Industrial scale-up of enantioselective hydrogenation for the asymmetric synthesis of rivastigmine

Article abstract of DOI:10.1021/op3003147

Two efficient processes for the synthesis of rivastigmine, one of the most potent drugs for the treatment of mild-to-moderate dementia of the type presenting in Alzheimer's disease, has been developed. Of particular note is the processes used for the asymmetric hydrogenation by applying the highly efficient chiral spiro catalyst, Ir-SpiroPAP. The first route was easy to scale up in industry and provided the commercial intermediate (S)-3-(1- dimethylaminoethyl)phenol, 6, which is suitable for the manufacture of rivastigmine in active pharmaceutical ingredient (API) demand. The second route was convenient for operation and purification and completed the synthesis of rivastigmine (1) in four steps and 84% overall yield.

Full text of DOI:10.1021/op3003147

Communication
pubs.acs.org/OPRD
Industrial Scale-Up of Enantioselective Hydrogenation for the
Asymmetric Synthesis of Rivastigmine
Pu-Cha Yan,† Guo-Liang Zhu,† Jian-Hua Xie,‡ Xiang-Dong Zhang,† Qi-Lin Zhou,‡ Yuan-Qiang Li,†
Wen-He Shen,† and Da-Qing Che*,†
†Zhejiang Jiuzhou Pharmaceutical Co., Ltd., 99 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province 318000, P.R. China
‡State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P.R. China
racemic mixture of 3-(1-dimethylaminoethyl)phenol (6),6,12
ABSTRACT: Two efficient processes for the synthesis of
rivastigmine, one of the most potent drugs for the
treatment of mild-to-moderate dementia of the type
presenting in Alzheimer’s disease, has been developed.
Of particular note is the processes used for the asymmetric
hydrogenation by applying the highly efficient chiral spiro
catalyst, Ir-SpiroPAP. The first route was easy to scale up
in industry and provided the commercial intermediate (S)-
3-(1-dimethylaminoethyl)phenol, 6, which is suitable for
the manufacture of rivastigmine in active pharmaceutical
ingredient (API) demand. The second route was
convenient for operation and purification and completed
the synthesis of rivastigmine (1) in four steps and 84%
overall yield.
that is time-consuming and labour intensive when run in
standard batch reactors. Foulkes, M. et al.13 at Novartis recently
reported an improved process by using a Ru-catalyzed
enantioselective hydrogenation of m-hydroxyacetophenone
(2) in degassed isopropanol to access optically pure alcohol
intermediate 3 with 98% ee and 85% yield after crystallization
at a ratio of substrate to catalyst (S/C) of 10,000. Further
transformation of 3 afforded (S)-3-(1-dimethylaminoethyl)-
phenol (6). Finally, the treatment of 6 with N-ethyl-N-methyl
carbamoyl chloride in the presence of base furnished the free
base of 1. In this report, we present an efficient, economical,
and suitable for scale-up process by applying a highly efficient
and stable chiral spiro-iridium catalyst developed by Zhou et
al.14 to produce of rivastigmine on kilogram scale.
RESULTS AND DISCUSSION
■
INTRODUCTION
■
The new iridium catalysts with chiral tridentate spiro ligands,
SpiroPAP, have proved to be extremely efficient for the
asymmetric hydrogenation of ketones, especially for the
acetophenone derivatives, TON up to 4,550,000.14 m-
Hydroxyacetophenone (2) was chosen as the starting material,
as it is commercially available and inexpensive. Rivastigmine (1)
can be synthesized through two different routes starting from 2
by applying catalyst Ir-SpiroPAP in asymmetric hydrogenation
as the key technology (Scheme 1, Route A, and Scheme 2,
Route B).
Alzheimer’s disease (AD) is the most common form of
dementia, a severe human health threat with more than 30
million sufferers worldwide.1 Rivastigmine, (S)-3-[1-
(dimethylamino)ethyl]phenyl ethyl (methyl) carbamate (1),
represents one of the most potent drugs for the treatment of
mild-to-moderate dementia of the Alzheimer’s type.2 In
addition, it is supposed to be effective in the treatment of
mild-to-moderate dementia related to Parkinson’s disease3 and
Lewy bodies.4 In 2006, it has been used in more than 6 million
patients worldwide. Clinical trials proved that the (S)-
enantiomer exhibits the desired cholinesterase inhibition,
which requires the drug in enantiomerically pure form.5 Its
tartrate salt is marketed under brand name Exelon.
To date, several methods for the synthesis of enantiomeri-
cally pure rivastigmine have been reported. Initial approaches
have been developed via resolution of racemates using various
chiral acids6 and copper-catalyzed addition of Me2Zn to
aldimine.7 Recent approaches are based on lipase-catalyzed
kinetic resolution,8 chemoenzymatic asymmetric synthesis,9 and
diastereoselective reductive amination.10 Transition metal-
catalyzed asymmetric transfer hydrogenation has also been
applied to the synthesis of rivastigmine,11 but the catalyst
loading was usually very high (10 mol % to 0.05 mol %). All of
these methods have certain drawbacks, such as complex
sequential operations, trace impurities of metals, or multiple
crystallization steps involving diastereomeric salts.
Route A is shown in Scheme 1. We initially carried out the
hydrogenation of 2 under conditions previously optimized for
the reaction of acetophenone (Ir-(S)-SpiroPAP-3-Me, S/C =
5000, S/B = 50, 10 atm H2, 25−30 °C).14 However, only 33%
conversion was obtained within 48 h (Table 1, entry 1). We
attributed the deactivation of catalyst to the acidity of the
phenolic hydroxy group in the substrate. When more than one
equivalent base (B/S = 1.06) was used, the hydrogenation
reaction could be completed smoothly within 2 h, giving (R)-3
in 95% ee (Table 1, entry 2). The reaction rate could be
accelerated by raising the reaction temperature to 50 °C, and
full conversion was obtained within 1 h without loss of
enantioselectivity (Table 1, entry 3). Screening of bases (Table
t
t
1, entries 4−7) revealed that both BuOK and BuONa (Table
1, entries 3 and 5) could provide 100% conversion and high ee.
t
Although the solubility of BuONa in ethanol was poor than
tBuOK, we chose tBuONa in the further studies taking the price
Currently, there is still no efficient large-scale production
method through asymmetric synthesis of rivastigmine. The
disclosed processes mostly rely on a kinetic resolution of a
Received: November 4, 2012
© XXXX American Chemical Society
A
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a
Scheme 1. Route A for the synthesis of rivastigmine
a
t
Reagents and conditions: (a) H2, Ir-(S)-SpiroPAP-3-Me, BuONa, EtOH, 50 °C; (b) MsCl, Et3N, THF, 0 °C; (c) Me2NH, THF, 0−20 °C; (d)
30% aq NaOH, 90 °C; (e) K2CO3, N-ethyl-N-methyl carbamoyl chloride, ethyl acetate, reflux.
a
Table 1. Laboratory studies of asymmetric hydrogenation of ketone 2
b
c
d
e
entry
ketone 2 (g)
S/C
base (B/S )
temp. (°C)
time (h)
conv. (%)
ee (%)
f
1
2
3
4
5
6
7
0.68
0.68
0.68
0.68
0.68
0.68
0.68
6.8
5000
5000
tBuOK (0.02)
tBuOK (1.06)
tBuOK (1.06)
KOH (1.06)
tBuONa (1.06)
EtONa (1.06)
MeONa (1.06)
tBuONa (1.06)
tBuONa (1.06)
tBuONa (1.06)
25
25
50
50
50
50
50
50
50
50
48
2
33
100
100
100
100
100
100
100
100
100
n.d.
95 (R)
95 (R)
92 (R)
95 (R)
96 (R)
95 (R)
96 (R)
97 (R)
97 (R)
5000
1
5000
10
1
5000
5000
3
5000
5
g
8
50000
100000
100000
8
g
9
13.6
50
24
24
b
g
10
a
c
Conditions: catalyst Ir-(S)-SpiroPAP-3-Me prepared in EtOH, PH = 10 atm unless otherwise noted. Substrate to catalyst ratio. Base to substrate
2
d
e
f
g
1
ratio. Determinde by H NMR ananlysis. Determined by HPLC on a chiral OD-H column. n.d. = not determined. PH = 30 atm (initial).
2
of tBuOK into account which was about 4 times as expensive in
comparison to that of BuONa. When the catalyst loading was
entry 10), the process was carried out for the first pilot batch
(Table 2, entry 1).15 Ultimately the premade catalyst was used
in the remaining pilot batches (Table 2, entries 2−4) and
provided a total of 51.7 kg of alcohol (R)-3 in 91−96% yield
with 96−97% ee. The ee value of 3 could be upgraded to >99%
by crystallization from ethyl acetate/heptanes.
t
lowered to 0.002 mol % (S/C = 50000), the hydrogenation
product (R)-3 was still obtained in 96% ee with 100%
conversion within 8 h under an initial hydrogen pressure of 30
atm (Table 1, entry 8). Lowering the catalyst loading further to
0.001 mol % (S/C = 100000), the reaction was completed
within 24 h, providing the product (R)-3 in 97% ee (Table 1,
entries 9 and 10).
Table 2. Pilot batches of asymmetric hydrogenation of
a
ketone 2
t
Although the reaction of 2 with BuONa was found to be
ketone 2
(kg)
time
(h)
yield
b
alcohol (R)-3
ee
(%)
purity
(area %)
t
c
c
almost not exothermic, dissolving BuONa in EtOH was
entry
(%)
(kg)
obviously exothermic. A procedure for the preparation of 3 was
1
2
3
4
5.0
12.5
12.5
25.0
30
24
24
20
96
92
95
91
4.9
11.7
12.0
23.1
96
97
97
96
97.8
98.1
98.6
98.3
developed which allowed operation safely on large scale. By
t
adding BuONa slowly to an ethanol solution of 2 at 0−5 °C,
while controlling the reaction temperature allowed for it to be
t
performed safely on scale-up. When BuONa was completely
a
dissolved, this solution was transferred to autoclave followed by
addition of the Ir-(S)-SpiroPAP-3-Me catalyst for hydro-
genation. After a final demonstration in the lab (Table 1,
Conditions: catalyst Ir-(S)-SpiroPAP-3-Me prepared in EtOH, PH
=
2
b
t
30 atm, 50 °C, 1.06 equiv BuONa, 12 vol EtOH. Isolated yield.
Determined by HPLC on a chiral OD-H column.
c
B
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With the alcohol (R)-3 in hand, the synthesis of 6 was
completed in a three-step process (Scheme 1). Both hydroxyl
groups on alcohol (R)-3 was mesylated by adding meth-
anesulfonyl chloride dropwise in the presence of Et3N in THF
at 0 °C. After addition, a slurry was formed and the stirring was
continued for one hour at 15−20 °C to ensure that the
mesylation was completed. The resulting compound 4 was used
directly in the subsequent reaction. Compound 4 was treated
with dimethylamine at 0−20 °C to afford 5 in >90% yield.
Upon complete consumption of 4, the previously formed amine
salt and other byproducts were removed by aqueous workup,
and the organic extracts were distilled in vacuo resulting a
yellow oil which was subjected to hydrolysis with 30% aqueous
NaOH solution. The hydrolysis was performed at 90 °C with
rapid stirring for 2−5 h, the initially biphasic solution became a
clear, yellow monophasic solution. The pH of the resulting
solution was adjusted to 7.5 with 6 M aqueous HCl at 0 °C and
extracted with ethyl acetate. Ethyl acetate was distilled off and
the product (S)-3-(1-dimethylaminoethyl)phenol (6) was
isolated in 86% yield and >99% ee by crystallization from
ethyl acetate/heptane (Table 3, entry 1). Pilot-plant operation
was performed in three batches to provide 35 kg of (S)-3-(1-
dimethylaminoethyl)phenol (6) (Table 3, entries 2−4).
purification of 1 was achieved by simple extraction and washing
operations under different pH values. By route B, rivastigmine
(1) was obtained in 84% yield without loss in optical purity
from the intermediate 8.
CONCLUSION
■
In conclusion, we have developed two efficient processes for
the preparation of rivastigmine via asymmetric hydrogenation
using the highly efficient chiral spiro catalyst Ir-SpiroPAP. The
first route was easy to scale-up in industry and provided (S)-3-
(1-dimethylaminoethyl)phenol (6), which is a suitable
intermediate for the manufacture of rivastigmine in API
demand.16 The second route was convenient for operation
and purification, giving rivastigmine in four steps in 84% overall
yield. The presented method towards rivastigmine represents
the shortest route published to date.
EXPERIMENTAL SECTION
General. H and 13C NMR spectra were recorded on a
■
1
Bruker Ultrashield 400 Plus spectrometer at 400 and 100.6
MHz, respectively. Melting points were determined on an open
capillary apparatus and uncorrected. Chiral separations for ee
determinations were conducted on Chiracel OD-H, 4.6 mm ×
250 mm × 5 μm column on an Agilent 1200 series instrument.
Optical rotations were determined using a SG WZZ-2S
automatic polarimeter. Mass spectra were recorded on Agilent
6530 Accurate-Mass Q-TOF LC/MS spectrometer with ESI
resource. The purity of intermediate 6 was analysed by reverse
phase HPLC on a Waters e2695 instrument according to the
following conditions: column XDB-C18, 4.6 mm × 250 mm ×
3.5 μm; eluent A, 0.1% v/v trifluoroacetic acid in purified water;
eluent B, 0.1% v/v trifluoroacetic acid in acetonitrile; flow rate,
1.0 mL/min.; wavelength, 225 nm; column temperature, 30 °C;
injection volume, 20 uL; at t = 0 min, 5% eluent B; at t = 20
min, 65% eluent B; at t = 20.1 min, 5% eluent B; at t = 25 min,
5% eluent B. The catalyst Ir-(S)-SpiroPAP-3-Me was prepared
per the reported method.14 Anhydrous EtOH was freshly
distilled from calcium hydride. All reagents and solvents were
used as received without further purification unless otherwise
noted.
Table 3. Conversion of alcohol (R)-3 to (S)-3-(1-
a
dimethylaminoethyl)phenol (6)
ee of
(R)-3
(%)
ee of
alcohol
entry (R)-3 (kg)
yield
b
(S)-6
(kg)
(S)-6
purity
(area %)
c
d
(%)
(%)
1
2
3
4
0.0075
10
99.4
99.6
99.8
99.9
86
82
84
85
0.0077
9.8
99.9
99.9
99.9
99.9
99.5
99.7
99.8
99.8
10
15
10.0
15.2
a
b
c
Conditions: see Experimental Section. Isolated yield. Determined
d
by HPLC on a chiral OD-H column. Determined by HPLC on a
XDB-C18 column.
The final step in the sequence was the amidoesterification of
6 with 1.1 equiv N-ethyl-N-methyl carbamoyl chloride in the
presence of K2CO3 under reflux in ethyl acetate to afford
rivastigmine (1) in 90−95% isolated yield with >99% ee
(Scheme 1).
Route A. (R)-3-(1-Hydroxyethyl)phenol (3). To a solution
of m-hydroxyacetophenone (2) (12.5 kg, 91.8 mol) in
t
Route B. In order to avoid the use of a stoichiometric
anhydrous ethanol (147 L), was added BuONa (9.4 kg, 97.3
t
amount of BuONa in the asymmetric hydrogenation step, we
mol) in portions at 0−5 °C over 15 min, maintaining a
tried to perform the synthetic route B as shown in Scheme 2,
which is the process for the synthesis 1 in four steps via the
intermediate 8.
temperature less than 15 °C. The reaction mixture was then
t
warmed to 20 °C and agitated for 1 h until all of the BuONa
dissolved into solution. The resulting solution was charged to a
300-L autoclave via cannula, and an ethanol (10 L) wash was
used to rinse the charging lines into the autoclave. Nitrogen
purging was done twice, and the solution was stirred with N2
bubbling through for a total of 15 min. Then the catalyst Ir-(S)-
SpiroPAP-3-Me (920 mg, 0.92 mmol) was transferred by
Schlenk techniques as a solution in anhydrous ethanol (100
mL) into the autoclave. The autoclave was then purged with
hydrogen (0.3 MPa, six times), and then pressurized with
hydrogen to 3.0−3.2 MPa. The reaction was agitated at 50−55
°C until the hydrogen uptake ceased, signifying the reaction
was complete (about 24 h). After the reaction mixture cooled
to 20 °C, hydrogen pressure was released, and the mixture was
purged with N2. The reaction mixture was distilled under
reduced pressure. To the resulting residue was added 3 M HCl
(33 L, 99 mol) and ethyl acetate (90 L) at 0−5 °C, followed by
The route B involved the condensation of m-hydroxyaceto-
phenone (2) with 1.1 equiv N-ethyl-N-methyl carbamoyl
chloride in ethyl acetate in the presence of K2CO3 as base to
give 7. After simple aqueous workup and extraction, the crude 7
was subjected to hydrogenation with the catalyst Ir-(S)-
t
SpiroPAP-3-Me. With 0.04 equiv BuONa and 0.001 mol %
catalyst, the hydrogenation of 7 proceeded smoothly at 50 °C
under 30 atm of H2 pressure and completed in 18 h, providing
the product 8 in 96% yield and >98% ee. Following distillation
of the solvent EtOH and with an aqueous workup, the organic
extracts were distilled into THF, and the solution was subjected
to mesylation with methanesulfonyl chloride in the presence of
Et3N. The resulting suspension was used directly in the
subsequent nucleophilic substitution with dimethylamine in
portions at 0−20 °C to afford 1. It is noteworthy that
C
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a
Scheme 2. Route B for the synthesis of rivastigmine
a
t
Reagents and conditions: (a) K2CO3, N-ethyl-N-methyl carbamoyl chloride, ethyl acetate, reflux; (b) H2, Ir-(S)-SpiroPAP-3-Me, BuONa, EtOH,
50 °C; (c) MsCl, Et3N, THF, 0 °C; (d) Me2NH, THF, 0−20 °C.
a
solution was cooled to 0 °C, and methanesulfonyl chloride
(19.9 kg, 173.8 mol) was added over 3 h, maintaining the
temperature <5 °C. The resulting suspension was agitated for 1
h further at 15−20 °C. The entire reaction solution was
vacuum purged, and dimethylamine gas was backfilled at 0−5
°C. The suspention was agitated at 15−20 °C for 16 h with
complementarity of dimethylamine in portions until complete
conversion to amino-methanesulfonate 5 by TLC monitoring.
Water (50 L) was added to dissolve the salts, and the resulting
solution was distilled under vacuum to remove THF. Ethyl
acetate (100 L) was then added followed by agitation, and the
layers were separated. The aqueous phase was removed, and
the organic layer was washed with water (50 L). The organic
phase was distilled under reduced pressure to remove ethyl
acetae. An aqueous solution of NaOH (40 kg, 30 wt %, 300
mol) was added to the residue, and the resulting biphasic
solution was heated to 90 °C and held for 3 h with rapid
agitation. A clear, yellow, monophasic solution was obtained
and was cooled to 0 °C. Ethyl acetate (100 L) and 6 M HCl
(37 L, 222 mol) were added to the cooled mixture until pH =
7.5, and after a few minutes of vigorous stirring the phases were
separated. The retained aqueous layer was extracted with ethyl
acetate (80 L × 3). The combined ethyl acetate layers were
distilled to a residual volume of 20 L at 80 °C, and then
heptane (50 L) was added slowly over 0.5 h. The resulting
slurry was granulated for 1 h; the temperature was then
adjusted to 20 °C at a rate of 1 °C/min, and the slurry
granulated overnight. The crystals were isolated by filtration,
washed with ethyl acetate/heptanes (1:5 (v/v), 10 L), and then
dried at 50 °C under vacuum to give (S)-3-(1-
dimethylaminoethyl)phenol (6) (9.8 kg, 82% yield, 99.9% ee)
as a white solid. Mp 115−116 °C; Chiracel OD-H, n-hexane/
IPA/DEA = 97:3:0.1, 1.0 mL/min, 35 °C, 277 nm UV detector,
tR = 10.89 min for (R)-6 and tR = 12.80 min for (S)-6. 1H NMR
(400 MHz, CDCl3): δ 9.11 (br s, 1H), 7.13 (t, J = 7.8 Hz, 1H),
Table 4. Asymmetric hydrogenation of ketone 7
b
c
entry ketone 7 (g) time (h) yield (%)
alcohol (R)-8 (g) ee (%)
1
2
3
4
15.5
22.1
22.1
36.5
18
20
16
20
96
97
96
98
15.0
21.6
21.4
36.1
98.2
98.7
98.4
98.4
a
Conditions: catalyst Ir-(S)-SpiroPAP-3-Me prepared in EtOH, PH
=
2
b
t
30 atm, 50 °C, 0.04 equiv BuONa, 3 vol EtOH. Isolated yield.
c
Determined by HPLC on a chiral OD-H column.
agitation for 1 h, and then the layers were separated. The lower
aqueous layer was extracted with ethyl acetate (70 L × 2). The
organic layers were combined and concentrated to dryness (50
°C/15 mmHg) to give crude 3 (12.0 kg, 95% yield, 97% ee) as
a pale-yellow solid. The crude 3 was dissolved in ethyl acetate
(35 L) at 70 °C. To the solution was added n-heptane (17.5 L)
over a 30-min period, and then the solution was cooled to 25
°C. The mixture was stirred for 5 h at ambient temperature and
cooled to 0−10 °C for 3 h. The precipitate was collected by
filtration and dried under vacuum at 50 °C to give 3 (10.8 kg,
85% yield, 99.8% ee) as an off-white solid. Mp 117−119 °C;
Chiracel OD-H, n-hexane/IPA = 90:10, 1.0 mL/min, 35 °C,
220 nm UV detector, tR = 11.72 min for (R)-3 and tR = 12.92
min for (S)-3. 1H NMR (400 MHz, CD3OD): δ 7.12 (t, J = 7.8
Hz, 1H), 6.82−6.80 (m, 2H), 6.67−6.65 (m, 1H), 4.74 (q, J =
6.8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CD3OD): δ 159.2, 150.0, 131.2, 118.6, 115.8, 114.1, 71.6, 26.4;
HRMS (ESI) calcd for [M + NH4, C8H14NO2]+: 156.1025,
Found 156.1037.
(S)-3-(1-Dimethylaminoethyl)phenol (6). To a 300-L glass-
lined reactor was added (R)-3-(1-hydroxyethyl)phenol (3)
(10.0 kg, 72.4 mol, 99.6% ee), THF (135 L), and Et3N (18.3
kg, 180.8 mol) under nitrogen. Stirring was continued at 20 °C
for 15 min before cooling down to 0 °C. After 0.5 h, the
D
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6.78−6.70 (m, 3H), 3.33 (q, J = 6.8 Hz, 1H); 2.23 (s, 6H), 1.40
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.3,
143.8, 129.7, 119.8, 115.8, 115.5, 66.0, 43.0, 19.4; HRMS (ESI)
calcd for [M + H, C10H16NO]+: 166.1232, Found 166.1233.
(S)-3-(1-(Dimethylamino)ethyl)phenyl ethyl(methyl)-
carbamate (1). To a 50-L glass-lined reactor was added (S)-
3-(1-dimethylaminoethyl)phenol (6) (3.3 kg, 20 mol, 99.9%
ee), K2CO3 (4.0 kg, 28.9 mol), ethyl acetate (27 L), and N-
ethyl-N-methyl carbamoyl chloride (2.6 kg, 21.4 mol) under
nitrogen. Ethyl acetate (1 L) was used as a line wash. The
resulting suspension was then warmed to reflux, and the batch
was agitated at this temperature for 3−5 h. After cooled to
room temperature, water (15 L) was added and the batch was
agitated for a further 0.5 h. The phases were separated, and the
aqueous layer was extracted with ethyl acetate (10 L × 2). The
combined ethyl acetate layers were distilled to a residual
volume of 10 L under vacuum, and then 3 M HCl (6.8 L, 20.4
mol) was added at 0 °C, and following agitation, the layers were
separated. The ethyl acetate phase was discarded. The acidic
aqueous phase was washed with ethyl acetate (5 L × 2), and
then it was basified by an aqueous solution of NaOH (2.8 kg,
30 wt %, 21 mol) at 0 °C. The resulting aqueous solution was
extracted with ethyl acetate (15 L × 3). The organic phases
were combined and concentrated to dryness (40 °C/15
mmHg) to give (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl-
(methyl)carbamate (1) (4.6 kg, 92% yield, 99.9% ee) as a pale-
yellow oil. Chiracel OD-H, n-hexane/EtOH/TFA/DEA =
92:8:0.2:0.1, 1.0 mL/min, 35 °C, 215 nm UV detector, tR =
was done twice, and the solution was stirred with N2 bubbling
through for a total of 15 min. Then the catalyst Ir-(S)-
SpiroPAP-3-Me (100 mg, 0.1 mmol) was transferred by
Schlenk techniques as a solution in anhydrous ethanol (15
mL) into the autoclave. The autoclave was then purged with
hydrogen (0.3 MPa, 6 times), and then pressurized with
hydrogen to 3.0−3.2 MPa. The reaction was agitated at 50−55
°C until the hydrogen uptake ceased, signifying reaction
completion (about 18 h). After the reaction mixture cooled to
20 °C, hydrogen pressure was released, and the mixture was
purged with N2. The reaction mixture was distilled under
reduced pressure to remove ethanol. To the resulting residue
was added water (5 L) and ethyl acetate (6 L). HCl (3 M, 66.7
mL, 0.2 mol) was added at 10 °C to adjust the pH to 7. After
0.5 h, the layers were separated. The lower aqueous layer was
extracted with ethyl acetate (4 L × 2). The organic phases were
combined and concentrated to dryness (50 °C/15 mmHg) to
give (R)-3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate (8)
(1.04 kg, 94% yield, 98.4% ee) as a pale-yellow oil. Chiracel
OD-H, n-hexane/IPA = 95:5, 1.0 mL/min, 35 °C, 220 nm UV
detector, tR = 18.37 min for (S)-8 and tR = 21.51 for (R)-8. 1H
NMR (400 MHz, CDCl3): δ 7.26 (t, J = 7.6 Hz, 1H), 7.11−
7.07 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 4.71 (q, J = 6.4 Hz,
1H), 3.68 (br s, 1H), 3.39 (dq, J = 6.8, 33.6 Hz, 2H), 2.97 (d, J
= 41.6 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.18 (dt, J = 6.8, 25.2
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 154.6 (d), 151.4,
147.9 (d), 129.0, 122.3, 120.3, 118.8, 69.4, 44.0, 34.2, 33.8, 25.0,
13.2, 12.4; HRMS (ESI) calcd for [M + K, C12H17KNO3]+:
262.0846, Found 262.0848.
1
14.51 min for (R)-1 and tR = 22.32 min for (S)-1. H NMR
(400 MHz, CDCl3): δ 7.29 (d, J = 8.0 Hz, 1H), 7.12−7.00 (m,
3H), 3.43 (dq, J = 7.2, 24.0 Hz, 2H), 3.24 (q, J = 6.8 Hz, 1H),
3.02 (d, J = 29.6 Hz, 3H), 2.20 (s, 6H), 1.36 (d, J = 6.8 Hz,
3H), 1.21 (dt, J = 7.2, 20.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 154.8 (d), 151.8, 146.0, 129.1, 124.5, 121.0, 120.5,
65.9, 44.3, 43.4, 34.4, 34.0, 20.3, 13.5, 12.7; HRMS (ESI) calcd
for [M + H, C14H23N2O2]+: 251.1760, Found 251.1765.
Route B. 3-Acetylphenyl Ethyl(methyl)carbamate (7). To
a 50-L glass-lined reactor was added m-hydroxyacetophenone
(2) (3.4 kg, 25 mol), K2CO3 (4.8 kg, 34.7 mol), ethyl acetate
(30 L), and N-ethyl-N-methyl carbamoyl chloride (3.3 kg, 27.1
mol) under nitrogen. Ethyl acetate (1 L) was used as a line
wash. The resulting suspension was then warmed to reflux, and
the batch was agitated at this temperature for 3−5 h. After the
batch cooled to room temperature, water (15 L) was added,
and the batch was agitated for a further 0.5 h. The phases were
separated, and the aqueous layer was extracted with ethyl
acetate (6 L × 2). The organic phase was combined and
concentrated to dryness (40 °C/15 mmHg) to give 3-
acetylphenyl ethyl(methyl)carbamate (7) (5.3 kg, 95% yield)
(S)-3-(1-(Dimethylamino)ethyl)phenyl ethyl(methyl)-
carbamate (1). To a 50-L glass-lined reactor was added (R)-
3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate (8) (893.1
g, 4 mol, 98.4% ee), THF (8 L), and Et3N (566.7 g, 5.6 mol)
under nitrogen. Stirring was continued at 20 °C for 15 min
before cooling down to 0 °C. After 0.5 h, the solution was
cooled to 0 °C, and methanesulfonyl chloride (550.0 g, 4.8
mol) was added over 1 h, while maintaining the temperature <5
°C. The resulting suspension was agitated for a further 1 h at
15−20 °C. The entire reaction solution was vacuum purged,
and dimethylamine gas was backfilled at 0−5 °C. The
suspension was agitated at 15−20 °C for 16 h with a
complementarity of dimethylamine in portions until complete
conversion to (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl-
(methyl)carbamate (1) by TLC monitoring. Water (5 L) was
added to dissolve the salts, and the resulting solution was
distilled under vacuum to remove the THF. Ethyl acetate (5 L)
was then added, and following agitation, the layers were
separated. The aqueous phase was removed, and the organic
layer was washed by water (3 L). To the organic layer was then
added 3 M HCl (1.5 L, 4.5 mol) at 0 °C, and following
agitation, the layers were separated. The ethyl acetate phase was
discarded. The acidic aqueous phase was washed with ethyl
acetate (1.5 L × 2) and then basified by an aqueous solution of
NaOH (640 g, 30 wt %, 4.8 mol) at 0 °C. The resulting
aqueous solution was extracted with ethyl acetate (4 L × 3).
The organic phases were combined and concentrated to
dryness (40 °C/15 mmHg) to give (S)-3-(1-(dimethylamino)-
ethyl)phenyl ethyl(methyl)carbamate 1 (901.2 g, 90% yield,
98.2% ee) as a pale-yellow oil. Chiracel OD-H, n-hexane/
EtOH/TFA/DEA = 92:8:0.2:0.1, 1.0 mL/min, 35 °C, 215 nm
UV detector, tR = 14.46 min for (R)-1 and tR = 22.23 min for
(S)-1. 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.0 Hz, 1H),
7.12−7.00 (m, 3H), 3.43 (dq, J = 7.2, 24.0 Hz, 2H), 3.24 (q, J =
1
as a pale-yellow oil. H NMR (400 MHz, CDCl3): δ 7.78 (d, J
= 7.6 Hz, 1H), 7.70 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.35−7.33
(m, 1H), 3.44 (dq, J = 7.2, 29.2 Hz, 2H), 3.04 (d, J = 34.4 Hz,
3H), 2.59 (s, 3H), 1.22 (dt, J = 7.2, 23.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 197.4, 154.3 (d), 151.9, 138.5, 129.6,
126.8 (d), 125.2 (d), 121.7 (d), 44.3 (d), 34.4, 34.0, 26.8, 13.4,
12.6; HRMS (ESI) calcd for [M+Na, C12H15NNaO3]+:
244.0950, Found 244.0956.
(R)-3-(1-Hydroxyethyl)phenyl ethyl(methyl)carbamate (8).
To a 10-L autoclave was charged 3-acetylphenyl ethyl(methyl)-
carbamate (7) (1.1 kg, 5 mol) and anhydrous ethanol (2.8 L).
To the resulting solution was added a solution of tBuONa (19.2
g, 0.2 mol) in anhydrous ethanol (0.2 L) over 10 min,
maintaining a temperature less than 20 °C. Nitrogen purging
E
dx.doi.org/10.1021/op3003147 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
temperature (60−70 °C) was also investigated; it showed that no
decomposition occurred during this strength reaction condition and
gave the same result as from the best conditions. Also, there was no
obvious heat generation observed under 3.0−3.2 MPa at 50−55 °C on
kilogram-scale run. The reaction was run under very safe conditions at
a well-protected facility.
6.8 Hz, 1H), 3.02 (d, J = 29.6 Hz, 3H), 2.20 (s, 6H), 1.36 (d, J
= 6.8 Hz, 3H), 1.21 (dt, J = 7.2, 20.8 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 154.8 (d), 151.8, 146.0, 129.1, 124.5, 121.0,
120.5, 65.9, 44.3, 43.4, 34.4, 34.0, 20.3, 13.5, 12.7; HRMS (ESI)
calcd for [M + H, C14H23N2O2]+: 251.1760, Found 251.1765.
(16) The residual metal in API was analysed by ICP, and showed the
residual Ir metal in API is 1.3 ppm.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dqche@zbjz.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Xiang Jun Wang and Xiao Guang Qu for analytical
support; Li Jun Yang, Xian You Zhou, and all the pilot-plant
operators and analysts are thanked for large-scale support; Wei
Lin Ruan is thanked for process safety work throughout the
project.
REFERENCES
■
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F
dx.doi.org/10.1021/op3003147 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX