GB2086886A - Process for the Preparation of Apovincaminic Acid Esters - Google Patents

Abstract

Apovincaminic acid esters of the general formula (I> <IMAGE> (wherein R<1> and R<2> independently represent alkyl groups having from 1 to 6 carbon atoms) may be prepared by reacting a hydroxyamino-E-homo- eburnane of the general formula (II> <IMAGE> (wherein R<1> and R<2> are as defined above) or an acid addition salt thereof with an organic sulfonic acid, in an aprotic organic solvent. The compounds of the general formula (I) are useful pharmaceuticals.

Description

SPECIFICATION Process for the Preparation of Apovincaminic Acid Esters The invention relates to a new process for the preparation of apovincaminic acid esters. More particularly, the invention concerns a process for preparing racemic or optically active apovincaminic acid esters of the general formula (1)

(wherein R' and R2 independently represent alkyl groups having from 1 to 6 carbon atoms).

According to the invention the apovincaminic acid esters of the general formula (I) are prepared by reacting a hydroxyamino-E-homo-eburnane of the general formula (11)

(wherein R' and R2 are as hereinbefore defined) or an acid addition salt thereof with an organic sulfonic acid, in an aprotic organic solvent.

In the definition of Fli and R2 the term "alkyl group havin from 1 to 6 carbon atoms" is used to refer to straight or branched chained alkyl groups with 1 to 6 carbon atoms, e.g. methyl, ethyl, npropyl, isopropyl, n-butyl, sec-butyl, etc.

It is well known that apovincaminic acid esters of the general formula (I), wherein R and R2 are as defined above, possess valuable pharmacological properties, and in particular the (+)- apovincaminic acid ethylester is known to be an excellent vasodilator.

According to Hungarian Patent Specification No. 163,143 these compounds have been prepared by subjecting the pharmaceutically active vincamine to hydrolysis and converting the vincaminic acid obtained into the corresponding ester. The corresponding apovincaminic acid ester was then prepared from the vincaminic acid ester by splitting off water. According to another method vincamine was first converted into apovincamine by splitting off water, whereupon apovincamine was hydrolysed and the apovincaminic acid obtained converted into the desired ester.

A disadvantage of these processes is that vincamine has first to be prepared by a multi-step synthesis and from this compound the corresponding apovincaminic acid esters can be obtained only with a yield of at most 60%.

According to another process disclosed in Published Japanese Patent Application 53061757 compounds of the above general formula (I) wherein R' and R2 are as hereinbefore defined have been prepared by reacting the corresponding 1 4-oxo- 1 5-hydroxy-im no-3a, 1 6a-E-homo- eburnane with the corresponding alcohol, in the presence of an acid.

The most important disadvantage of this process is that at the reaction temperature involved, which exceeds 100 to 1 04 C, a large amount of the ether corresponding to the alcohol used is also obtained. For example if ethyly alcohol is used as an alcohol in the reaction, large amounts of diethyl ether are also formed due to the presence of the dehydrating acid. The formation of ethers is particularly disadvantageous when the processes are to be used on an industrail scale since the presence of ethers leads to an increased danger of fire and expiosion, and accordingly extreme safety requirements.

A further drawback of this process is that generally concentrated sulfuric acid is used for dehydration and the highly reactive nature of this reagent gives rise to side reactions which decrease the yield and also worsen the quality of the end product.

It has now been found that it there is employed as starting material a compound which already has the ester group corresponding to the desired apovincaminic acid ester of the general formula (I), the use of alcohol can be eliminated and accordingly, no ether formulation takes place. For this purpose compounds of the general formula (II), wherein R1 and R2 have the meanings defined above, can be used to advantage.

Starting compounds of the general formula (II) may be prepared by reaction of the corresponding hexahydroindoloquinolizinium compounds with methylenemalonic acid diesters according to a process disclosed in Hungarian Patent Application Rl-7 13. In the process according to the invention the compounds of the general formula (II) can be employed as such or in the form of their acid addition salts with inorganic or organic acids, preferably the hydrochlorides.

It has further been found that if concentrated sulfuric acid is replaced in such reactions by less corrosive organic sulfonic acids, e.g. aliphatic or aromatic sulfonic acids, the danger of corrosion of the equipment used is considerably reduced.

The use of organic sulfonic acids instead of concentrated sulfuric acid also decreases side reactions due to corrosion, and thus not only the yield but also the quality of the end product is improved. The improvement in quality is of particular importance, since the compounds of the general formula (I) prepared by this process are intended for pharmaceutical use.

As aliphatic sulfonic acids sulfonic acids containing an aliphatic carbon chain having 1 to 1 2 carbon atoms, e.g. methanesulfonic acid, ethanesuifonic acid, dodecylsulfonic acid, 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, e.g.

benzenesulfonic acid, p-toluenesulfonic acid, anaphthylsulfonic acid, 13-naphthylsulfonic acid, etc. For 1 mole of a compound of the general formula (II) preferably 2 to 3 moles of sulfonic acid are used.

As a solvent aprotic organic solvents such as optionally halogenated aromatic hydrocarbons, e.g. benzene, toluene, xylene, chlorobenzene, or cyclic ethers, e.g. dioxane, can be employed.

The reaction is preferably performed at a temperature of 80 to 1 500C, more preferably 100 to 1 200C. The reaction time is a function of the temperature.

The reaction is preferably carried out under anhydrous conditions.

By the new process according to the invention either racemic or optically active compounds of the general formula (I) can be prepared starting from the appropriate racemic or optically active compounds of the general formula (II). Referance herein to optically active compounds of general formula (I) or (II) is to be taken to refer to the pure optically active compounds of mixtures of such compounds possessing optical activity.

A major advantage of the process of the invention over the processes known in the art is that by this process the apovincaminic acid esters of the general formula (I) can be prepared starting from readily available compounds, using less corrosive reactants which are easy to handle, giving rise to an increased yield and high purity.

The process provided is easy to carry out on industrial scale and does not involve safety problems.

According to the most preferred embodiment of the process according to the invention a compound of the general formula (II) or an acid addition salt, preferably the hydrochloride, thereof is boiled with dryp-toluenesulfonic acid in toluene for 1 to 2 hours.

Further details of the invention are illustrated by the following, non-limiting Examples.

Example 1 70 g. (0.1 moles) of (-)-1a- (carbomethoxyethyl)-la-ethyl- 1 ,2,3,4,6,7,12,1 2b-octahydro-indolot2,3- ajquinolizine-D-dibenzoyl tartarate are suspended in 300 ml. of toluene. To the suspension 70 ml. of concentrated aqueous ammonium hydroxide solution are added 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, whereupon the mixture is made up to 300 ml.

with toluene. To the toluene solution 36 ml. (31 g.) of tert-butyl-nitrite and 25 g. of sodium tert butylate are added and the mixture is stirred in nitrogen atmosphere, at 300C for 25 minutes. To the reaction mixture 300 ml. of ethanol are then added and it is stirred at 600C for 1 hour. The pH is adjusted to 2 by addition of 36% aqueous hydrochloric acid solution at room temperature, the mixture is cooled to 0 and the precipitated substance is filtered off at this temperature and washed with two 100-ml. portions of water. The product obtained is air dried and is then treated with 150 ml. of a 10% aqueous ammonium hydroxide solution.The product is filtered off, washed with three 50-ml. portions of water and dried. 20 g. of (-)-14-ethoxycarbonyl-14- hydroxyamino-3a,1 6a-eburnane are obtained, melting at 172 to 1 730C. Yield 52%.

(aJ020= 144.1 (c=1, chloroform) Example 2 199 (0.05 moles) of (-)-1 4-ethoxycarbonyl- 1 4-hydroxyamino-3c',1 6a-eburnane prepared according to Example 1 and 1 9.8g. (0.125 moles) or dry p-toluene-sulfonic acid are boiled in 350ml.

dry toluene for 1.5 hours. The reaction mixture is cooled to 200C, whereupon 200ml. of water are added and the pH of the mixture adjusted to 9 with about 20ml. concentrated ammonium hydroxide solution. The organic phase is separated and the aqueous phase extracted with 50ml. of toluene. The toluene phases are combined, dried on anhydrous sodium sulfate and filtered. The filtrate is then decolourised with 1 g.

of activated carbon and filtered. The filtrate is evaporated to dryness in vacuo, and the evaporation residue dissolved in 20ml. of ethanol, boiled for one minute and crystallized after cooling to OOC. 16.6g. of (+)-apovincaminic acid ethylester are obtained, melting at 144 to 1460C.

Yield 95%.

[a120-+(l 44 1145.1)0 (c=1, chloroform).

Purity: 99.8 to 100.19/0 (in glacial acetic acid, in the presence of indicator, using perchloric acid for titration).

Example 3 Water is eliminated by azeotropic distillation from a solution of 47.59. (0.23 moles) of ptoluene-sulfonic acid hydrate in 400ml. of toluene.Thereafter42g. (0.1 moles) of(-)-14- ethoxycarbonyl-1 4-hydroxyamino-3a, 1 6a- eburnane hydrochloride are added to the dry mixture, which is then refluxed for two hours with stirring. The reaction mixture is then cooled to + 10 C and 100ml. of water, 30ml. of a 25% aqueous ammonium hydroxide solution and 29. of celite are added and the reaction mixture stirred at + 1 00C for 5 minutes whereupon it is filtered.

The aqueous and a toluene phases of the filtrate are separated, the aqueous phase is extracted with 50ml. of toluene and the toluene phases are combined. The combined toluene phases are washed with 50ml. water, dried on 209. of anhydrous sodium sulfate and filtered. The filtrate is exaporated to dryness in vacuo, to the evaporation residue 40 ml. of ethanol are added, the solution obtained is boiled for one minute and is then cooled to OOC. The mixture is allowed to stand at 0 C for one hour, the precipitated product is filtered off, is washed by covering with two 20-ml. portions of ethanol of a temperature of 0 C and dried. 30g. (86%) of (+)apovincaminic acid ethylester are obtained, melting at 144 to 1460C.

[]D =+(141 to 146)0 (c=1,chloroform) Analysis for C22H2sN202 (molecular weight: 350.44): calculated: C 75.33%, H 7.45%, N 7.999f found: C 75.31%, H 7.42%, N 7.909( Example 4 Following the procedure described in Example 3 but starting from 38g. (0.1 moles) of (-)-14- ethoxycarbonyl- 1 4-hydroxyamino-3a. 1 6a- eburnane, 31 .5g (90%) of (+)-apovincaminic acid ethylester are obtained, melting at 144 to 1460C.

[a]o20=+(141 to 146)0 (c=1, chloroform).

Example 5 Following the procedure described in Example 3 but using 400ml. of benzene instead of 400ml.

of toluene as a solvent and carrying out the reaction in 12 hours, 23.4g (67,0%) of (+)apovincaminic acid ethylester are obtained, melting at 141 to 1450C.

[a]2 =+(141 to 144)0 (c=1,chloroform).

Example 6 Following the procedure described in Example 4 but using 400ml. of xylene instead of 400ml. of toluene as a solvent and carrying out the reaction in 30 minutes at a temperature of 1 400C 30.5g.

(87.3%) of (+)-apovincaminic acid ethylester are obtained, melting at 144 to 1 460C.

[a]D =+(141 to 146)0 (c=1,chloroform).

Example 7 Following the procedure described in Example 3 but using 400my. of chlorobenzene instead of 400ml. of toluene as a solvent and carrying out the reaction at 1 300C for 40 minutes, 30.8g.

(88%) of (+)-apovincaminic acid ethylester are obtained.

Example 8 Following the procedure described in Example 3 but using 43g. (0.25 moles) of dryp-toluenesulfonic acid instead of 47.59. (0.25 moles) of ptoluene-solfonic acid hydrate and 400ml. of dioxane instead of 400ml. of toluene,18.0g.

(51.5%) of (+)-apovincaminic acid ethylester are obtained, melting at 141 to 1430C.

[a]0=+(1 40 to 143)0 (c=1, chloroform).

Example 9 Following the procedure described in Example 3 but replacing 47.59. (0.25 moles) of p-toluenesulfonic acid hydrate by 27.59. (0.25 moles) of ethanesulfonic acid, 30.0g. (86%) of (+)apovincaminic acid ethylester are obtained, melting at 144 to 1460C.

[a]020=+(141 to 146)0 (c=1, chloroform).

Example 10 Following the procedure described in Example 3 but replaving 489. (0.25 moles) of p-toluenesulfonic acid hydrate by 39.59. (0.25 moles) of benzenesulfonic acid, 30.5g. (87.5%) (+)apovincaminic acid ethylester are obtained, melting at 144 to 146 OC.

[aS]DO=+( 141 to 146)0 (c=1, chloroform).

Claims (10)

Claims

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

(wherein R1 and R2 independently represent alkyl groups having from 1 to 6 carbon atoms), which comprises reacting a hydroxyamino-E-homoeburnane of the general formula (II)

(wherein R1 and R2 are as defined above) or an acid addition salt thereof with an organic sulfonic acid, in an aprotic organic solvent.

2. A process as claimed in clain 1, which comprises using p-toluene-sulfonic acid as the organic sulfonic acid.

3. A process as claimed in claim 1, which comprises using ethanesulfonic acid benzenesulfonic acid as the organic sulfonic acid.

4. A process as claimed in any one of claims 1 to 3, which comprises using as the aprotic organic solvent as aromatic hydrocarbon optionally substituted with halogen, or a cyclic ether.

5. A process as claimed in claim 4, which comprises using toluene as the aprotic organic solvent.

6. A process as claimed in claim 4, which comprises using benzene, xylene, chlorobenzene or diozane as the aprotic organic solvent.

7. A process as claimed in any one of claims 1 to 6, which comprises carrying out the reaction under an hydros conditions.

8. A process as claimed in any one of claims 1 to 7, which comprises carrying out the reaction at a temperature of 80 to 1 500C.

9. A process as claimed in claim 8, which comprises carrying out the reaction at a temperature of 100 to 1 200C.

10. A process for the preparation of racemic or optically active apovincaminic acid esters of the general formula (I) as defined above specifically as herein described with reference to Examples 2 to 10.

11 Racemic or optically active apovincaminic acid esters of the general formula (I), wherein R1 and R2 are as defined in claim 1, when ever prepared by a process as claimed in any one of claims 1 to 10.