Methods for preparing CETP inhibitors

Details Methods for preparing CETP inhibitors Methods for preparing CETP inhibitors

2002-04-30

2003-07-29

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

06600045

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for preparing certain cholesteryl ester transfer protein (CETP) inhibitors and intermediates useful in the preparation of said CETP inhibitors.
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, dyslipidernia 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.
PCT application publication number WO 00/02887 discloses the use of catalysts comprising certain novel ligands for transition metals in transition metal-catalyzed carbon-heteroatom and carbon—carbon bond formation.
Commonly assigned U.S. Pat. No. 6,140,343, the disclosure of which is incorporated herein by reference, discloses, inter alia, the CETP inhibitor, cis-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, and processes for the preparation thereof (e.g., procedure disclosed in Example 46).
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).
SUMMARY OF THE INVENTION
One aspect of this invention provides methods for preparing the compound of formula IA,
comprising combining the compound of formula VIIIA,
with a 3,5-bis(trifluoromethyl)benzyl halide in the presence of a base, wherein said base is preferably potassium t-butoxide.
In a preferred embodiment, said compound of formula VIIIA is prepared by a method comprising combining the compound of formula VIIA,
with ethyl chloroformate to form the compound of formula VIIIA. In a more preferred embodiment, said compound of formula VIIA is prepared by a method comprising reducing the compound of formula VI,
wherein R is methyl, with a reducing agent to form a reduced compound and cyclizing the reduced compound under acidic conditions to form a compound of formula VIIA. Even more preferably, said compound of formula VI is prepared by a method comprising combining the compound of formula IV,
with the compound of formula V,
wherein R is methyl, in the presence of a base to form the compound of formula VI. In an even more preferred embodiment, said compound of formula IV is prepared by a method comprising hydrolyzing the compound of formula III,
with a hydrolyzing agent selected from an acid and a base to form the compound of formula IV. Even more preferably, said compound of formula III is prepared by a method comprising coupling trifluoromethylbenzene para-substituted with a halogen or O-triflate with the compound of formula II,
to form the compound of formula III.
Another aspect of this invention provides methods for preparing the compound of formula VIIIB,
wherein R
1
is benzyl or substituted benzyl,
comprising combining the compound of formula VIIB,
wherein R
1
is as defined for formula VIIIB,
with isopropyl chloroformate in the presence of a base, preferably pyridine, to form the compound of claim VIIIB.
A further aspect of this invention provides methods for preparing the compound of formula IB
comprising the steps of:
a) reducing the compound of formula VIIIB,
 wherein R
1
is benzyl or substituted benzyl,
 with a reducing agent to form cis-4-amino-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
b) treating said cis-4-amino-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester first with 3,5-bis-trifluoromethyl-benzaldehyde under acidic conditions followed by a reducing agent to form cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
c) treating said cis-4-(3,5-3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester with an acetylating agent to form the compound of formula IB,
 wherein said compound of formula VIIIB is prepared by a method comprising combining the compound of formula VIIB,
 with isopropyl chloroformate to form the compound of claim VIIIB.
In a preferred embodiment, said compound of formula VIIB is prepared by a method comprising reducing the compound of formula VI,
wherein R
1
is benzyl or substituted benzyl, with a reducing agent to form a reduced compound and cyclizing the reduced compound under acidic conditions to form the compound of formula VIIB. Even more preferably, said compound of formula VI is prepared by a method comprising combining the compound of formula IV,
with the compound of formula V,
wherein R
1
is benzyl or substituted benzyl, in the presence of a base to form the compound of formula VI. In an even more preferred embodiment, said compound of formula IV is prepared by a method comprising hydrolyzing the compound of formula III,
with a hydrolyzing agent selected from an acid and a base to form the compound of formula IV. Even more preferably, said compound of formula III is prepared by a method comprising coupling trifluoromethylbenzene para-substituted with a halogen or O-triflate with the compound of formula II,
to form the compound of formula III.
An additional aspect of this invention provides the compound of formula VIIIA,
Another aspect of this invention is methods for preparing the compound of formula VIIIA,
comprising combining the compound of formula VIIA,
with ethyl chloroformate in the presence of a base, preferably pyridine base, to form the compound of formula VIIIA.
The term “substituted benzyl” with respect to compounds of formula V, VI and VII means benzyl that is substituted on the benzene ring with one or more substituents such that such substitution does not prevent: (a) the reaction of the applicable formula V compound with the compound of formula

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