Process for the preparation of Droxidopa
A novel process for the preparation of L-threo-dihydroxyphenylserine (Droxidopa) is described. It comprises of enantioselective hydrolysis of racemic (DL)-threo-N-acetyl-3-(3,4-methylenedioxyphenyl)-serine using commercially available L-amino acylase from Aspergillus sp. (EC 3.5.1.14) in the presence of cobalt ions, to obtain (L)-threo-3-(3,4-methylenedioxyphenyl)-serine followed by dealkylation to obtain Droxidopa. Protecting the amino group of (L)-threo-3-(3,4-methylenedioxyphenyl)-serine using either benzyloxycarbonyl or phthaloyl group before dealkylation followed by deprotection of the amino group results in obtaining Droxidopa in high yields and purity.
1. A process for the preparation of (L)-threo-3-(3,4-methylenedioxyphenyl)serine (Droxidopa) comprising:
a) acetylation of (DL)-threo-3-(3,4-methylenedioxyphenyl)serine of formula II with an acetylating agent
to obtain (DL)-threo-N-acetyl-3-(3,4-methylenedioxyphenyl)serine of the formula III, followed by
(b) enantioselective hydrolysis of racemic (DL)-threo compound of the formula (III) using
L-aminoacylase from Aspergillus sp.(EC 3.5.1.14) in the presence of cobalt ionstoobtain(L)-threo-3-(3,4-methylenedioxyphenyl)-serine of formula (IV) and
(c) converting (L)-threo isomer of formula (IV) to Droxidopa of formula (I)
(d) optionally protecting the amino group of (L)-threo isomer of formula (IV) with a protecting agent followed by demethylation and deprotection of the amino group to obtain Droxidopa of formula I.
2. A process according to claim 1 (a), wherein the acetylation is carried out using acetic anhydride.
3. A process according to claim 1 (b), wherein the hydrolysis is carried out at a temperature between 15° C. to 55° C.
4. A process according to claim 1 (b), wherein the hydrolysis is carried out at a pH of 5 to 8.5.
5. A process according to claim 1 (b),wherein the hydrolysis is carried out in the presence of cobalt ions where the ratio between cobalt ions and the substrate (DL)-threo compound of the formula (III) is 0.002: 1.0 to 0.11: 1.0.
6. A process according to claim 1 (d), wherein the (L)-threo isomer of formula (IV) is converted to Droxidopa of formula (I), by first converting(IV) to its N-benzyloxy carbonyl derivative of the formula (Va);
converting (Va) to a compound of the formula (VIa) and
converting the compound of the formula (VIa) to(I).
7. A process according to claim 1 (d), wherein the (L)-threo isomer of formula (IV) is converted to Droxidopa of formula (I), by first converting IV to its N-phthaloyl derivative of the formula (Vb) and
converting (Vb) to a compound of the formula (VIb) and
converting the compound of the formula (VIb) to (I).