U.S. patent application number 09/924665 was filed with the patent office on 2002-04-11 for methods of making quinoline amides.
Invention is credited to Tom, Norma J., Whritenour, David C..
Application Number | 20020042516 09/924665 |
Document ID | / |
Family ID | 26918654 |
Filed Date | 2002-04-11 |
United States Patent
Application |
20020042516 |
Kind Code |
A1 |
Tom, Norma J. ; et
al. |
April 11, 2002 |
Methods of making quinoline amides
Abstract
The present invention relates to methods of making quinoline
amides of Formula I below, which are microsomal triglyceride
transfer protein inhibitors and can be used as medicines. 1 The
present invention also relates to compounds that are used to make
quinoline amides of Formula I and methods of making these
compounds.
Inventors: |
Tom, Norma J.; (Waterford,
CT) ; Whritenour, David C.; (Groton, CT) |
Correspondence
Address: |
Gregg C. Benson
Pfizer Inc.
Patent Department, MS 4159
Eastern Point Road
Groton
CT
06340
US
|
Family ID: |
26918654 |
Appl. No.: |
09/924665 |
Filed: |
August 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60224366 |
Aug 11, 2000 |
|
|
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Current U.S.
Class: |
546/169 |
Current CPC
Class: |
C07D 215/38
20130101 |
Class at
Publication: |
546/169 |
International
Class: |
C07D 215/38 |
Claims
What is claimed is:
1. A method of making a compound of Formula Ia 95wherein each
R.sup.3 is independently hydrogen or C.sub.1-C.sub.6alkyl; A is 96X
is O or S; n is 0 to 6; each R.sup.b is independently hydrogen,
--CF.sub.3, --OC.sub.1-C.sub.6alkyl, halo, --SH,
--SC.sub.1-C.sub.6alkyl, phenyl, or --C.sub.1-C.sub.6alkyl; B is
hydrogen, 97each R is independently hydrogen or
C.sub.1-C.sub.6alkyl; each Y is independently phenyl, substituted
phenyl, pyridyl or substituted pyridyl, wherein any substituents
are independently selected from --CF.sub.3, halo,
--OC.sub.1-C.sub.6alkyl, or --C.sub.1-C.sub.6alkyl; and m is 0 to
5; the method comprising the steps of: a. reacting 98b. reducing
99c. reacting 100d. oxidizing 101e. coupling 102 with H.sub.2N--B
to form a compound of Formula Ia.
2. The method of claim 1 wherein A is 103
3. The compound: 104
4. The compound: 105
5. A method of making 106the method comprising the step of: a.
reacting 107to give
6. A method of making 108the method comprising the steps of: a.
reacting 109b. reducing 110
7. A method of making 111the method comprising the steps of: a.
reacting 112 to give b. reducing 113c. reacting 114
8. A method of making 115the method comprising the step of:
reacting 116 to form 117
9. A method of making a compound of Formula I 118wherein each
R.sup.3 is independently hydrogen or C.sub.1-C.sub.6alkyl; A is
119X is O or S; n is 0 to 6; each R.sup.b is independently
hydrogen, --CF.sub.3, --OC.sub.1-C.sub.6alkyl, halo, --SH,
--SC.sub.1-C.sub.6alkyl, phenyl, or --C.sub.1-C.sub.6alkyl; B is
hydrogen, 120each R is independently hydrogen or
C.sub.1-C.sub.6alkyl; each Y is independently phenyl, substituted
phenyl, pyridyl or substituted pyridyl, wherein any substituents
are independently selected from --CF.sub.3, halo,
--OC.sub.1-C.sub.6alkyl, or --C.sub.1-C.sub.6alkyl; and m is 0 to
5; the method comprising the steps of: 1. reacting 1212. reacting
122 to give 1233. hydrolyzing 124 to give 1254. reacting 126 with
H.sub.2N--B to provide a compound of Formula I.
10. The method of claim 9 wherein in step 1, the compound
poly(4-vinylpyridine) is used a base.
11. The method of claim 9, wherein in step 2 the 127is the sodium
salt and C.sub.1-C.sub.6alkyl is ethyl.
12. The method of claim 9 wherein R.sup.3 is hydrogen, A is 128
13. The compound: 129
14. A method of making 130the method comprising the step of:
reacting 131
15. A method of making a compound of Formula I 132wherein each
R.sup.3 is inependently hydrogen or C.sub.1-C.sub.6alkyl; A is 133X
is O or S; n is 0 to 6; each R.sup.b is independently hydrogen,
--CF.sub.3, --OC.sub.1-C.sub.6alkyl, halo, --SH,
--SC.sub.1-C.sub.6alkyl, phenyl, or --C.sub.1-C.sub.6alkyl; B is
hydrogen, 134each R is independently hydrogen or
C.sub.1-C.sub.6alkyl; each Y is independently phenyl, substituted
phenyl, pyridyl or substituted pyridyl, wherein any substituents
are independently selected from --CF.sub.3, halo,
--OC.sub.1-C.sub.6alkyl, or --C.sub.1-C.sub.6alkyl; and m is 0 to
5; the method comprising the steps of: A. reacting 135B.
hydrolyzing 136C. reacting 137D. hydrolyzing 138E. reacting 139
with H.sub.2N--B to provide a compound of Formula I.
16. The compound: 140wherein R.sup.3 is hydrogen or
C.sub.1-C.sub.6alkyl.
17. A compound in accordance with claim 16 wherein R.sup.3 is
hydrogen and C.sub.1-C.sub.6alkyl is ethyl.
18. A method of making 141wherein R.sup.3 is hydrogen or
C.sub.1-C.sub.6alkyl, the method comprising the steps of: 142
19. A method of resolving phenyl-(2-pyridyl)-methylamine to obtain
(S)-phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt, the method
comprising the steps of: a. reacting phenyl-(2-pyridyl)-methylamine
with (S)-(+)-.alpha.-methoxyphenylacetic acid in isopropanol, which
results in a precipitate being formed; and b. isolating the
precipitate, which is (S)-phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt.
20. The method of claim 19 wherein of the
(S)-(+)-.alpha.-methoxyphenylace- tic acid is present in the
reaction in an amount in the range of about 0.5 equivalents with
respect to the amine.
21. The method of claim 19 wherein the isolated precipitate is
purified by recrystallization.
22. The method of claim 19 wherein the
(S)-phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt is converted to the
(S)-phenyl-(2-pyridyl)-methylamine hydrochloride salt.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority of U.S. provisional
application No. 60/224,366, filed Aug. 11, 2000.
FIELD OF THE INVENTION
[0002] 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
[0003] Quinoline amides of Formula I and Ia (R.sup.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. 2
[0004] wherein
[0005] each R.sup.3 is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0006] A is 3
[0007] X is O or S;
[0008] n is 0 to 6;
[0009] each R.sup.b is independently hydrogen, --CF.sub.3,
--OC.sub.1-C.sub.6alkyl, halo, --SH, --SC.sub.1-C.sub.6alkyl,
phenyl, or --C.sub.1-C.sub.6alkyl;
[0010] B is hydrogen, 4
[0011] each R is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0012] each Y is independently phenyl, substituted phenyl, pyridyl
or substituted pyridyl,
[0013] wherein from 1 to 3 substituents are independently selected
from --CF.sub.3, halo, --OC.sub.1-C.sub.6alkyl, or
--C.sub.1-C.sub.6alkyl; and
[0014] m is 0 to 5.
[0015] 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.
[0016] 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
[0017] The present invention provides a method of making a compound
of Formula Ia 5
[0018] wherein
[0019] each R.sup.3 is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0020] A is 6
[0021] X is O or S;
[0022] n is 0 to 6;
[0023] each R.sup.b is independently hydrogen, --CF.sub.3,
--OC.sub.1-C.sub.6alkyl, halo, --SH, --SC.sub.1-C.sub.6alkyl,
phenyl, or --C.sub.1-C.sub.6alkyl;
[0024] B is hydrogen, 7
[0025] each R is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0026] each Y is independently phenyl, substituted phenyl, pyridyl
or substituted pyridyl,
[0027] wherein any substituents are independently selected from
--CF.sub.3, halo, --OC.sub.1-C.sub.6alkyl, or
--C.sub.1-C.sub.6alkyl; and
[0028] m is 0 to 5;
[0029] the method comprising the steps of:
[0030] a. reacting 8
[0031] b. reducing 9
[0032] c. reacting 10
[0033] d. oxidizing 11
[0034] e. coupling 12
[0035] with H.sub.2N--B to form a compound of Formula Ia.
[0036] In a preferred embodiment of the method, A is 13
[0037] The present invention also provides the compounds: 14
[0038] The present invention also provides the compound: 15
[0039] Also provided is a method of making 16
[0040] the method comprising the step of:
[0041] a. reacting 17
[0042] Also provided is a method of making 18
[0043] the method comprising the steps of:
[0044] a. reacting 19
[0045] and
[0046] b. reducing 20
[0047] Also provided is a method of making 21
[0048] the method comprising the steps of:
[0049] a. reacting 22
[0050] b. reducing 23
[0051] and 24
[0052] Also provided is a method of making 25
[0053] the method comprising the step of:
[0054] reacting 26
[0055] Also provided is a method of making a compound of Formula I
27
[0056] wherein
[0057] each R.sup.3 is inependently hydrogen or
C.sub.1-C.sub.6alkyl;
[0058] A is 28
[0059] X is O or S;
[0060] n is 0 to 6;
[0061] each R.sup.b is independently hydrogen, --CF.sub.3,
--OC.sub.1-C.sub.6alkyl, halo, --SH, --SC.sub.1-C.sub.6alkyl,
phenyl, or --C.sub.1-C.sub.6alkyl;
[0062] B is hydrogen, 29
[0063] each R is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0064] each Y is independently phenyl, substituted phenyl, pyridyl
or substituted pyridyl,
[0065] wherein any substituents are independently selected from
--CF.sub.3, halo, --OC.sub.1-C.sub.6alkyl, or
--C.sub.1-C.sub.6alkyl; and
[0066] m is 0 to 5;
[0067] the method comprising the steps of:
[0068] 1. reacting 30
[0069] to form 31
[0070] 2. reacting 32
[0071] to give 33
[0072] 3. hydrolyzing 34
[0073] to give 35
[0074] ; and
[0075] 4. reacting 36
[0076] with H.sub.2N--B to provide a compound of Formula I.
[0077] In a preferred embodiment of the method, in step 1, the
compound poly(4-vinylpyridine) is used a base.
[0078] In another preferred embodiment of the method, in step 2 the
37
[0079] is the sodium salt and C.sub.1-C.sub.6alkyl is ethyl.
[0080] In another preferred embodiment of the method, R.sup.3 is
hydrogen, A is 38
[0081] Also provided is the compound: 39
[0082] Also provided is a method of making 40
[0083] the method comprising the step of: reacting 41
[0084] to form
[0085] Also provided is a method of making a compound of Formula I
42
[0086] wherein
[0087] each R.sup.3 is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0088] A is 43
[0089] X is O or S;
[0090] n is 0 to 6;
[0091] each R.sup.b is independently hydrogen, --CF.sub.3,
--OC.sub.1-C.sub.6alkyl, halo, --SH, --SC.sub.1-C.sub.6alkyl,
phenyl, or --C.sub.1-C.sub.6alkyl;
[0092] B is hydrogen, 44
[0093] each R is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0094] each Y is independently phenyl, substituted phenyl, pyridyl
or substituted pyridyl,
[0095] wherein any substituents are independently selected from
--CF.sub.3, halo, --OC.sub.1-C.sub.6alkyl, or
--C.sub.1-C.sub.6alkyl; and
[0096] m is 0 to 5;
[0097] the method comprising the steps of:
[0098] A. reacting 45
[0099] B. hydrolyzing 46
[0100] C. reacting 47
[0101] to form 48
[0102] D. hydrolyzing 49
[0103] E. reacting 50
[0104] with H.sub.2N--B to provide a compound of Formula I.
[0105] The present invention also provides the compounds: 51
[0106] wherein R.sup.3 is hydrogen or C.sub.1-C.sub.6alkyl.
[0107] In a preferred embodiment of the immediately preceding
compounds, R.sup.3 is hydrogen and C.sub.1-C.sub.6 alkyl is
ethyl.
[0108] Also provided is a method of making 52
[0109] wherein R.sup.3 is hydrogen or C.sub.1-C.sub.6alkyl,
[0110] the method comprising the steps of:
[0111] a. reacting 53
[0112] Also provided is a method of resolving
phenyl-(2-pyridyl)-methylami- ne to obtain
(S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-.alpha.-methoxyph-
enylacetic acid salt, the method comprising the steps of:
[0113] a. reacting phenyl-(2-pyridyl)-methylamine with
(S)-(+)-.alpha.-methoxyphenylacetic acid in isopropanol, which
results in a precipitate being formed; and
[0114] b. isolating the precipitate, which is
(S)-phenyl-(2-pyridyl)-methy- lamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt.
[0115] In a preferred embodiment of the resolution method, the
(S)-(+)-.alpha.-methoxyphenylacetic acid is present in the reaction
in an amount in the range of about 0.5 equivalents with respect to
the amine.
[0116] In another preferred embodiment of the resolution, the
isolated precipitate is purified by recrystallization.
DETAILED DESCRIPTION OF THE INVENTION
[0117] The present invention provides methods of making compounds
of Formula I and Formula Ia (R.sup.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.
[0118] 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.
[0119] The following terms are used in the application and are
defined below.
[0120] 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.sub.1-C.sub.6alkyl.
[0121] The term "halogen" or "halo" means fluorine, chlorine,
bromine or iodine.
[0122] The term "cycloalkyl" means a cyclic hydrocarbon. Examples
of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl.
[0123] 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.
[0124] The symbol "--" means a covalent bond.
[0125] In one embodiment, the present invention provides a method
of making compounds of Formula Ia, 54
[0126] wherein
[0127] each R.sup.3 is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0128] A is 55
[0129] X is O or S;
[0130] n is 0to 6;
[0131] each R.sup.b independently hydrogen, --CF.sub.3,
--OC.sub.1-C.sub.6alkyl, halo, --SH, --SC.sub.1-C.sub.6alkyl,
phenyl, or --C.sub.1 -C.sub.6alkyl;
[0132] B is hydrogen, 56
[0133] each R is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0134] each Y is independently phenyl, substituted phenyl, pyridyl
or substituted pyridyl,
[0135] wherein any substituents are independently selected from
--CF.sub.3, halo, --OC.sub.1-C.sub.6alkyl, or
--C.sub.1-C.sub.6alkyl; and
[0136] m is 0 to 5;
[0137] the method comprising the steps of:
[0138] a. reacting 57
[0139] b. reducing 58
[0140] c. reacting 59
[0141] d. oxidizing 60
[0142] and
[0143] e. coupling 61
[0144] with H.sub.2N--B to form a compound of Formula Ia.
[0145] In step a of the above method, the nitro amide compound can
be made by coupling 3-nitroaniline (Aldrich, Milwaukee, Wis.) with
an acid chloride. An acid chloride, which is an activated
carboxylic acid, can be made from the corresponding carboxylic acid
following procedures that are well known in the art. A preferred
acid chloride is 4'-trifluoromethyl-biphenyl-2-carbonyl chloride.
Examples of reagents that can be used to make an acid chloride (or
acid halide) from an acid include oxalyl chloride, thionyl
chloride, PCl.sub.3, PBr.sub.3, Ph.sub.3P in CCl.sub.4, and
cyanuric fluoride. The coupling of an amine with a carboxylic acid
(typically, an activated carboxylic acid such as an acid chloride)
is well known in the art. A preferred coupling method of step a of
the present invention uses a base such as triethylamine in a polar,
aprotic solvent such as tetrahydrofuran. Many procedures that
couple a carboxylic acid or derivative with an amine to form an
amide have been reported. Many involve the activation of a
carboxylic acid to an acid chloride or anhydride followed by
coupling with an amine. Many coupling reagents directly activate an
acid for reaction with an amine including carbodiimides such as
dicyclohexylcarbodiimide (DCC), propanephosphonic anhydride, and
various hydroxybenzotriazole derivatives. In many cases it is
possible to interconvert from other carboxylic acid derivatives
such as an ester, nitrile, or amide to the desired amide. These
methods are summarized in Richard C. Larock, Comprehensive Organic
Transformations, 2nd ed, Wiley, N.Y., 1999, pp.1941-1949,
1953-1957, 1978-1982, 1988-1990, and 1973-1976.
[0146] In step b of the above method, the nitro amide made in step
a is reduced to an amino amide. The reduction of a nitro group to
an amino group is well known to those skilled in the art. For
example, in a preferred embodiment of the present invention,
palladium dihydroxide (also known as Pearlman's catalyst) and
ammonium formate in a mixture of isopropanol and ethyl acetate can
be used. The reduction of an aryl nitro group to an aryl amine has
been accomplished in many ways. Common methods include the
reduction with a metal catalyst such as palladium on carbon or
Rainey nickel and hydrogen gas. Transfer hydrogenation with
hydrazine/graphite or cyclohexene/palladium is also effective.
Other hydride sources, such as sodium borohydride with various
metal salts and lithium aluminum hydride may also be used. Nitro
reductions have also been accomplished with zinc or tin and
hydrochloric acid. These methods and others are summarized by
Richard C. Larock in Comprehensive Organic Transformations, 2nd ed,
Wiley, N.Y., 1999, pp. 821-828.
[0147] In step c of the above method, a quinoline ring system is
formed by reacting the amino amide produced in step b with the
diamine reagent
(2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane): 62
[0148] , preferably the bis(tetrafluoroborate) salt
(2BF.sub.4.sup.-). The diamine reagent used in this step can be
prepared by reacting bromoacetic acid or bromoacetyl chloride with
phosphorus oxychloride and N,N-dimethylformamide, followed by
tetrafluoroboric acid. The generation of this reagent is set forth
specifically below. The use of this reagent to form the quinoline
ring system is advantageous because it does not require a high
temperature cyclization step.
[0149] In step d above, the newly formed quinoline, which contains
an aldehyde group, is oxidized to form a quinoline carboxylic acid.
The oxidation of an aldehyde group to a carboxylic acid group is
well known to those skilled in the art. A preferred oxidation
method of the present invention uses sodium chlorite. Other
reagents than can be used to oxidize an aldehyde to a carboxylic
acid include potassium permanganate, sodium periodate, ruthenium
tetroxide, chromium trioxide, hydrogen peroxide, sodium
perchlorate, or the like.
[0150] Next, the quinoline carboxylic acid formed in step d above
is coupled with an amine having the formula H.sub.2N--B. The
coupling of an amine with a carboxylic acid to form an amide is
well known to those skilled in the art. A preferred coupling method
of the present invention uses
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
1-hydroxybenzotriazole, triethylamine, and dichloromethane. A
preferred amine is phenyl-(2-pyridyl)-methylamine. Many procedures
to convert a carboxylic acid or derivative to an amide have been
reported as described above.
[0151] The present invention is also directed to a method of making
compounds of Formula I: 63
[0152] wherein
[0153] each R.sup.3 is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0154] A is 64
[0155] X is O or S;
[0156] n is 0 to 6;
[0157] each R.sup.b is independently hydrogen, --CF.sub.3,
--OC.sub.1-C.sub.6alkyl, halo, --SH, --SC.sub.1-C.sub.6alkyl,
phenyl, or --C.sub.1-C.sub.6alkyl;
[0158] B is hydrogen, 65
[0159] each R is independently hydrogen or
C.sub.1-C.sub.6alkyl;
[0160] each Y is independently phenyl, substituted phenyl, pyridyl
or substituted pyridyl,
[0161] wherein any substituents are independently selected from
--CF.sub.3, halo, --OC.sub.1-C.sub.6alkyl, or
--C.sub.1-C.sub.6alkyl; and
[0162] m is 0 to 5;
[0163] the method comprising:
[0164] 1.) reacting 66
[0165] 2. reacting 67
[0166] 3. hydrolyzing 68
[0167] with H.sub.2N--B to provide a compound of Formula I.
[0168] In step 1 above, an amino aldehyde amide is formed by
reacting an acid chloride with 2,4-diaminobenzaldehyde, which is a
known compound. [See, for example, Merlic, C. A. et al., J. Org.
Chem., 1995, 60, 3365-3369.]. The acid chloride can be formed from
the corresponding carboxylic acid by procedures that are well known
in the art. 2,4-Diaminobenzaldehyde can also be obtained by
reducing 2,4-dinitrobenzaldehyde (Aldrich, Milwaukee, Wis.).
Reductions of a nitro group to an amino group are well known. A
preferred reduction uses iron dust, glacial acetic acid and ethyl
acetate. The reduction of an aryl nitro group to an aryl amine has
been accomplished in many ways. Common methods include the
reduction with a metal catalyst such as palladium on carbon or
Rainey nickel and hydrogen gas. Transfer hydrogenation with
hydrazine/graphite or cyclohexene/palladium is also effective.
Other hydride sources such as sodium borohydride with various metal
salts and lithium aluminum hydride may be used. Nitro reductions
have also been accomplished with zinc or tin and hydrochloric acid.
These reactions and others are summarized by Richard C. Larock in
Comprehensive Organic Transformations, 2nd ed, 1999, pp.
821-828.
[0169] The formation of the amino aldehyde amide is accomplished by
coupling an acid chloride with an amino group of
2,4-diaminobenzaldehyde. In a preferred embodiment of the method,
the coupling is accomplished using poly(4-vinylpyridine). The
poly(4-vinylpyridine) (CAS# 9017-40-7) can be obtained as 2% or 25%
crosslinked with divinylbenzene from Aldrich, Milwaukee, Wis. The
use of poly(4-vinylpyridine) provides for greater selectivity with
regard to reaction at the 4-amino group of the
2,4-diaminobenzaldehyde.
[0170] In step 2 above the amino aldehyde amide is reacted with
69
[0171] , preferably the sodium salt, to provide a quinoline ester.
The reaction can be run in glacial acetic acid.
[0172] In step 3 above, the quinoline ester is hydrolyzed to form a
quinoline carboxylic acid. The hydrolysis of esters is well known
to those skilled in the art. Preferred reagents that can be used
include a base such as sodium hydroxide in a mixture of methanol
and tetrahydrofuran. Other reagents that can be used to hydrolyze
an ester to a carboxylic acid include lithium hydroxide, potassium
hydroxide or barium hydroxide in methanol, tetrahydrofuran or
mixtures thereof. Additional reagents that can be used are set
forth in Organic Reactions, 1976, 24, 187; and E. Haslam in
Tetrahedron, 1980, 36, 2409- 2433.
[0173] In step 4 above, the quinoline carboxylic acid is coupled
with an amine H.sub.2N--B to provide a compound of Formula I. A
preferred amine is phenyl-(2-pyridyl)-methylamine. Many procedures
to couple a carboxylic acid or derivative with an amine to form an
amide have been reported as described above.
[0174] The compounds of Formula I can also be synthesized by the
following procedure:
[0175] A. reacting 70
[0176] B. hydrolyzing 71
[0177] C. reacting 72
[0178] D. hydrolyzing 73
[0179] with H.sub.2N--B to provide a compound of Formula I.
[0180] In step A above, a halo quinoline ester is reacted with
benzophenone imine to form a benzhydrylidene amino quinoline ester.
Preferred reagents used to accomplish the reaction include
benzophenone imine, tri(dibenzylidieneacetone)dipalladium,
2-(dicyclohexylphosphino)bi- phenyl, and sodium tert-butoxide in
toluene. The halo quinoline ester is known. See, for example,
Silva, Y. et al., Acta Cient Venez., 41, 130-131 (1990).
Alternatively, the halo quinoline ester can be made by reducing
4-chloro-2-nitrobenzaldehyde to 4-chloro-2-aminobenzaldehyde.
4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T.
International, Inc., Charlotte, N.C. The reduction of a nitro group
to an amino group is well known to those skilled in the art.
Examples of additional suitable reagents are set forth above. A
preferred reduction uses iron powder, hydrochloric acid and a
solvent of aqueous ethanol. Next, the 4-chloro-2-aminobenzaldehyde
is reacted with 3-hydroxy-acrylic acid ethyl ester, sodium salt, to
form the halo quinoline ester.
[0181] In step B above, the benzhydrylidene amino quinoline ester
is hydrolyzed to form an amino quinoline ester. Preferred
hydrolysis reagents are hydrochloric acid and ethanol. Other
hydrolysis reagents include mineral acids and water, hydrogen and
palladium on carbon, and hydroxylamine.
[0182] In step C above, the amino quinoline ester is reacted with
an acid chloride to form an amide quinoline ester. Preferred
reaction conditions include diisopropylamine in CH.sub.2Cl.sub.2.
The reaction of an acid chloride (i.e., an activated carboxylic
acid) with an amine to form an amide is well known to those skilled
in the art, and other suitable reagents are set forth above.
[0183] In step D above, the amide quinoline ester is hydrolyzed to
form an amide quinoline carboxylic acid. Preferred reagents include
sodium hydroxide in methanol and tetrahydrofuran. Other reagents
that can be used to hydrolyze an ester to a carboxylic acid include
lithium hydroxide, potassium hydroxide, barium hydroxide in
methanol or tetrahydrofuran or mixtures thereof. Other examples of
ester hydrolysis are set forth in Organic Reactions, 1967, 24, 187;
and Tetrahedron, 1980, 36, 2409.
[0184] In step E above, the amide quinoline carboxylic acid is
reacted with an amine of formula HN--B to form a compound of
Formula I.
[0185] In another aspect, the present invention provides a method
of resolving phenyl-(2-pyridyl)-methylamine to obtain the
(S)-phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt. The resolution
method comprises the steps of combining racemic
phenyl-(2-pyridyl)-methylamine, which can be obtained from Alfa
Aesar, Ward Hill, Mass., and (S)-(+)-.alpha.-methoxyphenylacetic
acid from Aldrich, Milwaukee, Wis., in isopropanol, which results
in the formation of a precipitate, which is
(S)-phenyl-(2-pyridyl)methylamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt. The precipitate is
isolated, and can be recrystallized using isopropanol one or more
times. Each recrystallization results in a greater enantiomeric
purity of the desired (S) isomer of the
phenyl-(2-pyridyl)-methylamine salt. It is preferable if about 0.5
mole equivalents of the (S)-(+)-.alpha.-methoxyph- enylacetic acid
is used with regard to the phenyl-(2-pyridyl)-methylamine.
[0186] The (S)-phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphen- ylacetic acid salt can be converted to
(S)-phenyl-(2-pyridyl)-methylamine hydrochloride salt as detailed
below.
[0187] All documents cited herein are hereby incorporated by
reference.
[0188] The examples presented below are intended to illustrate
particular embodiments of the invention and are not intended to
limit the scope of the specification, including the claims, in any
manner. The following abbreviations are used herein
1 AcOH Acetic Acid EtOH Ethanol EtOAc Ethyl Acetate DMF
Dimethylformamide THF Tetrahydrofuran MeOH Methanol mol Mole(s)
equiv Equivalent(s) TLC Thin layer chromatography HPLC High
pressure liquid chromatography IPO Isopropanol IPE diisopropylether
Et Ethyl APCl Atmospheric pressure chemical ionization Ph
Phenyl
EXAMPLES
[0189] The following procedures illustrate the methods of making
compounds of Formula I or Ia.
Method 1
[0190] 74
[0191] 2,4-Diaminobenzaldehyde
[0192] To a nitrogen purged 5 liter 4-neck flask fitted with a
condenser, mechanical stirrer, addition funnel, and temperature
probe, was added 325 mesh iron dust, which can be obtained from
Aldrich, Milwaukee, Wis. (220 g, 3.9 mol, 8 equiv), water (800 mL),
and glacial acetic acid (5 mL). Over the next hour, some frothing
occurred and the temperature rose to 28.degree. C. In a separate
container, 2,4-dinitrobenzaldehyde (97 g, 0.49 mol, 1 equiv) was
dissolved in 1:1 glacial acetic acid/ethyl acetate (800 mL).
2,4-Dinitrobenzaldehyde can be purchased from Aldrich, Milwaukee,
Wis. About 5 mL of the 2,4-dinitrobenzaldehyde solution was added
dropwise to the iron mixture, which led to a dissipation of the
frothing. The reaction mixture was warmed to 35.degree. C. with a
steam bath. Without further heating, the remaining
dinitrobenzaldehyde solution was added at such a rate as to
maintain the temperature below 50.degree. C. The addition was
completed after 6 hours. The reaction mixture was diluted with
water (1 L) and diatomaceous earth (BNL Fine Chemicals and
Reagents, Meriden, Conn.) was added (100 g). The reaction mixture
was stirred an additional 3 hours at which point the temperature
had dropped to 25.degree. C. The solids were removed by filtration.
The organic layer was separated and the aqueous layer was extracted
with ethyl acetate (3.times.400 mL). The extracts were then used to
wash the solids from the initial filtration. The organic layers
were combined and washed with water (400 mL) and saturated aqueous
NaHCO.sub.3 (3.times.400 mL). The combined organic layers were
dried over MgSO.sub.4 and Darco G-60.RTM. (activated charcoal; BNL
Fine Chemicals and Reagents, Meriden, Conn.) (10 g). After
filtration to remove the drying agents, the organic layers were
concentrated in vacuo to a slurry and diluted with 1 L of hexanes.
The precipitated solids were collected by suction filtration and
dried in air to give 2,4-diaminobenzaldehyde (48 g, 71%) as a light
yellow solid.
[0193] .sup.1H NMR (acetone-d.sub.6) .delta.5.48 (brs, 2H), 5.94
(d, 1H, J=1.9 Hz), 6.08 (dd, 1H, J=2.0, 8.6 Hz), 6.75 (br s, 2H),
7.20 (d, 1H, J=8.6 Hz), 9.51 (s, 1H). 75
[0194] 4'-Trifluoromethyl-biphenyl-2-carbonyl Chloride
[0195] To a nitrogen purged 3 liter 4-neck flask fitted with a
condenser, mechanical stirrer, temperature probe, and connected to
a 2M aqueous NaOH scrubber was added toluene (1 L),
4'-trifluoromethyl-biphenyl-2-carboxyli- c acid (250 g, 0.94 mol, 1
equiv), and DMF (5 mL). 4'-Trifluoromethyl-biph- enyl-2-carboxylic
acid can be obtained from Aldrich, Milwaukee, Wis. The solution was
heated to 60.degree. C. and thionyl chloride (110 mL, 1.5 mol, 1.6
equiv) was added at such a rate as to maintain the temperature
below 65.degree. C. The addition was complete after 30 minutes and
the reaction was heated to reflux. After 4 hours, the heating was
stopped and the reaction was allowed to stir overnight at room
temperature. The reaction mixture was concentrated in vacuo and the
residue was used in the next step without further purification. The
material crystallized to a solid at room temperature.
[0196] .sup.1H NMR (CDCl.sub.3) .delta.7.37 (dd, 1H, J=1.1, 7.6
Hz), 7.43 (d, 2H, J=8.1 Hz), 7.55 (td, 1H, J=1.3, 7.7 Hz), 7.66
(td, 1H, J=1.3, 7.5 Hz), 7.68 (d, 2H, J=8.1 Hz), 8.11 (dd, 1H,
J=1.2, 7.9 Hz). 76
[0197] 4'-Trifluoromethyl-biphenyl-2-carboxylic acid
(3-amino-4-formyl-phenyl)-amide
[0198] To a nitrogen purged 12 liter 3-neck flask fitted with a
mechanical stirrer and temperature probe was added THF (4.3 L) and
2,4-diaminobenzaldehyde (50 g, 0.37 mol, 1 equiv). After cooling
the solution to -70.degree. C. (dry ice/acetone bath),
poly(4-vinylpyridine), which can be obtained from Aldrich,
Milwaukee, Wis., 25% cross-linked, (210 g) was added. A solution of
4'-trifluoromethyl-biphenyl-2carbonyl chloride (105 g, 0.37 mol, 1
equiv) in THF (1 L) was added at such a rate as to maintain the
temperature below -60.degree. C. The light orange reaction mixture
was allowed to warm to room temperature over 4 hours to give a dark
red reaction mixture. (HPLC analysis showed an 18:1 mixture of
mono- (retention time (rt)=4.8 min) to di- (rt=3.1 min) acylated
products along with 5% residual starting material (rt=18.8 min),
(Zorbax SIL (150 mm) from Agilent Technologies, Palo Alto, Calif. 2
mL/min 90:10 hexanes/isopropanol, 0.1% diethylamine, 250 nm,
40.degree. C.). The reaction was quenched with 1 N NaOH (450 mL)
and allowed to stir overnight at 25.degree. C. The reaction mixture
was filtered and the solids were washed with ethyl acetate
(5.times.200 mL) and the combined organic layers were concentrated
in vacuo to give a brown oil. The oil was dissolved in
CH.sub.2Cl.sub.2 (1.5 L) and silica gel (EM Science, Gibbstown,
N.J., 230-400 mesh or 0.04-0.06 mm particle size) (410 g) and Darco
G-60.RTM. (10 g, BNL Fine Chemicals and Reagents) were added. The
slurry was stirred for 15 minutes and filtered. The silica was
washed with CH.sub.2Cl.sub.2 (5.times.200 mL). The combined organic
layers were concentrated in vacuo and the methylene chloride was
displaced with 1:1 hexanes/diisopropylether. The precipitated
product was collected by suction filtration and dried in air to
give 4'-trifluoromethyl-biphenyl-2- -carboxylic acid
(3-amino4-formyl-phenyl)-amide (40 g, 30%, 43:1 mono:bis acylated
by HPLC) as a light yellow solid.
[0199] MS (APCI) 385 (M+1).sup.+; 383 (M-1).sup.-
[0200] .sup.1H NMR (DMSO-d.sub.6) .delta.6.65 (dd, 1H, J=1.7, 8.7
Hz), 7.15 (br s, 2H), 7.25 (s, 1H), 7.38 (d, 1H, J=8.7 Hz),
7.46-7.68 (m, 6H), 7.74 (d, 2H, J=8.3 Hz), 9.57 (s, 1H), 10.51 (s,
1H). 77
[0201]
7-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid ethyl ester
[0202] A solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid
(3-amino4-formyl-phenyl)-amide (7 g, 18.2 mmol, 1 equiv) and
3-hydroxy-acrylic acid ethyl ester, sodium salt (2.52 g, 18.2 mmol,
1 equiv) in glacial acetic acid (70 mL, 10 volumes) was heated at
80.degree. C. for 2 hours. Additional 3-hydroxy-acrylic acid ethyl
ester, sodium salt (2.52 g, 18.2 mmol, 1 equiv) was added and the
solution heated for 15 hours. Again, additional 3-hydroxy-acrylic
acid ethyl ester, sodium salt (1.26 g, 9.1 mmol, 0.5 equiv) was
added and the solution heated for another 4 hours. The reaction
mixture was concentrated in vacuo. The residue was dissolved in
EtOAc (300 mL) and the organic layer was washed with a saturated
aqueous sodium carbonate solution (2.times.200 mL) and 1 N NaOH
solution (200 mL). The combined aqueous layers were back extracted
with ethyl acetate (200 mL). The combined organic layers were dried
over sodium sulfate and treated with Darco G-60.RTM. (7 g). The
solids were removed by filtration and the filtrate was concentrated
to afford crude 7-[(4'-trifluoromethyl-biphenyl-
-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester, which
was used in the next step without further purification.
[0203] MS (APCI) 465 (M+1).sup.+; 463 (M-1).sup.-
[0204] .sup.1H NMR (DMSO-d.sub.6) .delta.1.34 (t, 3H, J=7.1 Hz),
4.36 (q, 2H, J=7.1 Hz), 7.53-7.73 (m, 9H), 8.08 (d, 1H, J=8.7 Hz),
8.44 (d, 1H, J=1.3 Hz), 8.84 (d, 1H, J=2.1 Hz), 9.21 (d, 1H, J=2.1
Hz), 10.95 (s, 1H). 78
[0205]
7-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid
[0206] To a solution of
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-
-quinoline-3-carboxylic acid ethyl ester (8.45 g, 18.2 mmol, 1
equiv) in MeOH (85 mL) and THF (85 mL) was added 1 N NaOH (91 mL,
91 mmol, 5 equiv). The solution was stirred at room temperature for
4 hours. The organic layer was removed in vacuo and the aqueous
layer was washed with EtOAc (100 mL). The aqueous layer was then
acidified to a pH of about 4 with concentrated HCl and a
precipitate formed. The mixture was stirred for 48 hours and the
solids collected by filtration to provide
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic
acid (4.5 g, 57% over two steps) as a yellow solid.
[0207] MS (APCI) 437 (M+1).sup.+; 435 (M-1).sup.-
[0208] .sup.1H NMR (DMSO-d.sub.6) .delta.7.54-7.74 (m, 9H), 8.08
(d, 1H, J=8.7 Hz), 8.44 (s, 1H), 8.84 (d, 1H, J=1.7 Hz), 9.22 (d,
1H, J=2.0 Hz), 10.90 (s, 1H). 79
[0209]
(+)-(S)-7[-(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinolin-
e-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide
[0210] To a suspension of
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amin- o]-3-carboxylic
acid (10 g, 22.9 mmol, 1 equiv) and methylene chloride (168 mL,
16.8 volumes) was added (S)-phenyl-(2-pyridyl)methylamine,
hydrochloric acid salt (6.5 g, 29.8 mmol, 1.3 equiv),
3-ethyl-1-(3-diethylaminopropyl)-carbodiimide hydrochloride (EDAC)
(5.3 g, 27.5 mmol, 1.2 equiv), and hydroxy benzotriazole (HOBT)
(3.3 g, 24.1 mmol, 1.05 equiv). Diisopropylethylamine was added
dropwise (11.97 g, 92.6 mmol, 4.04 equiv). The resulting solution
was allowed to stir for 12 hours at room temperature. The solution
was then extracted with 0.5 N hydrochloric acid (3.times.80 mL),
saturated sodium hydrogen carbonate (2.times.80 mL) and saturated
sodium chloride (80 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo to give
(+)-(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-ca-
rboxylic acid (phenyl-pyridin-2-yl-methyl)-amide (12.2 g,
88.4%).
Method 2
[0211] 80
[0212] 4-Chloro-2-aminobenzaldehyde
[0213] To a 3-neck flask fitted with a reflux condenser and a
mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g,
135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL).
4-Chloro-2-nitrobenzaldehyd- e can be obtained from P.H.T.
International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich,
Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated
hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The
slurry was heated to 85.degree. C. for two hours, cooled to room
temperature, filtered through diatomaceous earth and rinsed with
ethanol (100 mL) and toluene (100 mL). The solution was transferred
to a separatory funnel and toluene (300 mL) were added. The organic
layer was washed with saturated sodium bicarbonate solution (300
mL) and brine (300 mL), then dried over sodium sulfate and then
concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83%)
as a yellow solid.
[0214] .sup.1H NMR (CDCl.sub.3) .delta.7.58 (dd, 1H, J=2.1, 8.7
Hz), 7.89 (d, 1H, J=8.7 Hz), 8.17 (s, 1H), 8.83 (d, 1H, J=1.7 Hz),
9.45 (br s, 2H). 81
[0215] 7-Chloro-quinoline-3-carboxylic acid ethyl ester
[0216] A solution of 4-chloro-2-aminobenzaldehyde (15 g, 96 mmol, 1
equiv) and 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 g,
48 mmol, 0.5 equiv) in glacial acetic acid (175 mL), was heated at
reflux for 3 hours. Additional 3-hydroxy-acrylic acid ethyl ester,
sodium salt (6.65 grams, 48 mmol, 0.5 equivalents) was added and
the reaction was heated at reflux for another 2.5 hours. Additional
3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol,
0.3 equiv) was added and the reaction was heated at reflux for an
additional 12 hours. Additional 3-hydroxy-acrylic acid ethyl ester,
sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction
was heated at reflux for 4 hours. The reaction mixture was cooled
and concentrated in vacuo. The residue was dissolved in ethyl
acetate (200 mL) and washed with saturated sodium bicarbonate
solution (200 mL). The organic layer was then washed with brine
(200 mL), dried over sodium sulfate, and treated with activated
charcoal (Darco G-60.RTM.) (20 g). The mixture was filtered through
diatomaceous earth. Silica gel (15 g) (EM Science, Gibbstown, N.J.,
230-400 mesh, 0.04-0.06 mm particle size) was added to the solution
and stirred for 3 hours. The slurry was filtered, rinsed with
toluene (100 ml) and then 10% ethyl acetate in toluene (200 mL).
The combined organic layers were concentrated and the resulting
solid was stirred in isopropanol overnight to yield
7-chloro-quinoline-3-carboxylic acid ethyl ester (3 g, 13% yield)
as a pale yellow powder.
[0217] .sup.1H NMR (CDCl.sub.3) .delta.1.38 (m, 3H), 4.45 (m, 2H),
7.57 (dd, 1H, J=2.1, 8.7 Hz), 7.87 (d, 1H, J=8.7 Hz), 8.16 (d, 1H,
J=1.3 Hz), 8.81 (d, 1H, J=2.1 Hz), 9.44 (d, 1H, J=2.1 Hz).
[0218] 3-Hydroxy-acrylic acid ethyl ester, sodium salt can be made
by the following procedure:
[0219] To a 20.degree. C. slurry of sodium ethoxide (250 g, 3.49
mol, 1.5 equiv) and ethyl acetate (750 mL, 4.2 volumes) was
dropwise added ethyl formate (178 g, 2.33 mol, 1 equiv) while
keeping the internal temperature below 35.degree. C. with external
cooling. The resulting light tan slurry was stirred for 4 hours at
room temperature and then diluted with hexanes (200 mL, 1.12
volumes). The off-white solids were collected by suction filtration
and dried in vacuo at 20.degree.-25.degree. C. to provide
3-hydroxy-acrylic acid ethyl ester, sodium salt (204.4 g, 63.5%)
82
[0220] 7-(Benzhydrylidene-amino)-quinoline-3-carboxylic acid ethyl
ester
[0221] 7-Chloro-quinoline-3-carboxylic acid ethyl ester (1 g, 4.24
mmol, 1 equiv), dry sodium t-butoxide (571 mg, 5.94 mmol, 1.4
equiv), tris(dibenzylideneacetone)dipalladium (19.5 mg, 21.2
.mu.mol, 1 mol % equiv), and 2-(dicylcohexylphosphino)biphenyl (30
mg, 84.8 .mu.mol, 4 mol % equiv) were placed in a round bottom
flask with a magnetic stir bar. The flask was flushed with
nitrogen. Benzophenone imine (783 .mu.L, 4.66 mmol, 1.1 equiv) and
toluene (8.5 mL) were added. The flask was fitted with a reflux
condenser and the reaction was heated at 100.degree. C. for 12
hours. The reaction mixture was cooled to room temperature and
diluted with ethyl acetate (20 mL). The reaction mixture was washed
with a saturated sodium bicarbonate solution (25 mL), saturated
ammonium chloride solution (25 mL), and brine (25 mL). The organic
layer was dried over sodium sulfate and then treated with activated
charcoal (Darco G-60.RTM.) (1 g). The mixture was filtered through
diatomaceous earth and concentrated. The residue was stirred in a
minimal amount of isopropanol (about 2 mL) to provide
7-(benzhydrylidene-amino)-quinoline-3-carboxylic acid ethyl ester
(199 mg, 12%) as a pale yellow solid.
[0222] MS (APCI) 381 (M+1).sup.+
[0223] .sup.1H NMR (CDCl.sub.3) .delta.1.42 (t, 3H, J=7.1 Hz), 4.42
(q, 2H, J=7.1 Hz), 7.06 (dd, 1H, J=2.1, 8.7 Hz), 7.14-7.22 (m, 5H),
7.38-7.51 (m, 4H), 7.69 (d, 1H, J=8.7 Hz), 7.79 (d, 2H, J=7.1 Hz),
8.67 (d, 1H, J=2.1 Hz), 9.31 (d, 1H, J=2.1 Hz). 83
[0224] 7-Amino-guinoline-3-carboxylic acid ethyl ester
[0225] Concentrated hydrochloric acid (1 mL, 2.5 volumes) was added
to a solution of 7-(benzhydrylidene-amino)-quinoline-3-carboxylic
acid ethyl ester (400 mg, 1.05 mmol, 1 equiv) in ethanol (4 mL, 10
volumes). The solution was stirred at room temperature for three
hours and then concentrated. The residue was dissolved in ethyl
acetate (20 mL, 50 volumes) and the organic layer was washed with 1
N hydrochloric acid (5.times.25 mL). The pH of the combined aqueous
layer was then adjusted to about 8 with solid sodium hydroxide. The
aqueous layer was then extracted with ethyl acetate (3.times.50
mL). The combined organic layers were dried over sodium sulfate and
concentrated to provide 7-amino-quinoline-3-carboxylic acid ethyl
ester (155 mg, 68%) as a yellow solid. The crude solid can be
further purified by flash column chromatography using silica gel
(EM Science, Gibbstown, N.J., 230-400 mesh) in 60% ethyl acetate in
hexanes if desired.
[0226] MS (APCI) 217 (M+1).sup.+
[0227] .sup.1H NMR (DMSO-d.sub.6) .delta.1.32 (t, 3H, J=7.0 Hz),
4.31 (q, 2H, J=7.1 Hz), 6.27 (br s, 2H), 6.92 (s, 1H), 7.02 (d, 1H,
J=8.7 Hz), 7.77 (d, 1H, J=8.7 Hz), 8.56 (s, 1H), 8.99 (d, 1H, J=2.1
Hz). 84
[0228]
7-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid ethyl ester
[0229] To a mixture of 7-amino-quinoline-3-carboxylic acid ethyl
ester (11 g, 51 mmol, 1 equiv), dichloroethane (220 mL, 20
volumes), and diisopropylethylamine (13.15 g, 101.7 mmol, 2 equiv)
was slowly added a solution of
4'-trifluoromethyl-biphenyl-2-carbonyl chloride (17.38 g, 61 mmol,
1.2 equiv) dissolved in dichloroethane (30 mL, 2.7 volumes). The
reaction was heated at 84.degree. C. overnight and then cooled to
room temperature. The reaction mixture was washed with 1 N
hydrochloric acid (2.times.150 mL) and the aqueous layer was back
extracted with dichloroethane (1.times.150 mL). The combined
organic layers were washed with 1 N sodium hydroxide (2.times.150
mL), water (150 mL), and saturated sodium chloride (2.times.150
mL). The combined organic layers were dried over sodium sulfate and
concentrated in vacuo to give a red-brown oil. The oil was
dissolved in hot toluene (32 mL) and isopropyl ether (16 mL) and
the resulting solution was allowed to cool with stirring to give a
beige slurry. The solids were collected by filtration to give
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic
acid ethyl ester (13.8 g, 58.4%). 85
[0230]
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid
[0231] To a solution of
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-
-quinoline-3-carboxylic acid ethyl ester (50 g, 114.5 mmol, 1
equiv) and methanol (750 mL, 15 volumes) was slowly added 1 N
sodium hydroxide (220 mL, 4.4 volumes). After stirring at room
temperature for 2 hours, the reaction was concentrated in vacuo.
Water (750 mL) was added to the residue and the pH was adjusted to
5.0 using 1 N hydrochloric acid (250 mL). The resulting slurry was
stirred for 30 minutes and the precipitated solids were collected
by filtration and dried in vacuo and then dissolved in methanol (75
mL) and ethyl acetate (675 mL). The solution was dried over sodium
sulfate and filtered, and concentrated in vacuo. The residue was
slurried in ethyl acetate (250 mL). The solids were collected by
filtration to give
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-qui-
noline-3-carboxylic acid (28.1 g, 60%). 86
[0232] To a suspension of
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amin- o]-3-carboxylic
acid (10 g, 22.9 mmol, 1 equiv) and methylene chloride (168 mL,
16.8 volumes) was added (S)-phenyl-(2-pyridyl)-methylamine,
hydrochloric acid salt (6.5 g, 29.8 mmol, 1.3 equiv),
3-ethyl-1-(3-diethylaminopropyl)-carbodiimide hydrochloride (EDAC)
(5.3 g, 27.5 mmol, 1.2 equiv), and hydroxy benzotriazole (HOBT)
(3.3 g, 24.1 mmol, 1.05 equiv). Diisopropylethylamine (11.97 g,
92.6 mmol, 4.04 equiv) was added dropwise. The resulting solution
was allowed to stir for 12 hours at room temperature. The solution
was then extracted with 0.5 N hydrochloric acid (3.times.80 mL),
saturated sodium hydrogen carbonate (2.times.80 mL) and saturated
sodium chloride (80 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo to give
(+)-(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-ca-
rboxylic acid (phenyl-pyridin-2-yl-methyl)-amide (12.2 g,
88.4%).
Method 3
[0233] 87
[0234] 4'-Trifluoromethyl-biphenyl-2-carboxylic acid
(3-nitro-phenyl)-amide
[0235] To a solution of 3-nitroaniline (28.8 g, 209 mmol, 1 equiv)
in THF (1000 mL, 35 volumes), was added triethylamine (70 mL, 500
mmol, 2.4 equiv). 3-Nitroaniline can be obtained from Aldrich,
Milwaukee, Wis. A solution of
4'-trifluoromethyl-biphenyl-2-carbonyl chloride (71.3 g, 250 mmol,
1.2 equiv) in THF (250 mL, 3.5 volumes) was added dropwise over 30
minutes. The reaction was stirred at room temperature for 48 hours.
The slurry was then filtered through diatomaceous earth and the
filtrate was concentrated. Water (700 mL, 24 volumes) was added and
the slurry was stirred at room temperature for 12 hours. The solids
were collected by filtration and dried under vacuum at 40.degree.
C. to provide 4'-trifluoromethyl-biphenyl-2-carboxylic acid
(3-nitro-phenyl)-amide (80.7 g, 100%) as a pale yellow powder.
[0236] MS (APCI) 387 (M+1).sup.+; 385 (M-1).sup.-
[0237] .sup.1H NMR (DMSO-d.sub.6) .delta.7.25-7.77 (m, 9H), 7.85
(dd, 1H, J=2.0, 8.3 Hz), 7.92 (dd, 1H, J=2.1, 7.9 Hz), 8.56 (t, 1H,
J=2.0 Hz), 10.92 (s, 1H). 88
[0238] 4'-Trifluoromethyl-biphenyl-2-carboxylic acid
(3-amino-phenyl)-amide
[0239] Ammonium formate (16.3 g, 258 mmol, 3 equiv), followed by
Pearlman's catalyst [Pd(OH).sub.2] (6.03 g, 4.30 mmol, 0.05 equiv)
was added to a solution of 4'-trifluoromethyl-biphenyl-2-carboxylic
acid (3-nitro-phenyl)-amide (33.2 g, 85.9 mmol, 1 equiv) in
isopropanol (330 mL, 10 volumes) and ethyl acetate (170 mL, 5
volumes). The mixture was heated at reflux for 3 hours. After
cooling, THF (500 mL) was added to the reaction mixture to help
solublize the product. The reaction mixture was filtered through
diatomaceous earth and the filtrate was concentrated to about 100
mL. Ethyl acetate (600 mL) and THF (200 mL) were added. The organic
layer was washed with saturated sodium bicarbonate solution (300
mL), dried over sodium sulfate, filtered, and concentrated to
afford 4'-trifluoromethyl-biphenyl-2-carboxylic acid
(3-amino-phenyl)-amide (28.7 g, 94%) as an off-white solid.
[0240] MS (APCI) 357 (M+1).sup.+; 355 (M-1).sup.-
[0241] .sup.1H NMR (DMSO-d.sub.6) .delta.5.00 (br s, 2H), 6.22 (dd,
1H, J=1.7, 9.5 Hz), 6.55 (d, 1H, J=8.7 Hz), 6.84 (t, 1H, J=7.9 Hz),
6.90 (s, 1H), 7.04-7.61 (m, 6H), 7.73 (d, 2H, J=8.3 Hz), 10.05 (s,
1H). 89
[0242] 2-Dimethylaminomethylene-1,3-bis(dimethylimmonio)propane
bis(tetrafluoroborate)
[0243] To a 2 L 3-neck round bottom flask equipped with a reflux
condenser and a mechanical stirrer, was added bromoacetic acid (50
g, 360 mmol, 1 equiv) and phosphorus oxychloride (100 mL, 1.08 mol,
3 equiv). The solution was cooled to 0.degree. C. and DMF (167 mL,
2.16 mol, 6 equiv) was added dropwise over 30 minutes via an
addition funnel. The resulting solution was heated at 110.degree.
C. for 3 hours, then was cooled to 0.degree. C. A solution of
aqueous 48% tetrafluoroboric acid in MeOH (200 mL) was added slowly
over 1 hour via an addition funnel. Isopropanol (200 mL) was added
to the dark viscous solution. Solids precipitated out and the
slurry was stirred at 0.degree. C. for 2 hours. The solids were
collected by filtration to provide
2-dimethylaminomethylene-1,3-bis(dimet- hylimmonio)propane
bis(tetrafluoroborate) (94.2 g, 73%) as a pale yellow solid.
[0244] .sup.1H NMR (DMSO-d.sub.6) .delta.3.35 (s, 6H), 3.51 (s,
12H), 8.38 (s, 3H). 90
[0245] 4'-Trifluoromethyl-biphenyl-2-carboxylic acid
(3-formyl-quinolin-7-yl)-amide
[0246] A slurry of 4'-trifluoromethyl-biphenyl-2-carboxylic acid
(3-amino-phenyl)-amide (6.5 g, 18.2 mmol, 1 equiv) and
2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane
bis(tetrafluoroborate) (19.5 g, 54.7 mmol, 3 equiv) in ethanol (200
mL, 30 volumes) was heated at reflux for 24 hours. The reaction
became homogeneous after heating for 4 hours. The solution was
concentrated and the residue was dissolved in THF (100 mL, 15
volumes) and 1 N HCl (100 mL, 15 volumes). The reaction mixture was
stirred at room temperature for 3 hours, then poured into a
saturated solution of sodium bicarbonate (100 mL), and extracted
with ethyl acetate (2.times.100 mL). The combined organic layers
were dried over sodium sulfate, treated with activated charcoal,
filtered, (6.5 g, 1 weight equiv) and a concentrated to afford
4'-trifluoromethyl-biphenyl-2-carboxylic acid
(3-formyl-quinolin-7-yl)-am- ide (7.65 g, 100% crude yield) as a
yellow foam. The crude product was clean by .sup.1H NMR and used in
the next step without further purification.
[0247] MS (APCI) 421 (M+1).sup.+; 419 (M-1).sup.-
[0248] .sup.1H NMR (DMSO-d.sub.6) .delta.7.54-7.77 (m, 9H), 8.10
(d, 1H, J=8.7 Hz), 8.46 (s, 1H), 8.80 (d, 1H, J=2.1 Hz), 9.20 (d,
1H, J=2.1 Hz), 10.20 (s, 1H), 10.95 (s, 1H). 91
[0249]
7-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carb-
oxylic acid
[0250] To a solution of 4'-trifluoromethyl-biphenyl-2-carboxylic
acid (3-formyl-quinolin-7-yl)-amide (7.65 g, 18.2 mmol, 1 equiv) in
acetonitrile (100 mL, 15 volumes) was added an aqueous solution of
potassium dihydrogen phosphate (1.25 M, 72.8 mL, 91 mmol, 5 equiv),
followed by sodium chlorite (6.17 g, 54.6 mmol, 3 equiv). The
slurry was stirred at room temperature for 12 hours. An aqueous
solution of sodium sulfite (1 M, 75 mL, 75 mmol, 4.1 equiv) was
added and the resulting slurry was stirred at room temperature for
15 minutes. 1 N HCl (50 mL) was added to bring the pH to about 3 to
4. The aqueous layer was extracted with ethyl acetate (2.times.100
mL). The combined organic layers were dried over sodium sulfate and
concentrated to about 75 mL of ethyl acetate. Hexanes (about 75 mL)
was added to the slurry and the resulting slurry was allowed to
stir at room temperature for 2 hours. The precipitate was collected
by filtration to provide
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic
acid (6.32 g, 80% over two steps) as a yellow powder.
[0251] MS (APCI) 437 (M+1 ).sup.+; 435 (M-1 ).sup.-
[0252] .sup.1H NMR (DMSO-d.sub.6) .delta.7.54-7.74 (m, 9H), 8.08
(d, 1H, J=8.7 Hz), 8.44 (s, 1H), 8.84 (d, 1H, J=1.7 Hz), 9.22 (d,
1H, J=2.0 Hz), 10.90 (s, 1H). 92
[0253]
(+)-(S)-7-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinolin-
e-3-carboxylic acid (phenyl-pyridin-2-yl-methyl)-amide
[0254] To a suspension of
7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amin- o]-3-carboxylic
acid (10 g, 22.9 mmol, 1 equiv) and methylene chloride (168 mL,
16.8 volumes) was added (S)-phenyl-(2-pyridyl)-methylamine,
hydrochloric acid salt (6.5 g, 29.8 mmol, 1.3 equiv),
3-ethyl-1-(3-diethylaminopropyl)-carbodiimide hydrochloride (EDAC)
(5.3 g, 27.5 mmol, 1.2 equiv), and hydroxy benzotriazole (HOBT)
(3.3 g, 24.1 mmol, 1.05 equiv). Diisopropylethylamine (11.97 g,
92.6 mmol, 4.04 equiv) was added dropwise. The resulting solution
was allowed to stir for 12 hours at room temperature. The solution
was then extracted with 0.5 N hydrochloric acid (3.times.80 mL),
saturated sodium hydrogen carbonate (2.times.80 mL) and saturated
sodium chloride (80 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo to give
(+)-(S)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-ca-
rboxylic acid (phenyl-pyridin-2-yl-methyl)-amide (12.2 g,
88.4%).
Resolution of phenyl-(2-pyridyl)-methylamine
[0255] 93
[0256] (S)-Phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphenylac- etic acid salt
[0257] (S)-(+)-.alpha.-Methoxyphenylacetic acid (22.5 g, 136 mmol,
0.5 equiv) was added to a solution of
phenyl-(2-pyridyl)-methylamine (50 g, 271 mmol, 1 equiv) in
isopropanol (800 mL, 16 volumes) and a precipitate formed. Racemic
phenyl-(2-pyridyl)-methylamine can be obtained from Alfa Aesar,
Ward Hill, Mass. After stirring overnight, the precipitate was
collected to provide (S)-phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.-methoxyphenylacetic acid salt as a 75/25 ratio of
enantiomeric salts. Recrystallization of the collected solid in 16
volumes of isopropanol improved the ratio to 95.3/4.7. An
additional recrystallization in 10 volumes of isopropanol then
improved the ratio to 99.6/0.4. (S)-Phenyl-(2-pyridyl)-methylamine,
(S)-(+)-.alpha.methoxypheny- lacetic acid salt was isolated as a
white solid (16.2 g, 34.2%).
[0258] Hydrochloride Salt 94
[0259] (S)-Phenyl-(2-pyridyl)-methylamine, hydrochloride salt
[0260] To a mixture of (S)-phenyl-(2-pyridyl)-methylamine,
(S)-.alpha.-methoxyphenylacetic acid salt (10 g, 28.5 mmol, 1
equiv) and isopropyl ether (100 mL, 10 volumes) was added 1 N
sodium hydroxide (1.14 g, 28.5 mmol, 1 equiv). The mixture was
stirred until two transparent layers appeared (1 hour). The layers
were separated and the aqueous layer was extracted with isopropyl
ether (2.times.25 mL). The combined organic phases were
concentrated in vacuo at 35.degree. to 40.degree. C. to 100 mL.
Gaseous HCl (1.6 g, 44.4 mmol, 3 equiv) was bubbled into the
solution and white solids precipitated immediately. After stirring
the mixture for 15 hours with slow agitation, the solids were
collected by filtration and dried in vacuo for 2 hours and
50.degree. C. to give (S)-phenyl-(2-pyridyl)-methylamine,
hydrochloric acid salt (5.0 g, 95.5%.
* * * * *