Synthesis of Impurities of Pramipexole Dihydrochloride

Article abstract of DOI:10.1021/acs.oprd.6b00182

Three impurities of pramipexole dihydrochloride were synthesized, and the possible generation mechanisms and the preparation methods of some impurities were reviewed. The desired configuration at C7 of 3 was built by a Mitsunobu reaction.

Full text of DOI:10.1021/acs.oprd.6b00182

Article
pubs.acs.org/OPRD
Synthesis of Impurities of Pramipexole Dihydrochloride
Tianwen Hu,†,‡,∥ Feipu Yang,†,‡,∥ Tao Jiang,†,‡ Weiming Chen,§ Jian Zhang,§ Jianfeng Li,†
Xiangrui Jiang,*,† and Jingshan Shen†
†CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai 201203, China
‡University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
§Topharman Shanghai Co. Ltd., Shanghai 201209, China
S
* Supporting Information
ABSTRACT: Three impurities of pramipexole dihydrochloride were synthesized, and the possible generation mechanisms and
the preparation methods of some impurities were reviewed. The desired configuration at C7 of 3 was built by a Mitsunobu
reaction.
KEYWORDS: pramipexole, Mirapex, impurities, synthesis, Mitsunobu reaction
pramipexole), and Impurity E. Gego et al.18 reported the
INTRODUCTION
Pramipexole dihydrochloride monohydrate (Figure 1),
developed as a second-generation nonergot dopamine
̈
■
synthesis of 3-4. Nishimura et al.16 completed the synthesis of
5 in 2012. Jia et al.19 reported the synthesis of 7, and Wu et
al.20 reported the synthesis of Impurity B. However, synthetic
methods for some of the other impurities have not been
reported. Herein we report the synthesis of 3 and two other
impurities (1 and 2).
Figure 1. Structure of pramipexole dihydrochloride monohydrate.
RESULTS AND DISCUSSION
■
1, 2, and 3 are generated by degradation of pramipexole. 1
and 2 may result from the mechanism of oxidation; 3 may be
generated by replacement or condensation reactions between
pramipexole and its oxidation impurities. Thus, the strategy of
degradation and subsequent isolation was first tried to prepare
these three impurities, but this approach failed.
receptor agonist by Boehringer Ingelheim, is the active
substance in the anti-Parkinson drug Mirapex.1,2 Pramipexole
binds to the D2 dopamine receptor subfamily with selectivity
for the D3 dopamine receptor.3,4 It is well-established as a
treatment option for motor symptoms at all stages of
Parkinson’s disease (PD).5,6 Also, this drug is effective in
the treatment of idiopathic and secondary restless legs
syndrome (RLS) and in treatment-resistant patients as
well.7−12 The methods for synthesizing pramipexole disclosed
in the original patent include three synthetic routes with 2,6-
diamino-4,5,6,7-tetrahydrobenzothiazole as the common inter-
mediate (Scheme 1).13,14
Seventeen impurities (Figure 2) were regulated in the
quality inspection standards of pramipexole dihydrochloride
tablets provided by the originator. Some of them originate
from the manufacturing process of the active pharmaceutical
ingredient (API). Others may be caused by oxidation or
degradation of pramipexole in the process of preparation and
storage.15 For instance, Nishimura et al.16 reported that 5
might be caused by photodegradation of pramipexole in the
preparation and explained possible mechanisms for this in the
solid state and the liquid state.
Synthesis of 1. Compound 1-2 was obtained by
bromination of 1-4 and subsequent replacement by thiourea
(Scheme 2). 1-1 was then synthesized from 1-2 by the
process of Gego et al.18 The desired compound 1 was
̈
furnished by the nucleophilic reaction between 1-1 and
propylamine.
Synthesis of 2. Compound 2-3 was synthesized from 1-1
on the basis of the research of Gego et al.18 (Scheme 3).
̈
Propylation and subsequent reduction of 2-2 followed by
selective reduction of 2-3 furnished 2-1 as a mixture of four
stereoisomers. Finally, 2 was obtained by resolution using
chiral chromatography.
Synthesis of 3. It was a challenge to construct the
substituted tertiary C6 and C7 in 3 (Figure 2) and find a
purification method for the highly polar final product. The
asymmetric construction of the nitrogen-substituted tertiary
carbon stereocenter was our foremost priority. With this
intention, we made use of kinetic resolution and a Mitsunobu
reaction to achieve the desired configuration.
Pramipexole impurity standards are essential for the quality
control of the API and tablets to ensure the safety and
efficacy of the drug. To date, syntheses of some of these
impurities have been reported. In 1986, Schneider and
Mierau17 provided synthetic routes for three impurities,
namely, Impurity A, Impurity D (the R enantiomer of
Received: May 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
a
Scheme 1. Three Synthetic Routes for Pramipexole
a
R = H and R1 = protecting group or R and R1 together form a protecting group. R2 is a leaving group such as halide, OTs, or OMs.
Amine 3-4 was prepared from 2−3 through 4 steps
according to literature (Scheme 4).18 In the initial attempt,
the amine 5 was reacted with propionaldehyde and NaBH4 to
obtain 3-4. The structure of 3-4 monosulfate was determined
by single-crystal X-ray diffraction, and the data indicated that
the asymmetric carbons of 3-4 monosulfate had a (6S,7S)
configuration (Figure 3). The absolute configuration of 3-5
was the same as that of 3-4 because the conversion from 3-5
to 3-4 did not involve a change in the configuration. After
acetylation, intermediate 3-3 was obtained. The Mitsunobu
reaction is commonly used for configuration inversion of
chiral carbons.21,22 3-3 was coupled with protected pramipex-
ole 4 to obtain 3-2, which had our desired configuration, in
the presence of DIAD and PPh3 by the Mitsunobu reaction.
Originally, we intended to cleave all of the amide bonds of 3-
2 to get the desired product. However, a comprehensive study
using various acidic conditions, such as HCl/ethanol,
concentrated HCl, concentrated HBr, and HOAc/concen-
trated H2SO4, gave exclusively 3-1. Stronger acidic and basic
conditions were tried but failed to convert 3-1 to 3, likely
because of the chemical stability of the acetyl group on the
secondary amine.
Stimulated by the failure of the initial route, an adjusted
synthetic plan was carried out to complete the synthesis of 3
(Scheme 5). Selective propionylation of 3-5 using propionyl
chloride in the presence of triethylamine produced amide 3-
11. Under the standard Mitsunobu reaction conditions, 3-10
was prepared from intermediates 4 and 3-11. It was expected
that 3-10 would be directly converted to 3-9, but instead,
only 3-8 was obtained. Subsequent selective alkylation using
propionaldehyde by the same method as used to synthesize 3-
4 generated the desired product 3. To identify the absolute
configuration of 3, many methods were tried to obtain a
single crystal of 3, but all of them failed. The absolute
configurations of C6 and C7 in 3-5 are same as in 3-4 and are
retained in the subsequent propionylation. The configuration
of C7 in 3-11 was inverted in the Mitsunobu reaction to
generate 3-10 (Scheme 5), and there was no major influence
on the configurations of C6 and C7 in the following steps.
Therefore, it was deduced that 3 has a (6S,7R) configuration.
CONCLUSION
■
Total syntheses of 1, 2, and 3, which are important and
valuable for the quality control of drug manufacturing, have
been accomplished. After the unsuccessful initial trial, the
optimized synthetic method for 3 was feasible and allowed to
give a sufficient amount of 3 efficiently. The configuration of
C7 in 3 was deduced to be (6S,7R) from the chemistry
leading from 3-5 to 3 and the single-crystal X-ray diffraction
analysis of the sulfate of 3-4, which is another impurity.
EXPERIMENTAL SECTION
■
General Procedures. All of the commercially available
materials and solvents were used without any further
purification. Thin-layer chromatography (TLC) analyses
1
were performed on Merck silica gel 60 F254 plates. H and
13C NMR spectra were recorded at room temperature on a
Bruker AMX-400 spectrometer using tetramethylsilane as an
internal standard. Mass spectra were recorded on a Finnigan
MAT-95/711 spectrometer. Reversed-phase HPLC analyses
were performed on an Agilent 1100 HPLC system with a
diode array detector (area normalization).
2-Bromocyclohexane-1,3-dione (1-3). To a solution of 1-4
(50 g, 446 mmol) in acetic acid (535 mL) was added bromine
(23 mL, 446 mmol) dropwise for 3 h. The reaction mixture
was stirred for an additional 1 h and then filtered. The
precipitate was washed twice with petroleum ether to afford
1
1-3 (64.8 g). H NMR (CDCl3, 300 MHz): δ 6.63 (s, 1H),
2.61 (t, J = 5.9 Hz, 4H), 2.03 (p, J = 5.9 Hz, 2H). MS (ESI,
ev): m/z = 191.9 [M + H]+.
2-Amino-5,6-dihydrobenzothiazol-7(4H)-one Dihydrobro-
mide (1-2). A mixture of 1-3 (120 g, 628 mmol) and thiourea
(57.3 g, 753 mmol) in ethanol (600 mL) was refluxed for 3 h
under N2. Then the reaction mixture was cooled to room
1
temperature and filtered to yield yellow solid 1-2 (109 g). H
NMR (DMSO-d6, 400 MHz): δ 8.65 (s, 4H), 2.71 (t, J = 6.1
B
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Figure 2. Structures of the 17 impurities found in the API and tablet.
Scheme 2. Synthetic Route for 1
Scheme 3. Synthetic Route for 2
Hz, 2H), 2.40 (m, 2H), 2.01 (m, 2H). MS (ESI, ev): m/z =
169.11 [M + H]+.
2-Amino-6-bromo-5,6-dihydrobenzothiazol-7(4H)-one (1-
1). To a solution of 1-2 (50 g, 122 mmol) in methanol (340
mL) was added concentrated H2SO4 (18.13 mL) at 18−23
°C. When 1-2 was dissolved completely, trimethyl orthofor-
mate (14.64 mL, 131 mmol) was added to the solution. The
reaction mixture was stirred for an additional 90 min at 20−
23 °C and then cooled to 0−5 °C. Bromine (6.26 mL, 122
mmol) was added dropwise at 0−5 °C within 45 min to 1 h,
C
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 4. Initial Synthetic Route for 3
cooled to 0−5 °C and neutralized with saturated NaHCO3
solution. The precipitate was filtered and washed with water
to give 1-1 (64 g). The structural data for 1-1 were identical
with those reported in the literature.17
2-Amino-6-(propylamino)-5,6-dihydrobenzothiazol-7(4H)-
one (1). A mixture of 1-1 (5.38 g, 21.8 mmol), K2CO3 (3.0 g,
21.8 mmol), and propylamine (1.79 mL, 21.8 mmol) in
CH3CN (50 mL) was stirred at 50 °C. When the starting
material was consumed, the mixture was purified to give 1
1
(700 mg). H NMR (CD3OD, 300 MHz): δ 3.36−3.41 (m,
1H), 2.70−2.92 (m, 2H), 2.53−2.67 (m, 2H), 2.32−2.40 (m,
1H), 1.78−1.92 (m, 1H), 1.48−1.61 (m, 2H), 0.93 (td, J =
1.1 Hz, 7.4 Hz, 3H). 13C NMR (CD3OD, 100 MHz): 184.04,
178.19, 170.88, 117.92, 61.24, 26.85, 20.83, 11.23. MS (ESI,
ev): m/z = 226.11 [M + H]+.
Figure 3. X-ray structure of 3-4.
2-Amino-6-azido-5,6-dihydrobenzothiazol-7(4H)-one (2-
3). To a solution of 1-1 (26.6 g, 107 mmol) in a mixture
of DMF (300 mL) and water (100 mL) was added NaN3 (8.4
g, 129 mmol) in portions. The reaction mixture was stirred
for 3 h. NaN3 (2.1 g, 32.3 mmol) was added again. Then the
after which the reaction mixture was stirred for 2 h at that
temperature and then allowed to warm slowly to room
temperature during the night. The next day, water (450 mL)
was added. Then the mixture was warmed to 45−50 °C and
kept that temperature for 1 h. The resulting mixture was
Scheme 5. Successful Synthetic Route for 3
D
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
mixture was warmed to room temperature and stirred
overnight. Water (520 mL) was added the next day, and
the mixture was stirred for 30 min. The precipitate was
filtered and washed with water (100 mL × 2) to give 2-3
(21.6 g). The structural data for 2-3 were identical to those
reported in the literature.17
2,6-Diamino-5,6-dihydrobenzothiazol-7(4H)-one (2-2).
To a solution of 2-3 (18.4 g, 87.9 mmol) in methanol (350
mL) was added Pd/C (10 wt %, 1.84 g) under N2. The
atmosphere was changed to H2, and the reaction mixture was
stirred for 19 h. The Pd/C catalyst was removed by filtration,
and the filtrate was concentrated to give 2-2 (16 g), which
was used in the next step without more purification.
mixture was stirred at 0 °C for 3 h. Then the precipitate was
filtered and washed with water to give 3-6 (8.3 g). The
structural data for 3-6 were identical to those reported in the
literature.17
(6S,7S)-2,6-Diamino-7-hydroxy-4,5,6,7-tetrahydrobenzo-
thiazole (3-5). A suspension of 3-6 (8.3 g) in water (25 mL)
was alkalized by the addition of 5 N NaOH solution. After 3-
6 was dissolved completely, a white solid precipitated, and the
reaction mixture was stirred for an additional 30 min. The
precipitate was filtered and washed with water to yield 3-5
(1.8 g). The structural data for 3-5 were identical to those
reported in the literature.17
(6S,7S)-2-Amino-7-hydroxy-6-(propylamino)-4,5,6,7-tetra-
hydrobenzothiazole (3-4). To a mixture of 3-5 (3.0 g, 16.2
mmol) and methanol (50.0 mL) was added propionaldeyde
(2.5 mL, 34.4 mmol) at −20 °C. The reaction mixture was
stirred for 45 min, and NaBH4 (850 mg, 22.5 mmol) was
added in small portions during 15 min. The mixture was
maintained at that temperature for 30 min, and then the
reaction was continued for 4 h after the temperature was
slowly increased to room temperature. The mixture was
concentrated to give the crude material, which was purified by
column chromatography to obtain 3-4 (4.3 g). 1H NMR
(DMSO-d6, 400 MHz): δ 6.78 (s, 2H), 4.46 (d, J = 3.3 Hz,
1H), 4.12 (s, 1H), 3.36 (d, J = 17.5 Hz, 1H), 2.54−2.68 (m,
2H), 2.40−2.48 (m, 2H), 2.28−2.38 (m, 1H), 1.58−1.69 (m,
2H), 1.34−1.44 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). MS (ESI,
ev): m/z = 228.04 [M + H]+. HPLC: tR = 10.35 min, 96%
purity.
(6S,7R)-2-Amino-7-hydroxy-6-(propylamino)-4,5,6,7-tetra-
hydrobenzothiazole (2). To a mixture of 2-2 (593 mg, 3.2
mmol) and methanol (10 mL) was added propionaldeyde
(467 μL, 6.5 mmol) at −15 °C, and the reaction mixture was
stirred for 3 h, after which NaBH4 (688 mg, 18.2 mmol) was
added in portions. The reaction mixture was maintained at
−15 °C for 3 h. Then the reaction was continued for 5 h after
the temperature was increased slowly to room temperature.
The mixture was concentrated to give the crude material,
which was purified by column chromatography to obtain 2-1
1
(260 mg). 2 was obtained from 2-1 by chiral resolution. H
NMR (DMSO-d6, 400 MHz): δ 6.70 (s, 2H), 5.25 (s, 1H),
4.24 (d, J = 5.9 Hz, 1H), 2.56−2.66 (m, 2H), 2.50−2.53 (m,
1H), 2.45−2.49 (m, 1H), 2.28−2.43 (m, 2H), 1.92−2.00 (m,
1H), 1.46−1.53 (m, 1H), 1.42 (dd, J = 7.3 Hz, 14.6 Hz, 2H),
0.87 (t, J = 7.3 Hz, 3H). 13C NMR (DMSO-d6, 100 MHz):
167.36, 146.02, 119.20, 68.24, 61.20, 48.91, 25.00, 24.18,
22.85, 11.78. MS (ESI, ev): m/z = 228.06 [M + H]+.
3-4 Monosulfate. To a solution of 3-4 in methanol was
added concentrated H2SO4 at 0 °C. The mixture was stirred
for 15 min and then filtered, and the filter cake was washed
with methanol to obtain the monosulfate of 3-4.
(S)-tert-Butyl (2-((tert-Butoxycarbonyl)amino)-4,5,6,7-tet-
rahydrobenzothiazol-6-yl)(propyl)carbamate (4). Pramipex-
ole (13.5 g, 64.0 mmol) and NEt3 (11.0 mL, 78.9 mmol)
were suspended in DCM (100 mL), and then (Boc)2O (16.2
mL, 70.4 mmol) was added dropwise at 0 °C. When TLC
indicated that the aliphatic amine was consumed totally, NEt3
(11.0 mL, 78.9 mmol) and (Boc)2O (16.2 mL, 70.4 mmol)
were added again, and the mixture was stirred at 35 °C. When
TLC indicated that the aromatic amine was converted
completely, the solvent was removed to obtain the crude
material, which was purified by column chromatography to
N-((6S,7S)-2-Acetamido-7-hydroxy-4,5,6,7-tetrahydroben-
zothiazol-6-yl)-N-propylacetamide (3-3). 3-4 (4.2 g, 18.5
mmol) and triethylamine (5.6 mL, 40.2 mmol) were
suspended in DCM (100 mL), and then acetyl chloride
(3.2 mL, 33.3 mmol) was added at 0 °C. When TLC
indicated that the reaction was finished, the reaction mixture
was quenched with methanol. The resulting mixture was
concentrated to obtain the crude material, which was purified
1
by column chromatography to give 3-3 (3.2 g). H NMR
1
give 4 (15.8 g). H NMR (CDCl3, 400 MHz): δ 9.02 (s, 1H),
(DMSO-d6, 400 MHz): δ 12.00 (s, 1H), 5.34 (d, J = 6.4 Hz,
1H), 4.63 (brs, 1H), 4.41 (d, J = 13.3 Hz, 1H), 3.26 (d, J =
11.2 Hz, 1H), 3.15 (m, 1H), 2.75 (d, J = 15.4 Hz, 1H), 2.65
(d, J = 16.2 Hz, 1H), 2.11 (s, 3H), 2.04 (d, J = 6.6 Hz, 3H),
1.44−1.88 (m, 4H), 0.81 (dt, J = 7.2 Hz, 24.8 Hz, 3H). MS
(ESI, ev): m/z = 312.40 [M + H]+.
4.21 (brs, 1H), 3.02−3.16 (m, 2H), 2.70−2.88 (m, 4H),
1.90−2.04 (m, 2H), 1.58−1.60 (m, 2H), 1.53 (s, 9H), 1.46 (s,
9H), 0.88 (t, J = 7.4 Hz, 3H). MS (ESI, ev): m/z = 412.41
[M + H]+.
2,6-Diamino-7-hydroxy-4,5,6,7-tetrahydrobenzothiazole
(3-7). To a suspension of 2-3 (21.6 g, 103 mmol) in
methanol (216 mL), cooled to 0 °C, was added NaBH4
(3.13g, 83 mmol) in portions. The reaction mixture was
stirred for 90 min at 20−23 °C. When the starting material
had disappeared, Pd/C (10 wt %, 2.16 g) was added after the
atmosphere was changed to N2. Then the mixture was
subjected to H2. The Pd/C catalyst was removed by filtration,
and the filtrate was concentrated to afford a solid. The solid
was washed with cold methanol to give 3-7. The structural
data for 3-7 were identical to those reported in the
literature.17
tert-Butyl ((6S,7R)-2-Acetamido-6-(N-propylacetamido)-
4,5,6,7-tetrahydrobenzothiazol-7-yl)((S)-6-((tert-
butoxycarbonyl)(propyl)amino)-4,5,6,7-tetrahydrobenzo-
thiazol-2-yl)carbamate (3-2). To a solution of 3-3 (20.0 g,
64.3 mmol) in THF (50 mL) were added PPh3 (35.3 g, 134.7
mmol) and 4 (26.0 g, 63.2 mmol). The solution was cooled
to 0 °C, and DIAD (26.7 mL, 134.7 mmol) was added
dropwise. The reaction mixture was allowed to warm to room
temperature and stirred overnight. When TLC showed the
consumption of 4, the reaction mixture was concentrated
under vacuum and purified by column chromatography to
1
(6S,7S)-2,6-Diamino-7-hydroxy-4,5,6,7-tetrahydrobenzo-
thiazole D-Tartrate Salt (3-6). To a solution of D-tartaric acid
(7.51 g, 50 mmol) in water (10 mL) was added a solution of
3-7 (9.24 g, 50 mmol) in water (50 mL). The reaction
give 3-2 (16.7 g). H NMR (CDCl3, 400 MHz): δ 9.56 (brs,
1H), 5.44−5.56 (m, 1H), 4.80−4.95 (m, 2H), 3.07 (m, 4H),
2.50−2.90 (m, 6H), 2.16−2.30 (m, 4H), 1.92−2.10 (m, 6H),
1.53−1.66 (m, 4H), 1.31 (dd, J = 8.6 Hz, 14.2 Hz, 9H), 1.24
E
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(dt, J = 6.8 Hz, 12.4 Hz, 9H), 0.81−0.97 (m, 6H). MS (ESI,
ev): m/z = 705.93 [M + H]+.
113.37, 58.70, 54.06, 53.81, 48.70, 48.37, 28.26, 28.17, 24.97,
24.61, 23.33, 22.24, 22.06, 10.62, 10.58. MS (ESI, ev): m/z =
420.87 [M + H]+. HRMS (ESI+): calcd for C20H33N6S2 [M +
N-((6S,7R)-2-Amino-7-(((S)-6-(propylamino)-4,5,6,7-tetra-
hydrobenzothiazole-2-yl)amino)-4,5,6,7-tetrahydrobenzo-
thiazol-6-yl)-N-propylacetamide (3-1). To a solution of 3-2
(500 mg, 1.15 mmol) in methanol was added concentrated
HCl (4 mL), and the reaction mixture was refluxed at 95 °C.
The reaction was stopped when TLC indicated disappearance
of the starting material. The reaction mixture was concen-
trated to obtain the crude material, which was purified by
H]+ m/z = 421.2203; found 421.2192. HPLC for 3: tR
=
13.85 min, 94.6% purity.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.6b00182.
1
column chraomatography to give 3-1. H NMR (DMSO-d6,
Spectra and data for the compounds listed in the
Experimental Section (PDF)
400 MHz): δ 7.56 (dd, J = 9.4 Hz, 71.2 Hz, 1H), 6.75 (d, J =
22.1 Hz, 2H), 4.87 (d, J = 71.2 Hz, 1H), 3.85 (d, J = 9.9 Hz,
1H), 2.94−3.14 (m, 3H), 2.86 (d, J = 11.1 Hz, 1H), 2.69 (t, J
= 7.3 Hz, 2H), 2.58 (d, 16.5 Hz, 1H), 2.30−2.49 (m, 4H),
2.06 (brs, 4H), 1.82−1.94 (m, 2H), 1.60−1.76 (m, 2H), 1.52
(dt, 7.0 Hz, 13.9 Hz, 4H), 0.90 (t, J = 7.4 Hz, 3H), 0.81 (dt, J
= 7.3 Hz, 22.5 Hz, 3H). 13C NMR (DMSO-d6, 100 MHz):
170.25, 167.93, 146.75, 144.87, 144.73, 117.87, 117.44, 60.23,
55.39, 54.08, 52.40, 47.96, 29.48, 28.29, 25.28, 23.26, 22.81,
22.66, 22.27, 21.90, 12.04. MS (ESI, ev): m/z = 463.06 [M +
H]+. HRMS (ESI+): calcd for C22H25ON6S2 [M + H]+ m/z =
463.2308; found 463.2296.
AUTHOR INFORMATION
Corresponding Author
■
*Fax: +86-21-20231000-2407. Telephone: +86-21-2023100-
2407. E-mail: jiangxiangrui@simm.ac.cn.
Author Contributions
∥T.H. and F.Y. contributed equally to this work. The
manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
N,N′-((6S,7S)-7-Hydroxy-4,5,6,7-tetrahydrobenzothiazol-
2,6-diyl)dipropionamide (3-11). 3-11 was prepared from 3-5
with propionyl chloride following the procedure described for
Notes
The authors declare no competing financial interest.
1
the synthesis of 3-3. H NMR (CDCl3, 400 MHz): δ 11.97
ACKNOWLEDGMENTS
(s, 1H), 9.82 (brs, 1H), 6.35 (d, J = 8.5 Hz, 1H), 4.83 (d, J =
3.4 Hz, 1H), 4.22−4.29 (m, 1H), 2.64−2.77 (m, 2H), 2.51
(q, J = 7.5 Hz, 2H), 2.28 (q, J = 7.5 Hz, 2H), 1.90−2.02 (m,
2H), 1.24 (t, J = 7.5 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H). MS
(ESI, ev): m/z = 298.26 [M + H]+.
■
We gratefully acknowledge financial support from the Science
and Technology Commission of Shanghai Municipality
(14431905500) and the National Natural Science Foundation
of China (81273366).
tert-Butyl ((S)-6-((tert-Butoxycarbonyl)(propyl)amino)-
4,5,6,7-tetrahydrobenzothiazol-2-yl)((6S,7R)-2,6-dipropiona-
mido-4,5,6,7-tetrahydrobenzothiazol-7-yl)carbamate (3-10).
3-10 was prepared from 3-11 following the procedure
ABBREVIATIONS
DIAD, diisopropyl azodicarboxylate; DCM, dichloromethane
■
1
described for the synthesis of 3-2. H NMR (CDCl3, 400
REFERENCES
■
MHz): δ 9.80 (brs, 1H), 7.75 (d, J = 55.1 Hz, 1H), 5.44 (brs,
1H), 4.96 (brs, 1H), 4.59 (brs, 1H), 2.57−2.90 (m, 3H), 2.49
(q, J = 7.6 Hz, 2H), 2.18−2.34 (m, 3H), 2.01 (d, J = 4.7 Hz,
2H), 1.83 (brs, 2H), 1.64 (brs, 4H), 1.42 (d, J = 5.0 Hz, 2H),
1.28 (dd, J = 7.5 Hz, 15.1 Hz, 18H), 1.22 (t, J = 7.6 Hz, 3H),
1.19 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H). MS (ESI,
ev): m/z = 691.83 [M + H]+.
(1) Perez-Lloret, S.; Rey, M. V.; Ratti, L.; Rascol, O. Expert Rev.
Neurother. 2011, 11, 925−935.
(2) Liyanage, S. H. Aging Health 2010, 6, 155−157.
(3) Ishibashi, K.; Ishii, K.; Oda, K.; Mizusawa, H.; Ishiwata, K. PLoS
One 2011, 6, e17723.
(4) Koffarnus, M. N.; Collins, G. T.; Rice, K. C.; Chen, J.; Woods,
J. H.; Winger, G. Behav. Pharmacol. 2012, 23, 331−338.
(5) Kano, O.; Ikeda, K.; Kiyozuka, T.; Iwamoto, K.; Ito, H.;
Kawase, Y.; Sato, R.; Fujioka, T.; Araki, Y.; Baba, S.; Iwasaki, Y.
Neuropsychiatr. Dis. Treat. 2008, 2008, 707−710.
(6S,7R)-N7-((S)-6-(Propylamino)-4,5,6,7-tetrahydrobenzo-
thiazol-2-yl)-4,5,6,7-tetrahydrobenzothiazole-2,6,7-triamine
(3-8). 3-8 was prepared from 3-10 following the procedure
(6) Sprenger, F.; Poewe, W. CNS Drugs 2013, 27, 259−272.
(7) Schattschneider, J.; Bode, A.; Wasner, G.; Binder, A.; Deuschl,
G.; Baron, R. J. Neurol. 2004, 251, 977−982.
1
described for the synthesis of 3-1. H NMR (CD3OD, 300
MHz): δ 5.29−5.38 (m, 1H), 3.56−3.64 (m, 1H), 3.05−3.16
(m, 1H), 2.55−2.86 (m, 3H), 2.16−2.35 (m, 2H), 1.95−2.15
(m, 3H), 1.66−1.90 (m, 2H), 1.51−1.65 (m, 2H), 1.41 (t, J =
9.3 Hz, 2H), 0.89 (t, J = 6.9 Hz, 3H). MS (ESI, ev): m/z =
379.56 [M + H]+.
(8) Brindani, F.; Vitetta, F.; Gemignani, F. Clin. Interventions Aging
2009, 4, 305−313.
(9) Oertel, W. H.; Stiasny-Kolster, K.; Bergtholdt, B.; Hallstrom, Y.;
̈
Albo, J.; Leissner, L.; Schindler, T.; Koester, J.; Reess, J. Mov. Disord.
2007, 22, 213−219.
(6S,7R)-N6-Propyl-N7-((S)-6-(propylamino)-4,5,6,7-tetra-
hydrobenzothiazol-2-yl)-4,5,6,7-tetrahydrobenzothiazole-
2,6,7-triamine (3). 3 was prepared from 3-8 following the
procedure described for the synthesis of 3-4. 1H NMR
(CD3OD, 400 MHz): δ 4.75 (d, J = 5.9 Hz, 1H), 3.16 (brs,
1H), 2.92−3.03 (m, 2H), 2.75−2.86 (m, 3H), 2.44−2.69 (m,
6H), 2.17 (d, J = 5.4 Hz, 2H), 1.72−1.91 (m, 2H), 1.64 (dd,
J = 7.6 Hz, 15.1 Hz, 2H), 1.56 (dd, J = 8.1 Hz, 14.3 Hz, 2H),
1.01 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR
(CD3OD, 100 MHz): 169.54, 167.29, 146.36, 144.04, 116.10,
(10) Ferinistrambi, L. Sleep. Med. 2002, 3, S23−S25.
(11) Jama, L.; Hirvonen, K.; Partinen, M.; Alakuijala, A.; Hublin,
C.; Tamminen, I.; Koester, J.; Reess, J. Sleep Med. 2009, 10, 630−
636.
(12) Lin, S. C.; Kaplan, J.; Burger, C. D.; Fredrickson, P. A. Mayo
Clin. Proc. 1998, 73, 497−500.
̌
(13) Zivec, M.; Anzic, B.; Gobec, S. Org. Process Res. Dev. 2010, 14,
1125−1129.
(14) Griss, G.; Schneider, C.; Hurnaus, R.; Kobinger, W.; Pichler,
L.; Bauer, R.; Mierau, J.; Hinzen, D.; Schingnitz, G. Tetrahydro-
F
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
benzothiazoles, their production and their use as intermediates or
drugs. European Patent 0186087, 1985.
(15) Vemic, A.; Malenovic, A.; Rakic, T.; Kostic, N.;
Jancicstojanovic, B.; Ivanovic, D.; Medenica, M. J. Braz. Chem. Soc.
2012, 23, 2084−2092.
(16) Nishimura, E.; Kugimiya, A.; Naoki, H.; Hamanaka, N. Bioorg.
Med. Chem. Lett. 2012, 22, 2951−2953.
(17) Schneider, C. S.; Mierau, J. J. Med. Chem. 1987, 30, 494−498.
́ ́
(18) Gego, C.; Fejes, I.; Garaczi, S.; Kovacs, I.; Lukacs, F.;
̈
Majercsik, O.; Schneider, G. Process for producing pramipexole.
European Patent 1878731, 2008.
(19) Jia, G.; Li, Z.; Li, J.; Zou, J.; Yang, Y. Method for preparing N-
(aminothiomethyl)-5-oxo-1-propyl-2-pyrrolidineacetamide. Chinese
Patent 103012233, 2013.
(20) Wu, S.; Tong, Y.; Yang, Q.; Deng, Y.; Wang, C.; Ge, J.; Jiang,
X.; Zhao, T.; Zhao, D.; Hu, S. Synthesis method for pramipexole
dihydrochloride related substance B. Chinese Patent 103724291,
2014.
(21) Shin, I.; Lee, M. R.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. J. Org.
Chem. 2000, 65, 7667−7675.
(22) Varasi, M.; Walker, K. A. M.; Maddox, M. L. J. Org. Chem.
1987, 52, 4235−4238.
G
DOI: 10.1021/acs.oprd.6b00182
Org. Process Res. Dev. XXXX, XXX, XXX−XXX