Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1998-06-19
2000-04-18
Kunz, Gary L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562540, 564123, C07C22900, C07C23300
Patent
active
060517344
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a process for the optical resolution of racemic 3-(p-chlorophenyl)-glutaramide (GAN) into its R and S isomers, and to the use of the R isomer for the production of R-baclofen or the use of the S isomer for the production of S-baclofen.
The biological activity and physical properties of racemic baclofen are well documented in the literature.sup.1,2. Further extensive pharmacological tests have concluded that the biological activity of the drug resides with the R-enantiomer (R-baclofen).sup.3. These selective activities have led to extensive research concerning methods of separating the optical isomers of baclofen. Several methods of resolution have since appeared in the literature. These are mainly chromatographic separations.sup.4-9, making use of either bonded chiral stationary phases, or mobile phases with chiral modifiers. Other methods include asymmetric syntheses.sup.10-12 as well as a chemoenzymatic synthesis.sup.13.
As is apparent from the literature, most chromatographic separations involve precolumn derivatization implying some form of protection and subsequent deprotection. Where the formation of covalent diastereomers is not necessary, the columns used involved either relatively expensive chiral stationary phases or chiral modifiers in the mobile phase. The asymmetric syntheses are mostly time consuming multistep reactions with relatively low yields.
The compound .alpha.-methylbenzylamine (MBA) is well known as a resolving agent in both covalent and dissociable diastereomer techniques.sup.16. MBA is a strong base widely used for resolution of acidic racemates and in particular carboxylic acids. Examples are MBA mandelate.sup.17, MBA phenylbutyrate.sup.18 and MBA hydrotropate.sup.19 salts. Concerning drug resolution, a good example is the early separation of the antibacterial fosfomycin.sup.20.
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a process for the optical resolution of racemic 3-(p-chlorophenyl)glutaramide into its R isomer: ##STR1## and its S isomer: S--COOH ##STR2## which process includes the steps of either: (1) reacting racemic 3-(p-chiorophenyl)-glutaramide dissolved in a suitable solvent with S-(-)-.alpha.-methylbenzylamine of the formula: H.sub.2 N--S' ##STR3## (2) precipitating out of the solution of step (1) R--CO.sub.2.sup.- H.sub.3.sup.+ N--S'; suitable acid; and solvent with R-(+)-.alpha.-methylbenzylamine of the formula H.sub.2 N--R' ##STR4## (6) precipitating out of the solution of step (5) S--CO.sub.2.sup.- H.sub.3 +N--R'; suitable acid, and
The precipitation of either salt is controlled by the choice of base resolving agent, i.e either S- or R-.alpha.-methylbenzylamine. In each case two salts are formed but these have vastly differing solubilities and thus only one of these is precipitated.
When S-(--)-.alpha.-methylbenzylamine H.sub.2 N--S' is reacted with racemic GAM (R,S--COOH) the following salts are formed: R--CO.sub.2.sup.- H.sub.3.sup.+ N--S' and S--CO.sub.2.sup.-.H.sub.3.sup.+N--S'.
However R--CO.sub.2.sup.- H.sub.3.sup.+ N--S' is much less soluble than S--CO.sub.2.sup.- H.sub.3.sup.+ N--S' and therefore precipitates from solution and can be filtered off. The opposite occurs when R-(+)-.alpha.-methylbenzylamine (R') is reacted with racemic GAM although the conditions may be identical in each case.
In step (1) and step (5), a suitable solvent is for example a lower alkanol such as methanol.
Step (1) and step (5) are preferably carried out at an elevated temperature up to about 60.degree. C.
In step (2) and step (6), the solution of step (1) or step (5), respectively, is allowed to stand, preferably in the absence of light, for a period of time, to allow precipitation to occur. Thereafter, the precipitated crystals may be filtered off, and dried.
In step (3) and step (7) the crystals of step (2) or step (6), respectively, are dissolved in water, preferably at an elevated temperature up to about 90.degree. C. Thereafter, there is added a suitable acid, such as for exa
REFERENCES:
Herdeis et al, Tetrahedron:Asymmetry, 3(9):1213-1221 (1992).
Schoenfelder et al, Synlett, 2:63-64 (1993).
Chenevert et al, Can. J. Chem., 72:2312-2317 (1994).
Allan et al, Aust. J. Chem, 34:2641-5 (1981).
Sioufi et al, J. Chromatogr., 450:222 (1988).
Wuis et al, J. Chromatography, 415:419-422 (1987).
Allenmark et al, Chirality, 1:154-160 (1989).
Vaccher et al, J. Chromatography, 645:95-99 (1993).
Sano et al, Kuromatogurafi, 15(4):234-5 (1994).
Weatherby et al, J. Neurosci. Methods, 10:23-28 (1984).
Vaccher et al, J. Chromatography, 542:502-507 (1991).
Caira Mino Rodolfo
Clauss Rainer
Easter Barratt Robert Dixon
Nassimbeni Liugi Renzo
Scott Janet Lesley
Farmarc Nederland B.V.
Kunz Gary L.
White Everett
LandOfFree
Process for the optical resolution of 3-(p-chlorophenyl)-glutara 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 optical resolution of 3-(p-chlorophenyl)-glutara, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the optical resolution of 3-(p-chlorophenyl)-glutara will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2337302