Process for the preparation of Droxidopa
Inventors
Divi, Satchandra Kiran • Rao, Mysore Aswatha Narayana • Rao, Ponnekanti Purnachandra • Nowshuddin, Shaik
Assignees
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Publication Number
US-9920342-B2
Publication Date
2018-03-20
Expiration Date
Abstract
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.
Core Innovation
The invention describes a process for the preparation of (L)-threo-3-(3,4-methylenedioxyphenyl)serine, i.e., Droxidopa, from (DL)-threo-3-(3,4-methylenedioxyphenyl)serine. The process first acetylates the racemic (DL)-threo compound with an acetylating agent to obtain the N-acetyl racemate of formula III, i.e., (DL)-threo-N-acetyl-3-(3,4-methylenedioxyphenyl)serine.
Next, the process performs enantioselective hydrolysis of the racemic compound of formula III using L-aminoacylase from Aspergillus sp. (EC 3.5.1.14) in the presence of cobalt ions to obtain the (L)-threo isomer of formula IV, i.e., (L)-threo-3-(3,4-methylenedioxyphenyl)-serine. This enzymatic resolution approach addresses limitations of prior resolution methods that rely on chiral bases or resolving agents and discusses prior limitations relating to acylase activity.
Finally, the process converts the (L)-threo isomer of formula IV to Droxidopa. Conversion may include optionally protecting the amino group of formula IV with a protecting agent, followed by demethylation and deprotection of the amino group to obtain Droxidopa, where protection routes are described in terms of benzyloxycarbonyl or phthaloyl derivatives prior to demethylation and deprotection.
Claims Coverage
The document provides one independent claim directed to a multistep route to Droxidopa, with optional amino protection, demethylation, and deprotection. The independent claim includes three inventive features.
Acetylation to the N-acetyl racemate (III)
Acetylation of (DL)-threo-3-(3,4-methylenedioxyphenyl)serine with an acetylating agent to obtain (DL)-threo-N-acetyl-3-(3,4-methylenedioxyphenyl)serine of formula III.
Cobalt-ion-assisted enantioselective hydrolysis with L-aminoacylase
Enantioselective hydrolysis of racemic (DL)-threo compound of formula III using L-aminoacylase from Aspergillus sp. (EC 3.5.1.14) in the presence of cobalt ions to obtain (L)-threo-3-(3,4-methylenedioxyphenyl)-serine of formula IV.
Conversion to Droxidopa (I) with optional amino protection, demethylation and deprotection
Converting the (L)-threo isomer of formula IV to Droxidopa, with optional protecting of the amino group followed by demethylation and deprotection of the amino group to obtain Droxidopa of formula I.
Claim coverage centers on conversion of (DL)-threo serine to an N-acetyl racemate, resolution by enantioselective hydrolysis using L-aminoacylase from Aspergillus sp. with cobalt ions, and conversion to Droxidopa, optionally through amino protection, demethylation, and deprotection.
Stated Advantages
This enzymatic resolution approach addresses limitations of prior resolution methods that rely on chiral bases or resolving agents.
The document discusses prior limitations relating to acylase activity.
Documented Applications
No documented applications found
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