CH646167A5 - METHOD FOR THE PRODUCTION OF APOVINCAMINIC ACID ESTERS. - Google Patents

Description

The invention relates to a new process for the preparation of apovincamic esters of the general formula I.

wherein R1 and R2 are as defined above, or acid addition salts thereof in aprotic solvents treated with organic sulfonic acids

In general formulas I and II the substituents R1 and R2 can be straight or branched alkyl groups having 1 to 6 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc. groups mean.

It is well known that the apovincamic acid esters of general formula I have valuable pharmacological properties; In particular, the (-t -) - apovincaminic acid ethyl ester should be emphasized due to its significant vasodilatory effect.

The apovincamic acid esters of the general formula I were prepared from the pharmaceutically valuable vincamine according to Hungarian Patent No. 163/434 (corresponds to DE-PS 2 253 750) in such a way that the vincamine obtained by hydrolysis of the vincamine was obtained Acid is first converted into the desired ester and then the corresponding apovincamic acid ester is obtained from this by elimination of water, or the vincamine is first subjected to elimination of water, the apovincamin obtained is hydrolyzed and then the apovincaminic acid thus obtained is converted into the desired ester.

Such processes have the disadvantage that the ss vincamine must first be prepared by a multistage synthesis, in order then to be able to convert it to the desired apovincamic acid ester in a yield of at most 60%.

According to Japanese Laid-Open Publication No. 53-147 100, apovincamic acid esters of the general formula I 60 are prepared in such a way that the corresponding 14-oxo-15-hydroxyimino-3a, 17a-E-homoeburnane in the presence of acids with a corresponding ester Alcohol.

This process has the disadvantage that at the required reaction temperature of at least 100 to 104 ° C, under the action of the dehydrating acid used, a substantial proportion of the alcohol present as the reactant is converted into the corresponding ether

3rd

646 167

that e.g. considerable amounts of diethyl ether are produced when using ethanol in the reaction mixture. This ether formation is particularly disadvantageous in the large-scale implementation of the method, since the resulting increased risk of fire and explosion promotes complicated and very difficult to implement safety measures in the construction of the operating device.

Another disadvantage of the above process is that the decomposing action of the concentrated sulfuric acid used as the dehydrating agent leads to various side reactions, which adversely affects both the yield and the purity of the end product.

It has now been found that if, for the preparation of the apovincamic esters of the general formula I, those starting materials are used in which the ester group desired in the end product is already present, as is the case with the compounds of the general formula II, the formation of the Double bond leading reaction can be carried out in the absence of alcohols, which eliminates the hazards arising from ether formation.

The starting compounds of the general form] II can be prepared from corresponding hexahydroindolo-quinolizini compounds by reaction with methylene malonic acid diesters; the further details of this method, first described in Hungarian patent application RI-713 (corresponds to BE-PS 883 576), can be seen from Example 1 below. The compounds of the general formula II can be used per se, or in the form of acid addition salts formed with inorganic or organic acids, particularly in the form of hydrochlorides, as starting materials for the process according to the invention.

It has also been found that instead of the highly corrosive concentrated sulfuric acid, the less corrosive and easier to treat organic sulfonic acids, e.g. can use aliphatic or aromatic sulfonic acids for this reaction; this also considerably reduces the corrosion stress on the operational equipment.

The use of aliphatic or aromatic sulfonic acids instead of the decomposing concentrated sulfuric acid also has the further advantage that the side reactions caused by undesired decomposition can also be largely eliminated, so that the end product is obtained in a higher yield and in substantially better quality. This advantage is particularly important in the present case, since it involves the manufacture of products to be used as medicines.

As aliphatic sulfonic acids, any sulfonic acids containing 1 to 12 carbon atoms in the aliphatic carbon chain, e.g. Methanesulfonic acid, ethanesulfonic acid, dodecyl sulfonic acid, etc. can be used; Aromatic sulfonic acids are any one or more aromatic rings and sulfonic acids bearing one or more identical or different substituents on the aromatic rings, e.g. Benzenesulfonic acid, p-toluenesulfonic acid, a- or ß-naphthalenesulfonic acid etc. 2 to 3 moles of sulfonic acid are expediently used per mole of the starting compound of the general formula II.

Aprotic organic solvents, e.g. aromatic hydrocarbons optionally substituted by halogen atoms, such as benzene, toluene, xylene, chlorobenzene etc. or cyclic ethers such as dioxane and the like. be used.

The reaction can be carried out at temperatures between 80 ° C and 150 ° C, advantageously at 100 to 120 ° C. The reaction time is largely dependent on the reaction temperature used.

The reaction is conveniently carried out under anhydrous conditions.

Both racemic and optically active compounds of the general formula I can be prepared by the process according to the invention, depending on whether racemic or optically active starting compounds of the general formula II are used.

The method according to the invention shows the important advantage over the known methods that it is based on easily accessible and easily treatable compounds and less corrosive reagents are used; The desired apovincamic acid esters of the general formula I are obtained by a reaction free of side reactions, under mild conditions, in good purity and in high yield.

In a particularly advantageous embodiment of the process according to the invention, the corresponding compound of the general formula II or an acid addition salt, especially the hydrochloride thereof, is boiled in anhydrous toluene for 1 to 2 hours with likewise anhydrous p-toluenesulfonic acid.

In the exemplary embodiments below, both the preparation of the starting materials of the general formula II and the practical implementation of the process according to the invention for the preparation of the apovincamic acid esters of the general formula I are illustrated in more detail; however, the invention is in no way limited to the content of these examples.

example 1

70 g (0.1 mol) of (-) - la- (methoxycarbonyl-ethyI) -la-ethyI-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizin- D-dibenzoyl tartrate was suspended in 300 ml of toluene. 70 ml of concentrated aqueous ammonium hydroxide solution was added to the suspension and the mixture was stirred at room temperature for 10 minutes. The toluene phase was then separated, dewatered by azeotropic distillation and the volume of the mixture was then made up to 300 ml with toluene. 36 ml (31 g) of tert-butyl nitrite and 25 g of sodium tert-butoxide were added to the toluene solution and the mixture was stirred in a nitrogen atmosphere at 30 ° C. for 25 minutes. The reaction mixture was then mixed with 300 ml of ethanol and stirred at 60 ° C. for one hour. The mixture was then acidified to pH = 2 with 36% aqueous hydrochloric acid, cooled to 0 ° C. and the precipitated product was filtered off at this temperature and washed twice with 100 ml of water each time. The product obtained in this way was air-dried and the dried product was then treated with 100 ml of 10% strength aqueous ammonium hydroxide solution, filtered off, washed with 50 ml of water three times and dried.

In this way, 20 g (-) - 14-ethoxycarbonyl-14-hydroxyamino-3a, 16a-eburnan (52% of theory) were obtained; Mp 172-173 ° C; [a] 2D ° = -114.1 ° (c = 1, in chloroform).

Example 2

19 g (0.05 mol) of (-) - 14-ethoxycarbonyl-14-hydroxyamino-3a, 16a-eburnan (prepared according to Example 1) and 19.8 g (0.125 mol) of anhydrous p-toluenesulfonic acid were dissolved in 350 ml of anhydrous toluene Cooked under reflux for 1.5 hours. The reaction mixture was then cooled to 20 ° C, 200 ml of water was added and the pH of the mixture was adjusted with about 20 ml of concentrated aqueous Ammo5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

646 167

nium hydroxide solution set to 9. The organic phase was separated and the aqueous phase extracted with 50 ml of toluene. The combined toluene phases were dried with anhydrous sodium sulfate, filtered off, the filtrate clarified with 1 g activated carbon and filtered off again, the filtrate clarified with 1 g activated carbon and filtered off again. The filtrate was evaporated to dryness in vacuo, the residue was dissolved in 20 ml of ethanol; this solution was boiled for 1 minute and cooled to 0 ° C; finally, the product crystallized from the cooled solution was separated and dried.

This gave 16.6 g of (+) - apovincaminic acid ethyl ester (95% of theory); Mp 144-145 ° C; [a] o = + 144.1- + 145.1 ° (c = 1, in chloroform). Purity of the product: 99.8-100.1% (titrated in glacial acetic acid in the presence of crystal violet indicator).

Example 3

47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate were dissolved in 400 ml of toluene, the solution was dewatered by azeotropic distillation, then with 42 g (0.1 mol) of (~) -14-ethoxycarbonyl- 14-hydroxyamino-3a, 16a-eburnan hydrochloride are added and the mixture is refluxed for two hours with stirring. The reaction mixture was cooled to + 10 ° C, 100 ml of water, 30 ml of 25% aqueous ammonium hydroxide solution and 2 g of Celite filter medium were added, the mixture was stirred at + 10 ° C for 5 minutes and filtered. The phases of the filtrate were separated, the aqueous phase was extracted with 50 ml of toluene and the toluene phases were combined, washed with 50 ml of water and dried with 20 g of anhydrous sodium sulfate. After filtering off, the filtrate was evaporated to dryness in vacuo, the residue was mixed with 40 ml of ethanol; the resulting solution was boiled for 1 minute, then cooled to 0 ° C and left at that temperature for one hour. The precipitated product was filtered off, washed with 20 ml of ethanol cooled to 0 ° C. and dried.

In this way, 30 g of (+) - ethyl apovincaminate (86% of theory) were obtained; Mp 144-146 ° C; [a] 2D ° = + 141- + 146 ° (c = 1, in chloroform).

Analysis for C22H25N2O2 (mol. Wt .: 350.44):

Calc .: C 75.33%; H 7.45%; N 7.99%;

Found: C 75.31%; H 7.42%; N 7.90%.

Example 4

The procedure was as described in Example 3, with the difference that 38 g (0.1 mol) of (-) - 14-ethoxycarbonyl-14-hydroxyamino-3 <%, 14a-eburnan were used as starting material. 31.5 g (+) - Apovinc-aminic acid ethyl ester (90% of theory) were obtained; Mp 144-146 ° C; [ate '= + 141- + 146 ° (c = 1, in chloroform).

Example 5

The procedure was as described in Example 3, with the difference that 400 ml of benzene were used as the solvent instead of toluene. The reaction time was 12 hours.

This gave 32.4 g of (+) - apovincaminic acid ethyl ester (67.0% of theory); Mp 141-145 ° C; [a] f "= +141 - + 144 ° (c = 1, in chloroform).

Example 6

The procedure was as described in Example 3, with the difference that 400 ml of xylene were used as solvent instead of toluene. The reaction was carried out at 140 ° C, the reaction time was 30 minutes.

In this way, 30.5 g of (+) - apovincamic acid ethyl ester (87.3% of theory) were obtained; Mp 144-146 ° C; [a] f "= +141 - + 146 ° (c = 1, in chloroform).

Example 7

The procedure was as described in Example 3, with the difference that 400 ml of chlorobenzene were used as the solvent instead of toluene. The reaction was carried out at 130 ° C, the reaction time was 40 minutes.

In this way, 30.8 g (+) - ethyl apovincamine (88% of theory) were obtained.

Example 8

The procedure was as described in Example 3, with the difference that instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate, 43 g (0.25 mol) of anhydrous p-toluenesulfonic acid and as a solvent instead of Toluene 400 ml of dioxane were used. The reaction was carried out at 100 ° C, the reaction time was 16 hours.

In this way, 18.0 g of (+) - apovincaminic acid ethyl ester (51.5% of theory) were obtained; Mp 141-143 ° C;

[a] 5 ° = + 140- + 143 ° (c = 1, in chloroform).

Example 9

The procedure was as described in Example 3, with the difference that instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate, 27.5 g (0.25 mol) of ethanesulfonic acid were used. 30.0 g (86% of theory) of (+) - Apovincaminic acid ethyl ester were obtained; Mp 144-146 ° C; [a] o = + 141- + 146 ° (c = 1, in chloroform).

Example 10

The procedure was as described in Example 3, with the difference that 39.5 g (0.25 mol) of benzenesulfonic acid were used instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate. This gave 30.5 g of (+) - apovincamic acid ethyl ester (87.5% of theory); Mp 144-146 ° C; [a] 2D ° = + 141- + 146 ° (c = 1, in chloroform).

4th

s

10th

15

20th

25th

30th

35

40

45

50

55

B

Claims (8)

646 167 PATENT CLAIMS 1. Process for the preparation of apovincaminic esters of the general formula I (I) wherein R1 and R2 are alkyl groups with 1 to 6 carbon atoms, characterized in that 14-hydroxyamino-14-alkoxycarbonyl-eburnane of the general formula II wherein R1 and R2 are alkyl groups having 1 to 6 carbon atoms, which is characterized in that is 14-hydroxyamino-14-alkoxycarbonyl-eburnane of the general formula II (II HO-NH 20th 25th 30th (II) U 0 wherein R1 and R2 have the meanings given above, or acid addition salts thereof in aprotic organic solvents with organic sulfonic acids. 2. The method according to claim 1, characterized in that p-toluenesulfonic acid is used as the organic sulfonic acid. 3. The method according to claim 1, characterized in that one uses ethanesulfonic acid or benzenesulfonic acid as organic sulfonic acid. 4. The method according to claims 1 to 3, characterized in that one uses an optionally substituted by halogen aromatic hydrocarbon or a cyclic ether as an aprotic organic solvent. 5. The method according to claim 4, characterized in that toluene is used as an aprotic organic solvent. 6. The method according to claim 4, characterized in that one uses benzene, xylene, chlorobenzene or dioxane as an aprotic organic solvent. 7. The method according to claims 1 to 6, characterized in that one carries out the reaction under anhydrous conditions. 8. The method according to claims 1 to 7, characterized in that one carries out the reaction at temperatures between 80 ° C and 150 ° C, especially at 100 to 120 ° C.