of the final product 2 is controlled by validated methods,
utilizing potentiometric titration assay and HPLC of related
substances. Related substances are characterized on the basis
of reference standards of pramipexole and each individual
impurity. To ensure the optical purity, both starting material
and product are checked for the presence of the R-isomer, which
is limited below 0.5%.
The whole synthetic process of the active substance was
evaluated regarding genotoxic impurities. Starting materials,
reagents, intermediates, and reaction byproducts were consid-
ered. Several compounds with genotoxic potential were identi-
fied, and safety limits were calculated on the base of TTC
(Threshold of Toxicological Concern) and maximal daily dose
or data from long-term carcinogenicity studies according to
EMEA Guideline on the limits of genotoxic impurities CPMP/
SW/5199/02. The quantities of these impurities were determined
by appropriate HPLC methods (using reference standards of
these impurities), and the results of analyses show that all
potential genotoxic impurities are absent or present at levels
below 30% of the acceptable limits.
CH3CN/CH3OH/H2O ) 6:3:1 (pH ) 10). The following
gradient was applied: 0 min, 20% B; 0-18 min, 20% B f
50% B; 18-24 min, 50% B f 70% B; 24-40 min, 70% B;
40-41 min 70% B f 20% B; 20% B re-equilibration 7 min;
T ) 25 °C.
Enantiomeric purity was determined using a Chiralpack IA
column (250 mm ×4.6 mm, 5 µm particles) with a flow rate
of 0.8 mL/min, detection at 263 nm, and a mobile phase of:
hexane/ethanol/diethylamine ) 75:25:0.05; T ) 25 °C. Reten-
tion times for the product and its enantiomer are 9.0 and 7.2
min, respectively. The content of the R-enantiomer is below
0.5%.
Preparation of (6S)-N-(2-Amino-4,5,6,7-tetrahydroben-
zothiazole-6-yl)-2-nitrobenzenesulfonamide 11. 2-Nitroben-
zenesulfonyl chloride (390 g, 1.76 mol) was dissolved in 4.0 L
of THF, and the solution was cooled to approximately -10
°C. TEA (740 g, 7.313 mol) and (6S)-4,5,6,7-tetrahydroben-
zotiazole-2,6-diamine (327 g, 1.932 mol) were added. The
suspension was heated during mixing to approximately 25 °C,
and allowed to react for 1 h. Precipitated triethylammonium
chloride was filtered off, and the filtrate was concentrated to
about one-third of the volume. Water was added (2.0 L) and
approximately half of the solvent was distilled off. Water was
added again (2.0 L), and the mixture was cooled to 25 °C and
mixed for about 1 h. The precipitated product was separated
by filtration and dried under vacuum at 50 °C, to obtain
sulfonamide 11 (590 g, 1.665 mol) as a pale yellow solid with
Conclusion
By using the Fukuyama protocol for the alkylation of
diaminobenzothiazole (S)-8, we were able to develop an
efficient telescoped process for the synthesis of pramipexole.
Although the number of steps needed to produce the final
product is increased by one step if compared to the reductive
alkylation method or the amide reduction method, this process
still offers many advantages. First, transformation of the highly
hydrophilic diamine ((S)-8) to a more lipophilic sulfonamide
(11) makes handling of the intermediates easier and enables
the use of extraction as an efficient purification method. Second,
the process provides high conversion rates of the intermediates
(the overall yield of the synthesis of crude pramipexole starting
from key intermediate (S)-8 was 54%), and avoids the formation
of undesired side products. Third, the process preserves high
optical purity throughout all of the steps; racemisation does not
occur at any of the steps in this process. Finally, the process
uses inexpensive reagents, which are also comparatively safe
and easy to handle, making it an industrially acceptable
synthesis.
1
a yield of 94.6% and a HPLC purity of more than 98%. H
NMR (300 MHz, DMSO-d6) δ 1.63-1.82 (m, 2H), 2.37-2.47
(m, 3H), 2.58-2.65 (m, 1H), 3.49-3.58 (m, 1H), 6.68 (s, 2H),
7.83-7.97 (m, 3H), 8.04-8.09 (m, 1H), 8.30 (bs, 1H). 13C
NMR (300 MHz, DMSO-d6) δ 24.5, 29.3, 29.6, 50.0, 111.6,
124.2, 129.6, 132.6, 133.4, 134.1, 144.1, 147.6, 166.3. FT-IR
(cm-1): 3418 (NH2 stretching), 3418 (N-H stretching of
R-SO2-NH), 2944 (C-H stretching of CH2), 1618 (CdN
stretching), 1525 (heteroaromatic ring skeleton), 1328 (R-
SO2-N asymmetric streching), 1156 (R-SO2-N symmetric
streching), 741 (ArC-H out of plane). EI-MS m/z 355.1 (M+).
Anal. Calcd for C13H14N4O4S2: C, 44.06; H, 3.89; N, 15.81.
Found: C, 44.07; H, 4.25; N, 15.50. Melting point: 227-
230 °C.
Preparation of (6S)-N-(2-Amino-4,5,6,7-tetrahydroben-
zothiazole-6-yl)-2-nitro-N-propylbenzenesulfonamide 12.
Potassium carbonate (1890 g, 13.675 mol), (6S)-N-(2-amino-
4,5,6,7-tetrahydrobenzothiazole-6-yl)-2-nitrobenzenesulfona-
mide (590 g, 1.665 mol) 11 and propyl bromide (1.09 L, 12
mol) were suspended in 4.1 L of acetonitrile. The mixture was
heated during stirring to about 60 °C, and left to react for
approximately 12 h. The end point of the reaction was
determined by HPLC (the content of 11 was less than 0.1%).
The mixture was cooled off to 25 °C, and the potassium
bromide and potassium carbonate were removed by filtration.
The solution was concentrated to about one-quarter of the
volume (not exceeding 60 °C) and cooled to room temperature.
Methylene chloride (2.0 L) and 1.0 M aqueous NaOH (2.43
L) were added, and the mixture was mixed for about 30 min.
The phases were separated, and the water phase was washed
again with methylene chloride (1.46 L). The organic phases
Experimental Section
Reagents and solvents were purchased and used as received.
1
The H and 13C spectra were recorded in dimethylsulfoxide
(DMSO) at 300 MHz on a VARIAN INOVA 300 MHz NMR
spectrometer. The chemical shifts were reported as δ ppm
relative to tetramethylsilane. The FT-IR spectra were obtained
as a potassium bromide pellet using a Spectrum 100 Perkin-
Elmer FT-IR spectrometer. Mass spectra were recorded on a
Q-TOF Premier spectrometer, using electron-spray ionization.
Melting points were determined on a Wagner & Munz hot-
stage microscope and are uncorrected. Elemental analysis was
performed on a Perkin-Elmer 2400 CHN Elemental Analyzer.
HPLC chromatographic purity was determined using a
Gemini C-18 110A column (150 mm ×4.6 mm, 5 µm particles)
with a flow rate of 1.0 mL/min, detection at 263 nm, and an
eluent system of: A ) 0.01 M KH2PO4 (pH ) 10); B )
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Vol. 14, No. 5, 2010 / Organic Process Research & Development