NL8104044A - PROCESS FOR THE PREPARATION OF APOVINCAMINIC ACID ESTERS AND THE USE THEREOF AS A MEDICINAL PRODUCT. - Google Patents

Description

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Short designation: Process for the preparation of apovincaric acid esters and their use as a medicine.

The invention relates to a process for the preparation of racemic or optically active apovincaric acid esters of general formula 1, indicated on the formula sheet, wherein and independently represent an alkyl group with 1-6 carbon atanes.

The invention further relates to the substances thus prepared and to a method of preparing the medicines in which these substances are present as active components.

The process according to the invention is characterized in that a hydroxyamino-E-homoeebburnane of general formula 2, wherein R 1 and R 2 have the same meaning as indicated above, or an acid addition salt thereof is reacted with an organic sulfonic acid in an aprotic organic solvent.

In the definition of R 1 and R 2, the designation "alkyl group of 1-6 carbon atoms" has been used to indicate a straight or branched alkyl group of 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl and the like.

It is well known that the apovincamic acid esters of formula I, wherein R 1 and R 2 have the same meaning as indicated above, have valuable pharmacological properties and in particular the (+) - apovincamic acid ethyl ester is an excellent vasodilator.

According to Hungarian patent 163,143, these compounds are prepared by subjecting the pharmacologically active vincamine compounds to a hydrolysis and converting the thus obtained vincamic acid into the corresponding ester. The apovincamic acid ester was obtained from the vincamic acid ester by splitting off water.

In another method, vincamine was first converted to apovincamine 30 by splitting off water, after which apovincamine was hydrolysed and the resulting apovincamic acid was converted to the desired ester.

A drawback of this method is that vincamine must first be prepared by a multi-stage synthesis, and from this compound the corresponding apovincamic acid ester can be obtained in a yield of only up to 60¾.

According to another method, described in Japanese patent application 53-061757, compounds of general formula 1 are obtained, ............... - 8104044 -1-22107 / Vk / fflb i '* ir Short designation: Process for the preparation of apovincaric acid esters and their use as a medicine.

4

The invention relates to a process for the preparation of racemic or optically active apovincamic acid esters of general formula 1, indicated on the formula sheet, wherein R 1 and R 2 independently represent an alkyl group of 1-6 carbon atoms. The invention further relates to the substances thus prepared and to a method of preparing the medicines in which these substances are present as active components.

The process according to the invention is characterized in that a hydroxyamino-E-homoeburnan of general formula 2, wherein and have the same meaning as indicated above, whether an acid addition salt thereof is reacted with an organic sulfonic acid in an aprotic organic solvent.

In the definition of and R2, the designation "alkyl group of 1-6 carbon atoms" has been used to indicate a straight or branched alkyl group of 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and such.

It is well known that the apovincamic acid esters of formula I, wherein R 1 and R 2 have the same meaning as indicated above, have valuable pharmacological properties and in particular the (+) - apovincamic acid ethyl ester is an excellent vasodilator.

According to Hungarian patent specification 163.1-3, these compounds are prepared by subjecting the pharmacologically active vincamine compounds to a hydrolysis and converting the thus obtained vincamic acid to the corresponding ester. The apovincamic acid ester was obtained from the vincamic acid ester by splitting off water. In another method, vincamihe was first converted to apovincamine 30 by splitting off water, then apovincamine was hydrolyzed and the resulting apovincamic acid was converted to the desired ester.

A drawback of this method is that vincamine must first be prepared by a multi-stage synthesis, and from this compound the corresponding apovincamic acid ester can be obtained in a yield of only up to 60%.

According to another method described in Japanese patent application 53-061757, compounds of general formula 1 are obtained, t 8104044 ^ * -2- - 22107 / Vk / mb, and having the same meaning as indicated above, by the corresponding 14-oxo -15-hydroxy-imino-3Ct> 16 OC-E-homo-eboranane to react with the corresponding alcohol in the presence of an acid. The main drawback of this process consists in that the reaction temperature is above 100-104 ° C, whereby a large amount of ether corresponding to the alcohol used is also obtained. For example, if ethyl alcohol is used in the reaction, large amounts of diethyl ether are formed by the presence of the dehydrating acid. The formation of ether is particularly disadvantageous when the process is used on an industrial scale, because the presence of ethers leads to an increased fire and explosion hazard and thus strict safety requirements are again imposed.

A further drawback of this method is that generally the very aggressive concentrated sulfuric acid is used for the tfe-hydration and thus side reactions take place, thereby reducing the yield and on the other hand reducing the quality of the final product.

It has now been found that when a starting material is used a compound which already has the ester group corresponding to the desired apovincamic acid ester of general formula 1, the presence of an alcohol is superfluous and therefore no ether formation takes place. For this purpose, compounds of formula II, which have the same meaning as indicated above, can be excellently used.

Starting materials of general formula 2 can be prepared according to a method as stated in Hungarian patent application RI-713, from the corresponding hexahydroindolequinolizinium compounds with methylmalonic acid diesters. In the process of the invention, compounds of general formula 2 are used as such or in the form of the acid addition salt with an inorganic acid, preferably in the hydrochloric acid form.

It has further been found that when concentrated sulfuric acid is replaced by less corrosive organic sulfonic acids such as aliphatic or aromatic sulfonic acids the risk of corrosion of the device used is considerably reduced.

The use of organic sulphonic acids instead of concentrated sulphonic acid also reduces the side reactions due to the corrosion, so that not only the yield but also the quality of the end product is improved t 8104044'c · t-22-107 / Vk / mb. The improvement of the quality is of great importance because the compounds of general formula 1, prepared according to this method, are used for the preparation of medicines.

As aliphatic sulfonic acids, sulfonic acids can be used with an aliphatic carbon chain having 1-12 carbon atoms, such as methanesulfonic acid, ethanesulfonic acid, dodecylsulfonic acid and the like. Aromatic sulfonic acids can also be used, such as sulfonic acids with one or more aromatic rings which may be substituted with one or more equal or different substituents such as benzenesulfonic acid, p-toluenesulfonic acid, OC-naphthyl sulfonic acid, and the like. Preferably 2 to 3 moles of sulfonic acid are used on 1 mole of the compound of general formula 2.

Aprotic organic solvents such as optionally halogenated aromatic hydrocarbons, in particular benzene, toluene, xylene, chlorobenzene and the like, or cyclic ethers such as dioxane, are used as the solvent.

The reaction is carried out at a temperature of 80-150 ° C, preferably at 100-120 ° C. The reaction time is a function of the temperature.

The reaction is preferably conducted under anhydrous conditions.

By applying the method according to the invention, racemic and optically active compounds of general formula 1 can be obtained by starting from racemic and optically active compounds of general formula 2, respectively.

A great advantage of the process according to the invention over the known processes is that the process according to the invention allows the aprovincamic acid esters of general formula 1 to be prepared starting from compounds which are readily available, by using hardly corrosive reagents which are easy to process and obtain an increased yield of desired product of high purity. The method obtained is easy to carry out on an industrial scale and does not pose any safety problems.

In the most preferred embodiment of the process of the invention, a compound of general formula 2, or an acid addition salt thereof, preferably its hydrochloride, is boiled with dry p-toluenesulfonic acid in toluene for 1 to 2 hours.

The invention will be further elucidated by means of the following non-limiting examples, 8104044-4-22107 / Vk / mb.

Example I

70 g (0.1 mol) (-) - 1OC- (carbomethoxy-ethyl) -1Ot-ethyl-1,2,3,4,6,7,12,12b-octahydroindole ^ 2 were added to 300 ml of toluene. 3-aJ quinolizine-5 D-dibenzoyl tartarate suspended. To this suspension, 70 ml of concentrated aqueous ammonium hydroxide solution was added and the reaction mixture was stirred at room temperature for 10 minutes. The toluene phase was separated from the aqueous phase and dried by azeotropic distillation, after which the mixture was made up to 300 ml with toluene. 36 ml (31 g) of tert-butyl nitrite and 25 g were added to this toluene solution

sodium tert-butylate was added and the mixture was stirred under nitrogen at a temperature of 30 ° C for 25 minutes. 300 ml of ethanol were then added to the reaction mixture and stirred at a temperature of 60 ° C for 1 hour. The pH was adjusted to 2 by adjusting it. 15 adding 36? aqueous hydrochloric acid at room temperature, the mixture was cooled to 0 ° C and the precipitated substance filtered off at this temperature and washed twice with 100 ml of water. The product obtained was air-dried and then mixed with 150 ml of 10? aqueous solution of ammonium hydroxide. The product was filtered off, washed three times with 50 ml of water and dried. Thus, 20 g of (-) - 14-ethoxy-carbonyl-14-hydroxyamino-3 16'-eburnane are obtained, which substance has a melting point of 172-173 ° C. The yield was 52? and the value for = -144.1 °, measured in chloroform with a concentration c - 1. Example II

Following the procedure described in Example I, 19 g (0.05 mol) (-) - 14-ethoxycarbony 1-14-hydroxyamino-3 Qt, 16 Oi-eburnane was prepared and with 19.8 g ( 0.125 mol) dried p-toluenesulfonic acid boiled in 350 ml dry toluene for 1.5 hours. The reaction mixture was cooled to 20 ° C after which 200 ml of water was added and the pH of the mixture was adjusted to 9 with about 20 ml of concentrated ammonium hydroxide solution. The organic phase was separated, the aqueous phase extracted with 50 ml of toluene. The toluene phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was decolorized with 1 g of activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure, the evaporation residue was dissolved in 20 ml of ethanol, boiled for one minute and after cooling. crystallized at 0 ° C. Thus, 16.6 g (+) - apovincamic acid ethyl ester were obtained with a melting range of 144-146 ° C. The yield * 8104044> 5 '' t -5- 22107 / Vk / rab

Mon o yy 3 + (144.1-145.1), measured in chloroform at a concentration of os 1. The purity, measured in glacial acetic acid in the presence of an indicator using perchloric acid for the titration, was 99.8 to 100.1¾ .

Example III

Water was removed by azetropic distillation from a solution of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate in 400 ml of toluene. Then 42 g (0.1 mol) (-) - 14-ethoxycarbonyl-14-hydroxyamino-3OC, 16QC-eburnane hydrochloride was added to the dry mixture, which mixture was refluxed for 2 hours with stirring. The reaction mixture was cooled to +10 ° C, then 100 ml of water, 30 ml of a 25% aqueous solution of ammonium hydroxide and 2 g of celite were added and the reaction mixture was stirred at a temperature of +10 ° C for 5 minutes after which it was filtered. The aqueous phase and the toluene phase were separated from the filtrate, the aqueous phase extracted with 50 ml of toluene and the toluene phases were combined. The combined toluene phases were washed with 50 ml of water, dried over 20 g of anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure, 40 ml of ethanol was added to the evaporation residue, the resulting solution boiled for 1 minute and then cooled to 0 ° C. The mixture was stored at 0 ° C for 1 hour, filtered off the precipitated product, washed by covering it twice with 20 ml of ethanol at 0 ° C and dried. Thus, 30 g (86¾) (+) - apovincamic acid ethyl ester with a melting range of 144-146 ° C were obtained.

The value for ~ + (141-146) °, measured in chloroform at a concentration of c = 1.

The data from the elemental analysis for the compound of formula C_oHoc.N-0- (molecular weight 350.44) were: dd do dd · 0 (¾) H (*) N (%) calculated 75.33 7.45 7 .99 found 75.31 7.42 7.90 - EXAMPLE IV- 8104044 -6- 22107 / Vk / mb

Example IV

The same procedure as indicated in Example 3 was followed, starting from 38 g (0.1 mol) (-) - 14-ethoxycarbonyl-14-hydroxyamino-3 (0.16 GC-eburnane), whereby 31.5 g (90?) (+) - apovincamic acid ethyl ester were obtained with a melting range of 144-146 ° C.

The value for ¢ (. = + (141-146) °, measured in chloroform at a concentration c = 1.

Example V

The procedure set forth in Example III was repeated using 400 ml of benzene instead of 400 ml of toluene as the solvent and the reaction was carried out in 12 hours with 23.4 g (67.0%) (+) - apo- vineamic acid ethyl ester was obtained with a melting range of 141-144 ° C. The value for 0 ^ 1 ^ ° = + (141-144) ° (c s 1, chloroform).

Example VI

The procedure set forth in Example IV was repeated using 400 ml of xylene in. instead of 400 ml of toluene as a solvent and the reaction was carried out at a temperature of 140 ° C for 30 minutes to obtain 30.5 g (87.3%) (+) - apovincamic acid ethyl ester with a melting range of 144 -146 ° C. The value for 20 [oc] 2 ° = + (141-146) ° (c s 1, chloroform).

Example VII

The same procedure outlined in Example III was carried out using 400 ml of chlorobenzene instead of 400 ml of toluene as a solvent and the reaction was carried out at a temperature of 130 ° C for 40 minutes, whereby 30.8 g ( 88%) (+) - apovincamic acid ethyl ester was obtained.

Example VIII

The same procedure outlined in Example III was repeated using 43 g (0.25 mol) of dry p-toluenesulfonic acid instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate and 400 ml of dioxane instead of 400 ml of toluene to obtain 18.0 g (51.5%) (+) - apovincamic acid ethyl ester with a melting range of 141-143 ° C. The value for = + (140-143) ° (C = 1, chloroform).

Example IX

The same procedure outlined in Example III was repeated using 27.5 g (0.25 mol) ethanesulfonic acid instead of 47.5 g (0.25 mol) p-toluenesulfonic acid hydrate. Thus, 30 g (86%) (+) - apovincamic acid ethyl ester were obtained with a melting range of * 8104044 -7-22107 / Vk / rab V 'v Γ.

144-146 ° C. The value for M ^ 0 = + 041-146) ° (c = 1, chloroform). Example X.

The procedure indicated in Example III was repeated, but 48 g (0.25 mol) of p-toluenesulfonic acid hydrate was replaced with 5 39.5 g (0.25 mol) of benzenesulfonic acid to give 30.5 g (87.5 () (+ apovincamic acid ethyl ester was obtained with a melting range of 144-146 ° C. The value for D *] * 0 = + (141-146) ° (o = 1, chloroform).

-CONCLUSIONS- i \ 0 8104044

Claims (10)

1. Process for the preparation of racemic or optically active apovincamic acid esters of general formula 1, indicated on the formula sheet, wherein and R 1 independently represent an alkyl group having 1-6 carbon atoms, characterized in that a hydroxyaraino-E-homoeburnan of formula 2, wherein R 1 and R 2 have the same meaning as indicated above or an acid addition salt thereof is reacted with an organic sulfonic acid in an aprotic organic solvent. Process according to claim 1, characterized in that p-toluene sulfonic acid is used as organic sulfonic acid. Process according to claim 1, characterized in that ethane sulfonic acid or benzene sulfonic acid is used as organic sulfonic acid. 4. Process according to claims 1-3, characterized in that the aprotic organic sulfonic acid is an aromatic hydrocarbon which can be substituted with halogen or a cyclic ether. Process according to claim 4, characterized in that toluene is used as an aprotic organic solvent. Process according to claim 4, characterized in that benzene, xylene, chlorobenzene or dioxane is used as an aprotic organic solvent. Process according to claims 1-6, characterized in that the reaction is carried out under anhydrous conditions. Process according to claims 1-7, characterized in that the reaction is carried out at a temperature of 80-150 ° C. Process according to claim 8, characterized in that the reaction is carried out at a temperature of 100-120 ° C. 10. A process for the preparation of medicaments based on an apovincamic acid ester, characterized in that an apovincamic acid ester is used, mentioned in claim 1 and prepared according to a method indicated in claims 1-9. Eindhoven, August 1981 t 8104044