Goura R,
Manabolu Surya SB,
*,
Katari NK,
Kodanda RA,
Rebelly P,
Chakilam N.
GITAM deemed to be University, Hyderabad, India
Scalable and Cost-Effective Synthetic Process for the Preparation of
l-3,4-Dihydroxyphenylalanine–Levodopa.
Org. Process Res. Dev. 2024;
28: 238-247
DOI:
10.1021/acs.oprd.3c00313
Key words
levodopa - DoE - process scale-up - ANOVA
Significance
l-3,4-Dihydroxyphenylalanine, or levodopa, is a key active pharmaceutical ingredient
(API) used to reduce motor impairments caused by Parkinson’s disease. Hoffman-La Roche
previously developed a synthesis of levodopa. However, the process involves several
steps. Notably, the route uses the pyrophoric reagent Raney nickel, which is responsible
for several serious industrial accidents. Other methods to access levodopa include
one developed by Monsanto which uses an expensive rhodium-DiPAMP catalyst, and a process
reported by Li et al. which employs toxic sodium cyanide. The authors of this paper
report an alternative, commercially scalable synthetic route which aims to eliminate
the use of toxic and hazardous reagents while increasing efficiency and reducing cost.
The optimized process route takes place in two steps, starting from l-Tyrosine. Bromination using hydrobromic acid is followed by a copper(I)-catalyzed
hydroxylation to yield levodopa with 42% isolated yield and 99% ee.
Comment
Differential scanning calorimetry (DSC) was conducted to assess the hazard of employing
DMSO in the bromination, which is known to exothermically decompose especially in
the presence of halides and acid. The DSC scan indicated only minor exothermic activity,
which was likely dampened by the thermal mass of the water and acetic acid in the
batch. The authors utilize design of experiments (DoE) to assess which factors impact
the yield and purity of the synthesis. The authors used a two-stage optimization approach
to test five process parameters in 46 trials for each reaction step. For the bromination,
reaction time, temperature, HBr equivalents, DMSO volume, and acetic acid volume were
studied. For the hydroxylation, reaction time, temperature, base equivalents, CuI
equivalents, and water volume were studied. Optimal synthesis conditions for both
reactions were identified via analysis of these results.
