The present invention relates to a process for the preparation of (-)-eserethole, of formula (I)

starting from (±)-eserethole, or from mixtures of (+)- and (-)-eserethole in which the latter enantiomer prevails.

(-)-Eserethole is known to be the main interme¬ diate for the synthesis of (-)-eserine (physostigmine) , which is a naturally occurring alkaloid of great interest for the treatment of Alzheimer\'disease (see, for example, L.J. Thai and coll., N. Engl. J. Med. 308, 720 (1983) and Ann. Neurol. 13, 491 (1983); L. Gustafson and coll., Psychopharmacol. 93, 31 (1987)).

In literature (T. Kobayashi, Annalen der Chemie 143-163 (1938), the resolution of (±)-eserethole by means of tartaric acid, following a very laborious pro¬ cedure and in unsatisfactory yields, is described. According to Kobayashi, (±)-eserethole is in fact treated in alcohol medium with (+)-tartaric acid in a 1:1 molar ratio. Thereby a mixture of (÷)-eserethole (÷)-tartrate and (-)-eserethole (+)-tartrate precipita¬ tes, the first one prevailing. (This mixture must be recrystallized at least 5 times from alcohol, to obtain pure (+)-eserethole (+)-tartrate in a 50% yield on

theory). Precipitation mother liquors are alkalinized, the free base, which is enriched in (-)-eserethole, is distilled, then treated in alcohol with (-)-tartaric acid, in a 1:1 molar ratio. Thereby (-)-eserethole (-)- tartrate precipitates which is brought to a complete optical purity after one/two crystallizations, in a 18% yield. In practice, since the desired (-)-eserethole is obtain from said tartrate in a, 98-99% yield, the process according to Kobayashi allows to obtain, from 100 g of racemate, only 9 g of (-)-eserethole (apart from any recovers, involving of course even more complex procedures).

Now it has been found that optically pure (-)-ese- rethole can be obtained with markedly higher yields and easier procedures from mixtures of (-)- and (+)-ese- rethole (usually from (±)-eserethole) , operating with a resolution agent amount lower than the stoichiometric amount, which amount ranges from 0.5 to 0.7 mole of resolution agent by mole of (±)-eserethole, preferably about 0.6 mole of resolution agent by mole of (±)-ese- rethole.

Moreover, it has been found that the process is particularly simple compared with the known one, when operating with such resolution agents as to yield a (-)-eserethole salt less soluble than the (+)-ese- rethole one. Preferably, according to the invention, the resolution of (±)-eserethole, or of other enantiomeric mixtures, is carried out with a resolution agent selected from the group consisting of D-(-)-tar- taric, D-(+)-malic and N-benzoyl-L-glutamic acids. Particularly favourable results are obtained with the

latter acid.

Suitable solvents according to the invention are lower alcohols (such as ethanol or isopropanol), lower ketones (such as acetone or methyl ethyl ketone), lower ethers (such as diethyl ether o diisopropyl ether), lower esters (such as ethyl acetate), or mixtures of said solvents.

The following examples further illustrate the process of the invention. Example 1

Use of D(-)tartaric acid

(±)-Eserethole (2.46 g; 0.01 mole) is dissolved in

95% ethanol (20 ml) then D(-)tartaric acid (0.9 g;

0.006 mole) is added. The mixture is heated to complete dissolution, cooled to 15 "C , stirred at 15°C for 1 hour, filtered. The solid is recrystallized from 95% ethanol (20 ml) to obtain 1.00 g of salt having m.p.

176-7 ^β C; d. ²⁰ _D -113.3 ^β C in water (lit. m.p. 173-4°C; d^ ²⁰ _D -115° in water). 50.5% yield on th. The solid (600 mg, 0.0015 mole) is dissolved in water (10 ml), alkalinized with N NaOH and extracted with ether (2x 10 ml).

The organic extract is dried over anhydrous

Na-SO., filtered and evaporated to dryness to obtain a residual oil (369 mg; 99% yield) identified as (-)-ese- rethole by means of I.R., H-NMR, mass spectra and by comparison with an authentic sample. ²⁰ _D -101.2° (C = 0.5% in ethanol) It is evident that, with only one recrystalliza- tion, according to this example, 25 g of (-)-eserethole can be obtained from 100 g of racemate.

Example 2

Use of N-benzoyl-L-glutamic acid

(±)-Eserethole (2.46 g; 0.01 mole) is dissolved in acetone (15 ml) then N-benzoyl-L-glutamic acid (1.43 g; 0.006 mole) is added. The solution is added with ethyl ether until turbidity and the mixture is stirred at room temperature overnight. The solid is filtered, suspended again in acetone, stirred 1 hour, filtered, dried under vacuum. 1.83 g of a salt are obtained, having m.p. 128-9°C; σ\ ² ° _D -75,0° (C = 0.5% in H ₂ 0) . 73,6% yield on th.

1 g of salt (0.002 mole) is treated as described in Example 1, to obtain (-)-eserethole (490 mg; 98% yield) having ^ ²⁰ _D -100.8° (C = 0.5% in ethanol)

Following the above procedure, therefore - with a single washing of the first precipitation salt - 36 g of (-)-eserethole are obtained from 100 g of racemate.

Example 3 Use of D(--)malic acid

(±)-Eserethole (2.46 g; 0.01 mole) is dissolved in 95% ethanol (20 ml) then D(+)malic acid (0.81 g; 0.006 mole) is added. The mixture is heated to complete dis¬ solution, cooled to 15°C, filtered. The solid is recrystallized from 95% ethanol (20 ml) to obtain 0.72 g of salt having m.p. 160-1°C; d?° _D -105.8°. 38% yield on th.

570 mg of salt (0.0015 mole) are treated as described in Example 1, to obtain (-)-eserethole (360 mg; 98% yield) having _f 3 ²⁰ _D -100.3° (C = 0.5% in ethanol)

In this case, therefore, from 100 g of racemate, about 18 g of (-)-eserethole are obtained.