Methods for the acylation of amine compounds

Details Methods for the acylation of amine compounds Methods for the acylation of amine compounds

1999-08-30

2001-04-03

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S538000, C560S042000, C564S142000

Reexamination Certificate

active

06211384

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the acylation of amine compounds. More particularly, the invention relates to forming acylated amines by reacting amine compounds and acyl halide compounds in the presence of a base or scavenger compound that has advantageous properties.
BACKGROUND OF INVENTION
When reacting acid chlorides with amines by known methods, those skilled in the art may be faced with certain concerns. It is generally desirable to conduct the acylation reaction using simple, practicable, high yielding, and environmentally friendly methods. In instances where the acylated amine product may be used as an intermediate in forming other compounds, additional criteria for the acylation reaction may arise. For example, classical Schotten-Baumann acylation conditions are impracticable for the acylation of prolinamide because both the starting material and the products are highly water-soluble and sparingly soluble in organic solvents. Although epoxypropane may possibly be used as an HCl scavenger in acylation reactions, epoxypropane has a low boiling point and may be considered environmentally unacceptable. Epoxypropane may also present an unacceptable carcinogenic risk. Finally, acylation with epoxypropane as the scavenger presents separate problems as the reaction in tetrahydrofuran is heterogeneous.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a method for reacting amines with acyl halides.
Another object of the present invention is to provide a method for reacting amines with acyl halides in a simple, practicable, high yielding and environmentally friendly manner.
Another object of the present invention is to provide an economical method to produce acylated amines that may be used as intermediates in the synthesis of additional compounds.
To achieve these and other objects of the present invention, a method for the acylation of an amine is disclosed in which the process includes reacting a first reactant containing an amine group with a second reactant containing an acyl halide group, wherein the reaction takes place in the presence of secondary carboxylic acid of formula I:
R
4
R
5
CHCOOH  I
wherein
R
4
is an alkyl group having 1 to 10 carbon atoms; and
R
5
is an alkyl group having 1 to 10 carbon atoms.
DETAILED DESCRIPTION OF INVENTION
In one aspect of the invention, the inventors have developed a simple, mild, and efficient method for the acylation of amines utilizing a secondary carboxylic acid salt of the formula I:
R
4
R
5
CHCOOH  I
wherein
R
4
is an alkyl group having 1 to 10 carbon atoms; and R
5
is an alkyl group having 1 to 10 carbon atoms. Preferably, R
4
is an alkyl group having 1 to 5 carbon atoms, more preferably 1 to 3 carbon atoms. Preferably, R
5
is an alkyl group having 2 to 8 carbon atoms, more preferably 3 to 7 carbon atoms, most preferably 4 to 6 carbon atoms.
In another preferred embodiment, at least one of the alkyl groups R
4
or R
5
has at least 4 carbon atoms.
In a most preferred embodiment, the secondary carboxylic acid salt of formula I is sodium 2-ethylhexanoate. Sodium 2-ethylhexanoate is a mild and inexpensive base that is readily soluble in organic solvents such as toluene, ethers, and tetrahydrofuran. Sodium 2-ethylhexanoate may be produced by known methods, such as the reaction of sodium hydride with ethylhexanoic acid, or it may be purchased from chemical suppliers such as Aceto Corporation, Lake Success, N.Y.
As used in the acylation, the secondary carboxylic acid is preferably in the alkaline salt form. The salt form may contain, for example, sodium, potassium, or lithium as the anion.
It is noted that it may also be beneficial to add a compound of formula I to the reaction medium as the free acid in an amount effective to solubilize the first reactant containing an amine group.
As mentioned, the first reactant contains an amine group. Preferred compounds for the first reactant include, for example, compounds of the formula II:
R
1
R
2
—NH  II
wherein
R
1
and R
2
are, independently of one another, hydrogen, methyl, saturated or unsaturated C
2
-C
20
alkyl, cycloalkyl, heterocyclyl, unsubstituted or substituted phenyl, with the proviso that both R
1
and R
2
are not hydrogen or
C
1
-C
20
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
heterocyclyl, C
6
-C
10
aryl, or C
5
-C
10
heteroaryl, which may be unsubstituted or substituted by halogen, carbonyl, —OH, -ester, acetoxy, CN, acetamido or
R
1
and R
2
together form a ring having 3-10 carbon atoms and the ring is unsubstituted or substituted by halogen, carbonyl, —OH, ester, acetyl, NH
2
(CH
2
)
x
CO—, R′OCO—, or CN, wherein x is 0 to 5.
In another preferred embodiment, R
1
and R
2
together form a ring having 3-10 carbon atoms and the ring is unsubstituted, or substituted by —CONH
2
or ester group.
In another preferred embodiment, R
1
and R
2
together form a ring having four carbon atoms and the ring is substituted by —CONH
2
. A still further preferred embodiment lies in the use of prolinamide as the first reactant, where the —CONH
2
group is attached to the ring at a carbon atom adjacent the nitrogen.
In other preferred embodiments, the amine compound used as the first reactant may be an anthranilate, amino acid ester.
As the second reactant containing an acyl halide may be used. The acyl halide containing second reactant may, in one preferred embodiment, be represented by formula III:
R
3
COCl  III
wherein R
3
is methyl; ethyl; or
a saturated or unsaturated, branched or unbranched C
3
-C
10
alkyl, C
3
-C
10
cycloalkyl, aryl, or heteroaryl, which may be unsubstituted or substituted by halogen, carbonyl, —OH, ester, acetyl, —OCOR′; or CN, CONH
2
.
In another preferred embodiment, R
3
is C
1
-C
10
alkyl, C
1
-C
10
alkyl monosubstituted with a halogen, branched or unbranched C
3
-C
10
alkyl, or C
6
H
5
(CH
2
)
y
— in which y is 0-10.
In more preferred embodiments, the acyl chloride used as the second reactant may be chloroacetyl chloride, bromoacetyl bromide, benzolyl chloride, or any activated ester group.
The acylation reaction may be conducted in typical organic solvents, including tetrahydrofuran, t-butyl methyl ether, ethyl or isopropyl acetate, heptane etc. The acylation reaction may be run at a temperature ranging from about −30 to about 40 C., preferably about −20 to about 25 C.
Depending on the intended use of acylated amine product, sodium chloride formed during the reaction may be washed out with water or separated by extraction into organic solvents.
In the preferred embodiment in which prolinamide is acylated, the acylated prolinamide may be used as an intermediate in the production of the N-(substituted glycyl) 2-cyanopyrrolidines. Because it has recently been discovered that certain N-(substituted glycyl)-2-cyanopyrrolidines (hereinafter “the cyanopyrrolidine compounds”) inhibit DPP-IV it has become desirable to produce N-(substituted glycyl)-2-cyanopyrrolidines as pharmaceutical products suitable for administration to mammals. Cyanopyrrolidine compounds that may be synthesized using the acylated prolinamide produced by our process are disclosed in WO 98/19998, the entire contents of which are incorporated herein by reference.


REFERENCES:
patent: 5625058 (1997-04-01), Pessa et al.
patent: 97/15579 (1997-05-01), None
patent: 98/19998 (1998-05-01), None
Fitt et al., “Sodium 2-Ethylhexanoate: A Mild Acid Scavenger Useful in Acylation of Amines,” Tetrahedron Letters 39, (1998), p. 6991-6992.
Bose et al., “A Pratical Method for the Preparation of Nitriles from Primary Amides Under Non-Acidic Conditions,” Synthesis 1999, No. 1, p. 64-65.
Highlights from the Literature: “Some Items of Interest of Process R&D Chemists and Engineers, Selected by the Editor,” Organic Process Research & Development, vol. 2, No. 6, (1998), p. 340-343.
Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,John Wiley & Sons, (1992), p. 430.

Affiliated with

Also associated with

Rating

Methods for the acylation of amine compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Methods for the acylation of amine compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for the acylation of amine compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2463451