Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-07-20
2002-10-08
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S512000, C562S553000, C562S561000
Reexamination Certificate
active
06462229
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the resolution of (±)-&agr;-difluoroniethylornithine of the formula:
using (−)-O,O′-di-p-toluoyl-L-tartaric acid. (±)-&agr;-Difluoromethylornithine is an inhibitor of ornithine decarboxylase and has numerous pharmacological actions (U.S. Pat. No. 4,413,141).
2. Background Art
It is known that the pharmacological activity of the (−)-isomer is significantly greater than that of the racemate (WO-A-98/25603).
The known methods for the preparation of the (−)-isomer, however, are laborious and unsatisfactory with respect to the yield and optical purity which can be achieved.
According to U.S. Pat. No. 4,413,141 or U.S. Pat. No. 4,309,442, for the purpose of resolution, DL-3-amino-3-difluoromethyl-2-piperidone of the formula:
is used, which first has to be prepared from racemric DL-&agr;-difluoromethylornithine monohydrochloride mono-hydrate via formation of the methyl ester and cyclization using alkoxide. The resolution of the piperidonie is described using classical resolving agents such as, for example, using (+)-camphor-10-sulphonic acid or using (+)- or (−)-binaphthyl-phosphoric acid.
BROAD DESCRIPTION OF THE INVENTION
The object of the invention consisted in developing an approach to the desired isomer which was simpler and improved with respect to yield and optical purity.
It has been found that (±)-&agr;-difluoromethylornithine can be cleaved using the commercially obtainable (−)-O,O′-di-p-toluoyl-L-tartaric acid, without circuitous routes and without having to take the disadvantages mentioned into account, and consequently it was thus possible to achieve the object in a surprisingly simple manner.
The invention therefore relates to diastereomeric salts of (+)- or (−)-&agr;-difluoromethylornithine of the formula:
with (−)-O,O′-di-p-toluoyl-L-tartaric acid, preferably the 1:1 diastereomeric salt of (+)- or (−)-&agr;-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acid and particularly preferably the 1:1 diastereomeric salt of (−)-&agr;-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acid.
In the preferred molar ratio of resolving agent to (−)-&agr;-difluoromethylornithine of 1:1, in principle two free amino groups are available for bonding. Fundamentally, both diastereomers are included by the invention.
A further subject of the invention is the process according to the invention. The invention process involves resolution of (±)-&agr;-(difluoromethyl)-ornithine of formula I. The resolution is carried out using (−)-O,O′-di-p-toluoyl-L-tartaric acid.
DETAILED DESCRIPTION OF THE INVENTION
The resolution of (±)-&agr;-difluoromethylornithine using (−)-O,O′-di-p-toluoyl-L-tartaric acid is expediently carried out in the presence of a mixture of water and a water-miscible polar organic solvent.
Suitable water-miscible polar organic solvents are, for example, lower aliphatic alcohols, such as methanol or ethanol, or acetonitrile. A preferred water-miscible polar organic solvent is acetonitrile.
The components are expediently dissolved by heating. On cooling, as a rule the desired diastereomer of (−)-&agr;-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acid crystallizes out, while the diastereomer of (+)-&agr;-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acid remains in solution.
Customarily, the mixture water/water-miscible polar organic solvent is selected such that the desired diastereomer of (−)-&agr;-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acid crystallizes out easily and quantitatively on cooling the solution.
Preferably, a mixture of acetonitrile/water of 0.9:1 to 1.3:1 is selected for the crystallization of the 1:1 diastereomer of (−)-&agr;-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acid.
The liberation of the (−)-&agr;-difluoromethylornithine monohydrochloride monohydrate from the diastereomer is carried out by acidifying with a mineral acid such as, with hydrochloric acid. By extraction with a suitable solvent, the (−)-&agr;-difluoromethylornithine monohydrochloride monohydrate can be obtained in high yield and high optical purity. The (−)-O,O′-di-p-toluoyl-L-tartaric acid can likewise be recovered from this extraction.
The diastereomer of (+)-&agr;-difluoromethylornithine with (−)-di-O,O′-p-toluoyl-L-tartaric acid, which as a rule is found in solution, can likewise be analogously liberated, e.g. after evaporation of the solution, as (+)-&agr;-difluoromethylornithine monohydrochloride monohydrate, which can then be recovered by extraction, by acidifying with a mineral acid.
REFERENCES:
patent: 4309442 (1982-01-01), Bey et al.
patent: 4414141 (1983-11-01), Bey et al.
patent: 0 365 213 (1989-10-01), None
patent: A20365213 (1990-04-01), None
patent: WO 98/14188 (1998-04-01), None
patent: WO 98/25603 (1998-06-01), None
F.J. Kearley & A.W. Ingersol,The Resolution of Amino Acids. IV. Lysine, Dec. 1951, pp. 5783 to 5785.
Journal of the American Chemical Society; David A. Jaegar, Michael D. Broadhurst, and Donald J. Cram, Jan. 31, 1979; pp. 717 to 732.
Tetrahedron Letters, vol. 38, No. 34, pp. 5965-5966, 1997.
J. Jacques et al., John Wiley & Sons, (1981), pp. 261-263.
Fisher Christen & Sabol
Lonza Ltd.
Reyes Hector M
Rotman Alan L.
LandOfFree
Process for the preparation 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..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2957280