JPS6232748B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to general formula (a) and/or (
b)

【formula】

The present invention relates to an improved method for producing apovincamic acid ester of the formula: wherein R represents a C _2-6 alkyl group. As is well known, apovincamic acid esters, mainly apovincamic acid ethyl ester, have useful pharmacological effects and can be applied as antihypertensive agents and vasodilators. It is also known that the simplest method for producing apovincamic acid methyl ester is to dehydrate the apovincamic acid methyl ester. Traditionally, dehydration has been carried out according to the following methods: (a) Heat treatment at 220°C [Tetrahedron
Letters 1961 , 702-6; Collection Czech,
Chem.Commun. 29 , 433-46 (1964)]; (b) boiling in acetic anhydride [Tetrahedron
Letters 1961 , 702-6; Letters 1962 , 1147-54;
Collection Czech.Chem.Commun. 29 , 433−46
(1964); Hungarian Patent Specification No. 151295
(c) boiling in formic acid [Tetrahedron Letters
1962 , 1147-54; Hungarian Patent Specification No.
151295; French Patent Specification No. 2191894]; (d) reaction with sulfuric acid in dichloromethane [Hungarian Patent Specification No. 160367]; (e) boiling in phosphorus oxychloride or diphosphorous pentoxide. or (f) boiling in alcohol in the presence of hydrochloric acid [Chem. Zvesti 17 , 41-53 (1963)]. This last method was also used when vincamic acid was used instead of vincamic acid methyl ester as the starting material. In this case, when vincamic acid is boiled with alcohol in the presence of acid, esterification and dehydration proceed simultaneously, resulting in an apovincamic acid ester corresponding to the applied alcohol (Hungarian Patent Specification No. 163434) . In this process, other strong mineral or organic acids such as sulfuric acid and alkylsulfonic acids can also be used instead of hydrochloric acid. The above method has the following drawbacks. With the exception of one method, only apovincamic acid methyl ester (apovincamine) can be prepared by these methods. Only one of these methods [method (c)] is applicable for the preparation of the ethyl ester. Processes (a), (b) and (c) have a common drawback of carrying out the dehydration under harsh reaction conditions, eg treating the starting materials at high temperatures for long periods of time. Under such conditions, the materials can be destroyed or decomposed very easily, the reaction mixture can darken, tarry substances appear, and undesirable side reactions can occur. Method (a) is
Produced at 220°C with only 61% target compound content
produced in a yield of . According to method (b), the final product is obtained with a yield of 75% by boiling the reaction mixture at 140° C. for 24 hours. Method (c) gives a yield of 97% only when the starting material is boiled in formic acid for 5 hours.
is achieved. After 1 hour of boiling, this yield is only 64%. A further disadvantage of this method lies in the application of formic acid. Formic acid is a powerful caustic, poisonous and blowing agent whose vapors attack mucous membranes and form explosive mixtures in the air. Therefore, some problems and inconveniences are encountered when using this method due to large scale production. In method (e) the yield of apovincamine is very low (approximately 42%). Things are slightly better with methods (d) and (f), but the common drawback of these two methods is that, like the previous methods, the dehydration is incomplete, so that the final product is The point is that it contains starting materials as impurities. However, we observed that the melting point of this final product did not reflect the presence of impurities. For example, from the melting point of the (+)-apovincamine product to the (+)- in the (+)-apovincamine
It is not possible to estimate the amount of vincamine. This is evident from the data in Table 1 below.

[Table] The references disclosing processes (c), (d) and (f) limit the final product only by its melting point, but
As mentioned above, it is inappropriate to limit the product based only on the melting point. For example, Tetrahedron
Letters 1962 , 1147-54 [method (c)].
The temperature is 162-164°C. However, the specific rotation of this substance is [α] ²⁰ _D = +121° (C = 1, in chloroform), which is the same as that of pure frame (+)-apovincamine {[α] ²⁵ _D = +145° (C = 1). , in chloroform)
}
[Helv.Chim.Acta 58 (4),
1131-45 (1975)]. When methods (d) and (f) were reproduced in our laboratory, it was found that a poor quality product was obtained which contained the starting material as an impurity. For example, according to the results of gas chromatography, about 14% of vincamine remained unreacted in the reaction of method (d). In addition to the dehydration method described above, apovincamic acid ester can also be prepared by esterification of apovincamic acid (Hungarian Patent Specification No. 163434). However, this method provides a low yield of the target compound (58-61%). Another disadvantage of the esterification reaction is that the apovincamic acid used as starting material is itself generally prepared by hydrolysis of esters of other apovincamic acids. The dehydration of vincamic acid ester to apovincamic acid ester is essentially an equilibrium reaction. Therefore, if the water separated during the reaction remains in the reaction mixture, the reaction can be reversed to some extent, so that some of the apovincamic acid ester is converted back into the vincamic acid ester.
This fact shows that if the water formed is continuously removed from the reaction mixture, the equilibrium reaction can be almost completely shifted in the direction of apovincamic acid ester formation. The inventors prepared the starting materials, i.e., vincamic acid esters, epivincamic acid esters and mixtures thereof, and strong acids in a water-immiscible solvent that forms an azeotrope with water at an elevated temperature, preferably at the boiling point of the mixture. It has been found that the starting material can be easily converted into apovincamic acid ester if the reaction is carried out in a stepwise manner and the water formed during the reaction is continuously removed from the mixture by azeotropic distillation. Since the equilibrium of the reaction is shifted in the direction of dehydration by continuous removal of water, the reaction proceeds almost quantitatively and an apovincamic ester free of starting vincamic ester is obtained. This advantage could not be achieved by any of the previous directions. Another advantage of the method according to the invention is that in the known methods the long boiling time (5 to 24
dehydration is carried out under mild conditions over a short period of time (approximately 0.5 hours). According to the invention, there is a further advantage that the final product is not destroyed or decomposed and no side reactions occur since the dehydration is carried out using a non-destructive acid. The yield of the process according to the invention is very high (95-98%). A further advantage of this new process is that, unlike previously known processes, its use is not limited to the conversion of methyl esters, but is equally applicable to higher esters (e.g. ethyl, propyl and butyl esters). It is possible to do so. However, the most important advantage of this new process is that it provides apovincamic acid ester of high purity. According to gas chromatographic analysis, the product obtained by this method is not contaminated by the starting vincamic acid ester. Dehydration can be carried out in a water-immiscible solvent that forms an azeotrope with water. A halogen-substituted or unsubstituted benzene-based aromatic solvent fully satisfies these requirements. Benzene, toluene, xylene, chlorobenzene, etc. can be advantageously applied as a solvent in the reaction according to the present invention. The reaction temperature depends on the boiling point of the chosen solvent. Dehydration can only be carried out in the presence of strong acids. The dissociation constant of the acid indicating acidity should be about 10 ^-2 or greater. A further requirement is that the applied acid must not form an azeotrope with water;
Its vapor pressure must be negligible at the dehydration temperature and must allow removal of water by distillation. Therefore, even though lower alkyl sulfonic acids and sulfuric acids are strong acids, they have strong water binding properties, and water cannot be completely removed by azeotropic distillation in the presence of such acids. It cannot be applied to invention methods. Examples of strong organic acids applicable to the dehydration process of the present invention include monocyclic and bicyclic aromatic sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfosalicylic acid, d-camphorsulfonic acid). acids, etc.), as well as organic monocarboxylic or dicarboxylic acids, such as oxalic acid. In the process of the invention, the vincamic acid ester used as starting material is preferably prepared by the synthetic method described in Hungarian Patent Specification No. 163143, which can be carried out easily under large-scale conditions. . One of the objects of the present invention is to provide a fairly large-scale process for producing extremely pure apovincamic acid ester in high yields.
It was decided to combine this known method with a new step. In the synthesis method described in the above-mentioned Hungarian patent specification, the general formula () Vincamic acid (wherein R is as described above) and general formula () (wherein R is as defined above) with epivincamic acid is obtained as the final product. The main object of the present invention is to convert this mixture to produce the respective apovincamic acid ester directly in the reaction mixture, rather than separating or converting the individual substances or epimers, and by methods described in the literature. I was able to devise a large-scale dehydration method that is also convenient. Such a process is preferred because vincamic acid ester and epivincamic acid ester yield the same apovincamic acid ester upon dehydration, so that two steps (separation of the starting material and separation or conversion of the individual epimers) can be omitted. It is particularly economically advantageous. Therefore, in a preferred method of the invention, first:
The procedure described in Hungarian patent specification no. 163143 is carried out. That is, general formula (a) and/or (b)

【formula】

[Formula] (wherein R is as described above) cis-1-ethyl-
1-(2'-hydroxy-2'-alkoxycarbonylethyl)-1, 2, 3, 4, 6, 7, 12, 12b
-Octahydro-indolo[2.3-a]quinolidine is oxidized with silver carbonate on Celite and then the vincamic acid ester of general formula () and the general formula () are A toluene solution of the mixture with the epimeric compound is obtained. Then, the method of the present invention is carried out. That is, a suitable acid is added to this toluene solution without isolation or epimerization of these compounds, and this solution is subjected to azeotropic distillation. Thus, both vincamic acid ester and epivincamic acid ester are converted into the desired apovincamic acid ester within a short time. Omitting the isomerization and separation steps not only increases the yield, but also
Significant technical advantages result from increased equipment throughput and reduced manufacturing times. In this particularly preferred process, simple tetracyclic indoquinolidine derivatives of general formulas (a) and (b), in which R is as previously described, are converted into pentacyclic apovincamic acid esters in three reaction steps. Can be converted (total yield: 70
~74%). The method of the invention will be explained in detail by the following examples, but the invention is not limited thereto. Example 1 Production of (+)-apovincamic acid ethyl ester (+)-vincamic acid ethyl ester 5.0 g, p
- A mixture of 5.0 g of toluenesulfonic acid and 300 ml of toluene was refluxed for 0.5 hour. During this time the water formed in the reaction was removed from the mixture by azeotropic distillation using a Marcusson trap. The progress of the reaction was monitored by thin layer chromatography (developed on silica gel (Kieselgel) plates with an 80:20:40 mixture of chloroform, ethanol and benzene and developed with iodine vapor). When the starting material could no longer be detected by thin layer chromatography, the reaction mixture was cooled to room temperature, washed with 200 ml of 5% aqueous sodium carbonate solution, then washed with 200 ml of water, dried over sodium sulfate, and the liquid was evaporated under reduced pressure to a final volume of approximately 10 ml. To this residue was added 80 ml of ethanol and the resulting solution was then concentrated under reduced pressure to a final volume of about 6-8 ml, and the product gradually began to precipitate out. The concentrate was kept at 0° C. for 1 hour, the precipitated material was separated off, washed with 5 ml of ethanol and finally dried. As a result, 4.55 g of the target compound was obtained. Melting point: 148-149°C, purity: 99.7% (measured by titration with perchloric acid), [α] ²⁰ _D +143.9° (C
=
1 in chloroform). Examples 2 to 11 Preparation of apovincamic acid ethyl ester The procedure described in Example 1 was repeated using mixtures with the compositions listed in Table 2. Product yield and confirmatory test data are shown in Table 2. Products prepared according to Examples 2 to 11
The IR and UV spectra were consistent with those of authentic samples of the compound of interest. Chromatography was carried out using silica gel plates of Kieselgel Merck, grade as the adsorbent and an 80:20:40 mixture of chloroform, ethanol and benzene as the solvent. The chromatograms were treated with a 1% solution of cerium ammonium sulfate in phosphoric acid and evaluated in UV light at 360 nm.
For example, if 100 mg of the product is applied on a plate, under these conditions spots of (+)-apovincamic acid ethyl ester (R _f : approx.
Only a few spots were observed other than 0.48).

【table】

[Table] Example 12 Production of (+)-apovincamic acid ethyl ester Dry silver carbonate/Celite reagent 60g, anhydrous toluene
600 ml and (-)-cis-1-ethyl-1-(2'-
Hydroxy-2'-ethoxycarbonylethyl)-
A mixture of 15 g of 1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolidine was boiled for 5 hours under an argon atmosphere. The progress of the reaction was monitored by thin layer chromatography as in Example 1. When the reaction is complete and no starting material is detected, the reaction mixture is (+)
-vincamic acid ester and (-)-epivincamic acid ethyl ester. At this stage, the silver carbonate/celite reagent was separated at 80°C and washed with toluene. The wash liquor and mother liquor were combined, p-toluenesulfonic acid-hydrate was added to the toluene solution, and the mixture was boiled for 0.5 hour. The water formed in the reaction during this time was removed from the mixture by azeotropic distillation using a Marcusson trap. The progress of the reaction was monitored by thin layer chromatography as in Example 1. After dehydration, cool the toluene solution to room temperature,
It was washed with 450 ml of a 5% aqueous sodium carbonate solution, and then extracted three times with 450 ml each of 0.25N aqueous hydrochloric acid. The aqueous-acidic extracts were combined, the pH of the solution was adjusted to 3 using concentrated aqueous ammonia, and the resulting solution was decolorized using 1.5 g of carbon. The pH of this decolorized solution was adjusted to 9 using concentrated aqueous ammonia, and the resulting alkaline solution was extracted three times with 180 ml of dichloromethane each time. The dichloromethane solutions were combined, dried over sodium sulfate, filtered, and the solution was reduced to a final solution of approximately 20
It was concentrated to 30 ml. To this concentrate was added 120 ml of 96% ethanol and the resulting solution was concentrated under reduced pressure to a final volume of approximately 20-30 ml. The concentrate was kept at 0° C. for 1 hour, then the precipitated material was separated and washed with 10 ml of 96% ethanol. As a result, 9.6 g (67.6%) of the target compound was obtained. Melting point: 145-147°C, purity: 99.8% (measured by titration with perchloric acid), [α] ²⁰ _D = +
148.2° (C=1, in chloroform). Example 13 Production of (+)-apovincamic acid ethyl ester 60 g of dry silver carbonate/Celite reagent, anhydrous toluene
600ml and (-)-cis-1α-ethyl-1-
(2'-hydroxy-2'-ethoxycarbonyl)-
A mixture of 15 g of 1.2.3.4.6.7.12.12bα-octahydro-indolo[2.3-a]quinolidine was boiled for 5 hours under an argon atmosphere. The progress of the reaction was monitored by thin layer chromatography in the same manner as in Example 1. At the end of the reaction, silver carbonate/
The Celite reagent was separated and washed with 90 ml of toluene. The mother liquor and wash liquor were combined, 15 g of p-toluenesulfonic acid monohydrate was added to the toluene solution, and the reaction mixture was boiled for 0.5 hour. During this time the water formed in the reaction was removed from the mixture by azeotropic distillation using a Marcusson trap. The progress of the reaction was monitored by thin layer chromatography as in Example 1. After the reaction, the toluene solution was cooled to room temperature and
% aqueous sodium carbonate solution, then 450 ml of water, dried over sodium sulfate,
and the liquid was evaporated to dryness under reduced pressure. Add 96% ethanol to this residue at 120%
ml and bring this solution to a final volume of approximately 20-30ml.
It was concentrated under reduced pressure. The concentrate was kept at 0° C. for 1 hour, then the precipitated crystals were separated and washed with 10 ml of ethanol. As a result, 10.4g (73.5%) of the target compound was obtained. Melting point: 145-147°C, purity: 98.6% (measured by titration with perchloric acid), [α] ²⁰ _D = +14
2
° (C=1, in chloroform).

Claims (1)

[Scope of Claims] 1 Vincamic acid ester of general formula (a) and/or (b) [Formula] [Formula] [wherein R is a C _2-6 alkyl group] and/or vincamic acid ester of general formula (a) ) and/or (b) [Formula] [Formula] [In the formula, R is as described above] by dehydrating the epivincamic acid ester of the general formula (a) and/or (b) [Formula] [Formula] ] A method for producing an apovincamic acid ester [wherein R is as described above], wherein the apovincamic acid ester has a dissociation constant of about 10 ^-2 or Carry out dehydration in a water-immiscible solvent that forms an azeotrope with water in the presence of a stronger organic acid and continuously remove the water formed during the reaction by azeotropic distillation. A manufacturing method characterized by: 2. The manufacturing method according to claim 1, wherein a halogenated or unsubstituted benzene-based aromatic hydrocarbon is used as the solvent. 3. The manufacturing method according to claim 1, wherein the strong acid is an aromatic sulfonic acid or a carboxylic acid.