Methods for Preparing N-Arylated Oxazolidinones Via A Copper Catalyzed Cross Coupling

Inactive Publication Date: 2007-03-01
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034] The term “aryl” as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.” The aromatic ring can be substituted at one or more ring positions with such substituent as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl,

Problems solved by technology

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.
No wholly satisfactory HDL-elevating therapies exist.
Niacin can significantly increase HDL, but has serious toleration issues resulting in reduced compliance.
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.

Method used

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  • Methods for Preparing N-Arylated Oxazolidinones Via A Copper Catalyzed Cross Coupling
  • Methods for Preparing N-Arylated Oxazolidinones Via A Copper Catalyzed Cross Coupling
  • Methods for Preparing N-Arylated Oxazolidinones Via A Copper Catalyzed Cross Coupling

Examples

Experimental program
Comparison scheme
Effect test

examples 1-6

Example 1

[0060]

(S)-4-(4-Isopropyl-2-oxo-oxazolidin-3-yl)-N-propyl-benzamide

K2CO3 (0.272 g / 2 mMol) and Cul (0.019 g / 0.1 mMol) were charged to a flask under N2. (S)-4-isopropyl-oxazolidin-2-one (0.155 g / 1.2 mMol) and 1-bromo-4-N-propyl-benzamide(0.242 g / 1 mMol) each diluted in 1 mL dioxane added to the flask followed by 1,2-diaminocyclohexane (0.012 mL / 0.1 mMol). The bright blue mixture was heated to 110° and held for 22 hours.

The cooled mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated to an amber oil and purified by silica chromatography to give the product in 75% yield.

Mass spec: 291.4 (m+1).

1H NMR (CDCl3) δ 0.77 (d, J=6.8, 3H), 0.88 (d, J=7.0, 3H), 0.91-0.95 (m, 3H), 1.57-1.63 (m, 2H), 2.07-2.15 (m, 1 H), 3.33-3.38 (m, 2H), 4.20-4.24 (m,1 H), 4.37-4.41 (m,1 H), 4.434.46 (m,1 H), 6.72-6.75 (m,1H), 7.48 (d, J=8.7, 2H), 7.77 (d, J=8.7, 2H).

13C NMR (CDCl3) δ 11.86, 14.34, 17.81, 23.05, 27.67, 42.02, 60.25, 62.78, 121.18, 128.28, 131.3...

example 2

[0061]

(R)-3,4-Diphenyl-oxazolidin-2-one

The procedure described in example 1 was used with the appropriate substitution of reagents as follows:

K2CO3 (0.275 g / 2 mMol), Cul (0.019 g / 0.1 mMol), (R)-4-phenyl-oxazolidin-2-one (0.163 g / 1 mMol), Bromobenzene (0.1 ml / 1 mMol), 1,2-diaminocyclohexane (0.012 mL / 0.1 mMol) and 1 mL dioxane. The product was recovered in 99% yield.

Mass Spec 240.3 (m+1).

1H NMR (CDCl3) δ 4.21 (dd, J=5.81, 6.22,1 H), 4.78 (t, J=8.71, 1 H), 5.40 (dd, J=6.22, 6.22, 1 H), 7.06 (t, J=7.47, 1 H), 7.24-7.40 (m, 9H).

13C NMR (CDCl3) δ 60.90, 70.07, 121.06, 124.91, 126.48, 129.14, 129.60, 137.23, 138.46, 156.19.

example 3

[0062]

(R)-4-(2-Oxo-4-phenyl-oxazolidin-3-yl)-benzonitrile

The procedure described in example 1 was used with the appropriate substitution of reagents as follows:

K2CO3 (0.276 g / 2 mMol), Cul (0.019 g / 0.1 mMol), (R)4-phenyl-oxazolidin-2-one (0.195 g / 1.2 mMol), 4-Bromobenzonitrile (0.182 g / 1 mMol), 1,2-diaminocyclohexane (0.012 mL / 0.1 mMol) and 1 mL dioxane. The product was recovered in 82% yield.

Mass Spec 265.2 (m+1).

1H NMR (CDCl3) δ 4.17 (dd, J=5.6, 8.7, 1H), 4.78 (t, J=8.7, 1H), 5.46 (dd, J=5.6, 8.7, 1H), 7.24-7.37 (m, 5H), 7.44 (d, J=8.9, 2H), 7.55 (d, J=8.7, 2H)

13C NMR (CDCl3) δ 60.19, 70.20, 107.31, 118.89, 120.18, 126.2, 129.42, 129.90, 133.17, 137.64, 141.40,155.48.

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Abstract

Methods for the preparation of N-arylated oxazolidinone compounds via a copper catalyzed cross coupling reaction are disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 423,328 filed Nov. 1, 2002.FIELD OF THE INVENTION [0002] This invention relates to intermediates useful in the preparation of CETP inhibitors and methods of preparation thereof. BACKGROUND OF THE INVENTION [0003] 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. [0004] 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 r...

Claims

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Application Information

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IPC IPC(8): C07D263/00C07D207/12C07D263/22C07D291/04
CPCC07D207/12C07D291/04C07D263/22A61P3/06A61P9/10
Inventor GHOSH, ARUNCARON, STEPHANESIESER, JANICE E.
Owner PFIZER INC
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