Method of preparing alkylated salicylamides

Details Method of preparing alkylated salicylamides Method of preparing alkylated salicylamides

2001-08-03

2002-06-04

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S061000, C554S062000, C554S063000, C554S067000, C544S094000, C562S445000, C562S450000

Reexamination Certificate

active

06399798

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of preparing alkylated salicylamides from salicylamides. The alkylated salicylamides prepared by this method are suitable for use in compositions for delivering active agents via oral or other routes of administration to animals.
BACKGROUND OF THE INVENTION
Carsalam (2H-1,3-benzoxazine-2,4(3H)-dionc) is known in the art as an analgesic (see Merck Index, 12th edition, #1915).
Alkylated salicylamides, such as those disclosed in U.S. Pat. No. 5,650,386, have been found to be highly effective as delivery agents for active agents, particularly for oral administration of active agents. Typically, these alkylated salicylamides are prepared by modifying an amino acid or an ester thereof. For example, these alkylated salicylamides may be prepared by acylation of an amino acid or an ester thereof with agents having a leaving group, such as a halogen, carbonyl group, or sulfonyl group, and an appropriate radical to yield the desired modification in the final product. See, for example, U.S. Pat. No. 5,650,386.
Alternate methods of producing alkylated salicylamides would be useful, especially where raw materials are expensive, yields are low, and/or reaction conditions are difficult.
Therefore, there is a need for simpler and less expensive methods of preparing alkylated salicylamides.
SUMMARY OF THE INVENTION
The present invention relates to a method of preparing an alkylated salicylamides from a protected and activated salicylamide (hereinafter referred to as a “protected/activated salicyamide”). The method comprises the steps of (a) alkylating the protected/activated salicylamide with an alkylating agent to form a protected/activated alkylated salicylamide and (b) deprotecting and deactivating the protected/activated alkylated salicylamide, simultaneously or in any order, to form the alkylated salicylamide. The alkylated salicylamides prepared by this method are suitable for use in compositions for delivering active agents via oral or other routes of administration to animals.
DETAILED DESCRIPTION OF THE INVENTION
The term “protected salicylamide” is defined herein as a salicylamide where the hydroxy moiety of the salicyl group has been protected to prevent reaction of the hydroxy moiety. The term “activated salicylamide” is defined herein as a salicylamide where the nitrogen atom of the amide group has been activated so that the nitrogen atom is in a more reactive condition, i.e., more prone to reaction.
Suitable protected/activated salicylamides include, but are not limited to, compounds having the formula
where
R
1
, R
2
, R
3
, and R
4
are independently hydrogen; halogen; C
1
-C
4
alkoxy, optionally substituted with —OH or F; —OH; C
1
-C
4
alkyl, optionally substituted with —OH or F; —COOH; —OC(O)CH
3
; —SO
3
H; nitrile; or —NR
9
R
10
;
R
9
and R
10
are independently hydrogen, C
1
-C
4
alkyl, or oxygen;
R
5
is a protecting group;
R
6
is an activating group; or
R
5
and R
6
are combined to form a cyclic group, i.e., R
5
and R
6
form a single group that forms a heterocycle with the oxygen atom and nitrogen atom of the amide moiety.
Preferred halogens for R
1
, R
2
, R
3
, and R
4
are chlorine, bromine, and fluorine. Preferred alkoxy groups for R
1
, R
2
, R
3
, and R
4
include, but are not limited to, methoxy and ethoxy.
Suitable protecting groups include, but are not limited to, —C(O)CH
3
; —C(O)F
3
; —S(O)
2
CH
3
; —S(O)
2
CF
3
; benzyl; silyl; tetrahydropyranyl; and methylenealkoxy, such as methylenemethoxy and methyleneethoxy. Suitable activating groups include, but are not limited to, —C(O)CH
3
; —C(O)CF
3
; —S(O)
2
CH
3
; and —S(O)
2
CF
3
. Preferably, R
5
and R
6
are combined to form a cyclic group which protects the hydroxy moiety and activates the nitrogen atom of the amide moiety. More preferably, combined R
5
and R
6
are —C(O)— or —S(O)
2
—.
Preferred protected/activated salicylamides include, but are not limited to, carsalam and derivatives thereof having the formula
where R
1
, R
2
, R
3
, and R
4
are defined as above.
Carsalam has the formula
Carsalam may be prepared by methods known in the art, such as those described in Shapiro et al.,
JACS
, 79:2811 (1957), and D. N. Dhar, A. K. Bag,
Indian J. Chem
., 21B:266 (1982). The aforementioned carsalam derivatives may be prepared by methods known for preparing carsalam substituting appropriate starting materials. These carsalam derivatives may also be prepared by adding the appropriate substituents to carsalam by methods known in the art.
One method of preparing the protected/activated salicylamide of the present invention comprises protecting the hydroxy moiety of a salicylamide and activating the amide moiety of the salicylamide. The protecting and activating steps may be performed in any order, but are preferably performed simultaneously. For example, the protecting step may be performed before performing the activating step.
Suitable (unprotected and unactivated) salicylamides include, but are not limited to, those having the formula
where R
1
, R
2
, R
3
, and R
4
are defined as above.
The hydroxy moiety of the salicylamide may be protected by methods known in the art. For example, the hydroxy moiety may be protected by reacting the salicylamide with a protecting agent, such as an activated halide. The resulting salicylamide has a protecting group attached to the oxygen atom of the hydroxy moiety. Examples of activated halides include, but are not limited to, acyl halides; silyl halides, such as silyl chlorides; benzyl halides; and methylene alkoxy halides, such as methylene methoxy halides and methylene ethoxy halides. Preferably, the reaction with an activated halide is performed in the presence of a base, such as potassium carbonate, triethylamine, or pyridine.
Another example of a protecting agent is an activated ether. Examples of activated ethers include, but are not limited to, dihydropyranyl ether. Preferably, the activated ether is reacted with the salicylamide under acid catalysis conditions, such as with sulfuric acid, paratoluene sulfonic acid, or camphor sulfonic acid in methylene chloride, tetrahydrofuran, or toluene.
The amide moiety of the salicylamide may be activated by methods known in the art. For example, the amide moiety may be activated by reacting the salicylamide with an activating agent, such as an acyl halide, acyl anhydride, sulfonyl halide, or sulfonyl anhydride. The resulting salicylamide has an activating group attached to the nitrogen atom of the amide moiety. Suitable acyl halides include, but are not limited to, those described above for protecting the hydroxy moiety of the salicylamide. Preferably, the activating agent is reacted with the salicylamide in the presence of a base, such as potassium carbonate, triethylamine, or pyridine.
The protecting and activating groups may be the same or different. The protecting and activating groups may be separate moieties (each attached to one of the hydroxy or amide moieties) or a single moiety (attached to both the hydroxy and amide moieties).
In the preparation of carsalam and the aforementioned derivatives thereof, the protecting and activating steps are typically performed simultaneously and the protecting and activating groups are a single group attached to both the hydroxy and amide moieties. One method of preparing carsalam and the derivatives thereof is by reacting the corresponding (unprotected and unactivated) salicylamide with an alkyl chloroformate, such as ethyl chloroformate; a phenyl chloroformate; or an imidazole alkoxy carbonyl.
The protected/activated salicylamide may be alkylated by the methods known in the art for alkylating phthalimide to form a primary amine. Sec, for example, Gibson and Bradshaw,
Angewandte Chemie
, International Edition in English, 7:919-930 (1968). The protected/activated salicylamide is substituted for the phthalimide in these methods.
The protected/activated salicylamide may also be alkylated by reacting the protected/activated salicylamide with an alkylating agent. The alkylating agent reacts with the nitroge

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