Ir/SpiroPAP Catalyzed Asymmetric Hydrogenation of a Key Intermediate of Montelukast: Process Development and Potential Impurities Study

Article abstract of DOI:10.1021/acs.oprd.5b00339

An efficient and robust process for the asymmetric hydrogenation of a key intermediate of Montelukast using the highly efficient and selective chiral spiro catalyst Ir/SpiroPAP is reported. The developed process was conducted at mild reaction temperature (30 °C) under a hydrogen pressure of 20 atm with low catalyst loading (S/C = 30000) and afforded the desired chiral alcohol intermediate in 99.5% ee. This process currently has been carried out at 30 kg scale. The process-related impurities (impurities I-V) were also identified, synthesized, and characterized by LC-MS and NMR techniques.

Full text of DOI:10.1021/acs.oprd.5b00339

Communication
pubs.acs.org/OPRD
Ir/SpiroPAP Catalyzed Asymmetric Hydrogenation of a Key
Intermediate of Montelukast: Process Development and Potential
Impurities Study
Guo-Liang Zhu,† Xiang-Dong Zhang,† Li-Jun Yang,† Jian-Hua Xie,‡,§ Da-Qing Che,†,§ Qi-Lin Zhou,‡,§
Pu-Cha Yan,*,† and Yuan-Qiang Li*,†
†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
§Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China
S
* Supporting Information
lectivity was developed as an alternative economical and simple
process to the (−)-DIP-Cl reduction.7f
ABSTRACT: An efficient and robust process for the
asymmetric hydrogenation of a key intermediate of
Montelukast using the highly efficient and selective chiral
spiro catalyst Ir/SpiroPAP is reported. The developed
process was conducted at mild reaction temperature (30
°C) under a hydrogen pressure of 20 atm with low catalyst
loading (S/C = 30 000) and afforded the desired chiral
alcohol intermediate in 99.5% ee. This process currently
has been carried out at 30 kg scale. The process-related
impurities (impurities I−V) were also identified, synthe-
sized, and characterized by LC-MS and NMR techniques.
The transition metal catalyzed asymmetric hydrogenation has
proved to be an efficient and economically feasible method for
preparing chiral compounds.8 However, there is still no efficient
large-scale process for asymmetric hydrogenation of ketone 4.
Researchers at Lonza5a used the [(R)-BINAP-RuCl2-(R)-
DAIPEN] system (up to S/C = 5000) to achieve the desired
transformation in 86% yield and up to 96.9% ee, though
chlorobenzene was used as the cosolvent. They also showed
that, under certain ruthenium- or iridium-catalyzed asymmetric
hydrogenantion conditions, the olefin-reduced compound is the
major product. A Ru-catalyzed asymmetric hydrogenation of a
related montelukast intermediate was reported by Fox et al.
earlier this year. Catalyst ((R)-Xyl-BINAP)((R,R)-DPEN)-
RuCl2 afforded an enantioselectivity of 99% ee in the
hydrogenation step on a multigram lab scale at S/C = 5000.9
Herein, we developed an economical and suitable for scale-up
process by applying a highly efficient, selective, and stable
catalyst Ir/SpiroPAP10 to obviate many previous problems and
limitations. Furthermore, a comprehensive study has been
undertaken to identify, synthesize and characterize five
impurities present in the hydrogenation of ketone 4 using
spectroscopic and spectrometric techniques.
INTRODUCTION
■
Montelukast sodium (Singulair) is a leukotriene receptor
antagonist (LTRA) developed by Merck & Co which is used
for the maintenance treatment of asthma and to relieve
symptoms of seasonal allergies.1 It acts as a selective antagonist
of the leukotriene D4 receptor which leads to the reduction of
bronchoconstriction and results in less inflammation.
The first and conventional process for production of
montelukast sodium (1) exploits commercially available alcohol
2 and thiol carboxylic acid 3 as starting materials (Scheme 1).2
Although its structure and consequently its synthesis is
complex, montelukast sodium has only a single stereocenter,
which is usually installed via asymmetric reduction of the bulky
and highly functionalized ketone 4. Various reduction method-
ologies have been developed for the preparation of optically
pure alcohol 5, including (−)-DIP-Cl3 or (R)-Me-CBS/borane4
reduction, transition metal catalyzed asymmetric hydrogena-
tion5 or transfer hydrogenation,6 and enzymatic or biomimetic
methods.7 The multiple functional groups in ketone 4 are labile
or sensitive to metal hydrides and/or hydrogenation conditions.
The widely used production process applied (−)-DIP-Cl as the
reduction reagent primarily because of its mild reaction
condition and selectivity. However, there are still shortcomings
associated with (−)-DIP-Cl reduction, such as corrosivity and
moisture sensitivity of the reagent, as well as poor atom
economy, tedious workup procedure, and heavy burden on the
waste treatment (at least 1.5−1.8 equiv is needed). Recently, a
KetoREDuctase (KRED) method with very high enantiose-
RESULTS AND DISCUSSION
■
The 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; the TON is up to 4 550 000.10a
Asymmetric Hygrogenation of 4. We initially carried out
the hydrogenation of 4 under similar conditions previously
optimized for the reaction of acetophenone (S/C = 2000, 0.04
equiv base, 15 atm H2, 30 °C). As indicated in Table 1, the
effects of ligands, solvents, and other reaction parameters on
reactivity and enantioselectivity were screened. Through a
preliminary comparison of various chiral SpiroPAP ligands, it
was found that introduction of an alkyl group at the 6- position
of the pyridine ring of the ligand reduced the enantioselectivity
Received: October 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.5b00339
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Communication
Scheme 1. Structure of Montelukast Sodium (1) and Installation of the Stereocenter
a
Table 1. Asymmetric Hydrogenation of Ketone 4 with Optimizing Reaction Conditions
b
c
d
entry
(R)-6
S/C
solvent (V/V)
EtOH
(5 + 5′):I:(II + III):IV:V (%)
time (h)
ee (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6b
6b
6b
6b
6b
6b
6b
6b
2000
2000
2000
2000
2000
2000
2000
2000
2000
2000
10000
30000
95.2:0:0.7:0.1:4.0
95.8:0:0.3:0.1:3.8
95.6:0:0.6:0.1:3.7
95.3:0:0.9:0.1:3.7
99.3:0:0.3:0:0.4
1
99.1
99.6
99.5
98.9
97.0
97.3
98.2
95.0
99.2
99.0
99.6
EtOH
0.5
1
EtOH
EtOH
1
MeOH
0.5
0.5
0.5
0.5
0.5
0.5
2
EtOH/DMF (5/1)
EtOH/Tol (5/1)
EtOH/DCM (5/1)
EtOH
91.4:2.2:2.0:0.1:4.3
93.8:1.7:0.4:0:4.1
87.7:0.2:4.1:0.2:7.8
90.2:0.5:5.5:0.6:3.2
88.6:1.2:6.4:0.1:3.7
96.0:0:0.3:0.1:3.6
95.6:0.1:0.5:0.1:3.7
e
9
f
10
EtOH
g
11
EtOH
g
12
EtOH
5
99.5
a
b
c
Reaction conditions unless otherwisely noted: 2.0 mmol scale, solvent (8.0 mL), 15 atm H2, 30 °C. Substrate to catalyst ratio. Determined by
d
HPLC analysis on a XDB-C8 column. Determined by HPLC analysis on a chiral AS-H column. The absolute configuration of 5 is S by comparing
the specific rotation with reported data. Reaction temperature was 50 °C. Reaction temperature was 70 °C. PH2 = 20 atm, 100 mmol scale.
e
f
g
(compare entry 4 with entry 1); however, the presence of an
alkyl group at either the 3- or 4-position of the pyridine ring
could increase the enantioselectivity (compare entries 2 and 3
with entry 1). The catalyst (R)-6b was the most efficient and
enantioselective catalyst; full conversion was obtained within 30
min and gave the product in 99.6% ee. We were pleased to find
that the byproducts with over reduction of the ethylene bridge
could be controlled to <1%. As the solubility of ketone 4 in
ethanol was extremely poor (∼1.4 g/L), other solvent systems
were tried in order to reduce the volume of solvent. Although
the solubility of ketone 4 in methanol was better than in
ethanol, the enantiomeric excess was reduced to 97% (Table 1,
entry 5). When cosolvent was used, the depression of
enantioselectivity had also been observed, and the impurities
increased (Table 1, entries 6−8). Solvent screening showed
that ethanol gave the best enantioselectivity. When the reaction
was performed at higher temperature, such as 50 or 70 °C, the
product was obtained with only a slightly lower enantiomeric
excess, but more impurities could be detected in the reaction
solution (Table 1, entries 9 and 10). When the catalyst loading
was lowered to 0.01 mol % (S/C = 10000), the hydrogenation
product (S)-5/5′ still could be obtained in 99.6% ee with full
conversion within 2 h under a hydrogen pressure of 20 atm
(Table 1, entry 11). Lowering the catalyst loading further to
0.0033 mol % (S/C = 30000), the reaction was completed
within 5 h, providing the product (S)-5/5′ in 99.5% ee (Table
1, entry 12).
During our initial development work, we were plagued with
inconsistent conversion under nominally identical conditions.
After some investigation, we find that this process is sensitive to
B
DOI: 10.1021/acs.oprd.5b00339
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Scheme 2. Formation and Structure of Potential Impurities
the purity of the substrate ketone 4, especially depends on the
remaining traces of palladium in ketone 4 from the former
coupling reaction.3a And careful refinement of ketone 4 was
necessary to ensure reproducibility of the hydrogenation
reaction.11 Therefore, we chose to conduct the large scale
experiments at S/C = 30 000 to ensure acceptable quality was
achieved. Further optimization of this step should focus on
reduction of the catalyst loading. The developed asymmetric
hydrogenation condition was applied on the large-scale
production for multiple batches (from 25 kg to a maximum
of 75 kg), and all gave the same results as from the lab scale.
Formation of Potential Impurities. In the aforemen-
tioned optimized reaction conditions, ethanol was the best
Overreduction of 5 and 5′ leaded to the ethane bridged
analogues impurity II and impurity III. The compounds 5 and
5′ were hydrolyzed to the corresponding acid (impurity IV)
under the basic condition when water existed.12 Another critical
impurity V was observed which lactonized from hydrogenation
products 5 and 5′. Although the reaction mixture seemed to be
complicated, it was pleasing to find that impurity V could be
transformed to product 5′ in the following workup steps. We
also examined the mixture of 5, 5′, and impurity V; all of these
compounds could react with MeMgCl to provide the same
product 2 in high yield. Typically, the hydrogenation reaction
was judged to be complete according to the HPLC analysis of
an aliquot, the total area % of 5, 5′, and impurity V was usually
>99%. After crystallization from an aqueous ethanol solvent
system, the monohydrates of (S)-5 and 5′ were obtained in
90−95% yield, >99.9% ee, and 99% chemical purity, which
were used to make Montelukast API (50 g), and the quality was
proved up to the USP 35 standard.
t
reaction solvent. The base BuOK is known to be critical as an
additive in the Ir/SpiroPAP catalyzed asymmetric hydro-
genation of ketone and ketone esters.10
Under the optimized reaction condition of asymmetric
hydrogenation of 4, it was found that the product was a mixture
of methyl and ethyl esters (5 and 5′) due to the occurrence of
ester exchange between the substance and the solvent. It was
obvious that the ratio of 5/5′ was dependent on the reaction
time, and the measured enantiomeric excess of 5 and 5′ was
almost the same. If the hydrogenation proceeded slowly, in
parallel to the hydrogenation, ketone 4 was subjected to
undesired reaction, namely, a intramolecular condensation
CONCLUSION
■
In conclusion, we have developed an efficient and robust
process for the asymmetric hydrogenation of a key intermediate
4 of Montelukast using the highly efficient and selective chiral
spiro catalyst Ir/SpiroPAP. The finalized process was
conducted at mild temperature (30 °C) under a hydrogen
pressure of 20 atm with low catalyst loading (S/C = 30 000)
and afforded the desired product 5 and 5′ in 99.5% ee. After
crystallization from an aqueous ethanol solvent system, the
monohydrates of (S)-5 and 5′ were obtained in 90−95% yield,
>99.9% ee, and 99% chemical purity, which were used to make
Montelukast API (50 g), and the quality was proved up to the
1
reaction that leads to impurity I (Scheme 2). In the H NMR
spectrum of this impurity, the singlet signal appearing at δ 3.56
ppm with two proton integration was evidence for the presence
of CH2 group in the indenol moiety. This was further
substantiated by the DEPT spectrum, which displayed a
methylene carbon signal (negative signal) at δ 33.97 ppm.
C
DOI: 10.1021/acs.oprd.5b00339
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Communication
USP 35 standard. Additionally, a comprehensive study has been
undertaken to identify, synthesize, and characterize five
impurities present in the hydrogenation of ketone 4. Further
optimization of this process should focus on reduction of the
catalyst loading.
136.1, 135.5, 135.3, 132.1, 131.1, 130.7, 129.7, 128.8, 128.7,
128.4, 128.0, 127.0, 126.5, 126.3, 126.0, 125.6, 124.8, 119.5,
73.1, 61.1, 41.4, 30.5, 14.3 ; HRMS (ESI) calcd for [M + H,
C29H27ClNO3]+: 472.1679, Found 472.1686.
Preparation of Impurity I. To the suspension of ketone 4
(9.1 g, 20 mmol) in 75 mL ethanol was added tBuOK (3.4 g, 30
mmol) at 0 °C, and the reaction mixture was stirred for 24 h.
The resultant slurry was filtrated. The cake was washed with 2
bed volumes ethanol and dried at 35 °C to afford impurity I as
EXPERIMENTAL SECTION
■
1
General. H and 13C NMR spectra were recorded on a
Bruker Ultrashield 400 Plus spectrometer at 400 and 100.6
MHz, respectively. Chiral separations for ee determinations of
the hydrogenation products 5 and 5′ were conducted on
Chiracel AS-H, 4.6 mm × 250 mm × 5 μm column on an
Agilent 1200 series instrument. Mass spectra were recorded on
Agilent 6530 Accurate-Mass Q-TOF LC/MS spectrometer with
ESI resource. An in-house HPLC (gradient mode) method was
developed for the analysis of the desired product and its
potential impurities (Agilent 1200 series HPLC device with
DAD detector) according to the following conditions: column
XDB-C8, 4.6 mm × 150 mm × 5 μm; eluent A, 0.2% (v/v)
acetic acid in purified water; eluent B, acetonitrile; flow rate, 1.0
mL/min; wavelength, 343 nm; column temperature, 30 °C;
injection volume, 10 μL; at t = 0 min, 60% eluent B; at t = 22
min, 82% eluent B; at t = 26 min, 98% eluent B; at t = 33 min,
98% eluent B; at t = 35 min, 60% eluent B, and this
composition was held to the end (overall time 40 min).
Anhydrous MeOH and EtOH was freshly distilled from
magnesium. All reagents and solvents were used as received
without further purification unless otherwise noted.
1
a yellow solid in 85% yield. H NMR (400 MHz, DMSO): δ
8.38 (d, J = 8.8 Hz, 1H), 8.10−7.89 (m, 5H), 7.66−7.56 (m,
3H), 7.46−7.22 (m, 6H), 3.56 (s, 2H). 13C NMR (100 MHz,
DMSO): δ 182.1, 157.0, 148.1, 145.4, 144.8, 136.5, 135.9,
134.2, 129.7, 129.3, 128.1, 127.9, 127.3, 127.2, 127.1, 126.5,
125.5, 125.5, 124.4, 121.1, 120.4, 106.3, 34.0; HRMS (ESI)
calcd for [M + H, C27H19ClNO2]+: 424.1104, Found 424.1110.
Preparation of Impurity II. To a 300 mL autoclave was
charged methyl ester 5 (9.2 g, 20 mmol) and anhydrous THF
(100 mL). To the resulting solution was added Raney-Ni (4.0
g, wet) and then purged with hydrogen (0.3 MPa, 3 times) and
then pressurized with hydrogen to 0.6−0.8 MPa. The reaction
was agitated at 30 5 °C until the hydrogen uptake ceased,
signifying reaction completion. After releasing the hydrogen
pressure, the mixture was filtered over Celite to remove Raney-
Ni, and the filtrate mother liquors was concentrated to dryness
in vacuo. The residual product thus obtained was purified by
crystallization from MeOH/H2O = 7/3 (v/v, 100 mL). After
drying at 50 °C, 8.2 g impurity II was obtained as monohydrate
1
in 90% yield. H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H),
Scale-up Hydrogenation Representative Procedure of
Ketone 4. To a 500 L autoclave was charged ketone 4 (30 kg,
65.8 mol) and anhydrous ethanol (240 L). To the resulting
7.96 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.63 (d, J =
8.8 Hz, 1H), 7.44−7.38 (m, 2H), 7.27−7.17 (m, 6H), 7.11 (d, J
= 7.2 Hz, 1H), 4.67−4.63 (m, 1H), 3.85 (s, 3H), 3.27−3.23 (m,
2H), 3.14−3.09 (m, 3H), 3.02−2.98 (m, 2H), 2.07−1.94 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 168.3, 163.0, 148.2,
145.0, 144.0, 141.3, 136.0, 135.2, 132.2, 131.1, 130.8, 129.3,
128.7, 128.4, 127.8, 127.5, 126.8, 126.1, 126.0, 125.1, 123.7,
121.8, 73.4, 52.1, 41.3, 40.8, 35.8, 30.5; HRMS (ESI) calcd for
[M + H, C28H27ClNO3]+: 460.1679, Found 460.1691.
t
slurry was added a solution of BuOK (295.3 g, 2.6 mol) in
anhydrous ethanol (5.2 L) over 5 min, maintaining a
temperature less than 20 °C. Nitrogen purging was done
twice, and the solution was stirred with N2 bubbling through
for a total of 15 min. Then the catalyst (R)-6b (2.2 g, 2.2
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, 5 times) and then
pressurized with hydrogen to 2.0−2.2 MPa. The reaction was
agitated at 25 5 °C until the hydrogen uptake ceased (8−10
h), signifying reaction completion. After releasing the hydrogen
pressure, the mixture was purged with N2. The reaction mixture
was added 1 M HCl (2.6 L, 2.6 mol) at 10 °C to adjust the pH
to 7. The solution was heated to 60 5 °C, and water (120 L)
was added slowly, during which time the product crystallized.
Preparation of Impurity III. To a stirred solution of impurity
t
II (2.8 g, 6 mmol) and ethanol (30 mL) was added BuOK
(337 mg, 3 mmol), and the reaction mixture was heated to 50
°C for 3 h. The reaction mixture was cooled to 25 °C and then
concentrated to dryness in vacuo. The residual product thus
obtained was purified through column chromatography using
ethyl acetate and hexanes (1:3, v/v) as eluent to afford impurity
III in 79% yield. 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H),
7.97 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.64 (d, J =
8.4 Hz, 1H), 7.44−7.39 (m, 2H), 7.27−7.17 (m, 6H), 7.11 (d, J
= 7.2 Hz, 1H), 4.66−4.63 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H),
3.27−3.23 (m, 2H), 3.14−3.10 (m, 3H), 3.05−2.98 (m, 2H),
2.04−1.95 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 168.0, 163.0, 148.2, 145.0, 143.8, 141.3, 136.0,
135.2, 132.1, 131.1, 130.7, 129.7, 128.7, 128.4, 127.8, 127.5,
126.8, 126.0, 126.0, 125.1, 123.6, 121.8, 73.3, 61.1, 41.3, 40.8,
35.8, 30.4, 14.3; HRMS (ESI) calcd for [M + H,
C29H29ClNO3]+: 474.1836, Found 474.1844.
Preparation of Impurity IV. To the stirred suspension of
ester 5 and 5′ (9.2 g, 20 mmol) in 50 mL MeOH was added 5
M NaOH (2.0 g, 50 mmol in 10 mL water) at 0 °C, and the
reaction mixture was heated to 50 °C and stirred for 5 h. The
reaction mixture was cooled to 25 °C and then concentrated to
dryness in vacuo. The resulting solid was resolved in CH2Cl2
and acidified with 3 M HCl inducing crystallization of the
The resultant slurry of product 5 and 5′ was cooled to 20
5
°C and aged for 3 h before filtration. The cake was washed with
two bed volumes of 1:2 mixture of water/ethanol. After drying,
29.6 kg of product 5 and 5′ were obtained as monohydrate in
94% yield, 99.9% ee as a pale yellow solid. Chiracel AS-H, n-
hexane/IPA = 85:15, 0.8 mL/min, 40 °C, 287 nm UV detector,
tR = 23.63 min for (S)-5 and tR = 18.14 for (R)-5; tR = 15.68
1
min for (S)-5′ and tR = 14.91 for (R)-5′. 5: H NMR (400
MHz, CDCl3): δ 8.12−8.09 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H),
7.74−7.64 (m, 4H), 7.53 (d, J = 7.2 Hz, 1H), 7.47−7.26 (m,
7H), 4.75 (t, J = 6.2 Hz, 1H), 3.90 (s, 3H), 3.19−3.06 (m, 3H),
2.14−2.08 (m, 2H); 5′: 1H NMR (400 MHz, CDCl3): δ 8.08−
8.05 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.70−7.60 (m, 4H),
7.50 (d, J = 7.2 Hz, 1H), 7.45−7.24 (m, 7H), 4.73 (t, J = 6.2
Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.37 (s, 1H), 3.18−3.06 (m,
2H), 2.14−2.07 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 168.1, 156.9, 148.5, 145.6, 143.7, 136.3,
D
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hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717,
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impurity IV, which was collected by filtration and rinsed with
further portion MeOH/water. After drying at 50 °C under
vacuum, the impurity IV, 7.8 g, was obtained as a yellow solid
in 88% yield. 1H NMR (400 MHz, CD3OD): δ 8.95 (d, J = 8.8
Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.32−8.19 (m, 3H), 7.88−
7.85 (m, 2H), 7.82 (s, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.58−7.42
(m, 4H), 7.30−7.25 (m, 2H), 4.74 (t, J = 6.4 Hz, 1H), 3.16−
3.08 (m, 1H), 3.04−2.97 (m, 1H), 2.07 (q, J = 7.2 Hz, 2H); 13C
NMR (100 MHz, CD3OD): δ 171.2, 155.5, 147.9, 147.3, 146.2,
144.9, 141.8, 140.0, 135.9, 133.0, 132.1, 131.9, 131.5, 131.3,
130.8, 130.4, 128.7, 127.5, 127.4, 127.1, 120.7 (d), 119.7, 74.3,
42.2, 31.8; HRMS (ESI) calcd for [M + H, C27H23ClNO3]+:
444.1366, Found 444.1360.
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Preparation of Impurity V. Impurity IV (6.7 g, 15 mmol)
and DMAP (3.7 g, 30 mmol) were charged to a round bottle,
followed by CH2Cl2 (100 mL). After the solution was stirred
for 15 min, DCC (4.1 g, 20 mmol) was added, and the reaction
mixture was stirred overnight at 25 °C. The undissolved
material was filtered off, followed by concentration of the
filtrate mother liquors to dryness in vacuo. The residual
product was purified through column chromatography using
ethyl acetate and hexanes (1:3, v/v) as eluent to afford impurity
1
V as an off-white solid in 92% yield. H NMR (400 MHz,
CDCl3): δ 8.12−8.06 (m, 2H), 7.79 (d, J = 7.2 Hz, 1H), 7.74−
7.70 (m, 3H), 7.63−7.54 (m, 3H), 7.46−7.30 (m, 6H), 5.13
(dd, J = 12.0, 4.4 Hz, 1H), 3.24−3.15 (m, 1H), 2.94−2.88 (m,
1H), 2.51−2.43 (m, 1H), 2.33−2.23 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 171.0, 156.6, 148.6, 139.6, 137.6, 136.7, 136.2,
135.5, 134.5, 132.9, 131.7, 130.2, 129.1, 129.0, 128.8, 128.7,
128.2, 127.6, 127.2, 127.1, 126.5, 125.7, 125.0, 119.7, 79.4, 36.5,
30.0; HRMS (ESI) calcd for [M + H, C27H21ClNO2]+:
426.1261, Found 426.1268.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.5b00339.
Copies of relevant NMR spectra and chromatograms
(PDF)
(8) (a) de Vries, J. G.; Elsevier, C. J. The Handbook of Homogeneous
Hydrogenation; Wiley-VCH: Weinheim, 2007. (b) Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029. (c) Xie, J.-H.; Zhou, Q.-L. Huaxue Xuebao
2012, 70, 1427.
(9) Bollikonda, S.; Mohanarangam, S.; Jinna, R. R.; Kandirelli, V. K.
K.; Makthala, L.; Sen, S.; Chaplin, D. A.; Lloyd, R. C.; Mahoney, T.;
Dahanukar, V. H.; Oruganti, S.; Fox, M. E. J. Org. Chem. 2015, 80,
3891.
(10) (a) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2011, 50, 7329. (b) Xie, J.-H.; Liu, X.-Y.; Yang,
X. H.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2012,
51, 201. (c) Xie, J.-H.; Zhou, Q.-L. Huaxue Xuebao 2014, 72, 778.
(d) Yang, X.-H.; Xie, J.-H.; Zhou, Q.-L. Org. Chem. Front. 2014, 1, 190.
(e) Yan, P.-C.; Zhu, G.-L.; Xie, J.-H.; Zhang, X.-D.; Zhou, Q.-L.; Li, Y.-
Q.; Shen, W.-H.; Che, D.-Q. Org. Process Res. Dev. 2013, 17, 307.
(f) Yan, P.-C.; Xie, J.-H.; Zhang, X.-D.; Chen, K.; Li, Y.-Q.; Zhou, Q.-
L.; Che, D.-Q. Chem. Commun. 2014, 50, 15987. SpiroPAP is the
abbreviation for Spiro Pyridine AminoPhosphine ligand.
(11) When the substrate with palladium was used, an incomplete
reaction and more impurities happened. In order to alleviate this issue,
the residual palladium in the substrate should be <10 ppm.
(12) When denature EtOH was used, the reaction proceeded slowly
or incompletely. Less than 0.1% water can be tolerated.
AUTHOR INFORMATION
■
Corresponding Authors
*Telephone: +86 571 87000701. Fax: +86 571 87000702. E-
mail: pcyan@zbjz.cn.
*E-mail: yqli@zbjz.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China (973 Program,
No. 2012CB821600), “111” Project of the Ministry of
Education of China (Grant No. B06005) for financial support.
REFERENCES
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DOI: 10.1021/acs.oprd.5b00339
Org. Process Res. Dev. XXXX, XXX, XXX−XXX