HU209927B - Process for the preparation of ethyl apovincaminate - Google Patents

Description

The present invention relates to a novel process for preparing ethyl apovincaminate by esterification of apovincaminic acid with ethanol in the presence of a pentafluorobenzene derivative of formula (ΠΙ):

X is OCH _3, -COCH _3, -NO _2i represents -CH ₃ or -CN polar organic solvent, organic base, it is carried out at room temperature.

(III)

CD

HU 209 927

Description: 4 pages (including 1 page illustration)

HU 209 927 Β

The present invention relates to a novel process for the preparation of ethyl apovincaminate.

The ethyl apovincaminamine produced by the process of the invention is used in the treatment of major brain disorders and is widely used in geriatrics.

More particularly, the present invention relates to a novel process for preparing ethyl apovincaminate using a catalyst derived from pentafluorobenzene (III).

Preparation of ethyl apovincaminate by esterification of apovincaminic acid with ethanol is well known in the art (DE 2,253,750 and 2,265,138, and AT 322,118), and the esterification of this process in a highly acidic medium in the conventional manner provides a yield of less than 75%. end product and ethyl ether as a by-product. Therefore, methods have been sought for the preparation of ethyl apovincaminate which are simple, provide higher yields and do not produce dangerous products on an industrial scale. According to the process described in ES 549.105, ethyl apovincaminate is prepared using 2-fluoro-1,3,5-trinitrobenzene and 4-N, N-dimethylaminopyridine catalyst. Based on the study of literature methods, several pentafluorobenzene derivatives have been experimentally tested and found to possess good electron-repellant groups, such as cyano or nitro, as catalysts for the esterification of apovincaminic acid.

The present invention thus provides a novel method for the treatment of cerebral disorders and for the preparation of ethyl apovincaminate (I), which is widely used in geriatrics. According to the invention, the apovincaminic acid of the formula (Π) in the presence of a pentafluorobenzene catalyst of the formula (III)

X is -OCH ₃ , -COCH ₃ , -NO ₂ , -CH ₃ or -CN - is reacted with ethanol.

The reaction is carried out in the presence of an organic base, preferably triethylamine or 4-N, N-dimethylaminopyridine, and in a polar solvent, preferably acetonitrile.

Pentafluorobenzonitrile is preferably used as a catalyst for the said esterification because it provides higher yields and virtually no by-products.

All of the above pentafluorobenzene derivatives are commercially available. There is also a sixth pentafluoro derivative of formula (IH), pentafluorobenzophenone, which is also commercially available, but has not been shown to provide the desired meaning.

The invention is further illustrated by the following examples wherein the esterification of apovincaminic acid and ethanol is carried out with 1.1 equivalents of pentafluorobenzene catalyst per 1 equivalent of apovincaminic acid. The reaction is carried out at room temperature (about 25 ° C) for 48 hours.

Example 1

To a solution of apovincamic acid (1.6 g) in acetonitrile (25 ml) was added pentafluorobenzonitrile (2.4 g). 2.6 g of 4-N, N-dimethylaminopyridine in 1 ml of ethanol are then added. The reaction mixture was stirred for 48 hours at 25 ° C. After completion of the reaction, the reaction mixture was extracted with dilute acid solutions and made basic with ammonium hydroxide in the presence of dichloromethane. The organic extract is evaporated to dryness and the residue is crystallized from ethanol. This gives 1.3 g of ethyl apovincaminate (m.p. 145-147 'C).

Example 2

A solution of 1.6 g of apovincamic acid in 25 ml of acetonitrile was added to which 1 g of pentafluoronitrobenzene was added. 1.3 g of 4-N, N-dimethylaminopyridine and 5 ml of ethanol are then added. The reaction mixture was stirred for 48 hours at 25 ° C. After completion of the reaction, the reaction mixture was extracted with dilute acid solutions and made basic with ammonium hydroxide in the presence of dichloromethane. The organic extract is evaporated to dryness and the residue is crystallized from ethanol. 0.16 g of ethyl apovincaminate is obtained (m.p. 145-147 'C). The mother liquors contain by-products.

Example 3

To a solution of 1.6 g apovincamic acid in 25 ml acetonitrile was added 1.3 g pentafluoromethoxybenzene. 1.3 g of 4-N, N-dimethylaminopyridine and 1 ml of ethanol are then added. The reaction mixture was stirred for 48 hours at 25 ° C. The reaction mixture was then filtered and extracted with dilute acid solutions. The acidic extracts are made basic with concentrated ammonium hydroxide in the presence of dichloromethane. The organic extract was then evaporated to dryness and the resulting product was purified by preparative chromatography to give 0.08 g of ethyl apovincaminate (m.p. 145-147 ° C).

Example 4

To a solution of apovincaminic acid (1.6 g) in acetonitrile (25 ml) was added pentafluorotoluene (1 g). 1.3 g of 4-N, N-dimethylaminopyridine and 1 ml of absolute ethanol are then added. The reaction mixture was stirred for 48 hours at 25 ° C. The reaction mixture was filtered and extracted with dilute acid solutions. The acidic extracts are made basic with concentrated ammonium hydroxide in the presence of dichloromethane. The organic extract is then evaporated to dryness and the product is purified by crystallization from isopropanol. 0.08 g of ethyl apovincaminate is obtained (m.p. 148-150 ° C).

The reaction is similarly carried out with pentafluoroacetophenone and pentafluorobenzophenone.

HU 209 927 Β

The yields of the above reactions are summarized in Table I below.

Table (I)

Reagent % ethyl apovincaminate Pentafluoro-methoxybenzene 10 Pentafluoro-benzophenone no reaction Pentafluoroacetophenone 5 Pentafluoro-nitrobenzene 10% + by-product Pentafluoroethyl toluene 5 Pentafluoroethyl-benzonitrile 80

From the data in Table I it can be seen that pentafluorobenzonitrile is the most suitable catalyst for the esterification of apovincaminic acid with ethanol under the conditions described above.

The above esterification was also carried out at temperatures above room temperature, but no improvement in yield or reaction time was observed.

Claims (3)

PATENT CLAIMS A process for preparing an ethyl apovincaminate of formula (I), comprising reacting the apovincaminic acid of formula (II) with ethanol in the presence of a catalyst of the pentafluorobenzene derivative of formula (III): X represents -OCH ₃ , -COCH ₃ , -NO ₂ , -CH ₃ or -CN in a polar organic solvent in the presence of an organic base at room temperature. 2. The process of claim 1 wherein the polar solvent is acetonitrile and the organic base is a tertiary amine, i.e. triethylamine, or 4- (N, N-dimethylamino) pyridine. The process according to claim 1, wherein the pentafluorobenzene derivative is pentafluorobenzonitrile. HU 209 927 Β Int.Cl. ⁵ : C 07 D 461/00