A novel synthesis of rasagiline via a chemoenzymatic dynamic kinetic resolution

Article abstract of DOI:10.1021/op500152g

A novel synthetic route for preparing rasagiline mesylate is presented using a dynamic kinetic resolution (DKR) as the key step, catalyzed by Candida antarctica lipase B (CALB) and a Pd nanocatalyst. The chiral intermediate (R)-2,3-dihydro-1-indanamine was obtained through the DKR of the racemic aminoindan rac-1 in high yield (>90%) and excellent enantioselectivity (>99% ee). The process could be conducted on a 73 g scale at 200 g/L. Rasagiline mesylate was synthesized in 25% overall yield and excellent enantioselectivity (99.9% ee) over 7 steps.

Full text of DOI:10.1021/op500152g

Article
pubs.acs.org/OPRD
A Novel Synthesis of Rasagiline via a Chemoenzymatic Dynamic
Kinetic Resolution
†
†
†
†
‡
‡
†
Guozhen Ma, Zhongqi Xu, Pengfei Zhang, Jinpo Liu, Xilin Hao, Jingping Ouyang, Ping Liang,
,†
,‡
Song You,* and Xian Jia*
†School of Life Sciences & Biopharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016,
China
‡
Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education,
Shenyang 110016, China
*
S Supporting Information
ABSTRACT: A novel synthetic route for preparing rasagiline mesylate is presented using a dynamic kinetic resolution (DKR) as
the key step, catalyzed by Candida antarctica lipase B (CALB) and a Pd nanocatalyst. The chiral intermediate (R)-2,3-dihydro-1-
indanamine was obtained through the DKR of the racemic aminoindan rac-1 in high yield (>90%) and excellent
enantioselectivity (>99% ee). The process could be conducted on a 73 g scale at 200 g/L. Rasagiline mesylate was synthesized in
25% overall yield and excellent enantioselectivity (99.9% ee) over 7 steps.
7
i
INTRODUCTION
et al. developed a pathway to rasagiline by using (R)-N-benzyl-
-indanamine intermediate resolved with L-(+)-tartaric acid
(
■
1
The demand of optically pure compounds is increasing in the
pharmaceutical, fine chemicals, and agrochemical industries in
recent years. Currently, the production of optically active
intermediates is relying more and more on biocatalysis
8a
Scheme 1 B). Colyer et al. reported an asymmetric synthesis of
the key chiral intermediate of rasagiline using a asymmetric
induction (Scheme 1C). Some disadvantages of these existing
methods are the 50% loss of yield due to the drawback of the
kinetic resolution process, severe reaction conditions such as
high-pressure catalytic hydrogenation, and the use of the costly
chiral auxiliary reagents9.
1
processes. Of the conventional methods to synthesize
enantiomerically pure molecules, kinetic resolution (KR) is
one of the most practical ways in pharmaceutical industry;
however, the one major limitation of this technique is that the
maximum theoretical conversion cannot exceed 50%. Dynamic
kinetic resolution (DKR), which combines KR with in situ
racemization of the undesired enantiomer, has the potential to
overcome this problem, and then theoretically 100% of the
racemic mixture can be converted to one enantiomer. The DKR
has been used in the synthesis of several chiral drugs, for instance,
Recently, Kim et al. disclosed a DKR process for primary
benzyl amines with a Pd nanocatalyst in the presence of CALB;
good chemical yields with high enantiomeric excess was
achieved, and their excellent work inspired us. We were
interested in exploring the possibility of improving upon the
current state for the synthesis of rasagiline by taking advantage of
the high selectivity of nano palladium-enzyme catalysis, which
may bypassing the limitation of a classical kinetic resolution by
converting the slow-reacting enantiomer to the fast reacting one.
Herein we report a practical process for the enantioselective
synthesis of rasagiline via a DKR. The chemo-enzymatic DKR
method was utilized in the enantio-determining step of the
synthetic route, and this process could be conducted in a
concentration of up to 200 g/L in lab which has the potential to
scale up for a commercial process.
2
3
4
5
duloxetine, odanacatib, roxifiban, and lamivudine, et al.
Parkinson’s disease (PD)the most prevalent neurodegener-
ative disorderaffects 6.3 million people worldwide today.
Rasagiline ((R)-N-propargyl-1-aminoindan, Figure 1) is an
Figure 1. Structures of rasagiline and its chiral synthetic precursor (R)-1.
RESULTS AND DISCUSSION
■
Rac-1 was obtained starting from the readily available material 3-
phenylpropionic acid through three steps: intramolecular
Friedel−Crafts acylation, oxime formation, and catalytic hydro-
genation (Scheme 2). Rac-1 was then reacted with butanedioic
acid to give a salt, which is more stable and suitable for storage.
Rac-1 was converted to the enantiomerically pure amide (R)-2 by
irreversible, selective monoamine oxidase (MAO) B inhibitor
6
for the treatment of PD. Several methods have been reported for
the synthesis of rasagiline, and most of them introduced the
chiral aminoindan motif via resolving the correct isomer from a
7
8
racemic mixture or by asymmetric synthetic methodologies.
7d
Allegrini et al. disclosed a process for preparation of
rasagiline which involves an efficient two-step pathway to
racemic N-propargyl-1-aminoindan and utilized a late-stage
kinetic resolution with L-(+)-tartaric acid (Scheme 1A). Gutman
Received: May 13, 2014
Published: September 19, 2014
©
2014 American Chemical Society
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Organic Process Research & Development
Article
Scheme 1. Synthetic routes to rasagiline
Scheme 2. Synthesis of rac-1
a
using our DKR process. The amide was hydrolyzed to give (R)-
Table 1. Kinetic resolution of 2,3-dihydro-1-indanamine
2
,3-dihydro-1-indanamine ((R)-1), and finally, a propargyl group
b
b
temperature
time
(h)
conv.
(%)
ee
was introduced via a nucleophilic alkynylation to give rasagiline.
entry
(°C)
enzyme:substrate
(%)
E
The lipase from Candida antarctica and the Pd nanocatalyst
9,10
1
2
3
4
5
6
7
50
60
70
80
70
70
70
1:1.2
1:1.2
1:1.2
1:1.2
1:1.6
1:2.4
1:1.2
6
6
6
6
6
6
9
15.7
20.1
43.4
48.7
42.7
41.6
50.4
99.5
97.9
97.5
94.8
96.7
97.2
95.1
375
were picked as the chemo-enzymatic catalyst.
antarctica lipase B (CALB) gene was cloned and overexpressed
The C.
226
173
116
178
175
145
11
in methylotrophic yeast Pichia pastoris. The crude enzymes
were directly immobilized utilizing Lewatit VP OC 1600 resin
without further purification. The activity and selectivity of the
immobilized CALB toward the resolution of primary benzyl
amines had been examined in the KR of (±)-1-phenylethyl-
amine, which using isopropyl 2-methoxyacetate as an acyl
a
Conditions: 2 mmol of (rac)-1, 2 mL of toluene, reacted under N
2
b
1
2
atmosphere. Measured by chiral HPLC.
donor.
First, the enzymatic KR process toward Rac-1 was studied
using isopropyl 2-methoxyacetate as an acyl donor (Scheme 3).
also observed that the conversion of substrate was increased with
the elevation of temperature; however, the ee value deteriorated
correspondingly, which we attribute to the effect of higher
temperatures on the selectivity of the enzyme. When the reaction
time was prolonged to 9 h, around 50% conversion of the
substrate was observed; however, the ee decreased to 95.1%.
The Pd nanocatalyst, Pd/AlO(OH), was chosen as the
racemising reagent for the amine which proceeds via an imine
intermediate state (Scheme 4). Pd/AlO(OH) was prepared as
Scheme 3. KR of rac-1
Scheme 4. Racemization of (S)-1
This ester produced good results in our earlier experiments, and
no other ester was examined. The effects of temperature and the
ratio of enzyme to substrate were studied. The results
demonstrated that the ee value decreased with the increase of
the conversion. The best result occurred where the desired
product was obtained at 43.4% yield with 97.5% ee (Table 1). We
1
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palladium nanoparticles entrapped in aluminum hydroxide
according to Kim’s method. The activity of the Pd nanocatalyst
desired product in 85% yield, and the ee of the product was
improved to >99% through recrystallization.
9
was monitored by the enantiomeric excess (ee) of (S)-2,3-
dihydro-1-indanamine during the racemization procedure. This
demonstrated the high activity of the Pd nanocatalyst. The
racemization was completed in 3 h in the presence of 1 mol % of
Pd in toluene at 70 °C (Table 2, entry 3), and when the
temperature decreased, the racemization time was prolonged
correspondingly.
The application of DKR to (±)-2,3-dihydro-1-indanamine
(rac-1) has been investigated for the multigram scale as well
under these optimized reaction conditions. When 40 g of rac-1 at
a substrate concentration of 200 g/L was run, 87.5% conversion
yield and 95.7% ee were obtained (Table 3, entry 2). This process
Table 3. Investigation of DKR on multigram scale for rac-1
weight of rac-1 (g)
a
Table 2. Racemization of (S)-2,3-dihydro-1-indanamine
[concentration/
1
c
d
ce
ee , (%)
entry
of rac-1 (g·L− )]
conv. (%)
yield (%)
b
entry amount of catalyst (mol %) temperature (°C) time (h) ee (%)
a
1
30 (150)
40 (200)
60 (300)
73 (200)
88.2
87.5
70
81.6
80.1
62.3
80.1
97.6 (99)
1
2
3
4
5
1
50
60
70
70
70
6
6
3
4
6
35
12
3
a
2
95.7 (98.9)
94.1 (96.8)
96.7 (99.2)
1
a
3
1
b
4
87.6
0.5
0.1
4
a
Conditions: 10 g of CALB, 15 g of Pd nanocatalyst, 10 g of Na CO ,
.5 equiv of acyl donor, 50 °C for 12 h. Conditions: 18.3 g of CALB,
2
3
7
b
1
a
b
Conditions: 2 mmol of (S)-1, 2 mL of toluene. Measured by chiral
HPLC.
27.5 g of Pd nanocatalyst, 18.3 g of Na CO , 1.5 equiv of acyl donor,
2 3
c d
50 °C for 12 h. Measured by chiral HPLC. Calculated by weight.
e
Measured after purification.
was repeated on a scale of 73 g at the same concentration of 200
g/L. However, when the concentration was increased to 300 g/L,
both the activity and the enantioselectivity of the catalyst were
inhibited, and the yield dropped.
We were pleased to observe that the activity of the chemo-
enzymic catalyst still maintained its relatively high activity and
enantioselectivity even after 9−10 recycles (Table 4). However,
The DKR efficiency for the desired enantiomer can be
dramatically improved by the combination of a selective kinetic
13
resolution process matched with a fast racemization. We
investigated the relationship between the amount of Pd
nanocatalyst charged in the racemization and the reaction
speed. We found that the racemization could completed in 4 h
even using only 0.5 mol % of Pd in toluene at 70 °C (Table 2,
8
entry 4), which is only half of the charge in the literature. This
Table 4. Investigation of recycling times of immobilized
suggests the rates of KR and racemization are compatible with
each other, leading to a good DKR.
a
CALB and Pd nanocatalyst
b
c
b
The above individual studies and data indicated that a DKR
strategy may be suitable for the preparation of (R)-1. We
supposed that the optimal condition for a successful DKR
employing CALB and Pd nanocatalyst can be carried out at a
temperature above 70 °C. However, the yield and the ee value of
the amide decreased with time, and about 25% (calculated by
peak area) of byproduct formed mainly due to the effect of the
crude enzyme. Some miscellaneous proteins were generated
during the course of overexpression. HPLC only poorly separates
the byproducts, and we were unsuccessful in separating and
identifying these by impurities. We believe they consist of
miscellaneous proteins derived from the crude enzyme and
byproducts caused by the reaction of the proteins with the imine
intermediate during the racemization at the higher temperatures.
After the studies on the effects of the reaction temperature in
our chemoenzymatic system, a modified DKR process was
determined to be optimum (Scheme 5). The byproducts were
kept to a minimum at 50 °C. Under the optimized reaction
conditions, the conversion yield of rac-1 to the desired product
was over 90% within 12 h, and only 5% HPLC A% of byproducts
formed. The amide was isolated and recrystallized to give the
entry
recycling times
conv. (%)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1
98.9
98.8
98.9
98.7
97.1
96.2
94.1
91.7
88.8
85.7
83.2
90.6
90.4
90.5
89.7
88.2
86.6
85.3
83.6
82.1
79.0
76.8
99.1
98.9
99.0
98.8
98.1
97.3
96.4
95.8
95.1
93.3
91.0
2
3
4
5
6
7
8
9
1
1
0
1
10
11
a
Conditions: 4 g of (rac)-1, 1 g of CALB, 1.5 g of Pd nanocatalyst, 1 g
of Na CO , 1.5 equiv of acyl donor, 20 mL of toluene, 50 °C for 12 h.
Measured by chiral HPLC. Calculated by weight.
2
3
b
c
for useful results, it appears that 5−6 recycles is a practical limit
for acceptable quality product. The recovered catalyst should be
used directly; otherwise, it should be stored under the protection
of nitrogen gas. Since no significant change in the catalyst’s
appearance was observed, we strongly suggest the user should
test the activity of the catalyst in a small scale of substrate after the
catalyst has been reused 5 times.
Scheme 5. DKR of rac-1
The ee value of the amide could be upgraded through
crystallization; over 99% ee could be obtained via crystallization
from amide of 97−98% ee. For the amide of 95−97% ee, two
recrystallizations were required.
By hydrolyzing the amide in triethanolamine with 40% NaOH,
the aminoindan (R)-1 was formed in over 76.2% yield with 99%
ee, followed by nucleophilic alkynylation with propargyl bromide
1
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at 30 °C to give rasagiline (R)-3 in 99.5% (w/w) purity with
mm, Daicel Chemical Industries) and a mobile phase of n-
hexanes/isopropanol (99:1, v/v) were used; the flow rate was 0.8
mL/min, the column temperature was set at 30 °C, and the UV
detection wavelength was 254 nm. The elution times were 13.0
9
9.9% ee. The amount of double alkylation byproduct was
decreased with the decrease in temperature; however, the
reaction time was prolonged as well, and therefore, 30 °C was
selected as the best compromise, and 59.7% yield was obtained.
The product was purified by forming the salt with butanedioic
acid.
1
min and 15.6 min for (S)-3 and (R)-3, respectively. H NMR
1
13
spectrum for (rac)-1 and HPLC, MS, IR, H, and C NMR
spectra for (R)-2 and (R)-4 are shown in the Supporting
Information.
CONCLUSION
In summary, we demonstrated a novel synthetic route for (R)-
rasagiline mesylate (Scheme 6). It is noteworthy that this new
Pd Nanocatalyst and CALB. Pd nanocatalyst was
■
9
synthesized according to a literature procedure. CALB was
prepared according to ref 11, and Lewatit VP OC 1600 resin (30
g) was added to the crude enzyme supernatant (100 mL). After
stirring at 28 °C for 24 h, the resin was filtered off, washed with
deionized water, and dried under vacuum until constant weight.
Scheme 6. Optimized synthesis of (R)-rasagiline mesylate
2
,3-Dihydro-1-indanamine (rac-1). Polyphosphoric acid
1000 g, 2.96 mol) was heated to 90 °C. 3-Phenylpropionic
acid (100 g, 0.67 mol) was added in portions. After stirring at 90
C for 30 min, the reaction mixture was added to 5000 mL of ice
(
°
water under vigorous stirring conditions and was cooled to room
temperature. The reaction mixture was extracted by dichloro-
methane (3000 mL/three times), and the combined organic
phase was washed by saturated aqueous sodium chloride solution
(
2000 mL/two times), dried over anhydrous sodium sulfate (50
g), and filtered. The solvent was removed by evaporation at 30
C under vacuum, leaving light-yellow crystals (86.4 g, yield:
°
9
8.2%).
To these crystals (86.4 g, 0.655 mol) were added 50% ethanol/
water solution (400 mL) followed by a solution of hydrox-
ylammonium chloride (69.0 g, 0.995 mol) in 50% ethanol/water
(
400 mL). The reaction mixture was heated to reflux, whereupon
aqueous sodium hydroxide (43 g, 1.08 mol in 196 mL deionized
water) was added over 15 min. After refluxing for 30 min, the
reaction mixture was cooled to room temperature. The
precipitated solid was filtered off, washed with deionized water
(
300 mL), and dried at 55 °C under vacuum until constant
weight to afford white needles (86.5 g, yield: 89.9%).
To these needles (86.5 g, 0.588 mol) were added ethanol (865
mL), followed by 10% Pd/C (5.9 g). The reaction mixture was
chemistry can be carried out under mild conditions and avoids
the waste of the undesired enantiomer or the use of the expensive
chiral auxiliary reagents. By employing the DKR method, (R)-1
was obtained in satisfactory yield and excellent enantioselectivity
in the enantio-determining step. We conducted the DKR
procedure of 2,3-dihydro-1-indanamine on a scale of 73 g in
the concentration of 200 g/L, which is indicative of a potential
commercial scale process once other aspects of the entire
operation are optimized.
heated at 70 °C under H atmosphere for 4 h. Pd/C was removed
2
by vacuum filtration. The filtrate was concentrated to dryness at
40 °C under vacuum to afford a colorless oily liquid (73.2 g, yield:
1
93.5%). Bp 96−98 °C/8 mmHg. H NMR (600 MHz, DMSO-
d ) (considering the stabilizing of the indanamine, proton NMR
6
data was detected with a succinate form) 7.49 (d, J = 7.3 Hz, 1H),
7.32−7.22 (m, 3H), 4.60 (t, J = 6.9 Hz, 1H), 3.01 (ddd, J = 15.9,
8.7, 4.7 Hz, 1H), 2.83 (ddd, J = 15.8, 8.4, 7.1 Hz, 1H), 2.43 (dtd, J
= 13.1, 8.1, 4.7 Hz, 1H), 2.27 (s, 4H), 1.89 (ddt, J = 13.2, 8.7, 6.7
Hz, 1H).
For the production of 1 kg of (R)-rasagiline mesylate, 1.65 kg
of rac-1 was needed. Therefore, 123.8 L of deionized water, 67.6
L of dichloromethane, 45.1 L of saturated aqueous sodium
chloride solution, 18.0 L of 50% ethanol/water solution, and 19.5
L of ethanol should be used in this step.
EXPERIMENTAL SECTION
General. KR, DKR, and racemization reactions were carried
■
out under dry nitrogen atmosphere using a standard Schlenk
1
4
technique. Dry toluene was obtained via distillation.
High-performance liquid chromatography (HPLC) analyses
were carried out with a JASCO LC-1500 system with a UV
detector. The conversion and ee values were determined by
chiral HPLC. For 2,3-dihydro-1-indanamine and its amide, a
Chiralpak OD-H chiral column (4.6 × 250 mm, Daicel Chemical
Industries) and a mobile phase of n-hexanes/isopropanol/
diethylamine (97:3:0.1, v/v) were used; the flow rate was 0.8
mL/min, the column temperature was set at 30 °C, and the UV
detection wavelength was 254 nm. The elution times were 9.3
min, 11.1 min, 12.6 min, and 21.1 min for (S)-1, (R)-1, (R)-2, and
General Procedure for KR. CALB (100 mg) and Na CO
2
3
(100 mg) were added to a vial. Rac-1 (0.14 g, 1 mmol) dissolved
in dry toluene (2 mL) was added to the vial, and the mixture was
stirred. After a few minutes, isopropyl 2-methoxyacetate (0.16 g,
1.2 mmol) was added to the reaction mixture. Samples for HPLC
analysis were collected with a syringe after 0.5, 2, 3, 4, 5, and 6 h.
General Procedure for Racemization. (S)-1 (13 mg, 0.10
mmol) was added to a suspension of Pd nanocatalyst (20 mg) in
dry and degassed toluene (1 mL). The reaction mixture was
stirred at 70 °C under nitrogen. After 1, 2, 3, 4, 5 and 6 h, the
(S)-2, respectively. For rasagiline, a Chiralpak AD-H (4.6 × 250
1
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reaction mixture was cooled to room temperature and collected a
sample for HPLC analysis.
0.335 mol) dissolved in ethyl acetate (200 mL) was added to the
filtrate to purify the product by forming a salt. After heating at
reflux for 1 h, the mixture was cooled to room temperature and
filtered. The residue was dissolved in deionized water (600 mL).
The pH was adjusted to 10 by saturated aqueous sodium
carbonate solution and extracted by ethyl acetate (600 mL/three
times). The organic phases were washed by saturated aqueous
sodium chloride solution (400 mL/two times), dried over
anhydrous sodium sulfate (15 g), and filtered. The solvent was
removed by evaporation at 30 °C under reduced pressure
remaining an oily liquid (34.2 g, yield: 59.7%, ee >99.9%).
For the production of 1 kg of (R)-rasagiline mesylate, 0.77 kg
of (R)-3 was needed. Therefore, 22.6 L of acetonitrile, 38.3 L of
deionized water, 45.1 L of ethyl acetate, and 22.5 L of saturated
aqueous sodium chloride solution should be used in this step.
(R)-N-(Prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine Me-
sylate ((R)-Rasagiline Mesylate, (R)-4). (R)-Rasagiline mesylate
General Procedure for DKR. CALB (100 mg), Na CO3
100 mg), and Pd nanocatalyst (200 mg) were added to a vial.
2
(
Rac-1 (0.14 g, 1 mmol) dissolved in dry toluene (2 mL) was
added to the vial, followed by isopropyl 2-methoxyacetate (0.16
g, 1.2 mmol). The reaction mixture was stirred under nitrogen
atmosphere. Samples for HPLC analysis were collected with a
syringe after 2, 4, 6, 8, 10, and 12 h.
Large-Scale DKR of 2,3-Dihydro-1-indanamine (rac-1). A
solution containing rac-1 (73.2 g, 0.55 mol), Pd nanocatalyst
(
27.5 g), CALB (18.3 g), sodium carbonate (18.3 g), and
isopropyl 2-methoxyacetate (108.9 g, 0.825 mol) in dry and
degassed toluene (366 mL) was stirred at 50 °C under nitrogen
atmosphere. After reacting for 12 h, the reaction mixture was
cooled to room temperature and filtered using filter paper. The
separated catalysts were washed with predried toluene. The
catalyst may be directly used for the next reaction or dried in
vacuum for 4 h under 50 °C and kept under nitrogen
atmosphere. The filtrate was concentrated, and the mixture
standing at 4 °C provided (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-
15
was prepared according to the procedure of Sathe. Rasagiline
(34.2 g, 0.2 mol) was dissolved in IPA (342 mL) under stirring. A
solution of methanesulfonic acid (0.25 mol, 24.3 g) in IPA (48
mL) was added dropwise to the above cooled solution. After
complete addition, the mixture was cooled to 5 °C and stirred for
30 min at 5−10 °C to get the white solid which was filtered and
1
methoxyacetamide ((R)-2) (90.3 g, yield: 80.1%, ee >99%); H
NMR (600 MHz, CDCl ) 7.29 (d, J = 7.2 Hz, 1H), 7.25 (s, 2H),
3
7
1
.23 (dd, J = 8.8, 4.9 Hz, 1H), 6.73 (s, 1H), 5.54 (q, J = 7.9 Hz,
H), 3.96 (s, 2H), 3.40 (s, 3H), 3.01 (m, 1H), 2.89 (m, 1H), 2.62
dried to furnish the product (R)-4. (44.38 g, yield: 83.1%, ee
1
>99.9%) H NMR (600 MHz, D
O) 7.55 (d, J = 7.7 Hz, 1H),
2
(
m, 1H), 1.84 (m, 1H).
7.52−7.41 (m, 2H), 7.36 (m, 1H), 5.01−4.93 (m, 1H), 3.97 (dd,
For the production of 1 kg of (R)-rasagiline mesylate, 2.03 kg
of (R)-2 was needed. Therefore, 8.2 L of toluene should be used
in this step.
J = 4.3, 2.6 Hz, 2H), 3.16 (m, 1H), 3.02 (m, 2H), 2.79 (d, J = 1.2
13
Hz, 3H), 2.63−2.52 (m, 1H), 2.27 (m, 1H). C NMR (600
MHz, D O) 148.14, 138.67, 133.20, 130.00, 128.52, 128.29,
2
(
R)-2,3-Dihydro-1-Indanamine ((R)-1). (R)-N-(2,3-Dihydro-
H-inden-1-yl)-2-methoxyacetamide ((R)-2) (90.3 g, 0.44 mol,
ee >99%) dissolved in triethanolamine (350 mL) was heated to
0 °C with stirring, whereupon 40% aqueous sodium hydroxide
220 mL) was added to the mixture over 15 min. The reaction
80.89, 76.15, 64.84, 41.32, 37.09, 32.48, 31.23.
For the production of 1 kg of (R)-rasagiline mesylate, 8.8 L of
IPA should be used in this step.
1
8
(
ASSOCIATED CONTENT
■
mixture was heated at reflux for 6 h. After cooling to the room
temperature, deionized water (2200 mL) was added to the
suspension with stirring, whereupon the remaining solution was
extracted by ethyl acetate (2400 mL/three times) and the
organic phases were washed by saturated aqueous sodium
chloride solution (1200 mL/two times), dried over anhydrous
sodium sulfate (50 g), and filtered. The solvent was removed by
evaporation at 30 °C under reduced pressure to leave an oily
liquid. The remaining oily liquid was distilled under reduced
pressure (9 mmHg). The distillation cut at 97−99 °C was
collected (44.6 g, yield: 76.2%, ee >99%).
*
S
Supporting Information
1
H NMR spectrum for (rac)-1; HPLC, MS, IR, H, and 13C
1
NMR spectra for (R)-2 and (R)-4. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Tel.: +86 24 23986456. E-mail: jiaxian206@163.com.
■
*Tel./Fax: +86 24 23986436. E-mail: yousong206@aliyun.com.
Author Contributions
G.-Z.M and Z.-Q.X. contributed equally to this study.
Notes
For the production of 1 kg of (R)-rasagiline mesylate, 1 kg of
R)-1 was needed. Therefore, 7.9 L of triethanolamine, 4.9 L of
0% aqueous sodium hydroxide, 49.6 L of deionized water, 54.1
(
4
The authors declare no competing financial interest.
L of ethyl acetate, and 27.0 L of saturated aqueous sodium
chloride solution should be used in this step.
ACKNOWLEDGMENTS
■
This work was supported by the Science and Technology
Research Projects, Ministry of Education of the People’s
Republic of China (213007A), Shenyang Municipal Scientific
and Technology Research Fund (F11-243-1-00, F13-316-1-17),
and Liaoning BaiQianWan Talents Program (No. 2012921035).
(
R)-N-(Prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine ((R)-
). Potassium carbonate (46.3 g, 0.335 mol) was added to a
solution of (R)-2,3-dihydro-1-indanamine (44.6 g, 0.335 mol, ee
99%) in acetonitrile (670 mL). Propargyl bromide (39.9 g,
.335 mol) dissolved in acetonitrile (335 mL) was added to the
reaction mixture with stirring at 30 °C. After stirring at 30 °C for
2 h, potassium carbonate was filtered off, whereupon
3
>
0
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