FI69628C - NOW FOERFARANDE FOER FRAMSTAELLNING AV APOVINKAMINSYRAESTRAR - Google Patents

Description

1 69628

New method for the preparation of apovincaminic acid esters -Now förfarande för framställning av apovinkaminsyraestrar

The invention relates to a new process for the preparation of esters of apovincamine-5 acid. In particular, the invention comprises a process for the preparation of racemic or optically active esters of apovincaminic acid of formula I, 1 'li ~~ p j X A H ^ n, u)

15 A, L

1 "- ^ R 0C - \ y - wherein R 1 and R 2 are independently alkyl groups having 1 to 6 carbon atoms.

The process according to the invention for the preparation of apovincamic acid esters of the formula I is characterized in that a hydroxyamino-E-homo-eburnan of the formula II, 25 fO '· <- - · —....... ·! ':! i

I M H

I II H

^ \ N (II) 30 j! 1. .1 «; HO-HN - and R 2 are groups as defined above, or an acid addition salt thereof, to react with an organic sulfonic acid in an aprotic organic solvent.

In the definition of the groups R 1 and R 2, "alkyl-_, - Γ ..

2,69628 group having 1 to 6 carbon atoms "straight or branched alkyl chain having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc."

It is well known that the estovincamic acid esters of the formula I, in which R1 and R2 are groups as defined above, have valuable pharmacological properties and in particular the ethyl ester of (+) - apovincaminic acid is excellent as a vasodilator.

According to HU Patent Publication 163,434 (DE Patent Publication 2,253,750), these compounds were prepared by hydrolyzing pharmaceutically active vincamine and converting the resulting vincamic acid to the corresponding ester. From the obtained vincamic acid ester, the corresponding apovincamic acid ester was prepared by cleaving water. According to another alternative, vincamine was first converted by water cleavage to apovincamine, after which apovincamine was hydrolyzed and the resulting apo-vincamic acid was converted to the desired ester.

The disadvantage of this method is that vincamine must first be prepared by a multi-step synthesis and the corresponding esters of apovincamic acid are obtained from this compound in only a maximum yield of 60%.

According to another method disclosed in JP Patent Publication No. 63-061757, compounds of formula I wherein R 1 and R 2 are as defined above were prepared by administering 14-oxo-15-hydroxyimino- (3C, ) -E-homo-eburnan to react with the corresponding alcohol in the presence of an acid.

The main disadvantage of this process is that at the reaction temperature used, which rises to 100-104 ° C, a large amount of ether corresponding to the alcohol used is also obtained. For example, if ethyl alcohol is used as the alcohol in the reaction, a large amount of diethyl ether is also formed by the presence of the dehydrating acid present. Ether formation is particularly disadvantageous in industrial processes, as the presence of ethers leads to an increased risk of fire and explosion and, accordingly, to very demanding safety measures.

3 69628 Another disadvantage of this process is that highly reactive concentrated sulfuric acid is usually used to remove the water, which results in side reactions that reduce the yield and degrade the quality of the final product.

According to DE-A-2 948 116, the compounds are prepared using a more complex compound than according to the invention as a starting material. The starting material according to the DE application is a compound containing an optionally substituted high-volume aralkyloxyamino group, again a simple hydroxyamino group is used according to the invention. On the one hand, the compound is more complex and, on the other hand, this complex starting material must be prepared before use, and this preparation brings an additional step to the process compared to the starting material used according to the invention. Thus, the method according to the invention 15 is more advantageous than the method of the DE application publication.

It has now been found that if a compound which already has the same ester group as the desired apovincamic acid ester of the formula I is used as starting material, the presence of the alcohol 20 can be eliminated and thus no ether is formed. For this purpose, compounds of the formula II in which and are groups as defined above can very well be used.

The starting materials of formula II are prepared according to the method described in BE-A-25 883 576 from the corresponding hexahydroindoloquinolizine compounds with methylenemalonic acid diesters.

In the process according to the invention, the compounds of the formula II can be used as such or their acid addition salts with inorganic or organic acids, preferably the hydrochloride.

In addition, it has been found that if concentrated sulfuric acid is replaced by less corrosive organic sulfonic acids, such as aliphatic or aromatic sulfonic acids, the risk of corrosion of the equipment used is considerably reduced.

The use of organic sulfonic acids instead of concentrated sulfuric acid also reduces the side reactions caused by corrosion, 4 69628 so not only the yield but also the quality of the final product is improved. The improvement in quality is particularly important because the compounds of formula I prepared by this method are intended for medical use.

As the aliphatic sulfonic acids, sulfonic acids having 1 to 12 carbon atoms in the aliphatic carbon chain can be used, for example, methanesulfonic acid, ethanesulfonic acid, dodecylsulfonic acid, etc. Aromatic sulfonic acids include one or more aromatic sulfonic acids having one or more aromatic or with several identical or different substituents, such as benzenesulfonic acid, p-toluenesulfonic acid, ° K-naphthylsulfonic acid, β-naphthylsulfonic acid, etc. It is suitable to use 2-3 moles of sulfonic acid per mole of the compound of formula II.

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

The reaction is carried out at a temperature of 80 to 150 ° C, preferably 100 to 120 ° C. The reaction time is temperature dependent.

The reaction is preferably carried out under anhydrous conditions.

According to a most preferred embodiment of the process according to the invention, the compound of the formula II or its acid addition salt is allowed to boil with dry p-toluenesulfonic acid in toluene for 1-2 hours.

The novel process according to the invention makes it possible to prepare racemic and optically active compounds of the formula I using the corresponding racemic or optically active compounds of the formula II as starting materials.

A major advantage of this process over known processes is that the process can produce apovincamic acid esters of formula I in higher yield and higher purity using readily available starting materials and low corrosive reactants. The method of the invention is easy to apply on an industrial scale and does not involve safety risks.

The following embodiments describe the invention in more detail.

Example 1 19 g (0.05 moles) of (-) - 14-ethoxycarbonyl-14-hydroxyamino-3Λ- (3 · Ι, ΙβΆ) eburnan (prepared according to BE patent-10 publication 883 576) and 19, 8 g (0.128 mol) of dry p-toluenesulfonic acid are boiled in 350 ml of dry toluene for 1.5 hours. The reaction mixture is cooled to 20 [deg.] C., after which 200 ml of water are added and the pH is adjusted to 9 with about 20 ml of concentrated ammonium hydroxide solution. 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 and decolorized with 1 g of activated carbon and filtered. The filtrate is evaporated to dryness under reduced pressure, the evaporation residue is dissolved in 20 ml of ethyl alcohol, boiled for one minute and crystallized after cooling to 0 ° C. 16.6 g of ethyl ester of (+) - apovincaminic acid with a melting point of 144-146 ° C are obtained. Yield: 95%. Z 10 ° = 7 (144.1-145.1) ° (c = 1, in chloroform). Purity: 99.8-100.1% (in acetic acid, in the presence of an indicator, titrated with perchloric acid).

Example 2 A mixture of 47.5 g (0.25 moles) of p-toluenesulfonic acid hydrate and 400 ml of toluene is dehydrated by azeotropic distillation. To the dry mixture is then added 42 g (0.1 mol) of (-) - 14-ethoxycarbonyl-14-hydroxyamino- (30 ° C, 16CK) eburnan hydrochloride, after which the mixture is refluxed with stirring for two hours. The reaction mixture is cooled to + 10 ° C, 100 ml of water, 30 ml of 25% ammonium hydroxide solution and 2 g of diatomaceous earth are added and the reaction mixture is stirred at + 10 ° C for 5 minutes, after which it is filtered. The aqueous and toluene phases of the filtrate are separated, the aqueous _____ - · I. ------- 6 69628 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 under reduced pressure, 40 ml of ethyl alcohol are added to the evaporation residue, the solution obtained is boiled for one minute and then cooled to 0 ° C. The mixture is allowed to stand at 0 ° C for 1 hour, the precipitated product is filtered off, washed by rinsing with two 20 ml portions of 0 ° C ethyl alcohol and dried. 10 g (86%) of (+) - apovincaminic acid ethyl ester with a melting point of 144-146 ° C are obtained. Z> S7p ° = - (141-146 °) (c = 1, in chloroform).

Calculated: C 75.33% H 7.45% N 7.99%

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

15 Example 3

Applying the procedure described in Example 2 starting from 38 g (0.1 mol) of (-) - 14-ethoxycarbonyl-14-hydroxyamino- (3'X, 16β) eburnan gives 31.5 g (90%) of (+) -apovincaminic acid ethyl ester with a melting point of 20,144-146 ° C. Λmax = + (144-146 °) (c = 1, in chloroform).

Example 4

Applying the procedure described in Example 2 using 400 ml of benzene instead of 400 ml of toluene as the solvent and carrying out the reaction for 12 hours, 23.4 g (67%) of ethyl 25 (+) - apovincaminic acid with a melting point of 141-145 ° C are obtained. [.Alpha.] D @ 20 = + (141 DEG-144 DEG) (c = 1, in chloroform).

Example 5

Applying the procedure described in Example 3 using 400 ml of xylene 30 instead of 400 ml of toluene as solvent and carrying out the reaction for 30 minutes at 140 ° C, 30.5 g (87.3%) of an ethyl ester of (+) - apovincaminic acid with a melting point of 144-146 ° C. Z * ° ^ 7p ^ = + (141-146 °) (c = 1, in chloroform).

Example 6 35 Applying the procedure described in Example 2 but using 400 ml of chlorobenzene instead of 400 ml of toluene as solvent and carrying out the reaction at 130 ° C 40 7 69628 per minute, 30.8 g (88%) of (+) - apovincaminic acid ethyl ester are obtained.

Example 7

Applying the procedure described in Example 2 but substituting 47.5 g (0.25 moles) of p-toluenesulphonic acid hydrate for 43 g (0.25 moles) of dry p-toluenesulphonic acid and using 400 ml of dioxane instead of 400 ml of toluene. 18.0 g (51.5%) of (-) - apovincaminic acid ethyl ester with a melting point of 141-143 ° C are obtained. = + 10 (140-143 °) (c = 1, in chloroform).

Example 8

Applying the procedure described in Example 2 but replacing 47.5 g (0.25 moles) of p-toluenesulfonic acid hydrate with 27.5 g (0.25 moles) of ethanesulfonic acid, 30.0 g (86%) of (+) -apovincaminic acid ethyl ester with a melting point of 144-146 ° C. [.Alpha.] D @ 20 = + (141-146 °) (c = 1, in chloroform).

Example 9

Applying the procedure described in Example 2 but replacing 48 g (0.25 moles) of p-toluenesulfonic acid hydrate with 39.5 g (0.25 moles) of benzenesulfonic acid, 30.5 g (87.5%) of (+) -apovincaminic acid ethyl ester with a melting point of 144-146 ° C. [.alpha.] D @ 20 = + (141-146 °) (c = 1, in chloroform).

Claims (9)

A process for the preparation of racemic or optically active esters of apovincamic acid of the formula I, il ......... il 'Ί M li u! | 'I: n; \, · N (I) io 'N' v 'i i. : 1. R OOC r2 wherein and R2 are independently alkyl groups having 1 to 6 carbon atoms, characterized in that a hydroxyamino-E-homoeburnan of the formula II is administered, 20 ·· '„il I 1! | H S ·' - '' ; n - N '. (II) I I l 25 HO-HN? : '... R 100C 1 R wherein R 1 and R 2 are groups as defined above, or an acid addition salt thereof, react with an organic sulfonic acid in an aprotic organic solvent. Process according to Claim 1, characterized in that p-toluenesulfonic acid is used as the organic sulfonic acid. Process according to Claim 1, characterized in that ethanesulfonic acid or benzenesulfonic acid is used as the organic sulfonic acid. 9,69628 Process according to one of the preceding claims, characterized in that an aromatic hydrocarbon optionally substituted by halogen or a cyclic ether is used as the aprotic organic solvent. Process according to Claim 4, characterized in that toluene is used as the aprotic organic solvent. Process according to Claim 4, characterized in that benzene, xylene, chlorobenzene or dioxane are used as the aprotic organic solvent. Process according to one of the preceding claims, characterized in that the reaction is carried out under anhydrous conditions. Process according to any one of Claims 1 to 7, characterized in that the reaction is carried out at a temperature of 80 to 150 ° C. 8 69628 Process according to Claim 8, characterized in that the reaction is carried out at a temperature of 100 to 120 ° C. 69628