Method of preparing alkylated salicylamides

• US 6,399,798 B2
• Filed: 08/03/2001
• Issued: 06/04/2002
• Est. Priority Date: 02/05/1999
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Bay, William E., Bernadino, Joseph N., Gschneidner, David
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US09/922,961
• Publication Number:
  US 20020013497A1
• Time in Patent Office: 305 Days
• Field of Search: 554/63, 554/35, 554/61, 554/62, 554/67, 544/94, 562/444, 562/450
• US Class Current: 554/35
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: C07C 231/00 Preparation of carboxylic acid amides
• CPC Class Codes: C07C 233/51 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/24 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/58 with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 235/64 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/74 of a saturated carbon skeleton
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 271/54 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/58 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 309/59 Nitrogen analogues of carboxyl groups
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 239/96 : Two oxygen atoms
• CPC Class Codes: C07D 265/26 : Two oxygen atoms, e.g. isatoic anhydride
• CPC Class Codes: C07D 311/18 : substituted otherwise than in position 3 or 7
• CPC Class Codes: C07D 317/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

The present invention relates to a method of preparing an alkylated salicylamide from a protected and activated salicylamide (hereinafter referred to as a “protected/activated salicylamide”). 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.

Claims

1. A method of preparing an alkylated salicylamide from a protected/activated salicylamide, the method comprising 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 to form the alkylated salicylamide.

2. The method of claim 1, wherein the protected/activated salicylamide has the formula

wherein

R¹, R², R³, and R⁴ are independently hydrogen;

halogen;

C₁-C₄ alkoxy, optionally substituted with —

OH or F;

—

OH;

C₁-C₄ alkyl, optionally substituted with —

OH or F;

—

COOH;

—

OC(O)CH₃;

—

SO₃H;

nitrile;

or —

NR⁹R¹⁰;

R⁹ and R¹⁰ are independently hydrogen, C₁-C₄ alkyl, or oxygen;

R⁵ is a protecting group;

R⁶ is an activating group;

or

R⁵ and R⁶ are combined to form a cyclic group.

3. The method of claim 2, wherein the protected/activated salicylamide has the formula

4. The method of claim 1, wherein the protected/activated salicylamide is prepared from a salicylamide having a hydroxy moiety and an amide moiety by

(i) protecting the hydroxy moiety of the salicylamide;

and

(ii) activating the amide moiety of the salicylamide, simultaneously or in any order to form the protected/activated salicylamide.

5. The method of claim 4, wherein the protecting and activating steps are performed simultaneously.

6. The method of claim 4, wherein the protecting and activating steps are performed by reacting the salicylamide with an alkyl chloroformate.

7. The method of claim 6, wherein the alkyl chloroformate is ethyl chloroformate.

8. The method of claim 4, wherein the protecting and activating steps are performed by reacting the salicylamide with acetic anhydride.

9. The method of claim 1, wherein the alkylating step is performed for from about 3 to about 5 hours.

10. The method of claim 1, wherein the molar ratio of protected/activated salicylamide to alkylating agent is from about 1:

0.8 to about 1;

0.99.

11. The method of claim 1, wherein the alkylating step is performed in the presence of a base.

12. The method of claim 11, wherein the base is sodium carbonate.

13. The method of claim 1, wherein the alkylating step is performed at a temperature of from about 20 to about 100°

C.

14. The method of claim 13, wherein the alkylating step is performed at a temperature of about 70°

C.

15. The method of claim 1, wherein the alkylated salicylamide has the formula

wherein

R¹, R², R³, and R⁴ are independently hydrogen;

halogen;

C₁-C₄ alkoxy, optionally substituted with —

OH or F;

—

OH;

C₁-C₄ alkyl, optionally substituted with —

OH or F;

—

COOH;

—

OC(O)CH₃;

—

SO₃H;

nitrile;

or —

NR⁹R¹⁰;

R⁹ and R¹ are independently hydrogen, C₁-C₄ alkyl, or oxygen;

R⁷ is a linear or branched, C₁-C₂₀ alkylene, alkenylene, or alkynylene;

R⁷ is optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, oxygen, nitrogen, sulfur, halogen, —

OH, C₁-C₄ alkoxy, aryl, heteroaryl, or vinyl;

R⁷ is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur; and

R⁸ is carboxyl or a salt thereof, carboxylate, nitrile, halogen, ester, amine or salt thereof, alcohol, or thiol.

16. The method of claim 1, wherein the alkylated salicylamide is N-(2-hydroxybenzoyl)-7-amino)heptanoic acid.

17. The method of claim 1, wherein the alkylated salicylamide is N-(2-hydroxybenzoyl)-8-amino)octanoic acid.

18. The method of claim 1, wherein the alkylated salicylamide is N-(2-hydroxybenzoyl)-10-amino)decanoic acid.

19. The method of claim 1, wherein the alkylated salicylamide is N-(2-hydroxy-5-chlorobenzoyl)-4-amino)butyric acid.

20. The method of claim 1, wherein the alkylated salicylamide is N-(2-hydroxy-5-chlorobenzoyl)-8-amino)octanoic acid.