Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-02-21
1997-03-11
Haley, Jacqueline
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20900
Patent
active
056103166
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage application of PCT/EP93/01908 filed Jul. 20, 1993 and published as WO 94/03457 on Feb. 17, 1994.
The present invention relates to a process for the preparation of (-)-eserethole, of formula (I) ##STR2## starting from (.+-.)-eserethole, or from mixtures of (+)- and (-)-eserethole in which the latter enantiomer prevails.
(-)-Eserethole is known to be the main intermediate 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. Thal and coll., N. Engl. J. Med. 308, 720 (1983) and Ann. Neurol. 13, 491 (1983); L. Gustarson 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 procedure 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. Therefor a mixture of (+)-eserethole (+)-tartrate and (-)-eserethole (+)-tartrate precipitates, the first one prevailing. This mixture must be recrystallized at least 5 times from alcohol, to obtain pure (+)-eserethole (+)-tartrate in a 50% yield. The 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 obtained 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 recovered material, involving of course even more complex procedures).
Now it has been found that optically pure (-)-eserethole can be obtained with markedly higher yields and easier procedures from mixtures of (-)- and (+)-eserethole (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 the resolution agent by mole of (.+-.)-eserethole, preferably about 0.6 mole of resolution agent by mole of (.+-.)-eserethole.
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 (+)-eserethole 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-(-)-tartaric, 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 example s further illustrate the process of the invention.
EXAMPLE 1
(.+-.)-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.degree. C., stirred at 15.degree. 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.degree.-7.degree. C.; .alpha..sup.20 .sub.D -113.3.degree. C. in water (lit m.p 173.degree.-4.degree. C.; .alpha..sup.20.sub.D -115.degree. in water). 50.5% yield.
The solid (600 mg, 0.0015 mole) is dissolved in water (10 ml), made alkaline with NaOH and extracted with ether (2.times.10 ml).
The organic extract is dried over anhydrous Na.sub.2 SO.sub.4, filtered and evaporated to dryness to obtain a residual oil (369 mg; 99% yield) identified as (-)-eserethole by means of I.R., .sup.1 H
REFERENCES:
Kobayashi, T. Annalen der Chemie pp. 143-163, (1938).
Dale, F. J. et al., J. Pharm. Pharmac., 1970, 22, pp. 889-896.
Belli Aldo
Chiodini Giorgio
Maiorana Stefano
Haley Jacqueline
Laboratorio Chimico Internazionale S.p.A.
LandOfFree
Process for the preparation of (-)-eserethole from mixtures of ( does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of (-)-eserethole from mixtures of (, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of (-)-eserethole from mixtures of ( will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-444756