METHOD FOR MAKING ALDEHYDE-FUNCTIONALIZED POLYSACCHARIDES

• US 20130303748A1
• Filed: 05/10/2012
• Published: 11/14/2013
• Est. Priority Date: 05/10/2012
• Status: Abandoned Application

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Arthur, Samuel D., Shuey, Steven W., Trost, Barry M.
• Application Number:
  US13/468,176
• Publication Number:
  US 20130303748A1
• Time in Patent Office: Days
• US Class Current: 536/53
• CPC Class Codes: C08B 15/06 containing nitrogen , e.g. carbamates
• CPC Class Codes: C08B 31/125 having a substituent containing at least one nitrogen atom, e.g. cationic starch
• CPC Class Codes: C08B 37/0018 Pullulan, i.e. (alpha-1,4)(alpha-1,6)-D-glucan; Derivatives thereof
• CPC Class Codes: C08B 37/0021 Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
• CPC Class Codes: C08B 37/0051 beta-D-Fructofuranans, e.g. beta-2,6-D-fructofuranan, i.e. levan; Derivatives thereof
• CPC Class Codes: C08B 37/0054 Inulin, i.e. beta-2,1-D-fructofuranan; Derivatives thereof
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Abstract

A method for making aldehyde-functionalized polysaccharides having pendant aldehyde groups is described. The method involves the hydroformylation of an alkene-functionalized polysaccharide. The resulting aldehyde-functionalized polysaccharides are useful for forming hydrogel tissue adhesives and sealants for medical applications.

Claims

1. A method for making an aldehyde-functionalized polysaccharide having pendant aldehyde groups, said method comprising the steps of:

a) reacting in a solvent, an alkene-functionalized polysaccharide with a mixture of carbon monoxide and hydrogen, said mixture having a ratio of carbon monoxide to hydrogen of about 4;

1 to about 1;

4 by volume, in the presence of a metal hydroformylation catalyst at a temperature of about 20°

C. to about 150°

C. and a pressure of about 1 atmosphere (101 kPa) to about 100 atmospheres (10 MPa) to form an aldehyde-functionalized polysaccharide having pendant aldehyde groups; and

b) recovering the aldehyde-functionalized polysaccharide having pendant aldehyde groups.

2. The method of claim 1, wherein the alkene-functionalized polysaccharide is made by a method comprising the steps of:

a) reacting in an anhydrous, polar aprotic solvent, a polysaccharide with an alkene-functionalized electrophilic compound, capable of reacting with hydroxyl groups of the polysaccharide to form ether bonds, in the presence of a strong base at a temperature of about 20°

C. to about 150°

C. to form an alkene-functionalized polysaccharide; and

b) recovering the alkene-functionalized polysaccharide.

3. The method of claim 2, wherein the alkene-functionalized electrophilic compound is selected from the group consisting of:

allyl chloride, allyl bromide, allyl iodide, allyl methanesulfonate, allyl toluenesulfonate, allyl glycidyl ether, 3-butenyl chloride, 3-butenyl bromide, 3-butenyl iodide, 2-butenyl chloride, 2-butenyl bromide, 2-butenyl iodide, 4-pentenyl chloride, 4-pentenyl bromide, 4-pentenyl iodide. 3-pentenyl chloride, 3-pentenyl bromide, 3-pentenyl iodide, 2-pentenyl chloride, 2-pentenyl bromide, 2-pentenyl iodide. 2-methylallyl chloride, 2-methylallyl bromide, and 2-methylallyl iodide.

4. The method of claim 3, wherein the alkene-functionalized electrophilic compound is allyl chloride.

5. The method of claim 2, wherein the polysaccharide is selected from the group consisting of:

dextran, carboxymethyldextran, starch, agar, cellulose, hydroxyethylcellulose, carboxymethylcellulose, pullulan, inulin, levan, and hyaluronic acid.

6. The method of claim 5, wherein the polysaccharide is dextran.

7. The method of claim 2, wherein the strong base is selected from the group consisting of:

sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, butyllithium, potassium t-butoxide, sodium t-butoxide, and lithium diisopropylamide.

8. The method of claim 2, wherein the anhydrous, polar aprotic solvent is selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethyacetamide, and N-methylpyrrolidone.

9. The method of claim 1, wherein the alkene-functionalized polysaccharide is made by a method comprising the steps of:

a) reacting in a solvent, a polysaccharide with an electrophilic alkene-functional compound, capable of reacting with hydroxyl groups of the polysaccharide to form ester, carbonate, or urethane bonds, at a temperature of about 20°

C. to about 150°

C. to form an alkene-functionalized polysaccharide;

b) recovering the alkene-functionalized polysaccharide.

10. The method of claim 9, wherein the alkene-functionalized electrophilic compound is selected from the group consisting of:

allyl isocyanate, 3-butenoic acid activated with a carbodiimide, 3-pentenoic acid activated with a carbodiimide, 4-pentenoic acid activated with a carbodiimide, N-hydroxysuccinimidyl ester of 3-butenoic acid, N-hydroxysuccinimidyl ester of 3-pentenoic acid, N-hydroxysuccinimidyl ester of 4-pentenoic acid, and allyl chloroformate,

11. The method of claim 10, wherein the alkene-functionalized electrophilic compound is allyl isocyanate.

12. The method of claim 9, wherein the polysaccharide is selected from the group consisting of:

dextran, carboxymethyldextran, starch, agar, cellulose, hydroxyethylcellulose, carboxymethylcellulose, pullulan, inulin, levan, and hyaluronic acid.

13. The method of claim 12, wherein the polysaccharide is dextran.

14. The method of claim 9, wherein the solvent is selected from the group consisting of:

dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethyacetamide, and N-methylpyrrolidone.

15. The method of claim 1, wherein the metal hydroformylation catalyst is a rhodium complex in combination with a phosphorus compound.

16. The method of claim 1, wherein the metal hydroformylation catalyst is a rhodium complex selected from the group consisting of:

Rh(CO)₂acetylacetonate, Rh(PPh₃)₂(CO)Cl, RhH(CO)(PPh₃)₃, Rh(CO)₃(Ph₃P)₂BPh₄, Rh(cyclooctadiene)(Ph₃P)₂BPh₄, [Rh(cyclooctadiene)(acetate)]₂, [Rh(cyclooctadiene)Cl]₂, and [Rh(cyclooctadiene)(trifluoroacetate)]₂, in combination with a triarylphosphine or a sulfonated triarylphosphine.

17. The method of claim 1, wherein the solvent is selected from the group consisting of:

water, methanol, ethanol, propanol, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethyacetamide.

18. The method of claim 1, wherein the aldehyde-functionalized polysaccharide comprises:

(i) a polysaccharide selected from the group consisting of dextran, carboxymethyldextran, starch, agar, cellulose, hydroxyethylcellulose, carboxymethylcellulose, pullulan, inulin, levan, and hyaluronic acid; and

(ii) an aldehyde functional group selected from the group consisting of allyl, butenyl, pentenyl, and methylallyl.

19. The method of claim 18, wherein aldehyde functional group is selected from the group consisting of allyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-pentenyl, 2-pentenyl, and 2-methylallyl.

20. A method for making an aldehyde-functionalized polysaccharide having pendant aldehyde groups, said method comprising the steps of:

a) reacting in an anhydrous, polar aprotic solvent, a polysaccharide with an alkene-functionalized electrophilic compound, capable of reacting with hydroxyl groups of the polysaccharide to form ether, ester, carbonate or urethane bonds, to form an alkene-functionalized polysaccharide;

b) recovering the alkene-functionalized polysaccharide,

c) reacting in a solvent, the alkene-functionalized polysaccharide with a mixture of carbon monoxide and hydrogen, said mixture having a ratio of carbon monoxide to hydrogen of about 4;

1 to about 1;

4 by volume, in the presence of a metal hydroformylation catalyst to form an aldehyde-functionalized polysaccharide having pendant aldehyde groups; and

d) recovering the aldehyde-functionalized polysaccharide having pendant aldehyde groups.