Process and intermediates for preparing poly(anhydride-esters)

• US 10,023,521 B2
• Filed: 06/10/2015
• Issued: 07/17/2018
• Est. Priority Date: 06/13/2014
• Status: Active Grant

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Uhrich, Kathryn E., Faig, Jonathan J., Smith, Kervin
• Primary Examiner(s): Valenrod, Yevgeny
• Assistant Examiner(s): Doletski, Blaine G
• Application Number:
  US15/318,306
• Publication Number:
  US 20170121267A1
• Time in Patent Office: 1,133 Days
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: C07C 67/08 by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

Abstract

Certain embodiments of the invention provide a method comprising treating a hydroxy-carboxylic acid compound with a compound of formula (I) in the absence of a solvent, to provide a diacid of formula (II), wherein R is a linker molecule; wherein each Y is independently a leaving group; and wherein X is a residue of a biologically active compound.

Claims

1. A method comprising treating a hydroxy-carboxylic acid compound:

2. The method of claim 1, further comprising treating the diacid of formula (II) with acid anhydride, heat and vacuum to provide the corresponding polymer.

3. The method of claim 1, wherein the biologically active compound is an antioxidant, an antimicrobial, an antifungal, an anticancer, an analgesic, an immunosuppressive or an anti-inflammatory.

4. The method of claim 3, wherein the biologically active compound is an anti-inflammatory compound.

5. The method of claim 4, wherein the anti-inflammatory compound is salicylic acid.

6. The method of claim 3, wherein the biologically active compound is an antioxidant.

7. The method of claim 1, wherein the base is pyridine, 2,4,6-collidine or poly(4-vinylpyridine).

8. The method of claim 1, wherein R is a branched aliphatic, linear aliphatic or oxygen-containing linker molecule.

9. The method of claim 1, wherein R is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—

O—

), (—

NR₁—

) or phenylene, and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or

     4) substituents selected from the group consisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy, and wherein each R₁ is independently selected from H or (C₁-C₆)alkyl.

10. The method of claim 1, wherein R is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.

11. The method of claim 1, wherein R is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—

O—

), (—

NR₁—

) or phenylene, and wherein each R₁ is independently selected from H or (C₁-C₆)alkyl.

12. The method of claim 1, wherein R is a divalent, branched or unbranched, hydrocarbon chain, having from 3 to 15 carbon atoms.

13. The method of claim 12, wherein R is a divalent hydrocarbon chain having 2 to 10 carbon atoms.

14. The method of claim 13, wherein R is —

CH₂CH₂CH₂CH₂—

.

15. The method of claim 1, wherein each Y is independently a leaving group selected from a halogen, alkylsulfonyl or arylsulfonyl leaving group.

16. The method of claim 1, wherein each Y is independently a leaving group selected from chloro, bromo, iodo, mesylate and tosylate.

17. The method of claim 1, wherein the compound of formula (I) is a compound of formula (Ia):

18. The method of claim 2, wherein the polymer has an average molecular weight of about 10,000 daltons to about 30,000 daltons.

19. The method of claim 2, wherein the polymer has an average molecular weight greater than about 20,000 daltons and less than about 30,000 daltons.

20. The method of claim 1, wherein the base is pyridine.