Preparation of anhydrous CETP inhibitor

Details Preparation of anhydrous CETP inhibitor Preparation of anhydrous CETP inhibitor

2002-09-27

2003-06-03

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06573383

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for preparing anhydrous CETP inhibitor, (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl acid ethyl ester.
BACKGROUND OF THE INVENTION
Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S.
Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D. J., et al.: “High-density Lipoprotein Cholesterol and Cardiovascular Disease”, Circulation, (1989), 79: 8-15).
High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues resulting in reduced compliance. Fibrates and the HMG-CoA reductase inhibitors raise HDL-C only modestly. As a result, there is a significant unmet medical need for a well-tolerated agent which can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.
Commonly assigned U.S. Pat. No. 6,197,786, the disclosure of which is incorporated herein by reference, discloses, inter alia, the CETP inhibitor, cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, and processes for the preparation thereof (e.g., procedure disclosed in Example 7).
Commonly assigned International Patent Application publication number WO 01/40190, the disclosure of which is incorporated herein by reference, discloses anhydrous (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and methods of preparing said anhydrous compound.
SUMMARY OF THE INVENTION
One aspect of this invention is methods for preparing anhydrous (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester comprising:
combining (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester with a solvent at a temperature that is sufficient to dissolve said (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester to make a solution, wherein said solvent is heptanes or a mixture comprising water and a polar solvent;
forming solid (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester wherein said forming comprises cooling said solution or evaporating solvent from said solution sufficiently to form said solid (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
isolating said solid (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester from said solvent to afford anhydrous (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
In a preferred embodiment of this invention, said solvent comprises heptanes.
In another preferred embodiment, said solvent comprises a mixture of water and C
1
-C
4
alkanol, preferably ethanol. In a more preferred embodiment, said mixture comprises about 10% to about 50% water, more preferrably about 10% water.
In a further preferred embodiment of this invention, said forming solid (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester further comprises seeding said solution with anhydrous (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.
DETAILED DESCRIPTION OF THE INVENTION
The CETP inhibitor, (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (hereafter the “CETP Inhibitor”) may be prepared according to the process disclosed in Example 7 of commonly assigned U.S. Pat. No. 6,197,786.
According to this invention, the anhydrous forms of the CETP Inhibitor may be prepared by dissolving the CETP Inhibitor in a non-polar solvent comprising heptanes (i.e., solvent comprising heptane isomers), at a temperature in the range 20-90° C. Said non-polar solvent may be a mixture of miscible organic solvents containing the heptanes in combination with solvents such as ethyl acetate, THF, xylene, or toluene. The solution is cooled or solvent is removed by evaporation, resulting in a supersaturated solution. Crystallization may be initiated by any of a variety of methods known to those skilled in the art. Such methods include seeding with a small quantity of the anhydrous form of the CETP Inhibitor and mechanical methods, such as using ultrasonic energy. The resulting product may be isolated by filtration followed by drying.
The anhydrous forms of the CETP Inhibitor may also be prepared by dissolving the CETP Inhibitor in an aqueous organic solvent mixture by heating the solution sufficiently to dissolve the CETP Inhibitor. Preferably, the aqueous organic solvent is an aqueous short chain alcohol, more preferably aqueous ethanol, most preferably aqueous ethanol in a ratio from 10% to 50% water in ethanol. The solution is then cooled, resulting in a supersaturated solution. Crystallization may be initiated by any of a variety of methods known to those skilled in the art, include the seeding and mechanical methods described above. The resulting product may be isolated by filtration followed by drying.
The CETP Inhibitor prepared by the methods of the invention may be administered orally to a subject in need thereof and may, accordingly, be used in combination with a pharmaceutically acceptable vehicle, carrier or diluent suitable for oral dosage forms.
The anhydrous form of the CETP Inhibitor prepared by methods of the instant invention may also be administered parenterally. For parenteral administration, the CETP Inhibitor may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable solutions prepared in this manner may then be ad

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