HU206347B - Process for producing 17,18-dehydro-apovincaminol-3',4',5',-trimethoxy-b-benzoate - Google Patents

Abstract

17,18-dehydro-apovincamimol -3',4',5',tri:methyoxy-benzoate (I) is prepd by dehydrating 17,18-dehydro- or 17,18-dehydro -epi vincamine or any arbitrary mixt of these, to yield a 17,18-dehydro-apooimcamine- complex (III) reduced by a metallic-hydride to 17,18-apovincaminol (II). This is esterified with 3,4,5-tri:methoxy-benzoyl-chloride, 17,18-dehydro or 17,18 dehydro-epi-vincamine or opt mixt, dissolved in an organic solvent, reacted at the b.pt. of the solvent in the presence of p-toluenesulphonic-acid. Water produced is removed simultaneously by distn. (III) reacts with Li-Al hydride in mixt. of a hydrocarbon and an ether. Acylation of 17,18-dehydro-apo -viacamine with 3,4,5 tri:methoxy-benzoyl- chloride takes place in the presence of an acid scavenger and the prod is isolated.

Description

The present invention relates to a novel improved process of formula (I)

17.18-dehydro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate.

The compound inhibits the phosphodiesterase enzyme and is thus useful in the treatment of psoriasis in dermatology. The preparation of the compound was first described in Hungarian Patent No. 183,323. Accordingly, it is of formula (IV)

17.18-dehydro-vincamine and 17,18-dehydro-epivincamine were reacted with acetyl chloride in a chloroform medium in the presence of formic acid to give 17,18-dehydro-apovincamine (III) in 93.7% yield. Subsequently, lithium aluminum hydride reduction afforded 95% yield of 17,18-dehydro-apovincaminol II, followed by 1.4-1.5 molar equivalents of 3,4,5-trimethoxybenzoyl chloride in the presence of pyridine in 80% yield. they received the

17.18-dehydro-apovincaminol 3 ', 4', 5'-trimethoxybenzoate. The combined yield of starting material was 71.2%.

The disadvantage of the process is that by the dehydration reaction with acetyl chloride, by-products are formed and therefore all intermediates have to be isolated and purified, which causes significant losses.

In order to overcome the above drawbacks, the authors of Hungarian Patent No. 192,932 reversed the order of the reactions by reducing the mixture of 17,18-dehydro-vincamine and 17,18-dehydro-epivincamine with lithium aluminum hydride and subsequently A mixture of 17,18-dehydro-vincaminol and 17,18-dehydroepivincaminol in equimolar amounts

Acylated with 3,4,5-trimethoxybenzoyl chloride and the resulting epimeric ester mixture was reacted with acetyl chloride in formic acid to give the desired end product in 80.3% yield, starting from the starting material. This process is a significant improvement over the previous one, since there is no need to isolate intermediates and yields increased by almost 10%.

However, the process has the disadvantage that a compound containing a primary and tertiary hydroxyl group has to be selectively acylated so that only an equimolar amount of acylating agent is used. However, the selectivity of the acylation reaction with acid chloride and in the presence of a catalyst is still not satisfactory: to a small extent, the tertiary hydroxyl group is also acylated, leaving unreacted starting material due to the use of equimolar amounts of acid chloride.

Thus, 17,18-dehydro-vincaminol can be converted into a diester and in this case the starting dihydroxy compound is left unreacted.

From the latter, in the next step of dehydration with acetyl chloride, the primary hydroxy group is acetylated and also contaminates the product.

The same side reactions also occur with 17,18dehydro-epivincaminol, i.e. epimers of the above impurities are formed.

It is an object of the invention to overcome the above drawbacks and to develop a process which minimizes side reactions and thereby improves yield and product quality.

It has been found that the 17,18-dehydro-vincamine, or an epimer thereof, or any mixture of epimers in the presence of an excess of p-toluenesulfonic acid, is reacted at a temperature in a solvent medium and the resulting water is distilled from the reaction mixture by dehydration. The resulting 17,18-dehydro-apovincamine can be practically quantitatively reduced to 17,18-dehydro-apovincamine in a complex metal hydride, tetrahydrofuran solvent, and after removal of the excess reagent and filtration, the

17.18-Dehydro-apovincaminol can be acylated, without isolation, with a small molar excess of trimethoxybenzoyl chloride in an excellent solvent mixture.

The present invention thus provides a process for the preparation of 17,18-dehydroapovincaminol 3 ', 4', 5'-trimethoxybenzoate of formula (I)

Dehydration of 17.18-dehydro-vincamine or 17,18-dehydro-epivincamine or a mixture thereof in any ratio, with the resulting 17,18-dehydro-apovincamine with lithium aluminum hydride, followed by reduction of the resulting compound of formula (II) By acylation of 17,18-dehydro-apovincaminol with 3,4,5-trimethoxybenzoyl chloride and isolation of the resulting product by dehydration in toluene at a boiling point of the solvent of 1.3-1.6 moles per dehydro-vincamine. The reaction is carried out by distillation of the water formed in the presence of p-toluenesulfonic acid followed by reduction without isolation in a 3: 1 to 5: 1 by volume mixture of toluene and tetrahydrofuran and acylation in a 3: 1 to 1: 1 by volume dichloromethane / toluene solvent mixture. without isolation, 1.06-1.12 moles of 3,4,5-trimethoxybenzoyl chloride were used.

In carrying out the process of the present invention, the dehydration reaction is generally carried out in such a way that 17,18-dehydro-vincamine or 17,18-dehydro-epivincamine or any mixture thereof, in particular a nearly 1: 1 mixture thereof, is significant. and toluene, para-toluenesulfonic acid was added and the reaction mixture was refluxed and the resulting water was distilled off continuously.

The boiling point of toluene is excellent for completing the dehydration reaction. The molar excess of p-toluenesulfonic acid is required to complete the dehydration reaction, preferably from 1.3 to 1.6 molar equivalents. The reaction is usually complete within 1 hour.

After completion of the dehydration reaction, the reaction mixture was washed with aqueous-alkaline and then with aqueous stirring to neutral, then used without further isolation for subsequent reactions. If necessary, evaporation to dryness yields 17,18-dehydro-apovincamine.

In a further step of the process, the solution of 17,18-dehydro-apovincamine is dehydrated by azeotropic distillation followed by addition of lithium aluminum hydride and tetrahydrofuran under cooling. The reaction proceeds very rapidly. An excess of 1.35 to 1.45 molar equivalents of the reagent is conveniently used.

The 17,18-dehydro-apovincaminol formed is isolated 2

HU 206 347 Β, but the invention is a preferred embodiment! In the same manner, water (three times the weight of the lithium aluminum hydride reagent) is added to the reaction mixture, and the precipitate, which is mainly aluminum hydroxide, is filtered off and the resulting filtrate is dried by addition of a desiccant and azeotropic distillation. directly used for the acylation reaction.

To the solution of 17,18-dehydro-apovincaminol obtained in the above manner is added 3,4,5-trimethoxybenzoyl chloride and a tertiary amine acid binder such as triethylamine and dichloromethane (2: 1) is added at elevated temperature. toluene solvent mixture at reflux temperature. A catalyst such as dimethylaminopyridine is preferred. The 3,4,5-trimethoxybenzoyl chloride reagent should be used in a small excess of 1.061.12 moles. This ensures that the reaction is complete. Smaller quantities result in significant yield degradation, while large surpluses significantly increase the amount of by-products.

After completion of the acylation reaction, the reaction mixture is purified from the by-products by washing with an alkali and then with water, and after evaporation and exchange of solvent, the product is crystallized and isolated.

The advantages of the present invention are summarized below:

1. The strong acid catalyzed dehydration reaction can be completed by azeotropic distillation to give pure 17,18-dehydro-apovincamine, which is also reduced to form a single product, and is acylated by reaction with very little excess acid chloride.

The perfect completion of the dehydration reaction is key to both yield and product purity. The very strong excess acid used at the boiling point of the solvent did not cause any noticeable adverse effect either, which is surprising considering that it is an indoloquinolysine derivative having a double bond at position 17,18.

2. Our process yields a very pure product since all three reactions are completely complete. Thus, no by-products are formed in the reaction sequence without isolation of intermediates.

3. The efficiency of the previous process has been greatly improved by practically obtaining a quantitative yield.

The following example illustrates our procedure:

Example A 1: 1 mixture of g (85 mmol) of 17,18-dehydro-vincamine and 17,18-dehydro-epivincamine, 150 mL of toluene and 21 g (110 mmol) of p-toluenesulfonic acid was mixed and heated using a Marcusson plug. water is continuously distilled. After 2 hours, the reaction was complete. The reaction mixture was then cooled and dichloromethane (300 mL) and cc (30 mL) were added. ammonia solution and 300 ml of water were added and the two phases were separated. The upper (organic) phase contains 17,18-dehydro-apovincamine, which is evaporated to dryness.

To the dry residue was added toluene (130 mL), cooled to 0 ° C, lithium aluminum hydride (4.5 g, 119 mmol) and tetrahydrofuran (30 mL) were added, and the reaction mixture was heated to 65 ° C for 2 hours. at this temperature.

The reaction mixture was cooled to 0 ° C again, water (15 mL) was added slowly, and the reaction mixture was quenched by the addition of sodium sulfate (22.5 g) and dichloromethane (300 mL), filtered, and washed with dichloromethane. the washings and the filtrate were combined and the solvent was distilled off (180 mL).

To this solution was added 0.6 g of dimethylaminopyridine,

12.6 ml of triethylamine and 21.0 g (91 mmol) of 3,4,5-trimethoxybenzoyl chloride are added and the mixture is heated to 40 ° C. The reaction was complete within 1 hour.

The reaction mixture was then washed with 2% sodium hydroxide solution (2 x 300 mL), water (2 x 300 mL), dried over sodium sulfate, treated with alum (30 g) and charcoal (3 g) and stirred for 15 min. The mixture was filtered, the clarifier was washed, the filtrate and the washings were combined, concentrated and replaced with absolute ethanol to a total volume of 75 ml.

The concentrate was allowed to stand in the refrigerator overnight, the precipitated crystals were filtered off, washed with absolute ethanol and dried.

Product: 42.0 g (83.9 mmol) of 17,18-dehydro-apovincaminol-3 ', 4', 5'-trimethoxybenzoate (yield 98.6% of theory).

Mp: 142-143 ° C.

Specific rotation: + 26.5 (c 1, chloroform) Content (HPLC): 99.2%

Chromatographic conditions:

column: Lichrosorb 10 RP 18; 150 x 4.6 mm (Crompack) eluent; acetonitrile - 0.01 M ammonium carbonate solution 8: 2 detection; 260 nm injection: from 0.5% solution (chloroform) 20 μΐ evaluation: by external standard method

Claims (1)

Patent Claim Point A process for the preparation of 17,18-dehydro-apovincaminol 3 ', 4', 5'-trimethoxybenzoate of formula (I), dehydration of 17,18-dehydro-apovincamine or 17,18-dehydro-epivincamine or any mixture thereof, to give (III) reduction of 17,18-dehydro-apovincaminamine of formula II with lithium aluminum hydride followed by acylation of the resulting 17,18-dehydro-apovincaminole of formula II with 3,4,5-trimethoxybenzoyl chloride and isolation of to dehydrate in toluene in the presence of 1.3-1.6 moles of p-toluenesulfonic acid per dehydrovincamine at the boiling point of the solvent by distilling off the water formed The reduction was carried out without isolation in a 3: 3-5: 1 by volume mixture of toluene and tetrahydrofuran, and the acylation was carried out in a 3: 1-1: 1 by volume dichloromethane-toluene solvent mixture, without isolation 1.06-1. , With 12 mol of 3,4,5-trimethoxybenzoyl chloride.