Method of preparing salicyloylamino acids

• US 5,962,710 A
• Filed: 05/09/1997
• Issued: 10/05/1999
• Est. Priority Date: 05/09/1997
• Status: Expired due to Fees

• Current Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Freeman, John, O'Toole, Doris, Gschneidner, David
• Primary Examiner(s): Geist, Gary
• Assistant Examiner(s): Davis, Brian J.
• Application Number:
  US08/853,752
• Time in Patent Office: 879 Days
• Field of Search: 554/109, 554/112, 562/455
• US Class Current: 554/112
• CPC Class Codes: C07C 231/02 from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Abstract

A method for preparing salicyloylamino acids is provided. An oligosalicylate and an amino acid are reacted to yield the salicyloylamino acid.

Claims

1. A method for preparing a salicyloylamino acid, said method comprising:

(A) reacting an oligosalicylate and an amino acid to yield said salicyloylamino acid.

2. A method as defined in claim 1, wherein said oligosalicylate has the formula:

##STR17## wherein R₁, R₂, R₃ and R₄ are independently hydrogen, fluorine, chlorine, bromine, iodine, C_1-9 linear or branched chain alkyl, C_1-9 linear or branched chain alkoxy, C_6-14 aryl, C_6-14 aryloxy or (C_6-14 aryl)(C_1-9 linear or branched chain alkyl); and

wherein n is an integer from about 1 to about 10.

3. A method as defined in claim 2, wherein said oligosalicylate has the formula:

##STR18## wherein R₁, R₂, R₃ and R₄ are independently hydrogen, fluorine, chlorine, bromine, iodine, C_1-9 linear or branched chain alkyl, C_1-9 linear or branched chain alkoxy, C_6-14 aryl, C_6-14 aryloxy or (C_6-14 aryl)(C_1-9 linear or branched chain alkyl); and

wherein n is an integer from about 1 to about 10.

4. A method as defined in claim 2, wherein said oligosalicylate has the formula:

##STR19## wherein R₁, R₂, R₃ and R₄ are independently hydrogen, fluorine, chlorine, bromine, iodine, C_1-9 linear or branched chain alkyl, C_1-9 linear or branched chain alkoxy, C_6-14 aryl, C_6-14 aryloxy or (C_6-14 aryl)(C_1-9 linear or branched chain alkyl and wherein n is an integer from about 1 to about 10.

5. A method as defined in claim 2, wherein said oligosalicylate has the formula:

##STR20## wherein R₁, R₂, R₃ and R₄ are independently hydrogen, fluorine, chlorine, bromine, iodine, C_1-9 linear or branched chain alkyl, C_1-9 linear or branched chain alkoxy, C_6-14 aryl, C_6-14 aryloxy or (C_6-14 aryl)(C_1-9 linear or branched chain alkyl and wherein n is an integer from about 1 to about 10.

6. A method as defined in claim 2, wherein said oligosalicyloyl is selected from the group consisting of oligosalicylate, oligo-methyl salicylate, and oligo-dichlorosalicylate.

7. A method as defined in claim 1, wherein said amino acid is selected from the group consisting of natural amino acids and non-natural amino acids.

8. A method as defined in claim 7, wherein said amino acid has the formula:

##STR21## wherein R⁵ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkyl, or C₂ -C₄ alkenyl;

R⁶ is C₁ -C₂₄ alkyl, C₂ -C₂₄ alkenyl, C₃ -C₁₀ cycloalkyl, phenyl, naphthyl, (C₁ -C₁₀ alkyl) phenyl, (C2-C₁₀ alkenyl) phenyl (C₁ -C₁₀ alkyl) naphthyl, (C₂ -C₁₀ alkenyl) naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₂ -C₁₀ alkenyl), naphthyl (C₁ -C₁₀ alkyl), or naphthyl (C₂ -C₁₀ alkyl) or naphthyl (C₂ -C₁₀ alkenyl);

R⁶ being optionally substituted with C₁ -C₄ alkyl, C₂ -C₄ alkyenyl, C₁ -C₄ alkoxy, --OH, --SH, --CO₂ R⁷, C₃ -C₁₀ cycloalkyl, C₃ -C₁₀ cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C₁ -C₁₀ alk)aryl, ar(C₁ -C₁₀ alkyl) or any combination thereof;

R⁶ being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

R⁷ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkenyl.

9. A method as defined in claim 8, wherein said amino acid is selected from the group consisting of alanine, arginine, asparagine, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxy proline, γ

-carboxyglutamate, phenylglycine, O-phosphoserine, β

-alanine, α

-amino butyric acid, γ

-amino butyric acid, γ

-(aminophenyl) butyric acid, α

-amino isobutyric acid, citrulline, ε

-amino caproic acid, 7-amino heptanoic acid, β

-aspartic acid, aminobenzoic acid, aminocaprylic acid, aminophenyl acetic acid, aminophenyl butyric acid, γ

-glutamic acid, cysteine (ACM), ε

-lysine, ε

-lysine (A-Fmoc), methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, aminodecanoic acid, and thioproline.

10. A method as defined in claim 9, wherein said amino acid is aminocaprylic acid.

11. A method as defined in claim 2, wherein said oligosalicylate is oligo-n-salicylate, said amino acid is aminocaprylic acid, and said salicyloylamino acid is N-(salicyloyl)-8-aminocaprylic acid.

12. A method as defined in claim 2, wherein said reacting is conducted in an aqueous medium.

13. A method as defined in claim 12, wherein said aqueous medium comprises water.

14. A method as defined in claim 13, wherein said aqueous medium further comprises sodium hydroxide.

15. A method as defined in claim 14, wherein said aqueous medium further comprises an organic solvent selected from the group consisting of dioxane, xylene, acetonitrile, tetrahydrofuran, and 1-methoxy-propanol.

16. A method as defined in claim 2, wherein said reacting occurs at a temperature ranging from about 25 to about 150°

C.

17. A method as defined in claim 2, wherein the molar ratio of said oligosalicylate to said amino acid ranges from about 0.5 to about 2.0.

18. A method as defined in claim 2, wherein said reaction is allowed to take place for about 0.5 to about 24 hours.

19. A method as defined in claim 2, further comprising

(B) isolating said salicyloylamino acid.

20. A method as defined in claim 19, wherein said isolating comprises filtering.

21. A method as defined in claim 20, wherein said isolating further comprises drying.