hydrochloride
0.33 g (0.82 mmol) of (+) - 9-bromo-14, 15-dioxo-E-homo-eburnan (3 alpha, 17 alpha) is dissolved in 15 ml of anhydrous methanol, one adds to the mixture. solution 30 mg of potassium tert-butoxide and the reaction mixture is stirred for 2 h at room temperature. The mixture is then neutralized with glacial acetic acid to pH 7 and concentrated in vacuo. 45 ml of a 5% aqueous sodium bicarbonate solution are added to the residue and the basic solution is extracted with 15, 10 and 5 ml of dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate. Filter and concentrate the filtrate in vacuo. The oily residue is crystallized from 10 ml of methanol saturated with hydrochloric gas.

0.21 g is obtained, ie a yield of 54.4% of white crystalline product, melting at 223-225 C.

Rotation optique : [&alpha;]## = + 14,8 (c = 1,52 de
D = + 14,80 (c = 1,52 de
la base libre dans le chloroforme
Exemple 5
10-bromo-14,15-dioxo-E-homo-éburnane (3 alpha, 17 alpha)
A une solution de 0,25 g (0,62 mmole) de 10-bromo 14-oxo-15-hydroxy-E-homo-éburnane (3 alpha, 17 alpha) dans 15 ml de dichlorométhane anhydre on ajoute 2,0 g de bioxyde de manganèse actif (Merck) tel quel ou déposé sur 4,1 g de
Celite et on agite le mélange à température ambiante pendant 7 h. On filtre la partie solide de la suspension, on lave avec 10 ml de dichlorométhane anhydre et on concentre les filtrats combinés sous vide. On cristallise le résidu solide dans 5 ml d'éther.Empirical formula: C21H26BrClN203 (molecular weight
width 469.82) IR spectrum (KBR): [# max 1735 cm-1

Optical rotation: [&alpha;]## = + 14.8 (c = 1.52 of
D = + 14.80 (c = 1.52 of
the free base in chloroform
Example 5
10-bromo-14,15-dioxo-E-homo-eburnan (3 alpha, 17 alpha)
To a solution of 0.25 g (0.62 mmol) of 10-bromo 14-oxo-15-hydroxy-E-homo-eburnan (3 alpha, 17 alpha) in 15 ml of anhydrous dichloromethane is added 2.0 g of active manganese dioxide (Merck) as such or deposited on 4.1 g of
Celite and stir the mixture at room temperature for 7 h. The solid part of the suspension is filtered, washed with 10 ml of anhydrous dichloromethane and the combined filtrates concentrated in vacuo. The solid residue is crystallized from 5 ml of ether.

0.15 g is obtained, ie a yield of 60.3% of the desired product in the crystalline state, melting at 172-1730C.

Empirical formula: C20H21BrN202 (molecular weight
401.31)
Infra-red spectrum (KBR): ro max 1705 cm

1765 cm-i (amide CO) 7
Mass spectrum: (m / e): 402, 401, 400, 399, 387,
385, 375, 373, 371, 359,
357, 346, 344, 331, 329,
317, 315, 277, 275, 180,
167, 153, 140.)
From the filtrate, 5% 10-bromovincamine (3 alpha, 16 alpha) can be isolated.

Example 6 i 0-bromo-vincamine
0.20 g (0.5 mmol) of 10-bromo-14,15-dioxo-E-homo-eburnan (3 alpha, 17 alpha) is dissolved in 10 ml of anhydrous methanol at 400 C and added to the solution. 10 mg of potassium tert-butoxide; it is left to stand at room temperature for 2 h.

The reaction mixture is neutralized to pH 7 with glacial acetic acid and concentrated in vacuo. To the solid residue, 15 ml of 5% aqueous sodium bicarbonate solution is added and the basic solution is extracted three times with 10 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is crystallized from 5 ml of methanol.

0.15 g is obtained, ie a yield of 69.5% of the desired product in the form of white crystals, melting at 221-2220C.

Elemental analysis: C21H25BrN203 (molecular weight
laire 433.35)
calculated: C 58.20%; H: 5.81S0; N: 6.46%
found: C 58.15%; H: 5.76%; N: 6.36%
IR spectrum (KBR): max 1750 cm1

s : 6,81 - 7,69 (m, 3H, H aromatique). NMR spectrum (in dentochloroform)
g: 0.88 (t.3H, CH3-CH2-) #: 3.77 (s, 3H,

s: 6.81 - 7.69 (m, 3H, aromatic H).

Mass spectrum (m / e): (434, 432, 419, 417, 375,
373, 345, 332, 330, 317,
315, 266, 195, 180, 167,
115.)
Example 7
11-bromo-14,15-dioxo-E-homo-eburnan (3 alpha, 17 alpha)
To a solution of 0.75 g (1.86 mmoles) of il-bromo-14-oxo-15-hydroxy-E-homo-eburnan (3 alpha, 17 alpha) in 20 ml of anhydrous dichloromethane is added 6.0 g of active manganese dioxide (Merck) and the mixture is stirred at room temperature for 5 h. The solid part of the suspension is filtered, washed with 10 ml of dry dichloromethane and the combined filtrates concentrated in vacuo. The oily residue is crystallized from 10 ml of ether.

0.484 g, ie a yield of 64.9%, of the desired product is obtained in the form of crystals, melting at 171-172 ° C.

Empirical formula -: C20H21N2 2Br (molecular weight
401, 31).

IR spectrum (KBR): [# max 1725 cm 1

Mass spectrum: (m / e): (402, 401, 400, 399, 387,
385, 375, 373, 371, 359,
357, 346, 344, 331, 329,
317, 315, 277, 180, 167,
153, 140.)
Example 8 il -bromo-1 4-oxo-1 5-hydroxyimino-E-homo-eburnan
(3 alpha, 17 alpha)
To a solution of 100 mg (0.25 mmol) of 11-bromo-14,15-dioxo-E-homo-eburnan in 0.5 ml of anhydrous pyridine is added 100 mg (1.42 mmol) of hydrochloride d anhydrous hydroxylamine and the reaction mixture was allowed to stand for 2 h at room temperature. Then poured into 2 ml of ice water and basified to pH 9 with concentrated ammonia.

The product which has precipitated is filtered off, washed with 25 ml of water, dried and crystallized in 2 ml of dichloromethane.

72 mg, ie a yield of 69%, of the desired product are obtained in the form of crystals, melting at 140 145 C.

IR spectrum (KBR):: max 3320 cm 1 (amide CO 7 1630 cm 1

10 mg of the 72 mg of base are dissolved in 1 ml of methanol and the pH of the solution is adjusted to 5 using a methanolic solution of HCl. The crystals which precipitate are filtered off, washed with 1 ml of methanol and dried. 10 mg of the hydrochloride of the above product are obtained, melting at 2570C.

Example 9 Il -bromo-vincamine
0.11 g (0.27 mmol) of 11-bromo-14,15dioxo-E-homo-eburnan (3 alpha, 17 alpha) is dissolved at 400C in 5 ml of anhydrous methanol, 10 mg of tert-butoxide are added potassium and the mixture is left at room temperature for 2 h.

The reaction mixture is neutralized to pH 7 with glacial acetic acid and concentrated in vacuo. 15 ml of a 5% aqueous sodium bicarbonate solution was added to the residue, and the alkaline solution was extracted three times with 10 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo.

The solid residue is crystallized from 2 ml of methanol.

61.5 mg of the desired product are obtained in the form of white crystals, melting at 215-2170C, ie a yield of 51.8%.

Empirical formula: C21H25N203Br (molecular weight
433.35).

IR spectrum (KBR): max 1735 cm1

Mass spectrum (m / e): (434, 432, 419, 417, 375,
373, 345, 332, 330, 317,
315, 266, 195, 180, 167,
115)
Example 10
(+) - 11-bromo-14,15-dioxo-E-homo-eburnan (3 alpha,
17 alpha)
To a solution of 1.0 g (2.48 mmol) of (+) - 11- bromo-14-oxo-15-hydroxy-E-homo-eburnan (3 alpha, 17 alpha) in 70 ml of anhydrous dichloromethane, 9.0 g of active manganese dioxide (Merck) are added and the reaction mixture is stirred for 1 hour 30 minutes. The insoluble part of the suspension is filtered off, washed three times with 10 ml of anhydrous dichloromethane and the filtrates are dried. combined under vacuum. The residue is crystallized from 5 ml of ether.

0.65 g is obtained, ie a yield of 65.3% of the desired product in the state of crystals, melting at 151-1530C.

1685 cm-1

d'amide)7
Rotation optique : ri 7 D5 = +45,00 (c = 1 dans le dichlo
rométhane)
Exemple li (+)" bromo-14-oxo-15-hydroxyimino-E-homo- éburnane (3.alpha, 17 alpha)
A une solution de 100 mg (0,25 mmole) de (+)-11- bromo-14,15-dioxo-E-homo-éburnane (3 alpha, 17 alpha) dans 0,5 ml de pyridine anhydre, on ajoute 100 mg (1,42 mmoles) de chlorhydrate d'hydroxylamine anhydre et on abandonne le mélange de réaction pendant 2 h à température ambiante.Empirical formula: C20H21BrN202 (molecular weight
re 401.31) IR spectrum (KBR): max 1715 cm-1

1685 cm-1

of amide) 7
Optical rotation: ri 7 D5 = +45.00 (c = 1 in the dichlo
romethane)
Example li (+) "bromo-14-oxo-15-hydroxyimino-E-homo-eburnan (3.alpha, 17 alpha)
To a solution of 100 mg (0.25 mmol) of (+) - 11- bromo-14,15-dioxo-E-homo-eburnan (3 alpha, 17 alpha) in 0.5 ml of anhydrous pyridine is added 100 mg (1.42 mmol) of anhydrous hydroxylamine hydrochloride and the reaction mixture was left for 2 h at room temperature.

The pyridic solution is poured into 2 ml of ice-cold water and basified to pH 9 with concentrated ammonia. The amorphous precipitate is filtered off, washed with 5 ml of water and dried. The dry solid product is purified by thin layer chromatography. A 14: 3 mixture of benzene and methanol is used as eluent (silica gel plate PF 254 + 366 in a layer of 20 cm × 1.5 mm). Elution is carried out with a 20: 3 dichloromethane / methanol mixture. After elution, 64 mg of the desired product are obtained in the form of an oil.

This product is dissolved in 1 ml of methanol and the solution is acidified to pH 5 at 0 C with methanol saturated with hydrogen chloride. The salt which has precipitated is filtered off, washed with 1 ml of methanol and dried. 60 mg of the hydrochloride of the above product is obtained, melting at 2350C.

d'amide); 1622 cm-i

IR spectrum (KBR): ro max 3460 cm1 (-OH); 1700 cm-

amide); 1622 cm-i

Optical rotation: ra 7 D) = + 45.60 (in dimethylformamide
Example 12 (+) - 11-bromo-vincamine
0.33 g (0.82 mmol) of (+) - 11-bromo i4,15-dioxo-E-homo-eburnan (3 alpha, 17 alpha) is dissolved in 15 ml of anhydrous methanol and 30 mg of potassium tert-butoxide; the mixture is stirred for 1 hour 30 minutes at room temperature. Neutralized to pH 7 with glacial acetic acid and concentrated in vacuo. 45 ml of a 5% aqueous sodium bicarbonate solution were added to the solid residue and extracted with 15, 10 and 5 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and the filtrate is concentrated in vacuo. The oily residue is crystallized from 3 ml of methanol.

0.19 g is obtained, ie a yield of 53.3% of product in the form of white crystals, melting at 221-2230C.

Empirical formula: C21H25BrN203 (molecular weight
433.35)
IR spectrum (KBR): rO max 1730 cuiT1

Optical rotation: rCn 7 D5 = + 8.40 (c = i in the
chloroform)
Example 13 (+) - 10-bromo-vincamine
1.2 g (26 mmol) of (+) - 10-bromo-14 oxo-15-hydroxyimino-E-homo-eburnan (3 alpha, 17 alpha) are dissolved in 240 ml of glacial acetic acid and added to the solution 24 g of anhydrous p-toluene sulfonic acid and 36 g of paraformaldehyde. The reaction mixture is heated for 3 hours 30 minutes at 110 ° C. in the absence of humidity and the mixture is poured into ice-cold water. The mixture is made alkaline to pH 9 with concentrated ammonia, the (+) - is filtered. 10 bromo-14,15-dioxo-E-homo-eburnan (13 alpha, 17 alpha) which precipitated, washed with water and dried over P205 in an exsiccator. 8.4 g of the desired product is obtained, melting at 1840C (decomposition), [IR spectrum (KBR) 1720 (CO), 1690 cm- (CO amide)], which can be used as it is, without further purification. In the subsequent reaction step, the product is dissolved in 400 ml of dichloromethane, filtered and the solvent removed in vacuo. To the residue is added 40 ml of the solution of 10 g of potassium tert-butoxide in 400 ml of anhydrous methanol. The mixture is heated to 400C and left to stand for 2 h.

The crystals formed are filtered off, washed with a little cold methanol and dried.

3.8 g are obtained, ie a yield of 33% of the desired product, melting at 220-2210C after recrystallization from methanol.

Example 14
(+) - 10-bromo-vincaminic acid
A solution of 2.5 g (5.77 mmol) of the (+) - 10-bromo-vincamine prepared in Example 13 and 3.4 g (i.e. 60 mmoles) is boiled under reflux for 2 h. ) potassium hydroxide in 75 ml of methanol. After cooling, the solution is acidified to pH 6 with glacial acetic acid and crystallized in the refrigerator. The crystals are filtered, washed twice with 10 ml of water and dried.

1.9 g is obtained, ie a yield of 78.5% of (+) - iO-bromo-vincaminic acid in the form of a white crystalline product, melting at 234-2360C.

Empirical formula: C20H23BrN203 (molecular weight
419.32) IR spectrum (KBR): [# max 1635 cm

Example 15
1 O-Bromo-apovincaminic acid ethyl ester hydrochloride
The mixture is refluxed for 10 h in a solution of 1.1 g (2.62 mmol) of the (+) - 10-bromo-vincaminic acid prepared in Example 14 in 40 ml of anhydrous ethanol and 3, 0 ml of concentrated aqueous sulfuric acid. When the reaction is complete, the mixture is concentrated in vacuo.

To the residue, 100 ml of water are added and the solution is basified to pH 10 with 40% sodium hydroxide solution. The alkaline solution is extracted with 50, 45 and 30 ml of dichloromethane, the organic extracts are dried over anhydrous magnesium sulfate and the filtrate is concentrated in vacuo.

The solid residue is redissolved in 5 ml of ethanol and the solution is adjusted to pH 5 with ethanol saturated with gaseous HCl. The acid solution is diluted with 15 to 20 ml of ether; crystals separate. 0.9 g, ie a yield of 73.6%, of (+) - 10-bromo-apovincaminic acid ethyl ester hydrochloride is obtained in the form of a white crystalline product, melting at 221-2230C.

Elemental analysis: C22H26BrClN202 (molar weight
cular 465.83)
calculate: C 56.73%, H 5.63 z6, N 6.01%
found: C 56.58%, H 5.49%, N 5.86%.

1625 cm 1 1605 cm1

IR spectrum (KRr): rg max 1725 cm 1

1625 cm 1 1605 cm1

Example 16
(+) - 9-bromo-apovincaminic acid ethyl ester
3.5 g of (+) -9-bromo-1 4-oxo-1 5-hydroxy-imino- are heated
E-homo-eburnan in a mixture of 70 ml of anhydrous ethanol and 24.5 ml of concentrated aqueous solution of sulfuric acid for 6 h at 900C in a nitrogen atmosphere. The reaction mixture is then basified to pH 9 by adding 25% ammonia. The basic solution is extracted three times with 70 ml of dichloromethane, the organic phase is dried after separation over anhydrous sodium sulfate, filtered and the filtrate is concentrated.

2.5 g are obtained, ie a yield of 75% of the desired product in the form of foamy oil which solidifies and then melts at 76-780C.

Optical rotation: r 7 25 = + 148.80 (c = 1 in the
D
dimethylformamide).

Example 17
(+) - 11-bromo-apovincaminic acid ethyl ester
The procedure is as described in Example 16 but starting with 3.5 g of (+) - 11-bromo-14-oxo15-hydroxy-imino-E-homo-eburnan hydrochloride. 3.0 g of the desired product are obtained in the form of a light yellow oil. 3.0 g of this oil are triturated with 5 ml of ether, the crystals are filtered off and dried.

Yield: 2.1 g, or 65% of ethyl ester of ii-bromo-apovincaminic acid in the form of white crystals melting at 158-1600C.

Optical rotation: rig 25 = + 80.20 (c = 1 in the
dimethylformamide).

Claims (5)

1) Process for the preparation of halogen-vincaminic and halogeno-apovincaminic ester derivatives corresponding to the general formulas

in which R1 and R2 represent alkyl groups of 1 to 6 carbon atoms and X represents a halogen, of their salts formed by addition with acids acceptable for pharmaceutical use and of their optical antipodes, characterized in that one treats a halogenated derivative of hydroxy-oxo-E-homo-eburnan corresponding to the general formula

in which R2 and X have the meanings indicated above, its epimers, optical antipodes or salts formed by addition with acids, by an oxidizing agent, the halogenated dioxo-E-homo-eburnan derivative obtained is reacted, which responds to the general formula

in which R2 and X have the meanings above, or the hydroxyimino-oxo-E-homo-eburnan derivative of the general formula

in which R2 and X have the meanings indicated above, obtained optionally after reaction with hydroxylamine or a salt of hydroxylamine, or its salts formed by addition with acids, optionally after resolution, with an alcohol of general formula R1OH in which R1 has the meanings indicated above, in the presence of an alkaline agent, if desired, the obtained halo-vincaminic ester derivative is treated, which corresponds to the general formula Ia in which R1, R2 and X have the meanings given above, with an acid suitable for the formation of a salt acceptable for pharmaceutical use, and / or it is resolved or hydrolyzed and the halo-vincaminic acid derivative is reacted obtained, which corresponds to the general formula

in which R2 and X have the meanings indicated above, or a hydroxyimino-oxo-E-homo-eburnan derivative of general formula IV in which R2 and X have the meanings indicated above, or a salt of this compound formed by addition with an acid, if desired after resolution, with an alcohol of the general formula R1-OH in which R1 has the meanings given above, in the presence of a dehydrating concentrated acid and, if desired, the halogeno-apovincaminic ester derivative obtained, which corresponds to the general formula Ib in which R1, R2 and X have the meanings indicated above, by an acid suitable for the formation of a salt acceptable for pharmaceutical use, and / or we solve it. 2) Process according to claim 1, characterized in that, for the oxidation of the halogenated derivative of hydroxyoxo-E-homo-eburnan of general formula II in which R2 and X have the meanings indicated in claim 1, is used as active manganese dioxide oxidizing agent. 3) Method according to claim 1, characterized in that the reaction of the halogenated derivative of dioxo-E-homo-eburnan of general formula III and of the hydroxyimino-oxo-E-eburnan derivative of general formula IV, in which R2 and X have the meanings given above, with an alcohol of the general formula R1-OH- in which R1 has the meanings given in claim 1, is carried out in an alkaline medium in the presence of an alkali metal tert-alcoholate. 4) Process according to claim 1, characterized in that the hydrolysis of the halogen-vincaminic ester derivatives of formula Ia in which R1, R2 and X have the meanings indicated in claim 1, is carried out using a solution of an inorganic base, preferably an alkali metal hydroxide, in an alkanol of 1 to 6 carbon atoms. 5) Method according to claim 1, characterized in that the reaction of hydroxyimino-oxo-E-homoéburnane derivatives of general formula IV and halogeno-vincaminic acid derivatives of general formula V in which R2 and X have the meanings indicated above, with an alcohol of general formula R1-OH in which R1 has the meanings indicated above, in the presence of a dehydrating concentrated acid, is carried out in the presence of a concentrated aqueous solution of sulfuric acid.