Methods of making quinoline amides

Details Methods of making quinoline amides Methods of making quinoline amides

2002-04-23

2003-12-02

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06657065

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods of making quinoline amides. The present invention also relates to compounds that are used to make quinoline amides and methods of making these compounds.
BACKGROUND OF THE INVENTION
Quinoline amides of Formula I and Ia (R
3
is hydrogen) below are microsomal triglyceride transfer protein (MTP) inhibitors and can be used to treat hypercholesterolemia, atherosclerosis, obesity, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, diabetes, stroke, restenosis, or Syndrome X.
wherein
each R
3
is independently hydrogen or C
1
-C
6
alkyl;
A is
X is O or S;
n is 0 to 6;
each R
b
is independently hydrogen, —CF
3
, —OC
1
-C
6
alkyl, halo, —SH, —SC
1
-C
6
alkyl, phenyl, or —C
1
-C
6
alkyl;
B is hydrogen,
each R is independently hydrogen or C
1
-C
6
alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein from 1 to 3 substituents are independently selected from —CF
3
, halo,
—OC
1
-C
6
alkyl, or —C
1
-C
6
alkyl; and
m is 0 to 5.
U.S. patents that disclose MTP inhibitors include U.S. Pat. Nos. 5,919,795, 5,595,872, 5,721,279, 5,739,135, and 5,789,197.
U.S. provisional patent application No. 60/164,803 discloses compounds of Formula I and sets forth specific methods of making the compounds disclosed in the application by starting with 4-hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester, which is a known compound [C. C. Price et al.,
Journal of the American Chemical Society,
69, 374-376 (1947)]. In one aspect, the present invention concerns improved methods of making compounds of Formula I. Unlike the method disclosed in the provisional application, the present methods do not require starting with 4-hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester, which is made using a high temperature cyclization to form the quinoline ring system. In addition, the present methods require fewer steps and form the quinoline ring system directly.
SUMMARY OF THE INVENTION
The present invention provides a method of making a compound of Formula
wherein
each R
3
is independently hydrogen or C
1
-C
6
alkyl;
A is
X is O or S;
n is 0 to 6;
each R
b
is independently hydrogen, —CF
3
, —OC
1
-C
6
alkyl, halo, —SH, —SC
1
-C
6
alkyl, phenyl, or —C
1
-C
6
alkyl;
B is hydrogen,
each R is independently hydrogen or C
1
-C
6
alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from —CF
3
, halo, —OC
1
-C
6
alkyl, or —C
1
-C
6
alkyl; and
m is 0 to 5;
the method comprising the steps of:
a. reacting
b. reducing
c. reacting
d. oxidizing
e. coupling
In a preferred embodiment of the method, A is
The present invention also provides the compounds:
The present invention also provides the compound:
Also provided is a method of making
the method comprising the step of:
a. reacting
Also provided is a method of making
the method comprising the steps of:
a. reacting
b. reducing
Also provided is a method of making
the method comprising the steps of:
a. reacting
b. reducing
c. reacting
Also provided is a method of making
the method comprising the step of:
reacting
 to form
Also provided is a method of making a compound of Formula I
wherein
each R
3
is independently hydrogen or C
1
-C
6
alkyl;
A is
X is or S;
n is 0 to 6;
each R
b
is independently hydrogen, —CF
3
, —OC
1
-C
6
alkyl, halo, —SH, —SC
1
-C
6
alkyl, phenyl, or —C
1
-C
6
alkyl;
B is hydrogen,
each R is independently hydrogen or C
1
-C
6
alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from —CF
3
, halo, —OC
1
-C
6
alkyl, or —C
1
-C
6
alkyl; and
m is 0 to 5;
the method comprising the steps of:
1. reacting
2. reacting
 to give
3. hydrolyzing
 to give
4. reacting
 with H
2
N—B to provide a compound of Formula I.
In a preferred embodiment of the method, in step 1, the compound poly(4-vinylpyridine) is used a base.
In another preferred embodiment of the method, in step 2 the
is the sodium salt and C
1
-C
6
alkyl is ethyl.
In another preferred embodiment of the method, R
3
is hydrogen, A is
Also provided is the compound:
Also provided is a method of making
the method comprising the step of:
reacting
Also provided is a method of making a compound of Formula I
wherein
each R
3
is independently hydrogen or C
1
-C
6
alkyl;
A is
X is O or S;
n is 0 to 6;
each R
b
is independently hydrogen, —CF
3
, —OC
1
-C
6
alkyl, halo, —SH, —SC
1
-C
6
alkyl, phenyl, or —C
1
-C
6
alkyl;
B is hydrogen,
each R is independently hydrogen or C
1
-C
6
alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from —CF
3
, halo, —OC
1
-C
6
alkyl, or —C
1
-C
6
alkyl; and
m is 0 to 5;
the method comprising the steps of:
A. reacting
B. hydrolyzing
C. reacting
D. hydrolyzing
E. reacting
 with H
2
N—B to provide a compound of Formula I.
The present invention also provides the compounds:
wherein R
3
is hydrogen or C
1
-C
6
alkyl.
In a preferred embodiment of the immediately preceding compounds, R
3
is hydrogen and C
1
-C
6
alkyl is ethyl.
Also provided is a method of making
wherein R
3
is hydrogen or C
1
-C
6
alkyl,
the method comprising the steps of:
a. reacting
Also provided is a method of resolving phenyl-(2-pyridyl)-methylamine to obtain (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-&agr;-methoxyphenylacetic acid salt, the method comprising the steps of:
a. reacting phenyl-(2-pyridyl)-methylamine
 with (S)-(+)-&agr;-methoxyphenylacetic acid in isopropanol, which results in a precipitate being formed; and
b. isolating the precipitate, which is (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-&agr;-methoxyphenylacetic acid salt.
In a preferred embodiment of the resolution method, the (S)-(+)-&agr;-methoxyphenylacetic acid is present in the reaction in an amount in the range of about 0.5 equivalents with respect to the amine.
In another preferred embodiment of the resolution, the isolated precipitate is purified by recrystallization.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods of making compounds of Formula I and Formula Ia (R
3
is hydrogen). The compounds of Formula I and Ia are inhibitors of microsomal triglyceride transfer protein (MTP) and can be used as pharmaceutical agents to treat diseases such as hypercholesterolemia, atherosclerosis, obesity, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, diabetes, stroke, restenosis, and Syndrome X.
In addition, the present invention provides compounds that are intermediates used in the synthesis of compounds of Formula I and Ia and methods of making these intermediates.
The following terms are used in the application and are defined below.
The term “alkyl” means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl. Preferred alkyl groups are C
1
-C
6
alkyl.
The term “halogen” or “halo” means fluorine, chlorine, bromine or iodine.
The term “cycloalkyl” means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term bicycloalkyl means a cyclic hydrocarbon that contains bridging atoms. Examples of bicycloalkyl groups include bicyclo [3.2.1] octane and bicyclo [1.1.0] butane.
The symbol “—” means a covalent bond.
In one embodiment, the present invention provides a method of making compounds of Formula Ia,
wherein
each R
3
is independently hydrogen or C
1
-C
6
alkyl;
A is
X is O or S;
n is 0 to 6;
each R
b
is independently hydrogen, —CF
3
, —OC
1
-C
6
alkyl, halo, —SH, —SC
1
-C
6
alkyl, phenyl, or —C
1
-C
6
alkyl;
B is hydrogen,
each R is independently hydrogen or C
1
-C
6
alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wher

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