Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-19
1999-09-14
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546112, C07D45106, C07D45114
Patent
active
059525053
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process by which esters of (+)- and (-)-tropic acid can be prepared with a high degree of purity and in good yields.
The problem of synthetically producing enantiomerically pure esters of (+)- and (-)-tropic acid has not hitherto been solved with any degree of satisfaction. The enantiomeric separation of racemic tropic acid esters also frequently comes up against surprising experimental problems and cannot generally be carried out. This applies particularly to the higher substituted homologues and analogues of atropine, such as N-isopropylnoratropine, the precursor of the commercial product ipratropium bromide.
The conventional synthesis of tropic acid esters according to I. Mamlock and R. Wolffenstein (Ber. dtsch. Chem. Ges. 41, 731 (1908) ), in which O-acetyltropic acid chloride is reacted with tropine hydrochloride does not produce satisfactory results, possibly on account of the poor solubility of tropine hydrochloride. The method has not been used for optically active tropic acid.
The process is problematic because side reactions can easily occur. This is true of basic conditions, with which there is a danger that water is eliminated, whilst on the other hand the use of salts of the amino alcohols, which are usually poorly soluble, requires elevated temperatures which can lead to the formation of highly disruptive by-products; mention should be made particularly of dehydrated compounds (apocompounds) and dimerization products.
It has now been found that substantially enantiomerically pure (+)- and (-)-tropic acid esters of amino alcohols of the formula ##STR2## wherein
Q denotes CH.sub.2 --CH.sub.2, CH.sub.2 --CH.sub.2 --CH.sub.2, CH.dbd.CH or ##STR3##
R denotes a straight-chained or branched C.sub.1-4 -alkyl group,
can surprisingly be prepared by into the acid chloride, optionally with the addition of excess aluminum oxide, with the methanesulphonate of an amino alcohol of formula I,
The (+)- and (-)-tropic acid required as starting material can be obtained from D,L-tropic acid by first preparing a salt with an optically active base in a manner known per se and recrystallising this salt several times. A suitable base might be, for example, (-)-quinine whilst the solvent for crystallization might be ethanol. The (+)-tropic acid thus prepared has a
The reaction according to (a) is preferably carried out at ambient temperature and the reaction according to (b), which is carried out immediately afterwards, is preferably performed at ambient temperature or slightly elevated temperature without intermediate isolation of the acetylated acid.
Step (c) takes place within a few days, when the methanesulphonate of a compound of formula (I) is reacted in an inert solvent, such as methylene chloride, at temperatures between 0.degree. C. and about 30.degree. C., preferably at ambient temperature, with stirring, whilst excess aluminium oxide may be used to bind the acid. Once the solvent has been eliminated under reduced pressure, the residue can be further processed directly.
In step (d), favourable results are obtained if the deacetylation is carried out with a dilute aqueous inorganic acid, such as 2-20% hydrochloric acid, preferably 3-10% hydrochloric acid, at ambient temperature. Thus, for example, total reaction is obtained with 5% hydrochloric acid within about 2 days.
The reaction product can be isolated as a base (step (e) ) by stirring the acidic reaction solution into excess dilute (e.g. 20%) sodium hydroxide solution or into aqueous alkali metal carbonate solution and filtering off the crystalline product precipitated. Temperatures of between -15 and +50.degree. C. may be used; it is preferable to use sodium carbonate solution at about 20.degree. C. The salts, e.g. the corresponding hydrochloride, can easily be prepared from the base by adding a stoichometric quantity of ethereal hydrochloric acid to the solution of the base, e.g. in methylene chloride.
The esters obtained in this way consist of more than 99% of the pure optically active compound, assuming that the starting ac
REFERENCES:
Synthesis, 1976, Stuttgart, DE, Seiten 311-312, XP002011575 V.A. Fung et al.: "A convenient systhesis of N-CD3 Labelled Tropine and Atropine"--siehe Seite 312.
"General Synthesis of Tropane Alkaloids via the Polybromo Ketone-Iron Carbonyl Reaction", Y. Hyakawa et al., J.Am. Chem. Soc. 100 (1978) 1786-1790.
Boehringer Ingelheim KG
Devlin M-E. M.
Raymond R. P.
Rotman Alan L.
Stempel A. R.
LandOfFree
Process for preparing pure enantiomers of tropic acid esters 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 preparing pure enantiomers of tropic acid esters, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing pure enantiomers of tropic acid esters will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1511133