Process research on the asymmetric hydrogenation of a benzophenone for developing the manufacturing process of the squalene synthase inhibitor TAK-475

Article abstract of DOI:10.1021/op2001673

A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene synthase inhibitor TAK-475 (1), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7, employed Noyori's ruthenium precatalyst of the type [RuCl ₂(diphosphine)(diamine). We focused on tuning of the chiral diphosphine, and have discovered a novel ligand, DADMP-BINAP (18c), for the catalyst that has allowed reduction of the operating pressure in the asymmetric hydrogenation. The precatalyst containing 18c performed effectively at low hydrogen pressure (<1 MPa) with sufficient enantioselectivity, and the result enabled us to successfully obtain enantiomerically pure 8 on a multikilogram scale.

Full text of DOI:10.1021/op2001673

ARTICLE
pubs.acs.org/OPRD
Process Research on the Asymmetric Hydrogenation of a
Benzophenone for Developing the Manufacturing Process of the
Squalene Synthase Inhibitor TAK-475
Mitsutaka Goto,*,† Takahiro Konishi, Shinji Kawaguchi, Masatoshi Yamada, Toshiaki Nagata, and
Mitsuhisa Yamano
†Chemical Technology Department, Takeda Pharmaceutical Co. Ltd., 4720, Takeda, Mitsui, Hikari, Yamaguchi 743-8502, Japan
Chemical Development Laboratories, CMC center, Takeda Pharmaceutical Co. Ltd., 2-17-85, Juso-Honmachi, Yodogawa-ku,
Osaka 532-8686, Japan
S Supporting Information
b
ABSTRACT: A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene
synthase inhibitor TAK-475 (1), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7,
employed Noyori’s ruthenium precatalyst of the type [RuCl2(diphosphine)(diamine)]. We focused on tuning of the chiral
diphosphine, and have discovered a novel ligand, DADMP-BINAP (18c), for the catalyst that has allowed reduction of the operat-
ing pressure in the asymmetric hydrogenation. The precatalyst containing 18c performed effectively at low hydrogen pressure
(<1 MPa) with sufficient enantioselectivity, and the result enabled us to successfully obtain enantiomerically pure 8 on a
multikilogram scale.
’ INTRODUCTION
For asymmetric synthesis of the benzhydrol 8, an attempt
at enantioselective borohydride reduction of prochiral ben-
zophenone 7, using LiBH4 in the presence of a chiral
bimetallic Lewis acid, was conducted, but only moderate
enantioselectivity was obtained.7e An alternative enantio
selective reduction of 7 via β-hydride transfer with (ꢀ)-DIP-
Chloride achieved high enantioselectivity.13 The enantio-
selective hydrogenation of substituted benzophenones using
[RuCl2{(S)-xylbinap}{(S)-daipen}] (12b)14 as a Ru preca-
talyst has generally given excellent results in terms of cata-
lyst efficiency (Scheme 2).11d Moreover, this technology has
been applied to the synthesis of 8 using [RuCl2{(S)-
xylbinap}{(S,S)-dpen}] (13b)14 for large-scale preparation
and has achieved high enantioselectivity (80ꢀ90% ee) and
high catalyst efficiency (S/C = 1700).15
However, further improvement was needed for large-scale
production, especially with regards to the use of high pressure.
The fine-tuning approach for Ru precatalyst, [RuCl2{(S)-
xylbinap}{(S,S)-dpen}] (13b) was conducted for optim-
izing the diphosphine moiety, while the diamine moiety was
strictly optimized to DPEN. For the chiral diphosphine,
while there are numerous ligands, a few ligands (e.g., BINAP,16
MeOBIPHEP17) are known for general use. Thus, we conducted
modification of BINAP analogues to develop a fine-tuned Ru
precatalyst (13), which performed well under low hydrogen pres-
sure for asymmetric hydrogenation of 7, retaining enantioselectivity
TAK-475 (1)1 is a potent squalene synthase inhibitor and was
expected to be a good candidate to lower plasma cholesterol.2 In
cholesterol biosyntheses, the inhibition of squalene synthase is a
unique target to control cholesterol without inhibiting the
biosynthesis of biologically important isoprenoids. Therefore, it
was supposed that squalene synthase inhibitors might be free
from side effects and effective in the treatment of hyperlipemia.3
TAK-475 (1) has a 4,1-benzoxazepine core structure
(Scheme 1), which has been constructed by intramolecular
Michael addition followed by condensation of the N-alkylated
benzhydrol derivative 9 with a fumaric acid derivative.2,4 In this
reaction, the thermodynamically stable 3,5-trans-isomer 10 was
obtained diastereoselectively by the screening of appropriate
reaction conditions. Therefore, the development of an efficient
synthesis of the enantiopure benzhydrol 8 was a significant
challenge in order to achieve the asymmetric synthesis of 1.
The optical resolution of the acetylated rac-8 with esterase was
conducted at early stage development.5 However, a catalytic
enantioselective method was needed for more efficient synthesis
of 8 on a large scale.
Catalytic enantioselective syntheses of substituted benzhy-
drols like 8 involve either reduction of prochiral benzophenones
or addition of air-sensitive phenyl nucleophiles to benzaldehyde
derivatives.6 Although the reduction methodologies are often
practical, they require discrimination between the two phenyl
moieties in order to achieve high enantioselectivity and have
only been reported for an extremely limited substrate range via
enantioselective borohydride and borane reduction,7 β-hydride
transfer,8 enantioselective hydrosilylation,9 enantioselective hydro-
gen transfer,10 asymmetric hydrogenation,11 and bioreduction.12
Special Issue: Asymmetric Synthesis on Large Scale 2011
Received: June 22, 2011
Published: August 03, 2011
r
2011 American Chemical Society
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|

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Scheme 1. Synthetic route of TAK-475 (1)
Scheme 2. Asymmetric hydrogenation of prochiral benzophenone derivatives
Scheme 3. Precedent for synthesis of BINAP and BINAP
analogues
’ RESULTS AND DISCUSSION
Preparation of BINAP Analogues for Phosphine Ligand
Tuning. After the first synthesis of BINAP was achieved in
1980 by Noyori,18 several methods for the preparation of BINAP
have been developed,11a which are nickel-catalyzed phosphine
insertion with diphenylphosphine (15) or diarylphosphine oxi-
des (16). Similarly, the Monsanto method,19 which is character-
ized by a nickel-catalyzed coupling reaction of diphenylchloro-
phosphine (17) in the presence of zinc, has been implemented
for large-scale production (Scheme 3). On the basis of these
methods, a large number of BINAP analogues have been
synthesized in a bid to increase catalyst activity.20 The successful
improvement was achieved by modification of the aryl groups on
phosphorus.
and catalyst efficiency. In this paper, we report a novel fine-tuned Ru
precatalyst that contains a novel BINAP analogue, and a large-scale
asymmetric hydrogenation for synthesis of the chiral key inter-
mediate (8) of TAK-475 (1).
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Scheme 4. Our method for synthesis of BINAP analogues 18
Table 1. Screening of BINAP analoguesa
Table 2. Asymmetric hydrogenation of 7 under mild condi-
tions; influence of hydrogen pressurea
entry
13b L: 18
H2 [MPa]
time [h]
% conv.
%ee(S)
1
2
3
4
18b
18b
18c
18c
4
1
4
1
65
65
48
50
>99
>99
>99
>99
94
90
95
96
a Reactions were carried out at 43 °C using 10 mmol of the substrate 7
with Ru complex25 and (S,S)-DPEN in 2-propanol/THF. Substrate/
Ru/(S,S)-DPEN/KOH = 1000:1:10:20. b 13 was prepared in situ by
charging (S,S)-DPEN with the Ru complex25 containing the corre-
sponding BINAP analogue (18).
entry
13b L: 18c
% conv.
% ee (S)
1
2
3
4
5
6
7
8
18a
18b
18c
18d
18e
18f
100
100
100
>99
6
59
94
95
90
Table 3. Asymmetric hydrogenation of 7 using 13c under low
6 (R)
36
hydrogen pressure; influence of reaction temperaturea
7
TOFb [hꢀ1
]
18g
18h
56
35
entry
temp. [°C]
time [h]
% conv.
% ee (S)
17
15
1c
2
23
30
40
60
60
50
45
24
85
>99
>99
>99
96
95
93
81
29.0
55.4
a Reactions were carried out at 4 MPa of H2 for 24 h at 43 °C using
3 mmol of the substrate 7 with Ru complex25 and (S,S)-DPEN in
2-propanol/THF. Substrate/Ru/(S,S)-DPEN/KOH = 1000:1:10:20.
b 13 was prepared in situ by charging (S,S)-DPEN with the Ru complex25
3
81.7
4
191.3
c
containing the corresponding BINAP analogue (18). 18aꢀ18h was
a Reactions were carried out at 1 MPa of H2 using 10 mmol of the
substrate 7 with 13c in 2-propanol/THF. Substrate/Ru/KOH =
1000:1:20. b Turnover frequency, which is defined as moles of the
product per mole of the catalyst per hour. c Entry 1 using Ru complex25
and (S,S)-DPEN instead of 13c.
prepared with our method for synthesis of BINAP analogues, which is
shown in scheme 4.
We developed an alternative method for the preparation of
BINAP analogues in our previous studies (Scheme 4).20c,21 The
advantage of our method is that phosphineꢀborane complexes
are used as a phosphine source and these are easier to handle
because of their greater stability towards oxygen and moisture,
compared to other phosphine sources such as diphenylpho-
sphine and diphenylchlorophosphine. A large number of phos-
phineꢀborane complexes (20) were directly synthesized from
the corresponding phosphine oxides (16) using a simple reaction
involving treatment with lithium aluminum hydride and sodium
borohydride activated by cerium chloride,22 or a reduction in
boraneꢀtetrahydrofuran solution (Scheme 4).23 More than 30
BINAP analogues, including novel compounds, were prepared
using the corresponding phosphineꢀborane complexes, and
some of them were synthesized on multihundred gram scale.
Screening of BINAP Analogues for Fine-Tuning of the Ru
Precatalyst 13. Optimization of the Ru precatalyst 13 for
asymmetric hydrogenation of the benzophenone 7 has been
studied, utilizing the available BINAP ligand diversity. The
screening of BINAP analogues was conducted for the asym-
metric hydrogenation of 7 using in situ prepared 13, by
charging (S,S)-DPEN with the Ru complex25 containing the
corresponding BINAP analogues (18). On the first screening, the
lower alkyl group substituents (such as methyl and ethyl groups) at
the 3,5-positions of the aryl moieties of the BINAPs (18bꢀd) were
found to markedly increase the enantioselectivity (Table 1, entries
2ꢀ4). Among the BINAPs, 18b and 18c24 led to the highest
enantioselectivity, affording 94ꢀ95% ee (entries 2, 3). This “3,5-
dialkyl meta-effect” has been described in several reports,26 and it
was supposed to arise from steric and electronic effects on the
phosphorus atom. Hence, when the meta substituents were bulkier
(such as tert-butyl group; 18e and 18f), both the enantioselectivity
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Table 6. Optimization of other conditions for scale-upa
amount of
entry
waterb [% v/v] S/C time [h] % conv. % ee (S) TOFc [hꢀ1
]
1
2
3
4
5
ꢀ
1000
1000
1000
2000
3000
45
45
45
65
96
99.9
99.8
99.6
99.9
99.3
93
91
91
90
90
81.7
84.8
64.0
68.5
73.5
0.35%
0.70%
ꢀ
ꢀ
Figure 1. Ru complexes for precursor of 13.
a Reactions were carried out at 1 MPa of H2 at 40 °C using 10 mmol of
the substrate 7 with 13c in 2-propanol/THF. Ru/KOH = 1:20ꢀ30. b To
entries 2 and 3 were added 0.35% and 0.70% of water, respectively.
c Turnover frequency, which is defined as moles of the product per mole
of the catalyst per hour.
Table 4. Asymmetric hydrogenation of 7; comparison of Ru
complexesa
entry Ru complexes time [h] % conv. % ee (S) TOFb [hꢀ1
]
1c
2
13c
22c
23c
39
40
60
>99
86
95
86
96
55.4
34.6
41.3
Furthermore, we evaluated the influence of reaction tempera-
ture for Ru precatalyst 13c containing 18c, and found that it also
strongly influenced the enantioselectivity (Table 3). There was a
clear tendency for increased enantioselectivity of 8 under milder
conditions, similar to that seen for reduced hydrogen pressure.
However, the reaction rate decreased at lower temperature.
Thus, the optimum reaction temperature was 30ꢀ40 °C, which
gave a balance of both selectivity and productivity. In the case of
reacting at higher temperatures, such as 60 °C, the enantioselec-
tivity sharply decreased to 81% ee.
Examination of Ru Precatalyst Preparation. To the best of
our knowledge, Noyori’s ruthenium precatalyst of the type
[RuCl2(diphosphine)(diamine)] is generally synthesized via
the Ru complexes, [RuC12(diphosphine)(dmf)n], [NH2(C2H5)2]-
[{RuCl(diphosphine)}2(μ-Cl)3], or [RuC1(diphosphine)(η6-are-
ne)]Cl by treatment with a chiral diamine (Figure 1).28 Some of
the Ru precatalysts containing BINAP analogues have been ob-
tained as isolated compounds, while many of them have been
prepared in situ.29 In the case of the in situ preparation of Ru
precatalyst (13), however, the reaction rate is remarkably decreased
compared to that obtained with the isolated ones.28,30 Regarding the
asymmetric hydrogenation of 7, we also confirmed that the isolated
13c gave the fastest reaction among these Ru complexes (Table 4).
Therefore, we decided to use the isolated 13c as the Ru precatalyst.
The synthesis of 13c was conveniently accomplished by the
reaction of 22c with (S,S)-DPEN. This reaction was incomplete
in 2-propanol at 25 °C, and 10ꢀ15% of 22c remained (observed
by 31P NMR). This incomplete formation of 13c has been
recognized as a major problem, as even a slight contamination
of 13c by 22c causes a decrease in the enantioselectivity.
(Table 4, entry 2) To further study the effect of contamination
of 13c by 22c, we confirmed that the presence of 22c adversely
affected the enantioselectivity by spike testing the asymmetric
hydrogenation with 22c (Table 5).
3
>99
a Reactions were carried out at 1 MPa of H2 at 30 °C using 10 mmol of
the substrate 7 with Ru complex and (S,S)-DPEN in 2-propanol/THF.
Substrate/Ru/(S,S)-DPEN/KOH = 1000:1:10:20. b Turnover frequency,
which is defined as moles of the product per mole of the catalyst per
hour. c (S,S)-DPEN was not added.
Table 5. Asymmetric hydrogenation of 7 using 13c; influence
on the residual amount of 22ca
entry
22c/ 13cb
% conv.
% ee (S)
TOFc [hꢀ1
]
1
2
3
<0.01
0.05
>99
>99
>99
95
94
89
55.4
ꢀ
0.11
37.2
a Reactions were carried out at 1 MPa of H2 at 30 °C using 10 mmol of
the substrate 7 with 13c in 2-propanol/THF. Substrate/Ru/KOH =
1000:1:20ꢀ30. b The ratio was calculated from the integral area of
31P NMR. c turn over frequency, which is defined as moles of the product
per mole of the catalyst per hour.
Scheme 5. Preparation of highly pure 13c
and the conversion rate of this reaction decreased remarkably
(entries 5, 6).
In a bid to complete the conversion to 13c, we found that it
was important to select the appropriate reaction conditions of
temperature and solvent (Scheme 5), and the reaction went to
completion in DMF at 90 °C. After crystallization from 2-pro-
panol, pure 13c was obtained in 79% yield.
On the other hand, the precursor 23 was generally synthesized
by treatment of [RuCl2(cod)]n with the diphosphine ligand in
the presence of triethylamine.31 However, the synthesis of [NH2-
(C2H5)2][{RuCl[(S)-dadmp-binap]}2(μ-Cl)3] (23c) gave only
low yield by the general method.
In the next step, we compared 18b and 18c under the mild
conditions that had given the best results on the first screen-
ing. Interestingly, hydrogen pressure affected the enantioselec-
tivity in this reaction (Table 2). When the hydrogen pressure was
decreased to 1 MPa, 18c gave a slightly increased ee value, up to
96% ee, whereas 18b gave a lower ee at this condition. Moreover,
the reaction rate when using 18c was shown to be three times
higher than that for 18b. Therefore, it is suggested that increasing
the electron density on the phosphorus, which will occur when
using aryl substituents with 4-dimethylamino groups, has a
desirable effect on the asymmetric hydrogenation of 7.27
Development of Robust Conditions for Scale-Up. It was
found that the asymmetric hydrogenation of 7 could be performed
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Scheme 6. Scale-up synthesis of 8
at high concentration by the addition of THF to the 2-propanol
solvent, to improve the solubility of 7. Next, we investigated the
effect of water on the reaction, and it was found that it slowed the
reaction significantly. This tendency was revealed by the fact that
the turnover frequency (TOF) dropped to 64 hꢀ1 with a slight
presence (0.70%) of water. Thus, the concentration of water in
the reaction system must be controlled to less than 0.35% to
achieve sufficient reaction rate in scale-up operations (Table 6,
entries 2, 3). Therefore, wedecidedtouse dehydrated solventsand
careful protocols as to degas and purge on large-scale operations in
order to prevent an invasion of water.
During our studies for optimization, the reaction could be
conducted easily on a preparative scale with a substrate to catalyst
(S/C) mole ratio of 1000. We challenged the reduction of catalyst
loading, and robustandreproducibleconversion could be achieved
at a lower loading level up to S/C 3000 (entries 4, 5). However,
when the catalyst loading was lower, the reaction rate was slowed
significantly, and TOF dropped to 69ꢀ74 hꢀ1. Consequently, we
decided to implement scale-up operations at S/C 2000.
Subsequently, for the purpose of confirming the robustness and
reproducibility on the optimum conditions, we could carry out scale-
up reaction in a pilot plant. Under these optimum conditions, we
successfully manufactured 8 on a large scale using a catalyst loading
of S/C 2000 and a hydrogen pressure of 0.85 MPa (Scheme 6)
without any incidents. The reaction gave full-conversion in 94%
ee.32 After recrystallization from ethylacetate/n-heptane, the per-
fectly enantiopure 8 (>99.9% ee) was obtained in 82% yield.
’ EXPERIMENTAL SECTION
1H NMR spectra were recorded on a Bruker DPX-300 (300
MHz) spectrometer or Bruker AVANCE III (500 MHz) spectro-
meter with chemical shifts given in ppm (with tetramethylsilane
as an internal standard). 13C NMR spectra were recorded on a
Bruker DPX-300 (75 MHz) spectrometer or Bruker AVANCE
III (126 MHz) spectrometer with chemical shifts given in ppm -
(with tetramethylsilane and CDCl3 as an internal standard). 31
P
NMR spectra were recorded on a Bruker DPX-300 (121 MHz)
spectrometer or Bruker AVANCE III (202 MHz) spectrometer
with chemical shifts given in ppm (with 85% H3PO4 as an
external standard). Infrared absorption spectra were recorded on
a Shimadzu IRPrestige-21. Elemental analyses were carried out
by Takeda Analytical Laboratories, Ltd. and are within (0.4% of
the theoretical values. Inductively coupled plasma (ICP) analysis
performed on a Hitachi P-4010 ICP instrument gave the con-
tents of ruthenium. HPLC was performed using an Inertsil ODS-
3 (150 mm ꢁ 4.6 mm I.D.). Conditions were as follows: mobile
phase, 30% 0.05 M KH2PO4 and 70% acetonitrile; flow rate,
1.0 mL/min; detection, UV 254 nm; temperature, 25 °C. Typical
relative retention times for 8 and 7 were 0.63 and 1.00,
respectively. Chiral HPLC was performed using a Chiralcel
OJ-RH (150 mm ꢁ 4.6 mm I.D.). Conditions were as follows:
mobile phase, 60% 0.05 M KH2PO4 and 40% acetonitrile; flowrate,
1.0 mL/min; detection, UV 254 nm; temperature, 25 °C. Typical
relative retention times for (S)-8 and (R)-8 were 1.00 and 1.20,
respectively. The following abbreviations are used: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad.
Preparation of (S)-2,20-Bis[bis(4-dimethylamino-3,5-dimethyl-
phenyl)phosphino]-1,10-binaphthyl (18c). To a stirred mixture of
magnesium (2.43 g, 0.10 mol) in THF (15 mL) was added a solution
of 4-dimethylamino-3,5-dimethylbromobenzene (19c) (31.25 g, 0.136
mol) in THF (50 mL). After being stirred for 1 h at 40 °C, to the
reaction mixture was added a solution of diethyl phosphite (4.69 g,
0.034 mol) in THF (15 mL) at 25 °C. The reaction mixture was stirred
for 1.5 h at 25 °C and then quenched with water (60 mL) at 5ꢀ10 °C.
After extraction with toluene (100 mL), the organic extracts were
washed with water (30 mL). Subsequently, the solvent was removed
under reduced pressure. After purification by flash chromatography on
silica gel (n-hexane/ethyl acetate, 6:4), the corresponding phosphine
oxide (16c) (4.64 g, 40% yield) was isolated as a colorless oil. 1HNMR
’ CONCLUSION
In conclusion, a highly enantioselective synthesis of the chiral
benzhydrol 8, which is the key intermediate of TAK-475 (1),
was established via asymmetric hydrogenation developed using
the fine-tuned Noyori’s ruthenium precatalyst (13c), which
consisted of a BINAP analogue 18c as the novel diphosphine
ligand. Using the precatalyst, asymmetric hydrogenation of the
prochiral benzophenone (7) proceeded with high enantios-
electivity under low hydrogen pressure (<1 MPa). Pure 13c
was isolated by crystallization for large-scale production to
achieve sufficient reaction rate and enantioselectivity in the
asymmetric hydrogenation. Finally, the large-scale synthesis
of 8 was implemented, and we obtained 34 kg of 8 in high
yield and excellent enantioselectivity, using the optimized
conditions.
(300MHz,CDCl3):δ2.29(12H,s),2.82(12H,s),7.31(4H, d,JPH
=
13.8Hz), 7.89(1H, d,JPH = 474.2 Hz). 13CNMR(75MHz, CDCl3):
δ 19.3 (d, JCP = 4.4 Hz), 42.3, 126.8 (d, JCP = 103.4 Hz), 131.1 (d,
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JCP = 11.9 Hz), 137.2 (d, JCP = 13.7 Hz), 153.8. 31P NMR (121 MHz,
CDCl3, 85% H3PO4): δ 22.51(dm, JPH = 474.2 Hz).
NMR (126 MHz, CDCl3): δ 17.8, 18.5, 41.1, 41.5, 61.8, 122.2,
124.5, 124.6, 125.4, 125.65, 125.71, 125.5ꢀ126.0 (m), 126.3,
126.4, 127.3, 129.3ꢀ129.9 (m), 131.7, 132.6ꢀ132.7 (m), 133.0
(brm), 133.0ꢀ133.5 (m), 133.8ꢀ133.9 (m), 134.5ꢀ134.7 (m),
136.0, 137.2 (d, J = 6.1 Hz), 137.3 (d, J = 6.1 Hz), 139.7, 148.1,
149.0. 31P NMR(202 MHz, CDCl3, 85% H3PO4): δ 42.9 (s). MS
m/z 1290 (M+). Anal. Calcd for C74H84N6Cl2P2Ru: C, 68.82; H,
6.56; N, 6.51; Cl, 5.49. Found: C, 68.42; H, 6.75 ;N, 6.44; Cl, 5.36.
Scale-Up Synthesis of (S)-(2-Amino-5-chlorophenyl)(2,3-
dimethoxyphenyl)methanol (8). In a 500-L autoclave, 7 (41.1
kg, 140.9 mol) and potassium hydroxide (118.7 g, 2.1 mol) were
placed and degassed by seven cycles of vacuum filling with argon.
Subsequently, anhydrous THF (72 L) and anhydrous 2-propanol
(72 L) were added to a 500-L autoclave via cannula. The
precatalyst 13c (91.1 g, 0.0705 mol) was transferred by Schlenk
techniques as a suspension in anhydrous THF (500 mL) and
anhydrous 2-propanol (500 mL) into a 500-L autoclave. The
autoclave was then purged with hydrogen (0.1 MPa, 10 times),
and then pressurized with hydrogen to 0.84ꢀ0.86 MPa, and
stirring for 42.5 h at 37ꢀ43 °C. After cooling to 25 °C, the
autoclave was carefully vented and completely replaced by argon.
To the reaction mixture was added activated carbon (481 g), and the
slurry was stirred for 3 h at 25 °C. After further addition of Celite
(70 g), the suspension was filtered and rinsed with THF (15 L). The
filtrate was removed under reduced pressure. The resulting residue
was dissolved in 2-propanol (75 L) at 75 °C. Subsequently, to the
mixture was added water (41 L) over 45 °C, and stirred 1 h at 25 °C,
and 3 h below 10°C. The precipitate was separated by centrifugation
and rinsed with 2-propanol (31 L). The collected compound was
dried under reduced pressure at 60 °C to give crude 8 (38.0 kg,
96.1% ee). The crude 8 was dissolved in ethyl acetate (103 L) at
70 °C. To the solution was added n-heptane (72 L) over a 30-min
period, and then the solution was cooled to 25 °C. The mixture was
stirred for 15 h at ambient temperature and cooled to 0ꢀ10 °C for
3 h. The precipitate was collected by filtration and dried under
reduced pressure at 60 °C to give 8 (34.0 kg, 82.2% yield, >99.9%
ee). 1H NMR (300 MHz, CDCl3): δ 3.30 (1H, m), 3.80 (3H, s),
3.86 (3H, s), 4.17 (2H, s), 6.00 (1H, d, J = 4.9 Hz), 6.54 (1H, d, J =
8.4 Hz), 6.88 (2H, d, J = 8.0 Hz), 6.99ꢀ7.08 (3H, m). 13C NMR
(75 MHz, CDCl3): δ 55.8, 61.0, 69.2, 112.3, 117.5, 119.7, 122.8,
124.6, 127.3, 128.2, 129.0, 134.8, 143.4, 146.3, 152.5. IR (KBr),
cmꢀ1: 3418, 1585, 1039, 789. Anal. Calcd for C15H16NO3Cl: C,
61.33; H, 5.49; N, 4.77; Cl, 12.07. Found: C, 61.32; H, 5.40; N, 4.67;
Cl, 12.13. Residual amount of ruthenium: 0.15 ppm.
To a solution of 16c (4.64 g, 0.014 mol) in toluene (30 mL)
was added boraneꢀtetrahydrofuran solution (71 mL, 0.076 mol)
upon slow addition for 2 h. After addition of boraneꢀtetrahydrofuran
solution, the reaction mixture was quenched with silica gel (8.7 g),
and stirred at room temperature for 1.5 h. The silica gel was filtered
off, and then the filtrate was concentrated under reduced pressure.
After purification by flash chromatography on silica gel (toluene) and
crystallization from n-hexane, the corresponding phosphineꢀborane
complex (20c) (3.00 g, 65% yield) was isolated as a white crystalline
powder. 1H NMR (300 MHz, CDCl3): δ 0.30ꢀ1.75 (3H, brdd, J =
ca. 95.5 Hz, 81.9 Hz), 2.28 (12H, s), 2.81 (12H, s), 6.11 (1H, dq,
JPH = 376.9 Hz, JBH = 6.8 Hz), 7.26 (4H, d, JPH =11.8Hz). 13CNMR
(75 MHz, CDCl3): δ 19.7, 42.7, 121.8 (d, JCP = 58.9 Hz), 133.7 (d,
JCP = 9.8 Hz), 137.8 (d, JCP = 11.2 Hz), 153.5. 31P NMR(121 MHz,
CDCl3, 85% H3PO4): δ ꢀ0.66 (dm, JPH = 376.9 Hz).
(S)-2,20-Di(trifluoromethylsulfonyl)-1,10-binaphthyl (14) (1.76 g,
3.21 mmol) and 20c (2.52 g, 7.38 mmol) in DMF (25 mL) was
treated at 105 °C with [1,2-bis(diphenylphosphino)ethane]dichloro
nickel (0.17 g, 0.321 mmol) and 1,4-diazabicyclo[2.2.2]octane (2.13 g,
19.26 mmol). The reaction mixture was stirred for 96 h and then
concentrated under reduced pressure. The resulting residue was
washed with methanol to give 18c (1.86 g) in 64% yield as a white
crystalline powder: mp 265 °C. [R]D = ꢀ76.5° (25 °C, c = 1.00,
1
CHCl3). H NMR (500 MHz, CDCl3): δ1.97 (12H, s), 2.00
(12H, s), 2.66 (24H, s), 6.58 (4H, d, J = 8.0 Hz), 6.67 (2H, d, J =
8.5 Hz), 6.77ꢀ6.81 (6H, m), 7.21ꢀ7.25 (2H, m), 7.48ꢀ7.50
(2H, m), 7.72 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5 Hz). 13C
NMR (126 MHz, CDCl3): δ 18.0, 18.1, 41.4, 41.5, 124.0, 124.9,
126.4, 126.7, 126.8, 129.6, 131.7ꢀ131.8 (m), 132.1, 132.3ꢀ132.7
(4C, m), 133.9ꢀ134.2 (2C, m), 134.6 (d, J = 23.9 Hz),
134.8ꢀ135.0 (2C, m), 136.2ꢀ136.3 (m), 143.6 (d, J = 20.1 Hz),
143.7 (d, J = 21.4 Hz), 148.0, 148.9. 31P NMR (202 MHz, CDCl3,
85% H3PO4): δ ꢀ15.7 (s). IR (ATR, cmꢀ1): 2779, 1443, 1414,
1333, 1209, 1099, 1059, 1049, 1024, 953, 860, 812, 742, 692. Anal.
Calcd for C60H68N4P2 0.5 CH3OH: C, 78.71; H, 7.64; N, 6.07; P,
6.71. Found: C, 78.67; H, 7.40; N, 6.12; P, 6.75.
[(S)-2,20-Bis[bis(4-dimethylamino-3,5-dimethylphenyl)
phosphino]-1,10-binaphthyl][(1S,2S)-1,2-diphenylethylenedi-
amine]ruthenium(II); [RuCl2{(S)-dadmp-binap}{(S,S)-dpen}]
(13c). In a 20-mL Schlenk flask, a mixture of [RuCl2(C6H6)]2
(132 mg, 0.264 mmol) and 18c (484 mg, 0.533 mmol) was
degassed. Subsequently, anhydrous DMF (4.8 mL) was added via a
cannula under argon atmosphere. Then, the resulting mixture was
stirred at 150 °C for 3 h. (S,S)-DPEN (121 mg, 0.570 mmol) was
prepared in a 10-mL Schlenk flask and dissolved by anhydrous
DMF (2.0 mL). This solution was added to the 20-mL Schlenk
flask via a cannula. After being stirred for 1 h at 90 °C, the solvent
was removed under reduced pressure. The resulting residue was
dried under reduced pressure at 50 °C to give crude 13c (753 mg)
as a yellow powder. The crude 13c was suspended with anhydrous
2-propanol (3.0 mL) and stirred for 3 h at 80 °C, for 1 h at room
temperature, and for 3 h at 10 °C under argon atmosphere. The
resulting precipitate was filtered off under argon atmosphere to
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra of 8, 13c, 18c,
b
18d, 18f, and 18h and crystallographic information files for 13c.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Telephone: +81-6-6300-6433. Fax: +81-6-6300-6251. E-mail:
Goto_Mitsutaka@takeda.co.jp.
1
give 13c (535 mg) in 79% yield as yellow powder. H NMR
(500 MHz, CDCl3): δ 1.68 (12H, s), 2.13 (12H, s), 2.38 (12H, s),
2.45 (12H, s), 2.77 (2H, brt, J = 9.3 Hz, NH), 2.99 (2H, brd, J = 8.7
Hz, NH), 4.06ꢀ4.09 (2H, m), 5.98 (2H, d, J = 8.6 Hz), 6.54ꢀ6.58
(2H, m), 6.69ꢀ6.71 (4H, m), 6.91ꢀ6.98 (6H, m), 6.99ꢀ7.03
(2H, m), 7.13ꢀ7.22 (4H, brm), 7.49ꢀ7.51 (4H, brm), 7.56 (2H,
d, J = 7.9 Hz), 7.75 (2H, d, J = 8.6 Hz), 8.34ꢀ8.37 (2H, m). 13C
’ ACKNOWLEDGMENT
We thank Ms. Keiko Higashikawa and Mr. Yoichi Nagano
for X-ray crystallographic analysis, Dr. Masahiro Kajino and
1183
dx.doi.org/10.1021/op2001673 |Org. Process Res. Dev. 2011, 15, 1178–1184

Organic Process Research & Development
ARTICLE
Dr. Atsuhiko Zanka for their fruitful discussions, Mr. Satoru Oi,
Mr. Yuzuru Saito, and Mr. Seiji Tajima for helpful discussions.
We also thank Takasago Int. Co. for cordial collaboration on
developing asymmetric hydrogenation.
(14) Abbreviations: (S)-XylBINAP (18b) = (S)-2,20-bis[bis(3,5-
dimethylphenyl)phosphino]-1,10-binaphthhyl. (S)-DAIPEN = (2S)-
1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine. (S,S)-DPEN =
(1S,2S)-1,2-diphenylethylenediamine.
(15) This technology has been developed in collaboration with
Takasago Int. Co.: Sakaguchi, T; Imai, T.; Miura, T.; Yamazaki, T.;
Okada, T. Chem. Abstr. 1997, 127, 262513.JP/09/235255 A 1997. For a
large scale preparation of 8 using 13b see: ref 4b.
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by the following procedure, [(i) LDA/THF, ꢀ55 °C; (ii) (ꢀ)-DIP-
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(ꢀ)-DIP-Chloride is a trademark of Sigma-Aldrich Corporation.
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