Boron-mediated amidation of carboxylic acids

Details Boron-mediated amidation of carboxylic acids Boron-mediated amidation of carboxylic acids

2001-02-05

2002-05-07

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S133000, C564S134000, C564S135000, C564S136000, C564S138000, C564S139000, C564S141000, C564S142000, C564S199000, C564S200000

Reexamination Certificate

active

06384278

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of amidating carboxylic acids with an aromatic amine in the presence of a boron containing compound, such as boric acid, and, optionally, a 2-pyridinylamine.
BACKGROUND OF THE INVENTION
Carboxamides, such as those disclosed in U.S. Pat. No. 5,773,647, have been found to be highly effective as delivery agents for active agents, particularly for oral administration of active agents.
Generally, carboxamides are prepared by an amidation reaction between a carboxylic acid and an amine. The carboxylic acid is typically converted into an electrophilic intermediate, usually an acid chloride. The acid chloride is then reacted with the amine in the presence of an activating agent. Many acid chlorides, however, are unstable or are not compatible with other functional groups present in the acid or amine. Therefore, protection and deprotection steps must be performed in order to stabilize the intermediate and protect various functional groups. This dramatically increases the cost of preparing the carboxamide.
Carboxamides may also be formed by reacting a carboxylic acid with 1-hydroxybenzotriazole in the presence of coupling agents, such as 1,3-dicyclohexylcarbodiimide (DCC) and ethylene dichloride (EDC). This method, however, forms urea byproducts which are often difficult to remove, especially in large scale preparations.
Boron trifluoride etherate, trialkylboranes, trialkoxyboranes, catecholborane, and arylboronic acids have also been reported to catalyze amidation reactions of carboxylic acids. See, for example, Trapani, G. et al.,
Synthesis,
1013 (1983); Tani, J. et al.,
Synthesis,
714 (1975); Pelter, A. et al.,
Tetrahedron,
26:1539 (1970); Collum, D. B. et al.,
J. Org. Chem.,
43:4393 (1978); Ishihara, K. et al.,
J. Org. Chem.,
61:4196 (1996).
Therefore, there is a need for an inexpensive and simple method for preparing carboxamides from carboxylic acids.
SUMMARY OF THE INVENTION
The present invention provides an inexpensive one-step method for preparing an aromatic carboxamide, such as a phenyl substituted carboxamide by reacting an aromatic amine (e.g. a phenylamine) and a carboxylic acid (e.g. an alkanoic acid or ester thereof) in the presence of a boron containing compound (e.g. boronic acid or boric acid) and, optionally, a chelating agent (e.g. a 2-pyridinylamine).
A preferred embodiment is a method for preparing a carboxamide having the formula
where
R
1
, R
2
, R
3
, R
4
, and R
5
are independently hydrogen, —OH, —O—R
7
, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, —OC(O)CH
3
, —SO
3
H, or —NR
13
R
14
;
R
6
is C
1
-C
12
alkyl;
R
6
is optionally substituted with one or more alkenyl, alkoxycarbonyl, carboxyl, —OH, or halogen;
R
7
is hydrogen, alkyl, or aryl; and
R
13
and R
14
are independently hydrogen, C
1
-C
4
alkyl, or oxygen.
The method comprises the step of reacting (a) an aromatic amine having the formula
with (b) an acid having the formula R
6
—COOH in the presence of a boron containing compound and, optionally, a chelating agent to form the carboxamide, where R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
are defined as above. A preferred acid has the formula
where R
15
is a C
1
-C
12
alkyl and R
16
is an alkyl (e.g. a C
1
-C
3
alkyl). A preferred chelating agent is a 2-pyridinylamine. Preferably the boron containing compound is boric acid and the 2-pyridinylamine is 2-amino-5-picoline. The carboxamide may be subsequently modified to include a carboxylic acid terminal on the R
6
group, if it does not already have such a terminal.
A more preferred embodiment is a method for preparing a carboxamide having the formula:
where
R
1
, R
2
, R
3
, R
4
, and R
5
are independently hydrogen, —OH, —O—R
7
, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, —OC(O)CH
3
, —SO
3
H, or —NR
13
R
14
;
R
7
is hydrogen, alkyl, or aryl;
R
13
and R
14
are independently hydrogen, C
1
-C
4
alkyl, or oxygen; and
R
15
is C
1
-C
12
alkyl.
The method comprises the steps of (i) reacting (a) an aromatic amine having the formula
with (b) an acid having the formula
where R
15
is a C
1
-C
12
alkyl and R
16
is an alkyl (e.g. a C
1
-C
3
alkyl), in the presence of a boron containing compound and, optionally, a chelating agent to form an intermediate having the formula
where R
1
, R
2
, R
3
, R
4
, R
5
, R
15
, and R
16
are defined as above; and (ii) hydrolyzing the intermediate to form the final carboxamide. Preferably, the boron containing compound is boric acid and the chelating agent is a 2-pyridinylamine, such as a 2-amino-5-picoline.
DETAILED DESCRIPTION OF THE INVENTION
The alkyl, alkenyl, alkoxy and aryl groups of R
1
, R
2
, R
3
, R
4
, and R
5
may be substituted with, for example, —OH, F, and alkyl and aryl groups. R
1
, R
2
, R
3
, R
4
, and R
5
may be C
1
-C
18
alkyl, C
2
-C
18
alkenyl, C
1
-C
18
alkoxy, or (C
1
-C
18
alkoxy)carbonyl. For example, R
1
, R
2
, R
3
, R
4
, and R
5
maybe C
1
-C
4
alkyl, C
2
-C
4
alkenyl, or C
1
-C
4
alkoxy. The alkoxycarbonyl group of R
1
, R
2
, R
3
, R
4
, and R
5
may be substituted with, for example, alkyl groups (such as C
1
-C
4
alkyl).
Suitable boron containing compounds include, but are not limited to, boronic acids, such as those having the formula R
8
—B(OH)
2
, where R
8
is —OH; aryl; C
1
-C
8
alkyl, optionally substituted with C
1
-C
3
alkyl; or a polymer. Preferably, the boron containing compound is boric acid, i.e., R
8
is —OH.
Without being bound by any theory, the inventors believe that boric acid forms a reactive complex with the carboxylic acid to form an acyloxyboron intermediate and water. After the water is removed, the acyloxyboron intermediate readily reacts with the aromatic amine to afford the desired carboxamide and regenerate boric acid, the amidation catalyst.
The chelating agent may be any chelating agent known in the art. Suitable chelating agents include, but are not limited to, electron donating chelating agents. Preferred chelating agents include, but are not limited to, 2-pyridinylamines. Suitable 2-pyridinylamines include, but are not limited to, those having the formula
where R
9
, R
10
, R
11
, and R
12
are independently hydrogen, substituted or unsubstituted C
1
-C
4
alkyl, or substituted or unsubstitued aryl. The alkyl and aryl groups of R
9
, R
10
, R
11
, and R
12
may be substituted with, for example, alkyl (such as C
1
-C
4
alkyl) and aryl groups. Preferably, the 2-pyridinylamine is 2-amino-4-picoline, 2-amino-5-picoline, 2-amino-6-picoline, 2-amino-4,6-dimethylpyridine, or any combination of any of the foregoing. More preferably, the 2-pyridinylamine is 2-amino-5-picoline.
The boron containing compound and, optionally, the 2-pyridinylamine catalyze the reaction between the aromatic amine and the acid. Without being bound to any theory, the inventors believe that the boron containing compound forms a complex with the 2-pyridinylamine. This complex may react with the acid to form an acyloxyboron intermediate which can readily react with the aromatic amine to yield the carboxamide.
The reaction may be performed at a temperature of from about 20° C. to about 200° C. The reaction may be performed in the solid or liquid phase.
The aromatic amine and acid are preferably dissolved in a solvent. Suitable solvents include, but are not limited to, aromatic solvents, such as benzene, xylene, mesitylene, and toluene; hydrocarbon solvents, such as hexane and octane; and any combination of any of the foregoing. Preferably, the solvent is toluene.
Water which is formed as a byproduct from the reaction of the aromatic amine and the acid is preferably removed during the reaction, such as, with a Dean-Stark separator.
The reaction is typically performed at atmospheric pressure. Preferably

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