GB2062619A - Preparation of apovincaminic acid esters - Google Patents

Abstract

A process for the preparation of apovincaminic acid esters having the general formulae (Ia) and/or (Ib), <IMAGE> wherein R is a C2-6 alkyl group, in which the respective vincaminic acid ester and/or epivincaminic acid ester is dehydrated in a water-immiscible organic solvent which forms azeotropic mixture with water, in the presence of a strong organic acid with a dissociation constant of about 10<-2> or higher, which acid is not capable of forming azeotropic mixture with water and has a low vapour pressure at the temperature of dehydration by continuously removing water from the system by azeotropic distillation.

Description

SPECIFICATION Process for the preparation of apovincaminic acid esters The invention relates to an improved process for the preparation of apovincaminic acid esters of the general formulae (la) and/or (Ib).

wherein R stands for a C26 alkyl group.

As known, apovincaminic acid esters, primarily the ethyl ester, possess valuable pharmaceutical effects and can be applied as hypotensive and vasodilating agents.

It is also known that the simplest method of obtaining apovincaminic acid methyl ester is to dehydrate vincaminic acid methyl ester. Up to now dehydration has been performed according to the following methods: a) heat treatment at 2200C (Tetrahedron Letters 1961, 702-6; Collection Czech. Chem.

Commun. 29, 433 46/1964/); b) boiling in acetic anhydride (Tetrahedron Letters 1961, 702-6, ibid. 1962, 1147-54; Collection Czech. Chem. Commun. 29, 433 46/1964/; Hungarian patent specification No. 151,295); c) boiling in formic acid (Tetrahedron Letters 1962, 1147-54; Hungarian patent specification No.

151,295; French patent specification No. 2,191,894); d) reaction with sulfuric acid in dichloromethane (Hungarian patent specification No. 1 60,367); e) boiling in phosphorous oxychloride, or reaction with phosphorous pentoxide or a phosphorous halide (Hungarian patent specification No. 151,295); f) boiling in an alcohol in the presence of hydrochloric acid (Chem. Zvesti 17, 41-53/1963/).

This latter method was also utilized when starting the reaction from vincaminic acid instead of its methyl ester. In this case, upon boiling vincaminic acid with alcohol in the presence of an acid, esterification and dehydration proceed simultaneously, yielding the apovincaminic acid ester corresponding to the alcohol applied (Hungarian patent specification No. 163,434). In this process hydrochloric acid can be replaced by other strong mineral or organic acids, such as sulfuric acid, alkylsulfonic acids, etc.

The above methods have the following disadvantages: With one exception, they enable one to prepare apovincaminic acid methyl ester (apovincamine) alone; only one of them (method c/) can be applied. to prepare the ethyl ester. Methods a), b) and c) have the common disadvantage that dehydration is performed under severe reaction conditions; e.g. the starting substance is treated at high temperatures for a prolonged period. Under such conditions the substances may be destroyed or decomposed very easily, the reaction mixture turns dark, tarry substances appear, undesired side reaction may occur, etc. Method a), performed at 2200C, provides the aimed compound with a yield of only 61%. According to method b) the reaction mixture is boiled at 1400C for 24 hours and the end-product is obtained with a yield of 75%.Method c) provides a yield of 97% only when the starting substance is boiled in formic acid for 5 hours. After boiling for one hour, the yield is only 64%. A further disadvantage of this latter method is the application of formic acid, a strongly corrosive, poisonous and vesicatory agent, the vapours of which attack the mocous membranes and form explosive mixtures with air. Thus in utilizing this method for the large-scale production several problems and inconveniences are encountered.

Method e) provides apovincamine with a very low yield (about 42%).

The situation is slightly better with methods d) and f). However, a common disadvantage of these two methods is that, like in the methods discussed above, dehydration is incomplete, and thus the endproduct is contaminted with a substantial amount of the starting substance. We observed, however, that the melting points of the end-products do not reflect the impurities of the substances; thus e.g. one cannot estimate the (+)-vincamine content of (+)-apovincamine from the melting point of a apovincamine product. This is clear from the data given in Table 1.

TABLE 1 Composition Melting point OC 100 % (+)-apovincamine 161-162 95 % (+)-apovincamine + 5% (+)-vincamine 159-161 90 % (t)-apovincamine + 10% (+)-vincamine 1 58-159 85 % (+)-apovincamine + 15% (+)-vincamine 1 58-160 The references disclosing methods c), d) and f) qualify the end-product by its melting point alone, which, as shown above, is sufficient for this purpose.Thus e.g. (+)-apovincamine prepared as described in Tetrahedron Letters 1962, 1147-54 (method c/) melts at 1 62-1 640C. The specific rotation power of this substance is, however, rather low, [ai20 = + 121 (c = 1, in chloroform), compared to that of pure (+)-apovincamine ([a]D0= +145 /c= 1,in chloroform/,see HeIv. Chim.Acta 58/4/, 1131-45/1975).

Methods d) and f) were reproduced in our laboratory, and were found to provide products of poor quality, being contaminated with the starting substance. Thus e.g., according to gas chromatographic results, about 14% of the vincamine remained unreacted in a reaction according to method d).

Apovincaminic acid esters can also be prepared, beside the dehydration methods discussed above, by esterifying apovincaminic acid (Hungarian patent specification No. 1 63,434). This process provides, however, the aimed compounds with low yields (58 to 61%). A further disadvantage of the esterification reaction is that apovincaminic acid itself, utilized as starting substance, is prepared generally by hydrolyzing an other apovincaminic acid ester.

The dehydration of vincaminic acid esters into apovincaminic acid esters is essentially an equilibrium reaction. Consequently, if the water split off in the reaction remains in the reaction mixture, it is able to reverse the reaction to a certain extent, and thus a certain amount of apovincaminic acid reconverts into vincaminic acid ester. This fact has led us to the recognition that if the water formed is removed continuously from the reaction mixture, the equilibrium reaction can be shifted practically completely towards the formation of apovincaminic acid esters.

Thus it has been found that vincaminic acid esters, epivincaminic acid esters and mixtures thereof can be converted simply into apovincaminic acid esters, when the starting substance is reacted at an elevated temperature, preferably at the boiling point of the mixture, with a strong acid in a waterimmiscible solvent which forms azeotropic mixture with water, and water formed in the reaction is removed continuously from the mixture by azeotropic distillation. The continuous removal of water shifts the equilibrium of the reaction towards dehydration, thus the reaction proceeds practically quantitatively, and apovincaminic acid ester free of the starting vincaminic acid ester is obtained. This advantage could not be attained by any of the prior methods.A further advantage of the process according to the invention is that dehydration is conducted under mild conditions within a short time (about 0.5 hours), in contrast to the lengthy boiling (frequently lasting for 5 to 24 hours) applied in the known methods. According to the invention dehydration is performed with a non-destructive acid, which has the additional advantage that the end-product is not destroyed or decomposed and side reactions do not occur. The yield of the process according to the invention is very high (95 to 98%). An additional advantage of the new process is that, unlike the dehyration methods known so far, its use is not restricted to the conversion of the methyl ester, but can be applied for the dehydration of higher esters (such as ethyl, propyl and butyl esters) as well.The most important advantage of the new process is, however, that it provides the apovincaminic acid ester in high purity. According to gas chromatographic analysis, the product obtained by the new process is not contaminated with the starting vincaminic acid ester.

Dehydration can be performed in any water-immiscible solvent which forms azeotropic mixture with water. Aromatic solvents of the benzene series, optionally haldgen-substituted, fully meet these requirements. Benzene, toluene, xylene, chlorobenzene and the like can be applied to advantage as solvents in the reaction according to the invention. The reaction temperature depends on the boiling point of the solvent selected.

Dehydration can be performed only in the presence of a strong acid. The acidic dissociation constant of the acid. characteristic of the acid strength, must be about 10-2 or higher. As further requirements, the acid applied must not form azeotropic mixture with water, its own vapour pressure at the temperature of dehydration should be negligible, and should allow the removal of water by distillation. Therefore, lower alkylsulfonic acids and sulfuric acid, which are, in fact, strong acids, cannot be applied in the process of the invention, since, owing to their strong water-binding character, they do not allow the total removal of water by azeotropic distillation.

Examples of the strong organic acids applicable in the dehydration process of the invention are monocyclic acnd bicyclic aromatic sulfonic acids (such as benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfosalicylic acid, d-camphersulfonic acid, etc.), furthermore organic monoor dicarboxylic acids, such as oxalic acid.

The vincaminic acid esters utilized as starting substances in the process of the invention are prepared preferably by the synthesis, easy to perform under large-scale conditions, too, described in the Hungarian patent specification No. 163,143. One of our aims was to combine this known synthesis with a new step in order to provide a reasonable large-scale method for the production of very pure apovincaminic acid esters with high yield. The synthesis described in the cited Hungarian patent specification yields as end-product a mixture of a vincaminic acid of the general formula (lit)

and an epivincaminic acid of the general formula (IV),

wherein R is as defined above.Our major aim was to convert this mixture, without separating or converting the individual substances or epimers, into the respective apovincaminic acid ester possibly directly in the reaction mixture, and to elaborate a large-scale method for dehydration more convenient than those described in the literature. Such a method has particular economical advantages, since both vincaminic and epivincaminic acid esters yield the same apovincaminic acid ester upon dehydration, and thus two steps of processing (separation of the starting substances, and separation or conversion of the individual epimers) can be omitted.

Thus, according to a preferred method of the invention, the procedure described in the Hungarian patent specification No.163,143 is performed first, i.e. a cis-1 -ethyl-1 -(2'-hydroxy-2' alkoxywarbonylethyl)-1,2,3,4,6,7,12,12b-octahydro-indoloL2,3-aSquinolisine of the general formulae (Ila) and/or (llb),

wherein R is as defined above, is oxidized with silver carbonate on celite, thereafter the oxidizing agent is removed to obtain a toluene solution of a mixture of a vincaminic acid ester having the general formula (III) and the epimeric compound having the general formula (IV). The method of the present invention is then carried out, i.e. an appropriate acid is added to the toluene solution, without isolating or epimerizing the compounds, and the solution is subjected to azeotropic distillation. In this way both the vincaminic acid ester and the epivincaminic acid ester convert into the required apovincaminic acid ester within a short time. The omission of the isomerization and separation steps not only increases the yield but also provides significant technological advantages by increasing the throughput of the equipment and decreasing the time required for the production. According to this particularly preferred method the simple tetracyclic indoloquinolisine derivatives of the general formulae (ill) and (llb), wherein R is as defined above, can be converted into the pentacyclic apovincaminic acid esters in as few as three reaction steps with an overall yield of 70 to 74%.

The process of the invention is elucidated in detail by the aid of the following non-limiting Examples.

EXAMPLE 1 Preparation of(+)-apovincaminic acid ethyl ester A mixture of 5.0 g of (+)-vincaminic acid ethyl ester, 5.0 g of p-toluenesuifonic acid and 300 ml of toluene is refluxed for 0.5 hours. During this period the water formed in the reaction is removed from the mixture by azeotropic distillation, utilizing a Marcusson trap. The progress of the reaction is monitored by thin layer chromatography (run with a 80:20:40 mixture of chloroform, ethanol and benzene on a silica gel/Kieseigel/plate and developed in iodine vapour).When the starting substance cannot be detected by thin layer chromatography, the reaction mixture is cooled to room temperature, washed with 200 ml of 5% aqueous sodium carbonate solution and then with 200 ml of water, dried over sodium sulfate, filtered, and the filtrate is evaporated in vacuo to a final volume of about 10 ml. 80 ml of ethanol are added to this residue, and the resulting solution is concentrated in vacuo to a final volume of about 6 to 8 ml, whereupon the product starts to separate slowly. The concentrate is maintained at OOC for one hour, the separated substance is filtered off, washed with 5 ml of ethanol, and finally dried.

4.55 g of the title compound, melting at 148-1 490C, are obtained. Purity grade: 99.7% (determined by titration with perchloric acid); [a]20 = + 143.90 (c = 1, in chloroform).

EXAMPLES 2 TO 11 Preparation of apo vincaminic acid ethyl esters One proceeds as described in Example 1 with the difference that reaction mixtures of the compositions as given in Table 2 are utilized. The yields and the identification data of the products are listed in Table 2.

The IR and UV spectra of the products prepared according to Examples 2 to 11 were identical with those of the authentic samples. Chromatographic examinations were performed by utilizing Kieselgel Merck grade silica gel plates as adsorbent and a 80:20:40 mixture of chloroform, ethanol and benzene as solvent. The chromatograms were developed with a 1% solution of ceric ammonium sulfate in phosphoric acid, and the chromatograms were evaluated in UV light at 360 nm. Under such conditions when e.g. 100 mg of the product were applied onto the plate, only a trace spot could be observed beside the spot of (+)-apovincaminic acid ethyl ester (R,: about 0.48).

Remarks to Table 2: * C = 1, in chloroform ** determined by titration with perchloric acid.

TABLE 2 Example Composition of the reaction mixture Reaction Yield [&alpha;] 20 Purity ** time, min. g % M.p. C D grade 2 5.0 g of (+)-vincaminic acid ethyl ester 5.0 g of p-toluenesulfonic acid. H2O 300 ml of benzene 30 4.60 97.0 148-149 +147.8 100.0 3 5.0 g of (+) - vincaminic acid ethyl ester 5.0 g of p-toluenesulfonic acid. H2O 300 ml of xylene 30 4.50 94.8 148-149 +146.2 99.3 4 5.0 g of (-)-vincaminic acid ethyl ester 5.0 g of p-toluenesulfonic acid. H2O 300 ml of toluene 30 4.53 95.5 144-145 -144.7 98.6 5 5.0 g of (#)-vincaminic acid ethyl ester 5.0 g of p-toluenesulfonic acid. H2O 30 4.58 96.4 126-127 0 99.5 6 5.0 g of a mixture of (#)-cincaminic acid ethyl ester and (-)-spivincaminic acid ethyl ester 30 4.52 95.8 147-148 +143.9 98.8 5.0 g of p-toluenesulfonic acid. H2O 300 ml of toluene 7 5.0 g of (#)-vincaminic acid ethyl ester 5.0 g of benzenesulfonic acid 300 ml of to toluene 30 4.58 96.5 148-149 +146.88 99.2 8 5.0 g of (#)-vincaminic acid ethyl ester 6.0 g of naphthalene-2-sulfonic acid H2O 300 ml of toluene 30 4.51 95.1 146-149 +146.0 99.8 Reaction Yield [&alpha;;] 20 * Purity ** Example Composition of the reaction mixture time, min. g % M.p. C D grade 9 5.0 g of (+)-vincaminic acid ethyl ester 6.5 g of D-camphersulfonic acid 300 ml of toluene 30 4.57 96.1 148-149 +144.2 98.6 10 5.0 g of (+)-vincaminic acid ethyl ester 12.5 g of oxalic acid 300 ml of toluene 30 4.50 94.8 147-148 +143.8 98.8 11 6.0 g of (+)-vincaminic acid ethyl ester 6.0 g of 5-sulfosalicylic acid 300 ml of toluene 30 4.56 96.0 148-150 +146.5 99.1 EXAMPLE 12 Preparation of(+)-apovincaminic acid ethyl ester A mixture of 60 g of dry silver carbonate/celite reagent, 600 ml of abolute toluene and 1 5 g of (-) cis- 1-ethyl- 1 -(2'-hydroxy-2'-ethoxycarbonylethyl)-1 ,2,3,4,6,7, 12,1 2b-octahydro-indolo[2,3- a]quinolisine is boiled for 5 hours under argon atmosphere.The progress of the reaction is monitored by thin layer chromatography as described in Example 1. When the reaction is over and no starting substance can be detected, the reaction mixture contains only (+)-vincaminic acid ethyl ester and (-)epivincaminic acid ethyl ester. At this stage the silver carbonate/celite reagent is filtered off at 800C and washed with toluene. The wash and the mother liquor are combined, and 1 5 g of p-toluenesulfonic acid monohydrate are added to the toluene solution. The reaction mixture is boiled for 0.5 hours. During this period the water formed in the reaction is removed from the mixture by azeotropic distillation, utilizing a Marcusson trap. The progress of the reaction is monitored by thin layer chromatography as described in Example 1.

At the end of the dehydration the toluene solution is cooled to room temperature, washed with 450 ml of 5% aqueous sodium carbonate solution, and then extracted thrice with 450 ml of 0.25 n aqueous hydrochloric acid, each. The aqueous-acidic extracts are combined, the pH of the solution is adjusted to 3 with concentrated aqueous ammonia, and the resulting solution is decolourized with 1.5 g of carbon. The pH of the decolourized solution is adjusted to 9 with concentrated aqueous ammonia, and the resulting alkaline solution is extracted thrice with 180 ml of dichloromethane, each. The dichloromethane solutions are combined, dried over sodium sulfate, filtered, and the filtrate is concentrated to a final volume of about 20 to 30 ml. 120 ml of 96% ethanol are added to the concentrate, and the resulting solution is concentrated in vacuo to a final volume of about 20 to 30 ml.

This concentrate is stored at OOC for one hour, thereafter the separated substance is filtered off, and washed with 10 ml of 96% ethanol.

9.6 g (67.6%) of the title compound are obtained; m.p.: 145-1 470C, purity grade: 99.8% (determined by titration with perchloric acid) [a]20 = +148.20 (c = 1, in chloroform).

EXAMPLE 13 Preparation of l+J-apovincaminic acid ethyl ester A mixture of 60 g of dry silver carbonate/celite reagent, 600 ml of absolute toluene and 1 5 g of (-)-cis- 1 cz-ethyl- 1 -(2'-hydroxy-2'-ethoxycarbonyl)- 1,2,3,4,6,7,12,12ba-octahydro-indolol2,3- a]quinolisine is boiled for 5 hours under argon atmosphere. The progress of the reaction is monitored by thin layer chromatography as described in Example 1. When the reaction is over, the silver carbonate/celite reagent is removed by filtration and washed with 90 ml of toluene. The mother liquor and the wash are combined, and 1 5 g of p-toluenesulfonic acid monohydrate are added to the toluene solution. The reaction mixture is boiled for 0.5 hours.During this period the water formed in the reaction is removed from the mixture by azeotropic distillation, utilizing a Marcusson trap. The progress of the reaction is monitored by thin layer chromatography as described in Example 1.

At the end of the reaction the toluene solution is cooled to room temperature, washed with 450 ml of 5% aqeuous sodium carbonate solution and then with 450 ml of water, dried over sodium sulfate, filtered, and the filtrate is evaporated to dryness in vacuo. 1 20 ml of 96% ethanol are added to the residue, and the solution is concentrated in vacuo to a final volume of about 20 to 30 ml. The concentrate is stored at OOC for one hour, thereafter the separated crystals are filtered off and washed with 10 ml of ethanol.

10.4 g (73.5%) of the title compound are obtained; m.p.: 1 45--1 47 OC, purity grade: 98.6% (determined by titration with perchloric acid) [a]20 = +1420 (c = 1, in chloroform).

Claims (7)

1. A process for the preparation of an apovincaminic acid ester of the general formulae (la) and/or (lb),

wherein R is a C26 alkyl group, by dehydrating a vincaminic acid ester of the general formulae (Illa) and/or (ill),

wherein R is as defined above, and/or an epivincaminic acid ester of the general formulae (IVa) and/or (IVb),

wherein R is as defined above, characterized by performing the dehydration in a water-immiscible solvent which forms an azeotropic mixture with water, in the presence of a strong organic acid with a dissociation constant of about 10-2 or higher, which acid is not capable of forming an azeotropic mixture with water and has a low vapour pressure at the temperature of dehydration, and removing continuously the water formed in the reaction by azeotropic distillation.

2. A process as claimed in claim 1, characterized by utilizing an aromatic hydrocarbon of the benzene series, optionally halogenated, as solvent.

3. A process as claimed in Claim 1 or Claim 2, characterized by utilizing an aromatic sulfonic acid or a carboxylic acid as strong acid.

4. A process as claimed in any of claims 1 to 3 wherein a mixture of the starting materials (Illa), (Illb), (IVa) and (IVb) is employed.

5. A process as claimed in claim 4 wherein the mixture is prepared by oxidation of a cis-l -ethyl-l - (2-hydroxy-2-alkoxycarbonylethyl)-l ,2,3,4,6,7,12,1 2bsctahydro-indolo[2,3-a]quinolisine ester.

6. A process as claimed in claim 1 substantially as hereinbefore descibed.

7. A process as claimed in claim 1 substantially as hereinbefore described with reference to the Examples.