FR2489824A1 - PROCESS FOR THE PREPARATION OF APOVINCAMINIC ACID ESTERS AND PRODUCTS THUS OBTAINED - Google Patents

Abstract

The invention relates to a novel process for preparing apovincamine acid esters of the general formula I in which R<1> and R<2> denote alkyl groups having 1 to 6 carbon atoms, which process is characterised in that corresponding 14-hydroxyamino-14-alkoxycarbonyleburnanes are reacted with organic sulphonic acid esters in aprotic organic solvents.

Description

Process for the preparation of esters of apovincaminic acid and products thus obtained.

dans laquelle R et R indépendamment représentent des groupes alkyle ayant de
1 à 6 atomes de carbone.The present invention relates to a new process for the preparation of esters of apovincaminic acid. More particularly the invention relates to a process for the preparation of racemic or optically active esters of apovincaminic acid having the general formula (I)

wherein R and R independently represent alkyl groups having
1 to 6 carbon atoms.

dans laquelle R et R2 ont la désignation ci-dessus, ou bien un sel d'addition acide de celui-ci, avec un acide sulfonique organique dans un solvant organique aprotique. According to the present invention, esters of apovincaminic acid having the general formula (I) are prepared by reacting a hydroxyamino-E-homo-eburnan having the general formula (II)

wherein R and R 2 have the above designation, or an acid addition salt thereof, with an organic sulfonic acid in an aprotic organic solvent.

In the definition of R and R, the term alkyl having 1 to 6 carbon atoms is used to refer to straight or branched chain alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, etc.

It is known that the esters of apovincaminic acid having the general formula (I) in which R and R2 have the above definitions, possess valid pharmacological properties and in particular ethyl (+) - apovincaminate is an excellent vasodilator.

According to Hungarian Patent Application No. 163,143, these compounds are prepared by subjecting the pharmaceutically active vincaminea to hydrolysis and converting the resulting vincaminic acid into the corresponding ester. From the ester of vincaminic acid produced, the corresponding ester of apovincaminic acid is prepared by leaving water. According to another method, the vincamine is first converted into apovincamine by leaving water, after which the apovincamine is hydrolyzed and the resulting apovincaminic acid is converted into the desired ester.

A disadvantage of this process lies in the fact that first the vincamine has to be prepared by a multistep synthesis and that from this compound the corresponding apovincaminic acid esters can be obtained only with a maximum yield of 60 %.

According to another process disclosed in published Japanese patent application No. 53-061757, the compounds of general formula (I)> where R and R have the preceding definition, are prepared by reacting 14-oxo-15-hydroxy-imino- 3o, 16-E-homo-eburnan with the appropriate alcohol in the presence of an acid.

The most important disadvantage of this process is due to the fact that at the temperature of the reaction involved, which exceeds 100-1040C, a large amount of the ether corresponding to the alcohol used is also obtained. For example if ethyl alcohol is used as the alcohol in the reaction, large amounts of diethyl ether are also formed due to the presence of the dehydrating acid. The formation of the ether is particularly disadvantageous in the technique to be used industrially since the presence of the ethers leads to an increased risk of fire and explosion and consequently to extreme safety conditions.

Another disadvantage of this process is due to the fact that generally the extremely aggressive concentrated sulfuric acid is used for the dehydration and therefore side reactions take place which decrease the yield and moreover make the quality of the final product poor.

The authors of the present invention have now discovered that if, as the starting compound, a compound is used which already has the ester group corresponding to the desired apovincaminic acid ester of the general formula (I), the presence of alcohol can be eliminated and therefore there is no production of ether. For this purpose, the compounds of general formula (II), in which R1 and R2 have the same definitions as above, can be used in particular.

The starting compounds of general formula (II) are prepared according to a process disclosed in the Hungarian patent application RI-713 starting from the appropriate hexahydroindoloquinolizinium compounds with methylenemalonic acid diesters. In the process according to the present invention, the compounds of general formula (II) can be used as such or in the form of their acid addition salt with mineral or organic acids, preferably in the form of their hydrochloride.

The inventors have further discovered that if the concentrated sulfuric acid is replaced by less corrosive organic sulfonic acids, for example aliphatic or aromatic sulfonic acids, the risk of corrosion of the equipment used is reduced considerably.

The use of organic sulphonic acids instead of concentrated sulfuric acid also decreases side reactions due to corrosion, thus improving not only the yield, but also the quality of the end product. The improvement in quality is particularly important since the compounds of general formula (I) prepared by this process are envisioned for pharmaceutical applications.

As aliphatic sulfonic acids, sulfonic acids containing an aliphatic carbon chain having 1 to 12 carbon atoms, for example methanesulfonic, ethanesulfonic, dodecylsulfonic, etc. can be used. Aromatic sulfonic acids include sulfonic acids containing one or more aromatic rings which may be substituted with one or more identical or different substituents, for example benzenesulfonic, p-toluenesulfonic, oC-naphthylsulfonic, t-naphthylsulfonic, etc.

For 1 mole of a compound of general formula (II), it is preferred to use 2 to 3 moles of sulfonic acid.

As organic aprotic solvents, solvents such as optionally halogenated aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc. can be used. or cyclic ethers such as dioxane, etc.

The reaction is carried out at a temperature of 80 ° to 1500 ° C., preferably 100 to 120 ° C. The duration of the reaction depends on the temperature.

The reaction is preferably carried out under anhydrous conditions.

By the new process in accordance with the present invention, racemic and optically active compounds of general formula (I) can also be prepared starting from racemic and optically active compounds of general formula (II); respectively.

A great advantage of the process of the present invention over the processes known in the art, is due to the fact that by this process, the esters of apovincaminic acid of general formula (I) can be prepared starting from easily accessible compounds, by hardly corrosive reagents, which are easy to handle, with increased yield and with high purity.

The process provided is easy to perform on an industrial scale and does not involve any safety problem.

Therefore, the most preferred embodiment of the process according to the present invention is to boil a compound of the general formula (II), or an acid addition salt, preferably its hydrochloride, with p-toluenesulfonic acid. dry in toluene for 1 to 2 hours.

The present invention is illustrated by the descriptive and non-limiting examples below.

Example 1
70 g (0.1 mol) of (-) - ld- (carbomethoxy-ethyl) -1 &alpha; -ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo tartrate [2, 3-a] quinolizine-D-dibenzoyl are suspended in 300 ml of toluene. To the suspension is added 70 ml of a concentrated aqueous solution of ammonium hydroxide, and the reaction mixture is stirred at room temperature for 10 minutes. The toluene phase is separated from the aqueous phase and is dried by azeotropic distillation, after which the mixture is made up to 300 ml with toluene. To the toluene solution, 36 ml (31 g) of tert-butylnitrite and 25 g of sodium tert-butoxide are added and the mixture is stirred under nitrogen at 300C for 25 minutes. To the reaction mixture, 300 ml of ethanol are added and the whole is stirred at 600C for 1 hour. The pH is adjusted to 2 with a 36% aqueous hydrochloric acid solution. at room temperature, the mixture is cooled to Oc and the precipitated substance is filtered off at this temperature and washed with two 100 ml portions of water. The product obtained is dried in air and then treated with 150 ml of a 10% aqueous solution of ammonium hydroxide. The product is filtered off, washed with three 50 ml portions of water, and dried. 20 g of (-) - 14 ethoxy-carbonyl-14-hydroxyamino-Rt, 16ct-eburnane are obtained, melting at 172-1730C. Yield: 52%.

ÈiD20 = -144.1 (c = 1, chloroform).

Example 2
19 g (0.05 mole) of (-) - 14-ethoxycarbonyl-14-hydroxy amino-30C, 16c / -eburnane prepared according to Example 1, and 19.8 g (0.125 mole) of p-toluenesulfonic acid dry, are boiled in 350 ml of dry toluene for 1.5 hours. The reaction mixture is cooled to 200C, after which 200 ml of water are added and the pH of the mixture is adjusted to 9 with about 20 ml of concentrated ammonia. The organic phase is separated and the aqueous phase is extracted with 50 ml of toluene. .The toluene phases are combined, dried over anhydrous sodium sulfate, filtered; the filtrate is decolorized with 1 g of activated carbon and then filtered. The filtrate is evaporated to dryness in vacuo, the evaporation residue is dissolved in 20 ml of ethanol, boiled for 1 minute, and is crystallized after cooling to OOC . This gives 16.6 g of ethyl (+) - apovincaminate, melting at 144-146 ° C. Yield: 95%.

[&Alpha;] D = + (144.1-145.1) (c = 1, chloroform).

Purity: 99.8 to 100.1% (in glacial acetic acid, in the presence of an indicator, using perchloric acid for the titration).

Example 3
From a solution of 47.5 g (0.25 mol) of hydrated p-toluenesulfonic acid in 400 ml of toluene, the water is removed by azeotropic distillation. After that, 42 g (0.1 mole) of (-) - 14-ethoxycarbonyl-14-hydroxy-amino-3CC 16 α-eburnane hydrochloride are added to the dry mixture which is then heated under reflux for 2 hours with stirring. The reaction mixture is cooled to +10 C, 100 ml of water, 30 ml of a 25% aqueous ammonium hydroxide solution and 2g of celite are added; and the reaction mixture is stirred at + 10C for 5 minutes, after which it is filtered. The aqueous and toluene phases of the filtrate are separated, the aqueous phase is extracted with 50 ml of toluene, and the toluene phases are combined The combined toluene phases are washed with 50 ml of water, dried over 20 g of anhydrous sodium sulfate and filtered. The filtrate is evaporated to dryness in vacuo; 40 ml of ethanol are added to the evaporation residue, the solution obtained is boiled for 1 minute and then cooled to 0 C. The mixture is left to stand at 0 C for 1 hour, the precipitated product is separated by filtration , washed by covering it with two 20 ml portions of ethanol at a temperature of 0 C and dried. 30 g (86%) of ethyl (+) apovincaminate are obtained, melting at 144 -146 C.

COC2D = + (141 to 146) (c = 1, chloroform).

Analysis for C22H25N2O2 (molecular weight: 350.44) Calculated: C 75.33%, H 7.45%, N 7.99%; Found: C 75.31%, H 7.42%, N 7.90%.

Example 4
Following the process described in Example 3, but starting with 38 g (0.1 mol) of (-) - 14-ethoxycarbonyl-14-hydroxy amino-3 &alpha;, 16 &alpha; -eburnan, 31.5 g (90 %) of (+) - ethyl apovincaminate, melting at 1440-1460C, are obtained.

[&alpha;] D20 = + (141 to 146) (c = 1, chloroform).

Example 5
According to the process described in Example 3> but using 400 ml of benzene instead of 400 ml of toluene, as solvent and by carrying out the reaction for 12 hours, 23.4 g (67%) of (+ ) -ethylapovincaminate melting at l410-1450C.

[&alpha;] D20 = + (141 to 144) 0 (c = 1, chloroform).

Example 6
Following the process described in Example 4, but using 400 ml of xylene instead of 400 ml of toluene, as solvent, and by carrying out the reaction in 30 minutes at a temperature of 1400C, 30.5 g (87 , 3%) of (+) - ethyl apovincaminate melting at 1440-1460C.

= y = + (141-146) 0 (c = 1, chloroform).

D
Example 7
Following the process described in Example 3, but using 400 ml of chlorobenzene instead of 400 ml of toluene, as solvent, and carrying out the reaction at 130 ° C. for 40 minutes, 30.8 g (88%) are obtained. ) of (+) - ethyl apovincaminate.

Example 8
According to the process described in Example 3, but using 43 g (0.25 mol) of dry p-toluenesulfonic acid instead of 47.5 g (0.25 mol) of hydrated p-toluenesulfonic acid, and 400 ml of dioxane instead of 400 ml of toluene, 18 g (51.5%) of (+) - ethyl apovincaminate are obtained, melting at 141 -143 C.

220 = + (140-143) 0 (c = 1, chloroform).

D
Example 9
Following the process described in the example, but replacing 47.5 g (0.25 mole) of hydrated p-toluenesulfonic acid with 27.5 g (0.25 mole) of ethanesulfonic acid, 30 g (86 %) of (+) - ethyl apovincaminate, mp 144-146 C.

[&alpha;] 20 = + (141 to 146) (c = 1, chloroform).

D
Example 10
Following the process described in the example, but replacing 48 g (0.25 mol) of hydrated p-toluenesulfonic acid with 39.5 g (0.25 mol) of benzenesulfonic acid, 30.5 g (87 , 5%) of (+) - ethyl apovincaminate, mp 144 -146 C.

[&alpha;] 20 = + (141 to 146) (c = 1, chloroform).

Claims (10)

1. Process for the preparation of racemic or optically active esters of apovincaminic acid, of general formula (I)

in which R and R independently represent alkyl groups having from 1 to 6 carbon atoms, characterized in that a hydroxyamino-Ehomo-eburnan of general formula (II) is reacted

in which R and R2 have the above definitions, or an acid addition salt of this compound, with an organic sulfonic acid) in an aprotic organic solvent. 2. Method according to claim 1, characterized in that p-toluenesulfonic acid is used as organic sulfonic acid. 3. Method according to claim 1, characterized in that ethanesulfonic acid or benzenesulfonic acid is used as organic sulfonic acid. 4. Method according to any one of claims 1 to 3, characterized in that the aprotic organic solvent uses an aromatic hydrocarbon optionally substituted with halogen, or else a cyclic ether. 5. Method according to claim 4, characterized in that toluene is used as aprotic organic solvent. 6. Method according to claim 4, characterized in that benzene, xylene, chlorobenzene or dioxane are used as aprotic organic solvent. 7. Method according to any one of claims 1 to 6, characterized in that the reaction is carried out under anhydrous conditions. 8. Method according to any one of claims 1 to 7, characterized in that the reaction is carried out at a temperature of 80 to 1500C. 9. Method according to claim 8, characterized in that the reaction is carried out at a temperature of 1000 to 120C 10. Racemic or optically active esters of apovincaminic acid of general formula (I) in which R and R have the definitions given in claim 1, prepared according to any one of claims 1 to 9.