FR2591225A1 - New process for the preparation of vincamine and its derivatives - Google Patents

Abstract

Process for the preparation of the compounds of formula I: in which Alk means an C1-C4 alkyl group and R represents hydrogen, a halogen, or a hydroxyl, alkyl or alkoxy group. According to the process of the invention, the product obtained by treating a compound of formula II: under acidic and anhydrous conditions, is treated under basic conditions, in the presence of a C1-C4 alkanol in anhydrous medium and then in the presence of water.

Description

 The present invention relates to a new process for the preparation of vincamine and its derivatives.

 Vincamine is an indole alkaloid which has been isolated from the small periwinkle Vinca minor L.

(Apocinaceae family) and which corresponds to formula A

 It has particularly interesting pharmacological properties and is used in therapy, notably as a cerebral vasodilator.

Because of its pharmacological properties, vincamine has been the subject of numerous syntheses (W.DOEPKE in "The Alkaloids, ed. RHF MANSKE and RGA RODRIGO,
Academic Press, New-York, 1981, 20, 297, and ATTA-UR-RAHMAN and M. SULTANA, "Heterocycles", 1984, 22, 841-858).

We have now found a new process for preparing vincamine and its derivatives with good yields.

dans laquelle Alk signifie un groupe alkyle en C1-C4 et
R représente un atome d'hydrogène, un atome d'halogène
ou un groupe hydroxy, alkyle en C1 -C4 ou alcoxy en
C1-C4, et de leurs sels d'addition d'acides, procédé selon lequel on traite sous des conditions basiques ,en presence d'un alcanol en C1 -C4 en milieu anhydre puis en présence d'eau, le produit obtenu en traitant un compose de formule II

dans laquelle R a la signification donnée ci-dessus, sous des conditions acides et anhydres, et on recupare le compose de formule I résultant, sous forme de base ou sous forme d'un sel d'addition d'acide-;
Par halogène, on entend le fluor, le chlore ou le brome.Lorsque R signifie un groupe alkyle ou alcoxy, il s'agit de préference d'un groupe methyle ou methoxy. Le substituant R peut etre situé en position 9, 10, 11 ou 12,de préférence en position 10 ou 11. R signifie de préférence l'hydrogène ou un atome de brome en position 11. Alk signifie de préférence un groupe méthyle.The present invention therefore relates to a process for the preparation of the compounds of formula I

in which Alk signifies a C1-C4 alkyl group and
R represents a hydrogen atom, a halogen atom
or a hydroxy group, C1-C4 alkyl or alkoxy in
C1-C4, and their acid addition salts, process according to which the product obtained by treating under basic conditions, in the presence of a C1 -C4 alkanol in an anhydrous medium and then in the presence of water a compound of formula II

in which R has the meaning given above, under acidic and anhydrous conditions, and the resulting compound of formula I is recovered, in the form of the base or in the form of an acid addition salt;
Halogen means fluorine, chlorine or bromine. When R signifies an alkyl or alkoxy group, it is preferably a methyl or methoxy group. The substituent R may be located in position 9, 10, 11 or 12, preferably in position 10 or 11. R preferably means hydrogen or a bromine atom in position 11. Alk preferably means a methyl group.

 The process of the invention can be carried out according to known methods. Treatment under basic conditions can be carried out using an inorganic or organic base, for example an alkali metal hydroxide such as sodium or potassium hydroxide, a basic salt such as sodium carbonate or potassium, or an alkali metal alcoholate such as sodium methylate. As a base, preferably sjum carbonate is used.

The base is used in excess, advantageously e "an excess representing from 3 to 10 times the theoretical molar quantity, preferably 6 times the theoretical molar quantity, relative to the compound of formula II subjected to the treatment under acid conditions. We operate in the presence an anhydrous C1-Ca alkanol, preferably methanol, optionally mixed with anhydrous tetrahydrofuran.

After reaction in the presence of the alkanol, the reaction mixture is then treated according to known methods with water, for example by washing. All the operations are advantageously carried out at a temperature between 0 and room temperature, preferably at room temperature.

The starting products involved in the
process of the invention are obtained by treating according to
known methods a compound of formula II
under acidic and anhydrous conditions. The treatment can be carried out using a mineral or organic acid such as hydrochloric acid, camphosulfonic acid or p-toluenesulfonic acid, preferably hydrochloric acid. The operation is carried out in an anhydrous organic solvent and advantageously at a temperature between room temperature and the boiling point of the reaction mixture, preferably at the boiling temperature of the reaction mixture. As solvent, a hydroxylated organic solvent and / or anhydrous aprotic, such as a lower alkanol or tetrahydrofuran, preferably a lower alkanol, for example a C1-C4 alkanol such as methanol, optionally mixed with tetrahydrofuran. Advantageously, the procedure is carried out in the same medium as that used for the treatment under basic conditions, that is to say in a C1-C4 alkanol, preferably in methanol or a mixture of methanol and tetrahydrofuran.

The treatment under the acid conditions is preferably carried out in hydrochloric methanol obtained by addition at low temperature, preferably at OC, of acetyl chloride to anhydrous methanol.

 According to a preferred variant of the process of the invention, the treatment under acidic conditions and the treatment under basic conditions are carried out successively in the same reaction medium, without prior isolation of the compound obtained by treatment of the compound of formula II under acidic conditions .

For example, the compound of formula II is treated under acidic conditions as defined above, the reaction mixture is cooled to ambient temperature and, without isolating the product obtained, the reaction medium is then treated under basic conditions such as defined above, for example by adding the base directly, then with water.

où Alk signifie un groupe alkyle en C1 -C4, de preférence un groupe méthyle et YO signifie l'anion de l'acide, par exemple C1 dans le cas de l'acide chlorhydrique.In all likelihood, the preparation of the compounds of formula I from the compounds of formula II takes place according to the following reaction mechanism:

where Alk signifies a C1-C4 alkyl group, preferably a methyl group and YO signifies the anion of the acid, for example C1 in the case of hydrochloric acid.

In accordance with the above, the invention also relates to a process for the preparation of the compounds of formula I comprising a) the cyclization of a compound of formula V, such as
specified above, or b) hydrolyzing a compound of formula IV, such as
specified above, and cyclization of the compound obtained,
or c) the treatment of a compound of formula III, such as
specifies above, under basic conditions,
in the presence of a C1-C4 alkanol in an anhydrous medium
then in the funny presence
Processes a), b) and c) can be carried out according to known methods, for example under the same conditions as those indicated above.

The cyclization of the compound of formula V can be carried out, for example, in a neutral, basic or acid medium, preferably in a basic medium as described above.

 The compounds of formula I thus obtained can then be isolated and purified according to the usual methods. The compounds of formula I can be converted into their acid addition salts according to the usual methods, and vice versa.

 The compounds of formula I other than vincamine, that is to say the compounds of formula I in which R has a meaning other than hydrogen, are known and are described, for example, in German patent application No. 2,458,164.

 The compounds of formula II used as starting materials are new compounds.

They are part of the present invention as well as their preparation process.

dans laquelle
R a la signification donnee ci-dessus avec un isocyanoacétate d'alkyle inférieur en présence d'une base dans un solvant aprotique. In accordance with the invention, to prepare the compounds of formula II, a compound of formula VI is condensed

in which
R has the meaning given above with a lower alkyl isocyanoacetate in the presence of a base in an aprotic solvent.

 The condensation of the compounds of formula VI with the alkyl isocyanoacetate can be carried out according to known methods. As the lower alkyl isocyanoacetate, a C1-C4 alkyl isocyanoacetate is advantageously used, preferably methyl isocyananoacetate. As a base, an alkali metal alcohol can be used, for example a lithium, sodium or potassium alcoholate, such as sodium methylate or tert. potassium potassium butylate, or a hard friend such as lithium diisopropylamide or lithium hexamethyl disilylanide. Preferably, potassium tert.-butoxide is used as the base. The aprotic solvent may be a cyclic or open-chain ether such as diethyl ether or tetrahydrofuran, dinethylformamide or a hydrocarbon such as benzene. As the aprotic solvent, tetrahydrofuran is preferably used. It is advantageous to operate at low temperature, for example between -70 and 09, and under an inert atmosphere, for example under an argon or nitrogen atmosphere.

 The compounds of formulas II thus obtained can then be isolated and purified according to known methods. According to a variant of the process of the invention, the resulting reaction mixture is directly treated under acidic then basic conditions, without isolating the intermediate product of formula II obtained.

The starting product of formula VI in
which R represents hydrogen, is described
for example in Helv. Chim. Acta 1977, 60, page 1801.

dans laquelle R a représente un atome d'halogène ou un groupe hydroxy,
alkyle en C1 -C4 ou alcoxy en C1-C4 sont des composes nouveaux et font partie de la présente invention.The compounds of formula VIa

in which R a represents a halogen atom or a hydroxy group,
C1-C4 alkyl or C1-C4 alkoxy are new compounds and form part of the present invention.

dans laquelle
R a la signification donnée précédemment,
a avec un composé de formule VIII

dans laquelle
X représente un atome de brome ou d'iode. On opère comme décrit dans la demande de brevet allemand citée précédemment.They can be obtained according to known methods or in a similar manner to that described in German patent application No. 2318329, for example by reacting a compound of formula VII

in which
R has the meaning given above,
a with a compound of formula VIII

in which
X represents a bromine or iodine atom. The procedure is as described in the German patent application cited above.

qui peut etre obtenue sous forme racémique ou sous forme
d'un énantiomère pur D'après cette synthèse, le composé de formule B est ensuite transforme en vincamine selon une séquence de réactions comprenant 6 étapes.Among the total syntheses of vincamine, the synthesis described by W. Oppolzer et al. in
Helv. Chim. Acta 1977, 60, 1801, uses, as intermediate compound, indoloquinolizidine.de formula B

which can be obtained in racemic form or in
of a pure enantiomer According to this synthesis, the compound of formula B is then transformed into vincamine according to a sequence of reactions comprising 6 steps.

However, this process has the drawback of supplying vincamine with low yields, the overall yield of this transformation being approximately 6%. The process of the invention surprisingly makes it possible to prepare vincamine and its derivatives from an indoloquinolizidine in only two steps and even in one step, with an overall yield of 45% or 61%.

 The following examples illustrate the present invention without in any way limiting its scope. In these examples, the temperatures are given uncorrected and are indicated in degrees Celsius.

Example 1 a) Preearation of the compound of formula II in which
R = H
To a solution of 0.295 g (2.63 mmol) of potassium tert.-butoxide in 5.7 ml of anhydrous tetrahydrofuran, 0.174 g (0.159 ml, 1.75 mmol) is added to 10 and under an argon atmosphere. 'methyl isocyanoacetate. After allowing the mixture to stand for 10 minutes at 100, the reaction mixture is cooled to -70 and 0.239 g (0.846 mmol) of the aldehyde of formula VI (R = H) is added to 5 ml of tetrahydrofuran. The reaction mixture is gradually brought to 0, it is kept for 10 minutes at this temperature and 20 ml of a 10% aqueous solution of sodium carbonate are added. The reaction mixture is then extracted 3 times with 50 ml of ether each time, the organic phase is washed with water, dried over MgSO 4, filtered and evaporated in vacuo. 0.251 g (0.72 mmol) of the compound of formula II is thus obtained in which R signifies hydrogen (yield = 85%). Rf = 0.5 (silica gel, hexane / ethyl acetate system 50:50).

NMR spectrum (400 MHz) X = Oppm (TMS): 8.50 (d, 1H, J = 7Hz) C12-H; 8.38 (s, 1H) CHO; 8.25 (sl, 1H)
NHCO; 7.65 (s, 1H) C17-H; 7.39 (d, 1H, J = 7 Hz) Cg-H; 7.32 (dd, J = 7Hz, 1H) and 7.27 (dd, J = 7Hz, 1H) Clo-H and C11-H; 4.27 (s, 1H) C21-H; 1.05 (t, J = 7Hz, 3H) C18H3.

 Mass spectrum: 350, 349 Me, 348, 334, 320.

IR spectrum: 3380, 1690, 1640, 1600 cm -l
UV spectrum (EtOH): 263 and 320 nm; (EtOH ++
H30 +): 263 and 320 nm.

b) Preearation of the compound of formula I in the laguelle
R = H
Heated for 4 hours at reflux 0.079 g
(0.225 mmol) of the compound of formula II obtained under
a), dissolved in hydrochloric methanol Epré
shields by adding 0.048 ml (0.67 mmol) of 0 to
acetyl chloride to 3.5 ml of anhydrous methanol].

The solution is cooled to 15 and then treated with
0.143 g (1.35 mmol) of sodium carbonate. We hand
keep the reaction mixture under stirring for
15 minutes then take it up with 30 ml of dichloro
methane, washed with water saturated with chloride
of sodium, we dry it, we filter it and we evaporate it
under vacuum, which gives 0.070 g of crude product.

After purification of the crude product by chromatography
phie on silica gel column (eluent CH2C12 /
MeOH, 95: 5), 0.058 g (0.164 mmol) of
vincamine (yield = 72.5%).

By proceeding in a similar manner but in uti
reading the compound of formula VI in which R signi
put a bromine atom in position 10, we get suc
continually composes it of formula II in which
R represents a bromine atom at position 11,
then the compound of formula I in which R signifies
a bromine atom in position 11.

Example 2 Direct preparation of vincamine (compound of formula I in which R signifies hydrogen)
To a solution of 460 mg (4.1 mmol) of tert. potassium birtylatie in 9 ml of tetrahydrofuran, 257 mg (235 μl, 2.6 mmol) of methyl isocyanoacetate are added. The reaction mixture is left for 10 minutes at 15 and then cooled to -700. A solution of 340 mg (1.3 mmol of the compound of formula VI in which R signifies hydrogen, is then added to 8 ml of tetrahydrofuran and the mixture is gradually heated to 20 over the course of 2 and a half hours.

Then 40 ml of hydrochloric methanol [prepared by adding 0.5 ml (7.7 mmol) of acetyl chloride to 40 ml of anhydrous methanol] are added and the mixture is heated at reflux for 3 hours. After cooling to 20, 1.65 g (15.6 mmol) of sodium carbonate are added and the mixture is stirred for 30 minutes. The excess meta nol is evaporated under vacuum, the residue is taken up in 50 ml of dichloromethane, it is washed with distilled water, the organic phase is dried over Na2SO4, it is filtered and it is evaporated under vacuum, which gives 460 mg of crude product. After purification on a column of sticky silica gel CH2Cl2 / CH30H, 95: 5) 210 mg of vincamine are obtained (yield = 45%).

By proceeding in an analogous manner and using, as starting material, the compound of formula VI in which R signifies a bromine atom in position 10, the compound of formula I is obtained in which
R signifies a bromine atom in position 11.

Claims (18)

1.- Process for the preparation of the compounds of formula I

 in which Alk signifies a C-C4 alkyl group and R represents a hydrogen atom, a halogen atom or a hydroxy, C1-C4 alkyl or alkoxy group C1-C4, and their acid addition salts, characterized in  that we treat under basic conditions, in the presence of an alkanol  in C 1-C4 in an anhydrous medium then in the presence of water, the product  obtained by treating a compound of formula II

 wherein R has the meaning given above, under acidic and anhydrous conditions, and the resulting compound of formula I is recovered in the form of the base or in the form of an acid addition salt.  2.- A process according to claim 1, characterized in that it comprises a) the cyclization of a compound of formula V

 in which Alk signifies a C 4 alkyl group and  R has the meaning given to claim i, or b) hydrolysis of a compound of formula IV

 in which Alk signifies a C1-C4 alkyl group and  R has the meaning given to claim 1,  and cyclization of the compound obtained, or c) the treatment of a compound of formula III

 in which Y # represents the anion of an acid and  R has the meaning given to claim 1,  under basic conditions, in the presence of an alkanol in  C1-C4 in an anhydrous medium then in the presence of water.  3.- A process according to claim 1 or 2, characterized in that the reaction is carried out using a mineral or organic base, at a temperature between Oe and room temperature.  4. A process according to claim 3, characterized in that an alkali metal hydroxide, a basic salt or an alkali metal alcoholate is used as the base.  5. A method according to claim 4, characterized in that sodium carbonate is used.  6.- A method according to any one of claims 3 to 5, characterized in that an excess of base is used.  i.- A process according to any one of claims 1 to 6, characterized in that the reaction is carried out in the presence of anhydrous methanol or an anhydrous mixture of methanol and tetrahydrofuran.  8.- A process according to claim 7, characterized in that the reaction mixture obtained after treatment in the presence of alkanol is treated with water.  9.- A method according to any one of claims 1 to 8, characterized in that it operates at room temperature.  10.- A method according to any one of claims 1 to 9, characterized in that the treatment of the compound of formula II under acidic and anhydrous conditions is carried out using a mineral or organic acid in an organic solvent hydroxylated and / or aprotic anhydrous and at a temperature between room temperature and the boiling point of the reaction mixture.  11. A process according to claim 10, characterized in that the treatment is carried out with hydrochloric acid in methanol and at the boiling temperature of the reaction mixture.  12.- A method according to any one of claims 1 to 11, characterized in that the treatment of the compound of formula It under acidic conditions and the treatment under basic conditions of the compound obtained are carried out successively in the same reaction medium without prior isolation of the intermediate product. 13.- Process for the preparation of the compounds of formula II

 in which R represents a hydrogen atom, a halogen atom or a hydroxy group, C1-C4 alkyl or C1-C4 alkoxy, characterized in that a compound of formula VI is condensed

 in which R has the meaning given above, with a lower alkyl isocyanoacetate in the presence of a base in an aprotic solvent.  14.- A process according to claim 13, characterized in that an alkali metal alcoholate or an amide is used as the base.  15.- A process according to claim 14, characterized in that the base is potassium tert.-butoxide.  16.- A method according to any one of claims 13 to 15, characterized in that the aprotic solvent is tetrahydrofuran.  17.- A method according to any one of claims 13 to 16, characterized in that it operates at low temperature.  18.- A process according to any one of claims 1 to 12, characterized in that the reaction mixture obtained according to any one of claims 13 to 17 is directly treated, without isolating the intermediate product of formula II.  19.- The compounds corresponding to formulas II, III, IV, V and VI

 in which R represents a hydrogen atom, a halogen atom or a hydroxy, C1-C4 alkyl or C1-C4 alkoxy group, Alk represents a C1-C4 alkyl group, Ra represents a halogen atom or a hydroxy group, alkyl in C1-C4 or C1-C4 alkoxy and represents the anion of an acid.