Methods of synthesizing a levodopa ester prodrug

1. A method of synthesizing (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate comprising reacting 3-(3,4-dihydroxyphenyl)-(2S)-[tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt with (1R)-2-chloro-isopropyl benzoate in N-methyl-2-pyrrolidone to provide (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.

2. The method of claim 1 , wherein reacting 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt with (1R)-2-chloro-isopropyl benzoate in N-methyl-2-pyrrolidone to provide (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate is carried out at a temperature ranging from about 70° C. to about 80° C.

3. The method of claim 1 , comprising reacting (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate with an acid in a second solvent to provide the corresponding (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate salt.

4. The method of claim 1 , comprising reacting (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate with methanesulfonic acid in a second solvent to provide (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

5. The method of claim 4 , wherein the second solvent is chosen from acetonitrile, acetone, ethyl acetate, toluene, isopropanol, dichloromethane, and a mixture of any of the foregoing.

6. The method of claim 5 , wherein the second solvent is chosen from acetonitrile and dichloromethane.

7. The method of claim 4 , wherein reacting (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate with methanesulfonic acid in a second solvent to provide (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate is carried out at a temperature ranging from about 30° C. to about 50° C.

8. The method of claim 4 , comprising cooling the second solvent to form crystalline (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

9. The method of claim 8 , comprising seeding the cooled second solvent with crystalline (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

10. The method of claim 8 , comprising recrystallizing (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

11. The method of claim 10 , wherein recrystallizing (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate comprises:

dissolving (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate in a third solvent; and

cooling the third solvent to form crystalline (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

12. The method of claim 11 , wherein the third solvent is chosen from acetonitrile, acetone, ethyl acetate, water, and a mixture of any of the foregoing.

13. The method of claim 12 , wherein the third solvent is chosen from acetonitrile and a mixture of acetonitrile and water.

14. The method of claim 1 , wherein (1R)-2-chloro-isopropyl benzoate is prepared comprising:

reacting N,N-dimethylbenzamide with phosphoryl halogen in a fourth solvent to provide dimethylbenzamide Vilsmeier salt; and

reacting dimethylbenzamide Vilsmeier salt with (2R)-propane-1,2-diol to provide (1R)-2-chloro-isopropyl benzoate.

15. The method of claim 14 , wherein phosphoryl halogen is phosphoryl chloride.

16. The method of claim 15 , wherein reacting N,N-dimethylbenzamide with phosphoryl chloride to provide dimethylbenzamide Vilsmeier salt is carried out at a temperature ranging from about 70° C. to about 95° C.

17. The method of claim 15 , wherein the fourth solvent is dichloromethane.

18. The method of claim 15 , wherein reacting dimethylbenzamide Vilsmeier salt with (2R)-propane-1,2-diol to provide (1R)-2-chloro-isopropyl benzoate is carried out at a temperature ranging from about 0° C. to about 10° C.

19. The method of claim 1 , wherein 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt is prepared comprising:

reacting (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid with di-tert-butyl dicarbonate and tetraalkylammonium hydroxide to provide 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt.

20. The method of claim 19 , wherein reacting (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid with di-tert-butyl dicarbonate and tetraalkylammonium hydroxide to provide 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt is carried out in a mixture of an alcohol and water.

21. The method of claim 20 , wherein the mixture of an alcohol and water comprises from about 0%-b.v. to about 4%-b.v. water.

22. The method of claim 20 , wherein the alcohol is chosen from methanol, ethanol, isopropanol, and a mixture of any of the foregoing.

23. The method of claim 19 , wherein reacting (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid with di-tert-butyl dicarbonate to provide 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt is carried out at a temperature ranging from about 30° C. to about 50° C.

24. The method of claim 1 , wherein reacting 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetraalkylammonium salt with (1R)-2-chloro-isopropyl benzoate in N-methyl-2-pyrrolidone to provide (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate is carried out at a temperature of at least 100° C., and provides a yield of (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate of at least 40%.