DD201680A5 - PROCESS FOR PREPARING APOVINCAMINE ACID ESTERS - Google Patents

Abstract

The invention relates to a novel process for the preparation of Apovincaminsaeureestern the general formula I, wherein R is 1 and R is high 2 alkyl groups having 1 to 6 carbon atoms, which is characterized in that corresponding 14-hydroxyamino-14-alkoxycarbonyl-eburnane in aprotic organic solvent with organic sulfonic acid esters.

Description

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Process for the preparation of apovincamic acid esters

Field of application of the invention:

The invention relates to a novel process for the preparation of Apovincaminsäureestern of the general formula I, wherein

12

R and R are alkyl groups having 1 to 6 carbon atoms, which is characterized in that 14-hydroxyamino-14-alkoxycarbonyl-eburnane of the general

1 2 Formula II, wherein R and R have the above meaning, or acid addition salts thereof in aprotic solvents treated with organic sulfonic acids.

In the general formulaol and II, the substituents

R and R have straight or branched alkyl groups of 1 to 6 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, m-butyl, sec-butyl, etc. groups.

Characteristic of the known technical solutions:

It is well known that the apovincamic acid esters of the general formula I possess valuable pharmacological properties, especially the (+) - apovincamic acid ethyl ester is to be emphasized because of its significant vasodilatory effect.

I jj υ 3 / σ

The Apovincaminsaureester the general formula I were prepared according to the Hungarian Patent No. * 163 143 (corresponding to DE-PS 2 222 186) from the pharmaceutically valuable vincamine, in such a way that the obtained by hydrolysis of vincamine Vincarainsaure first in the desired Transferred ester and then obtained from this by dehydration of the corresponding Apovincaminsaureester, or first subjecting the vincamine dehydration, hydrolyzing the obtained apovincamine: and then converted the thus obtained Apovincarainsäure in the desired ester «

Such processes have the disadvantage that one must first prepare the vincamine by a multi-step synthesis in order to then convert this in maximum 60% yield in the desired Apovincaminsaureester can.

After aer Japanese Unexamined Patent Publication No. 53-147100 * Apovincaminsaureester of the general formula Γ manufactured such that the corresponding 14-0XO-15-hydroxyimino-3 dj, LYCO-E-homoeburnane in the presence of acids with a, the desired ester entsprehcenden alcohol, implemented.

This method shows dan disadvantage that is converted at the required Reaktionssteraperatur of at least 100 to 104 ⁰ C, under the action of the dehydrating acid used as a reactant alcohol to a considerable extent in the appropriate ether, so that, for example * in the application of ethanol significant amounts of diethyl ether are formed in the reaction mixture. This ether formation is particularly disadvantageous in the large-scale implementation of the method, since the resulting increased risk of fire and explosion requires complicated and very difficult executable safety measures in the construction of the operating device.

A further disadvantage of the above process is that various side reactions occur due to the decomposing action of the concentrated sulfuric acid used as a dehydrating agent, whereby both the yield and the purity of the end particle are adversely affected *

Object of the invention:

The aim of the invention is the removal of the o.g. Disadvantage.

Presentation of the essence of the invention:.

It has now been found, that if one uses for the preparation of Apovincarainsäureester of the general formula I those starting materials in which the desired ester group in the end product is already present, as is the case with the compounds of general formula II, the case may Formation of the double bond leading reaction can be carried out in the absence of alcohols, whereby the risks arising from the etherification are eliminated ·

The starting compounds of general formula II can be prepared from corresponding hexahydroindolo-quinoliziniumverbindungen by reacting with methylenemalonic diesters; the details of this method first described in Hungarian Patent Application RI-713 can be seen in Example 1 below. The compounds of general formula II can be used per se, or in the form of acid addition salts formed with inorganic or organic acids, especially in the form of hydrochlorides as starting materials of the process according to the invention.

It has also been found that, instead of: the highly corrosive concentrated sulfuric acid, it is advantageous to add the less corrosive and more easily treatable organic sulfonic acids, eg, aliphatic or aromatic sulfonic acids. can use this reaction; As a result, the corrosion stress of the operating equipment is significantly reduced. ,

The use of aliphatic or aromatic sulfonic acids instead of the decomposing concentrated sulfuric acid; also brings with it the further advantage that the side reactions caused by undesired decompositions can be largely eliminated, so that the end product is obtained in higher yield and in essentially better quality. This advantage is particularly important in the present case, since it is the production of products to be used as a medicinal product.

As the aliphatic sulfonic acids, any sulfonic acids containing 1 to 12 carbon atoms in the aliphatic carbon chain, e.g. Methanesulfonic acid, ethanesulfanic acid, oodecylsulfonic acid, etc .; as aromatic sulfonic acids are any, one or more aromatic rings and on the aromatic rings one or more, identical or different substituent bearing sulfonic acids, e.g. Benzolsulf onsäure, p-toluenesulfonic acid, <= ε - or ß-Naphthaiinsulfonsäure etc .. in consideration.- to 1 mol of the starting compound of the general formula II are suitably used 2 to 3 moles of sulfonic acid.

Reaction media may be aprotic organic solvents. for example, optionally halogen atom-substituted aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc., or cyclic ethers such as dioxane and the like. be used.

Ii ό U 3 / D

The reaction can be carried out at temperatures between 80 ⁰ C and 150 ⁰ C, advantageously at 100 to 120 ° C. The reaction time is: largely dependent on the reaction temperature used.

The reaction is conveniently carried out under anhydrous conditions *

According to the process according to the invention, both racemic and optically active compounds of the general formula I are prepared, yes after using racemic or optically active starting compounds of general formula IX.

The erfindungsgernäße process shows the important advantage over the known methods that it is assumed here of easily accessible and easily treatable compounds and less corrosive reagents are used; the desired Apovincaminsäureester of general formula I are obtained by a reaction free of side reactions, under mild conditions, in good purity and in high yield.

In. a particularly advantageous embodiment of the method according to the invention, the corresponding compound of general formula II or an acid addition salt ,, ,, especially the hydrochloride thereof in anhydrous toluene, with also; Anhydrous toluenesulfonic acid, boiled for 1 to 2 hours »

In the following embodiments, both the preparation of the starting materials of the general formula II and the practical embodiment of the process according to the invention for the preparation of the apovincamic acid esters of the general formula I are illustrated in more detail, but the invention is in no way limited to the content of these examples.

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EXAMPLES example 1

70 g (0.1 mol) of (~) -lc6 - (Methoxycarfaonyl-ethyl) -l -IcO-ethyl, 2,3 _# 4,6,7,12, .l2b-octahydroindol.o ^ ~ 2.3 -a7-quinolizine-0-dibenzoylta'trate was suspended in 300 ml of toluene. The suspension was treated with 70 ml of concentrated aqueous ammonium hydroxide solution and the mixture was stirred at room temperature for 10 minutes. The toluene phase was then separated, dehydrated by azeotropic distillation and the volume of the mixture was then made up to 300 ml with toluene. To the toluene solution was added 36 ml (31 g) of tert-butyl nitrite and 25 g of sodium tert-butoxide and the mixture was stirred in a nitrogen atmosphere at 30 ° C. for 25 minutes. .. The reaction mixture was then treated with 300 ml of ethanol, and stirred at 60 ⁰ C for one hour. The mixture was then acidified to pH 2 with 36 % strength aqueous hydrochloric acid, cooled to 0 ° C., and the precipitated product was filtered off at this temperature and washed twice with 100 ml of water each time. The product thus obtained was dried in air and the dried product was then treated with 100 ml of 10% aqueous ammonium hydroxide solution, filtered off, washed with 50 ml of water three times and dried.

20 g of this way (-) - (.. 521% of theory) l4-ethoxy-carbonyl-L4 -hydroxyamino-3 obtained pC, 16 ^ -eburnan, F. 172-173 ⁰ C, l " ki7 ² Q = -114.1 ° (c = 1, in chloroform).

Example 2 '.

19 g (0.05 mol) of (-) - l4-ethoxycarbonyl-l4-hydroxyamino-3sO, 16o6-eburan (prepared according to Example 1) and 19.8 g (0.125 mol) of anhydrous p-toluenesulfonic acid were in

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350 ml of anhydrous toluene refluxed for 1.5 hours. The reaction mixture was then cooled to 20 ⁰ C, with 200 ml of water and the pH of the mixture was adjusted to 9 with about 20 ml of concentrated aqueous ammonium hydroxide solution. The organic phase was separated and the aqueous phase extracted with 50 ml of toluene ». The combined extracts were dried with anhydrous sodium sulfate, filtered, the filtrate clarified with 1 g of activated carbon and filtered again, the filtrate clarified with 1 g of activated carbon and filtered again. The filtrate was evaporated in vacuo, evaporated to dryness, the residue dissolved in 20 ml of ethanol, this solution was boiled for 1 minute and cooled to ⁰ ° C., finally the product crystallized from the cooled solution was separated and dried.

There were thus obtained 16.6 g of (+) - apovincamic acid ethyl ester (95 % of theory ), mp .: 144-145 ° C, U & JJη ^a -. ⁺ l44, l. · - + 145.2 ° (c = 1, in chloroform). Purity of the product: 99.8 - 100.1 % (in glacial acetic acid, in the presence of; crystal violet indicator titrated)

i

Example 3

47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate were dissolved in 400 ml of toluene, the solution was dehydrated by azeotropic distillation, then with 42 g (0.1 mol) of (-) - l4-hydroxy-amino-ScO , le ^ O-eburnan hydrochloride and boiled under reflux for two hours with stirring. The Reaktionsgeraisch was cooled to +10 ⁰ C, treated with 100 ml of water, 30 ml of 25% aqueous ammonium hydroxide and 2 g of Celite filter media, stirred for 5 minutes at + 1O ⁰ C and filtered. The phases of the filtrate were separated from each other, the aqueous phase was extracted with 50 ml of toluene and the toluene phases were combined, washed with 50 ml of water and with 20 g of anhydrous sodium sulfate

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dried. After filtration, the filtrate was evaporated to dryness in vacuo, 40 ml of ethanol were added to the residue, the resulting solution was boiled for 1 minute, then cooled to 0 ° C. and allowed to stand for one hour at this temperature. The precipitated product was filtered off, washed with 20 r nol and dried.

was filtered, cooled down with 20 ml on ⁰ ° C Ätha-

Bs were thus obtained in this way 30 g (+) - apovincamic acid ethyl ester (86 % ά .. Th.), F.: 144-146 ° C, ^ cO / q ⁰ = -41 - + 146 ° (c = 1 in chloroform).

Analysis for ^C 22 ^H 25 ^N 2 ° 2 ( ^Mo1 x Wt. 350.44): Calculated: _{Q 7S> z 3% H 7/45 % N 7> gg %>} Found: C 75.31 % H 7.42 % H 7.90 %.

Example 4

The procedure was carried out in the manner described in Example 3, with the difference that 38 g (0.1 mol) of (-) - l4-Äthoxycarbonyl-l4 ~ hydroxyamino-3 MJ, 14 oC -Burnan were used as starting material 31.5 g of (+) - -povincamic acid ethyl ester (90 % of theory ) were obtained, F: 14 form).

Example 5

F .: 144-146 ° C, IcLj ² ^ = +141 - + 146 ° (c = 1, in Ghloro-

The procedure described in Example 3 was used, with the difference that instead of toluene 400 ml of benzene were used as solvent. The reaction time was 12 hours.

There were obtained in this way 32.4 g (+) -Apov.incarainsäure- ethyl ester (67.0 % ά. Th.), F.: 141-145 ° C, ~ ⁺¹⁴¹ - + 144 ° (c = 1, in chloroform).

Example 6

The procedure described in Example 3 was used, with the difference that instead of toluene 400 ml of xylene were used as solvent. The reaction was carried out at 140 ⁰ C, the reaction time was 30 minutes.

There were thus obtained 30.5 g (+) - apovincaric acid ethyl ester (87.3 % of theory ), mp .: 144-146 ° C, / J (i = ^ +141 - + 146 ° (c = 1, in chloroform).

' Example 7 ,

It was carried out in the manner described in Example 3, with the difference that instead of toluene 400 ral chlorobenzene were used as solvent. The reaction was carried out at 130 ° C, the reaction time was 40 minutes.

In this way, 30.8 g of (+) - apovincamic acid ethyl ester (88 % of theory ) were obtained.

Example 8

The procedure was as described in Example 3, with the difference that instead of 47.5 g (0.25 mol) of p-toluenesulfonic hydrate 43 g (0.25 mol) of anhydrous p-toluenesulfonic acid and as a solvent instead of Toluene 400 ml dioxane were used. The reaction was carried out at 100 ⁰ C, the reaction time was 16 hours.

There were obtained in this way 18.0 g (+) - Aüovincaminsäureäthylester (51.5 % d .. Th.). F .: 141-143 ° C, / JiJ Ϊ ⁰ = +140 - + 143 ° (c = 1, in chloroform).

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Example 9

The procedure described in Example 3 was followed, with the difference that instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate 27.5 g (0.25 mol) Äthansulfonsäure were used. 30.0 g (86 % of theory ) of (+) - apovimcarainic acid ethyl ester were obtained. M.p .: 144-146 ⁰ C,% = ^{l41 +} - ⁺ 146 ° (c = 1, chloroform).

; Example 10

The procedure described in Example 3 was followed, with the difference / that instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate 39.5 g (0.25 mol) Benzolszlfonsäure were used. 30.5 g of (+) - apovincamic acid ethyl ester (87.5 % of theory ) were obtained in this manner,

² ^

F .: 144-146 ⁰ C IkJ ² ^ y = +141 - + 146 ° (c = 1, in. Chloroform).

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Claims (8)

23309 7 6 Invention claim 1 2 general formula I, wherein R and R are alkyl groups having 1 to 6 carbon atoms, characterized in that 14-hydroxyaraino-14-alkoxycarbonyl-eburnane "12 of general formula II in which R and R have the above meanings, or acid addition salts thereof in aprotic organic solvents with organic sulfonic acids 1 ", process for the preparation of Apovincaminsaureestern the 2. The method according to item 1, characterized in that p-toluenesulfonic acid is used as organic SuIfansäure. 3 ... Method according to item 1, characterized in that one uses Äthansulfonsäure or benzenesulfonic acid as the organic sulfonic acid. 4 * Process according to the items 1 to 3, characterized in that one uses an optionally substituted by halogen aromatic hydrocarbon or a cyclic ether as aprotic organic solvent. 5. The method according to item 4, characterized in that toluene is used as aprotic organic solvent. 6. The method according to item 4, characterized in that one uses benzene, xylene, chlorobenzene or dioxane as aprotic organic solvent. 7. Process according to items 1 to 5, characterized in that aa & the reaction is carried out under anhydrous conditions * - 12 - 8. The method according to points 1 to 7, characterized in that one carries out the reaction at temperatures between 80 ° C and 15O ° C, especially at 100 to 12Q ° C. - For this a Forraelblatt -