Synthesis of tyrosine derived polyarylates

Patent metadata

Field	Value
Publication number	US-10793670-B2
Application number	US-201815972836-A
Country	US
Kind code	B2
Filing date	May 7, 2018
Priority date	Jun 7, 2017
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

A method for preparing tyrosine derived polyarylates includes combining a desaminotyrosyl-tyrosine ethyl ester, a desaminotyrosyl-tyrosine benzylester, succinic acid and a catalyst in a flask to produce a first mixture. Methylene chloride is added to the first mixture to produce a first suspension. Diisopropylcarbodiimide (DIPC) is added to the first mixture to produce a first solution. The first solution is added to a non-solvent to produce a precipitate. The precipitate is dissolved in methylene chloride to form a polymer solution. The polymer solution is blended with a slurry to produce polymer shreds. The polymer shreds are blended with a second slurry to produce a tyrosine derived polyarylate.

First claim

What is claimed is:

1. A method for preparing a polyarylate having the formula:

the method comprising:
combining a desaminotyrosyl-tyrosine ethyl ester having the formula:

a desaminotyrosyl-tyrosine benzylester having the formula:

succinic acid and a catalyst in a flask to produce a first mixture;
adding methylene chloride to the first mixture to produce a first suspension;
adding diisopropylcarbodiimide (DIPC) to the first mixture to produce a first solution;
adding the first solution to a non-solvent to polymerize the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine ethyl ester and produce a precipitate;
dissolving the precipitate in methylene chloride to form a polymer solution;
blending the polymer solution with a slurry of 2-propanol and dry ice to produce polymer shreds; and
blending the polymer shreds with a second slurry of 2-propanol and dry ice to produce the polyarylate.

2. A method as recited in claim 1 , wherein the first mixture comprises a stoichiometric ratio of 1 mole of the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester to 1 mole of the succinic acid.

3. A method as recited in claim 1 , wherein the first mixture comprises an excess of the succinic acid relative to the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester.

4. A method as recited in claim 1 , wherein the first mixture comprises a 1-5% excess of the succinic acid relative to the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester.

5. A method as recited in claim 1 , wherein the first mixture comprises a 2% excess of the succinic acid relative to the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester.

6. A method as recited in claim 1 , wherein about 308.6 g of the desaminotyrosyl-tyrosine ester, about 40.3 g of the desaminotyrosyl-tyrosine benzylester and about 113.4 g of succinic acid are added to the flask to produce the first mixture.

7. A method as recited in claim 1 , wherein desaminotyrosyl-tyrosine ester, desaminotyrosyl-tyrosine benzylester and succinic acid are added in the mole ratio 0.864:0.086:0.96 to the flask to produce the first mixture.

8. A method as recited in claim 1 , further comprising:
titrating the first mixture to obtain COOH and OH equivalent numbers; and
adjusting the ratio of the succinic acid relative to the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester to maintain a constant COOH and OH ratio.

9. A method as recited in claim 1 , wherein:
the first mixture comprises about a 5% excess of the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester relative to the succinic acid; and
the ratio of the succinic acid relative to the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester is adjusted until a 1:1.02 ratio of the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester is achieved.

10. A method as recited in claim 1 , wherein:
the first mixture comprises about a 1% to about a 5% excess of the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester relative to the succinic acid; and
the ratio of the succinic acid relative to the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester is adjusted until a 1:1.02 ratio of the desaminotyrosyl-tyrosine ethyl ester and the desaminotyrosyl-tyrosine benzylester is achieved.

11. A method as recited in claim 1 , wherein the catalyst is dimethyllaminopyridine and P-toluenesulfonic acid (DPTS).

12. A method as recited in claim 11 , wherein the catalyst comprises about 696.5 g of DPTS.

13. A method as recited in claim 1 , further comprising adding at least one acid to the first solution.

14. A method as recited in claim 13 , wherein the at least one acid comprises at least one of succinic acid, adipic acid and glutaric acid.

15. A method as recited in claim 13 , further comprising cooling the first solution to room temperature and stirring the first solution.

16. A method as recited in claim 15 , wherein the first solution is stirred overnight.

17. A method as recited in claim 1 , further comprising collecting the polyarylate from the blended polymer shreds and second slurry and drying overnight under a stream of air.

18. A method as recited in claim 17 , further comprising dissolving the polyarylate in methylene chloride to produce a second solution.

19. A method as recited in claim 18 , further comprising adding an acid to the second solution to produce a third solution.

20. A method as recited in claim 1 , wherein the method does not use NaCl.

Assignees

• Tyrx Inc
• Medtronic Inc

Inventors

• Pulapura Satish
• Buevich Fatima
• Chen Xiangji
• Lyu Suping

Classifications

• C08G63/6856 Primary

  Dicarboxylic acids and dihydroxy compounds · CPC title

• C08G63/81 Primary

  using solvents (C08G63/79 takes precedence) · CPC title