Methods of synthesizing a levodopa ester prodrug

1. A method of synthesizing (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate salt comprising:

reacting (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid with di-tert-butyl dicarbonate and tetrabutylammonium hydroxide in a mixture of alcohol and from 0%-b.v. to 4 b.v. water at a temperature from 20° C. to 60° C. in an inert atmosphere, to provide 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetrabutylammonium salt; and

reacting the 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetrabutylammonium salt with (1R)-2-chloro-isopropyl benzoate in N-methyl-2-pyrrolidone at a temperature from 50° C. to 120° C. to provide (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino] propanoate.

2. The method of claim 1 , wherein the reacting (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid with di-tert-butyl dicarbonate and tetrabutylammonium hydroxide was carried out at a temperature from 20° C. to 60° C.

3. The method of claim 1 , wherein the alcohol is selected from methanol, ethanol, isopropanol, and a mixture of any of the foregoing.

4. The method of claim 1 , wherein,

the alcohol is methanol; and

the purity of the (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate is greater than 97%.

5. The method of claim 1 , comprising, after reacting the 3-(3,4-dihydroxyphenyl)-(2S)-[(tert-butoxy)carbonylamino]propanoate tetrabutylammonium salt with (1R)-2-chloro-isopropyl benzoate:

reacting (2R)-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate with methanesulfonic acid in a solvent to provide (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate

wherein the purity of the (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate prior to recrystallization is greater than 95%.

6. The method of claim 5 , wherein reacting (2R)-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate with methanesulfonic acid 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.

7. The method of claim 1 , comprising cooling the solvent to form crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

8. The method of claim 7 , comprising seeding the cooled solvent with crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

9. The method of claim 7 , comprising recrystallizing (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate.

10. The method of claim 9 , 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 solvent; and

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