Intermediates of CETP inhibitors

Details Intermediates of CETP inhibitors Intermediates of CETP inhibitors

2002-04-30

2004-02-10

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C558S389000, C564S163000, C546S159000

Reexamination Certificate

active

06689897

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to intermediates useful in the preparation of CETP inhibitors and methods of preparation thereof.
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 is the compound of formula III,
Another aspect of this invention is the compound of formula IV,
A further aspect of this invention is compounds of formula VI,
wherein R is selected from methyl, benzyl and substituted benzyl.
An additional aspect of this invention is compounds of formula VII,
wherein R is selected from methyl, benzyl and substituted benzyl.
In a preferred embodiment of the compound aspects of this invention, R in the compounds of formula VI and the compounds of formula VII is selected from methyl, benzyl and benzyl substituted with one or more substituents each independently selected from (C
1
-C
3
)alkyl, (C
1
-C
3
)alkyloxy and a halogen.
A further aspect of this invention is methods for preparing the compound of formula 111, above, comprising coupling trifluoromethylbenzene that is para-substituted with a halogen or O-triflate with the compound of formula II,
to form the compound of formula III.
In a preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a transition metal, preferably palladium.
In another preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a phosphine ligand, preferably a dialkylphosphinobiphenyl ligand, more preferably selected from 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 2-dicyclohexylphosphino-2′-methylbiphenyl.
In an additional preferred embodiment of the method aspect of this invention relating to preparing the compound of formula III said coupling of said trifluoromethylbenzene compound with said compound of formula II occurs in the presence of a base, preferably cesium carbonate.
Another aspect of this invention is methods for preparing the compound of formula IV, above, comprising hydrolyzing the above compound of formula III, with a hydrolyzing agent selected from an acid and a base, preferably an acid, more preferably sulfuric acid with water, to form the compound of formula IV.
A further aspect of this invention is methods for preparing compounds of formula VI, above, comprising combining the compound of formula IV, above, with a compound of formula V,
wherein R is selected from methyl, benzyl and substituted benzyl, in the presence of a base, preferably lithium t-butoxide, to form compounds of formula VI.
An additional aspect of this invention is methods for preparing compounds of formula VII, above, comprising reducing the above compounds of formula VI, wherein R is selected from methyl, benzyl and substituted benzyl, with a reducing agent, preferably sodium borohydride in the presence of a Lewis acid, preferably calcium ions or magnesium ions, to form a reduced compound and cyclizing the reduced compound under acidic conditions to form a compound of formula VII.
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 IV to form the applicable formula VI compounds, (b) the reduction and cyclization of the applicable formula VI to form the applicable formula VIIB compound, (c) the acetylation of the formula VIIB compound to form the formula VIIIB compound or (d) the deprotection step to remove the applicable substituted benzyloxycarbonyl group in forming the formula IB compound from the compound of formula VIIIB. Preferred substituents are (C
1
-C
3
)alkyl and (C
1
-C
3
)alkoxy and halogens.
Chemical structures herein are represented by planar chemical structure diagrams that are viewed from a perspective above the plane of the structure. A wedge line (
) appearing in such chemical structures represents a bond that projects up from the plane of the structure.
DETAILED DESCRIPTION OF THE INVENTION
Reaction Scheme A illustrates the process for preparing the chiral isomer of formula II from (R)-2-amino-1-butanol. Scheme B illustrates the process of preparing the cholesterol ester transfer protein inhibitors of formula IA and formula IB.
According to Scheme B, the formula III compound is prepared by combining the chiral isomer compound of formula II ((R)-3-amino-pentanenitrile) with trifluoromethylbenzene that is para-substituted with a halogen or O-triflate (—O—S(O)
2
CF
3
) in the presence of a metal catalyst, preferably Pd. For opt

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