The development of an asymmetric hydrogenation process for the preparation of solifenacin

Article abstract of DOI:10.1021/op3000543

The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4- dihydroisoquinoline to 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl] ₂-(S)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1-2 equiv of H₃PO₄, 60 °C, 20 bar H₂, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).

Full text of DOI:10.1021/op3000543

Article
pubs.acs.org/OPRD
The Development of an Asymmetric Hydrogenation Process for the
Preparation of Solifenacin
Milos Ruzic,*,† Anica Pecavar,† Darja Prudic,† David Kralj,† Corina Scriban,‡
̌
̌
̌
̌
̌
and Antonio Zanotti-Gerosa*,‡
†
̌
Krka, d.d., Novo Mesto, Smarjesk
̌
a cesta 6, 8501 Novo Mesto, Slovenia
‡Johnson Matthey, Catalysis and Chiral Technologies, Unit 28, Cambridge Science Park, Cambridge CB4 0FP, United Kingdom
S
* Supporting Information
ABSTRACT: The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the
hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline to 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This
represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-
azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate. Suitable reaction conditions were identified
through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl]2-
(S)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1−2 equiv of H3PO4, 60 °C, 20 bar H2, were reproduced
on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).
been reported,7,8 1-aryl-3,4-dihydroisoquinolines are particu-
INTRODUCTION
(1S)-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-
■
larly challenging substrates. Only a very limited number of
transfer hydrogenation9 and hydrogenation10 catalysts have
2(1H)-isoquinoline carboxylate (1), solifenacin, is a urinary
antispasmodic.1 The succinate salt of 1, commercialized as
been reported to be successful.
1. Substrate Preparation. Imine 2·HCl was prepared
Vesicare, is FDA approved for the treatment of overactive
according to published procedures.4g,11 The research work
bladder. Several synthetic strategies have been devised, by both
reported here focused on the direct asymmetric hydrogenation
academic2 and industrial research groups.3,4 The strategy used
of the hydrochloride salt 2·HCl, which could be conveniently
on industrial scale for the synthesis of solifenacin involves a
prepared and purified prior to the hydrogenation step.
Bischler−Napieralski cyclization followed by achiral reduction
Attempts to hydrogenate the crude starting material as free
of the resulting imine 2 (Scheme 1). Commonly, diastereo-
base 2 with or without purification gave lower activity (see
meric resolution of the tartrate salt of racemic 3 provides (S)-
Supporting Information).
2. Catalyst Screening. Screening of selected ruthenium,
rhodium, and iridium chiral catalysts was performed on the
3,5 which then reacts with a (halo)alkyl haloformate to yield the
desired 1. A variation of the reaction describes the use of an
alkali metal salt of (R)-3-quinuclidinol in reaction with the (S)-
substrate 2·HCl on small scale under transfer hydrogenation
1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate interme-
and hydrogenation conditions. We tested ruthenium-sulfonyl-
diate.4d Alternatively, the diastereoisomers of 1 can be resolved
by chromatography.4e
diamine catalysts under both transfer hydrogenation12,7 and
hydrogenation conditions,13 ‘Noyori-type’ catalyst [BINAP−
RuCl2−DAIPEN],14 ruthenium and rhodium hydrogenation
catalysts bearing chiral phosphines,6 as well as iridium catalysts
bearing P∧N ligands.15,8c All of these classes of catalysts showed
only moderate to low conversions and low enantioselectivity
(full results of the catalyst screen are reported in the Supporting
Information).
The common feature of most of these approaches is the use
of 1-phenyl-1,2,3,4-tetrahydroisoquinoline 3 as the key
intermediate. It is widely accepted that asymmetric catalysis
in industrial processes can provide superior yield and reduce
the waste streams during the synthesis of pharmaceutical
intermediates. In this contribution we report the synthesis of
enantiomerically enriched (S)-3 from the hydrochloride salt of
its imine precursor, 2·HCl, using iridium-catalyzed asymmetric
hydrogenation (Scheme 2).4g
2.1. Iridium Catalysts with Diphosphine Ligands. BINAP is
the most widely applicable chiral phosphine ligand.16 We chose
to run a set of initial experiments (30 bar H2, 50 °C, 18 h,
molar substrate to catalyst ratios, S/C, of 85/1) forming the
catalyst in situ from [Ir(COD)Cl]2 and (R)-BINAP in the
presence of the substrate 2·HCl.17 High conversion (>90%)
was observed in MeOH, i-PrOH, 1,2-dichloroethane (DCE),
tetrahydrofuran (THF), and toluene, although in toluene,
substrate 2·HCl was found to have limited solubility. MeOH
RESULTS AND DISCUSSION
■
The catalytic asymmetric reduction of prochiral CN bonds
has been widely investigated, and the number of imines have
been reduced with high activity and selectivity using Ir, Rh, Pd,
and Ru chiral catalysts under a variety of reaction conditions.6
Cyclic imines are of particular interest. Contrary to 1-alkyl-3,4-
dihydroisoquinolines (alkyl = benzyl, linear alkyl), for which a
number of efficient asymmetric reduction methodologies have
Received: March 5, 2012
© XXXX American Chemical Society
A
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Scheme 1. Synthetic routes to 1
Scheme 2. Asymmetric hydrogenation of 2·HCl
gave racemic 3, while i-PrOH and the aprotic solvents
produced, under these very preliminary reaction conditions,
enantioselectivity varying between 53% and 66% ee. Following
these encouraging results, a wider screen of catalysts prepared
in situ from [Ir(COD)Cl]2 and chiral phosphine ligands was
undertaken in DCE (Figure 1, see also Supporting
Information).18
Figure 1. Screening of [Ir(COD)Cl]2-phosphine catalysts in DCE (S/
C 43/1, 50 °C, 30 bar H2, 3 h); 1: (S)-BINAP; 2: (R)-Tol- BINAP; 3:
(R)-Xyl-BINAP; 4: (R)-P-Phos; 5: (S)-Tol-P-Phos; 6: (R)-Xyl-P-Phos;
7: (R,R)-Ph-BPE; 8: (S,S)-Me-DuPhos; 9: (R,R)-i-Pr-DuPhos; 10:
(R,R,S,S)-DuanPhos; 11: CatAsium D(R); 12: (R)-Binaphane; 13:
(R)-PhanePhos; 14: (S)-Xyl-PhanePhos; 15: (S)-Me-BoPhoz; 16: (R)-
PhEt-(S)-BoPhoz; 17: (R)-JafaPhos; 18: (R)-(S)-JosiPhos; 19: (S,S)-
BDPP; 20: (Ra,Sc)-Naphth-Quinaphos; 21: CatASium T2.19.
Catalysts incorporating ligands of the BINAP and P-Phos20
families (Figure 2) were the best catalysts in DCE. Under the
conditions used, the P-Phos catalyst gave higher enantiose-
lectivity (Figure 2, entry 4, 84% ee) than the BINAP catalyst
(entry 1, 60% ee). Tol-BINAP and Tol-P-Phos produced in
DCE enantioselectivity comparable to that of the ‘parent’
ligands BINAP and P-Phos (entries 2 and 5, 67% ee and 78%
ee, respectively) while Xyl-BINAP and Xyl-P-Phos showed
significantly lower enantioselectivity (entries 3 and 6, 50% ee
and 49% ee, respectively).21
Phospholanes and P-cyclic phosphines (Ph-BPE, DuPhos,
DuanPhos, CatASium D(R), Binaphane) showed low con-
version and selectivity, with the exception of Binaphane (entry
12, 95% ee but only 24% conversion).10 Paracyclophane-based
(PhanePhos family) and ferrocenyl-based phosphines (BoPhoz
family, JafaPhos, JosiPhos) showed low enantioselectivity with
the exception of [Ir(COD)Cl]2-Xyl-PhanePhos (entry 14, 78%
ee), which gave only 19% conversion. Several catalysts were
also tested in MeOH, but most of them gave racemic or very
low ee products. Notably, iridium catalysts bearing the BDPP
Figure 2. BINAP and P-Phos family of ligands.
and phospholane ligands (DuPhos, Ph-BPE) were the only
ones that gave similar results in DCE and in MeOH with
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enantioselectivity in the 35−51% ee range (see Supporting
Information).
solvents and two acidic additives was carried out at 50 °C, 30
bar, 16 h (Table 1). Among other positive leads identified from
the experiments of Figure 3, we did not pursue the use of chiral
acids due the potential cost contribution.
2.2. Screening of Additives. It has been reported in the
literature that iridium-catalyzed asymmetric hydrogenation of
imines is very sensitive to the presence of additives,6 and
therefore, the hydrogenation of imine 2·HCl was studied with
the [Ir(COD)Cl]2-BINAP catalyst in the presence of a variety
of additives (Figure 3, see Supporting Information). THF was
used as the solvent to try and maximize solubility of the
different additives.
CH2Cl2. CH2Cl2 was used as representative chlorinated
solvent in replacement for DCE, used in previous experiments.
The reactions in CH2Cl2 (clear solutions) gave full conversion
at S/C 170/1 overnight (50 °C, 30 bar) with both
[Ir(COD)Cl]2-BINAP (81% ee) and [Ir(COD)Cl]2-P-Phos
(85% ee) catalysts in the absence of any additive (entry 1). The
addition of phosphoric acid (entry 2) gave a cloudy solution
and suppressed the reaction, while the addition of AcOH (entry
3) was either neutral (BINAP: 81% ee) or slightly favorable (P-
Phos: 87% ee). In the absence of any additive, the
enantioselectivity decreased when the catalyst loadings were
reduced (entry 4). Upon addition of AcOH the enantiose-
lectivity at S/C 425/1 (entry 5) was higher than in the absence
of an additive (entry 6), although not as high as at S/C 170/1
(entry 3).
Toluene. Modest enantioselectivity was obtained in neat
toluene with [Ir(COD)Cl]2-BINAP (60% ee, entry 6, similar to
the 57% ee obtained in preliminary experiments). The behavior
seen for the reactions in CH2Cl2 was mirrored by the results of
reactions in toluene: conversion decreased with phosphoric
acid (entry 7), and a good increase in enantioselectivity was
seen when AcOH was added (entry 8, up to 82% ee with
BINAP).
i-PrOH. [Ir(COD)Cl]2-BINAP gave moderate enantioselec-
tivity at S/C 170/1 in neat i-PrOH (72% ee, entry 10) and in
the presence of AcOH (entry 12, 70% ee). i-PrOH/H3PO4 was
the only solvent/acid system tested where the BINAP-based
catalyst (entry 11, 90% ee at 30 bar, S/C 170/1) matched or
surpassed the enantioselectivity obtainable with the P-Phos-
based catalyst (entry 11, 86% ee at 30 bar, S/C 170, and entry
13 and 91% ee at 5 bar, S/C 425/1).
Figure 3. Screening of additives for reactions catalyzed by [Ir(COD)-
Cl]2-BINAP catalysts, in THF (S/C 43/1, 50 °C, 30 bar H2, 3 h).
Amount of additive expressed in equivalents to substrate. 1: No
additive; 2: NaI 0.2 equiv; 3: MgI2 0.2 equiv; 4: BuN4I 0.2 equiv; 5:
BuN4Br 0.2 equiv; 6: DABCO 0.2 equiv; 7: Piperazine 0.2 equiv; 8:
H3PO4 (anhydrous) 1.2 equiv; 9: H3PO4 (aq) 1.2 equiv (85% w/w in
water); 10: H3PO4 (anhydrous) 2.4 equiv; 11: H3PO4 (anhydrous) 2.4
equiv + KI 0.1 equiv; 12: AcOH 1.2 equiv (AcOH in THF); 13:
AcOH 12 equiv (AcOH in THF); 14: p-TSOH 1.2 equiv; 15: HBF4
(aq) 1.2 equiv (48% w/w in water); 16: (R)-1,1′-binaphthyl-2,2′-diyl
hydrogenophosphate 1.2 equiv; 17: HCl 1.2 equiv (HCl 5 N in i-
PrOH); 18: HCOOH 1.2 equiv (HCOOH 96% in water).
Me-THF. Both [Ir(COD)Cl]2-BINAP and [Ir(COD)Cl]2-P-
Phos gave low enantioselectivity at S/C 170/1 (36−39% ee) in
neat Me-THF (entry 14) and in the presence of AcOH (entry
16). Enantioselectivity with [Ir(COD)Cl]2-BINAP in Me-
THF/H3PO4 was significantly higher (78% ee, entry 15), but
not as high as the one detected in THF/H3PO4 (entries 17−
20).
The benchmark reaction with [Ir(COD)Cl]2-BINAP in THF
without any additive showed 76% conversion to amine 3 over 3
h with 75% ee (S isomer) (Figure 3, entry 1). Iodide and
bromide salts (entries 2−5), as well as amines (entries 6, 7)
reduced the enantioselectivity of the reaction. Most strikingly,
22
the addition of H3PO4 increased both activity to >97%
THF. The enantioselectivity obtained in neat THF with
[Ir(COD)Cl]2-BINAP (66% ee, entry 17) was significantly
increased by addition of H3PO4 (entry 18, 87% ee). In this
specific solvent, THF, the use of AcOH had already been
proven to be inferior to the use of H3PO4 (see Figure 3, entries
12 and 13). The use of [Ir(COD)Cl]2-P-Phos in THF/H3PO4
(entries 18−24) provided the highest enantioselectivity values
so far encountered (entries 23 and 24, up to 95% ee). The
enantioselectivity of the reaction was not generally improved by
the use of lower reaction temperature (40 °C, entry 19) nor by
the use of lower hydrogen pressures (entries 18, 19, and 24, 5
bar). Contrary to the preliminary result reported in Figure 3,
the addition of 0.1 equiv of KI in the presence of H3PO4
produced no advantage once retested at S/C 170/1 (entry 21)
and was not further investigated. A small increase in the
reaction temperature from 50 °C (entry 23) to 60 °C (entry
24) gave full conversion at S/C 425/1 without affecting the
enantioselectivity. From the point of view of practicality, it was
determined that the use of aqueous phosphoric acid (85%
H3PO4 in water, diluted in THF prior to addition to the
reaction mixture, entries 18 and 22) was equally effective as the
conversion and enantioselectivity: 87% ee with 1.2 equiv of
either anhydrous H3PO4 (entry 8) or aqueous H3PO4 (85% w/
w in water diluted to a 0.1 M solution in THF, entry 9), 82% ee
with 2.4 equiv of anhydrous H3PO4 (entry 10). A positive
combined effect of H3PO4 and KI was also detected (entry 11,
94% ee), and even higher enantioselectivity was seen in the
presence of a chiral acid (entry 16, 96% ee). AcOH gave
reduced enantioselectivity (entries 12 and 13, 72−78% ee). The
use of other acids was discarded due to reduced activity despite
the good enantioselectivity: p-TsOH (entry 14, 30% conv., 90%
ee), HBF4 (entry 15, 20% conv., 90% ee), HCOOH (entry 18,
77% conv., 87% ee). HCl (entry 17) gave very low conversion.
In addition to the experiments in THF described in Figure 3,
we tested the use of KI (10%) and iodine (20%) in toluene (S/
C 85/1, 50 °C, 30 bar, 16 h). In this solvent, both the use of KI
(95% conversion and 42% ee) and iodine (57% conversion and
29% ee) did not improve on the benchmark reaction (95%
conversion and 51% ee) (see Supporting Information).
3. Small-Scale Optimization. Having identified [Ir-
(COD)Cl]2-BINAP and P-Phos catalysts as promising leads,
a more systematic evaluation of the effect of four different
C
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a
Table 1. Hydrogenation of 2·HCl with [Ir(COD)Cl]2-BINAP and P-Phos catalysts with different acids and solvents
(S)-BINAP
(S)-P-Phos
b
b
b
b
entry
S/C
additive (equ iv)
3 (%)
3 ee (%)
3 (%)
3 ee (%)
CH2Cl2
1
2
3
4
5
170/1
170/1
170/1
425/1
425/1
−
H3PO4 (s) (2.4)
AcOH (2)
−
>97
10
81
nd
81
67
74
>97
6
85
nd
87
72
80
>97
>97
>97
>97
>97
>97
AcOH (2)
Toluene
6
7
8
9
170/1
170/1
170/1
425/1
−
>97
55
60
nd
82
77
H3PO4 (s) (2.4)
AcOH (2)
>97
>97
94
88
86
AcOH (2)
>97
i-PrOH
10
11
12
170/1
170/1
170/1
425/1
−
96
>97
>97
72
90
70
H3PO4 (s) (2.4)
>97
94
86
91
AcOH (2)
c
13
H3PO4 (s) (2.4)
MeTHF
THF
14
15
16
170/1
170/1
170/1
−
88
82
74
36
78
38
H3PO4 (s) (2.4)
2 (AcOH)
88
39
17
85/1
43/1
−
>97
66
d
e
18
H3PO4 (aq) (1.2)
>97
87 (88)
f
e
e
e
e
19
43/1
H3PO4 (s) (2.4)
25(30)
86 (87)
17 (18)
88
g
20
170/1
170/1
170/1
340/1
425/1
H3PO4 (s) (2.4)
98
>97
87
82
>97
>97
>97
97
94
92
93
95
21
22
23
H3PO4 (s) (2.4) + KI (0.1 )
H3PO4 (aq) (1.2)
H3PO4 (s) (2.4)
h
e
24
H3PO4 (s) (2.4)
>97
95 (92)
a
Reactions run in Biotage Endeavour: substrate, [Ir(COD)Cl]2 (1 mg, 0.0015 mmol), phosphine (0.0033 mmol) in 3−5 mL solvent + additive.
b
c
Reactions were run at 50 °C, 30 bar, 16 h. Conversion and enantioselectivity measured by HPLC (CHIRALPAK AD-H column). Reaction run at
65 °C, 5 bar, 40 h. Reactions run for 3 h. In brackets conversion and ee obtained under the same conditions at 5 bar hydrogen. Reactions run for 3
h at 40 °C. Reactions run at 5 bar. Reaction run at 60 °C. nd = not determined.
d
e
f
g
h
use of the anhydrous phosphoric acid that was added as a solid
to the reagents at the screening stage.
Table 2. Best reaction conditions with [Ir(COD)Cl]2-(S)-P-
Phos catalyst in THF/phosphoric acid in Biotage
a
The results reported in Table 1 highlight the remarkable
dependence of the reaction’s enantioselectivity upon the
combination of solvent and acidic additive. Several choices
were open at this stage of the research. Not yet having
developed an effective crystallization process for ee upgrade of
product 3, it was decided to pursue the option that had been
demonstrated to provide the highest enantioselectivity: [Ir-
(COD)Cl]2-P-Phos in THF/H3PO4. Small-scale optimization
in the Biotage Endeavour was continued using [Ir(COD)Cl]2-
P-Phos in THF with aqueous phosphoric acid (Table 2). The
reactions were driven to full conversion at progressively lower
catalyst loadings by the combined effect of increased reaction
temperatures, reaction pressure and longer reaction times. At
S/C 850/1 the combination of 65 °C/20 or 30 bar (entries 2
and 3) was found to be more effective than the combination of
70 °C/10 bar (entry 4). A good result was finally obtained at S/
C 1275/1, 60 °C, 30 bar with full conversion and 94% ee (entry
5). The use of lower pressure (10 bar) led to incomplete
conversion, even after 64 h reaction time (entry 6).
Endeavour.
equiv
conc temp press time
3
(%)
3 ee
b
b
entry
S/C
H3PO3 (M)
(°C) (bar)
(h)
(%)
1
2
3
4
5
6
850/1
850/1
1.8
1.8
2.4
1.8
1.8
1.8
0.64
0.64
0.64
0.64
0.75
0.75
60
65
65
70
60
60
30
20
30
10
10
30
72
72
72
72
64
64
95
>198
>98
95
96
95
96
96
95
94
850/1
850/1
1275/1
1275/1
68
98
a
Reactions run in Biotage Endeavour: substrate, [Ir(COD)Cl]2 and
1.1−1.2 equiv of phosphine per Ir in 3−6 mL solvent + additive.
b
Conversion and enantioselectivity measured by HPLC (CHIRAL-
PAK AD-H column).
following experiments in standalone Parr autoclaves (50 mL,
100 and 600 mL autoclaves, benchtop Parr Microreactors series
5500) mainly aimed at demonstrating the reaction feasibility
within the constraints of the equipment available for scale-up (a
10 L Biazzi reactor operating at 20 bar maximum hydrogen
pressure). The parameters of substrate concentration and the
related parameter of phosphoric acid concentration were fixed
respectively at 0.37−0.41 M and 1.8 equiv, of H3PO4/substrate
(Scheme 3, Table 3).
4. Hydrogenations on Multigram Scale. While the
conclusion that could be drawn from the experiments of Table
2 was that the reaction would benefit from the use of highest
achievable pressure and high substrate concentration, the
D
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highlighting the importance of achieving efficient mixing and
dissolution of the starting material. Two hydrogenations were
run in 600 mL autoclaves at S/C 850/1 on 20.7 g scale (85
mmol, entry 11) and on 15.5 g scale (64 mmol, entry 12),
giving full conversion and 94−95% ee. A third reaction was run
on 15.5 g scale (64 mmol, entry 13) at S/C 1275/1 giving just
92% conversion after 68 h. The reduced conversion was
attributed to a problem with the stirrer, which limited agitation
of the reaction. After 68 h the reaction was opened to air, the
problem with the stirrer was corrected; the reaction was
allowed to proceed for further 65 h to give full conversion and
95% ee.
Scheme 3. Best reaction conditions for asymmetric
hydrogenation of 2·HCl
Table 3. Hydrogenation of 2·HCl with [Ir(COD)Cl]2-(S)-P-
Phos catalysts (solvent THF, additive 1.8 equiv of H3PO4
a
(aq), 60°C and 20 bar H2)
Different work up procedures were tested (see Supporting
Information). Concentration of the reaction mixture by
removal of THF followed by workup with dichloromethane
or AcOEt and diluted aqueous base (KOH or ammonia) gave
high mass recovery of amine 3. A recrystallization procedure
was developed (see Supporting Information) from i-PrOH/
water to give pure amine 3 with enantiopurity upgrade from
97% ee to 99% ee, in 78% yield.23 Larger batches of 200 g of
imine 2·HCl were subjected to hydrogenation (entries 14 and
15) according to the best procedure developed on small scale,
which was repeated without problems. The crude product
mixture showed in both cases >97% HPLC purity and,
pleasingly, a slightly higher enantioselectivity than previously
detected (97% ee and 95.5% ee respectively, based on a more
accurate analytical method that had been developed in the
meantime). An improved workup procedure using KOH/
EtOAc was applied and afforded the product 3 in quantitative
yield. An improved recrystallization procedure from i-PrOH/
H2O 1/3 (95% isolated yield) led to increased HPLC purity
(99.2%), with an enantiomeric purity of 98% ee.24
scale
conc
(M)
time
(h)
b
b
entry
S/C
(mmol)
3 (%) 3 ee (%)
50 mL Autoclave
1
850/1
850/1
5.1
5.1
5.1
5.1
5.1
5.1
5.1
6.4
0.41
45
45
72
72
72
60
60
90
>99
>99
>98
>99
>99
>99
>99
>99
95
93
c
2
0.41
3
4
1060/1
1275/1
1275/1
1275/1
1700/1
2125/1
0.41
93.5
95
0.41
c
5
d
0.41
95
6
0.41
87
7
8
0.41
95
0.47
95
100 mL Autoclave
f
9
850/1
15.3
12.8
0.41
72
60
>99
95
95
e
f
10
1275/1
0.41
98
600 mL Autoclave
11
850/1
850/1
85.0
63.8
63.8
0.41
0.38
0.38
68
65
>99
>99
92
95
94
95
95
e
12
e
13
1275/1
68
133
>99
g
10 L Reactor
14
15
1060/1
1060/1
830.8
0.37
0.37
47
48
98
97
97
CONCLUSIONS
■
1158.2
95.5
We have demonstrated the feasibility of an efficient process for
the asymmetric hydrogenation of the hydrochloride salt of 1-
phenyl-3,4-dihydro-isoquinoline (2·HCl). Unlike many other
members of the class of 1-substituted-3,4-dihydroisoquinolines,
phenyl-substituted imine 2 is a challenging substrate for
asymmetric reductions. We found that the use of the
hydrochloride salt as the substrate gave increased reactivity in
the presence of iridium catalysts prepared in situ from readily
available biaryl-phosphine chiral ligands (BINAP and P-Phos).
Through a broad screen of catalysts followed by extensive
small-scale optimization with different combinations of solvents
and acids we have identified specific reaction conditions
providing high enantioselectivity at acceptably low catalyst
loadings (S/C > 1000/1). The robustness of the reaction has
been proven by reproducing it on 200 g scale to give (S)-3 with
95% isolated yield, 98% ee, and >99% HPLC purity.
a
Reaction conditions: substrate, [Ir(COD)Cl]2 and phosphine (1.1 to
1.2 equiv to Ir) were placed in the autoclave and purged with nitrogen;
then a solution of H3PO4 (85% in H2O) in THF was added. The
reaction was purged with nitrogen and hydrogen, pressurized with
hydrogen, and heated. Conversion and enantioselectivity were
measured by HPLC on a CHIRALPAK AD-H column. Reactions
run at 65 °C and 10 bar H2. [Ir(COD)Cl]2-(S)-BINAP catalyst.
HPLC grade solvent used without predegassing. 96% conversion
after some solid stuck on top of the autoclave was dissolved and added
to the solution. Conversion measured by HPLC on Ascentis Express
b
c
d
e
f
g
C8 and enantioselectivity measured by HPLC on CHIRALPAK IB
column.
The best reaction conditions obtained in the Biotage
Endeavour were tested in 50 mL Parr autoclaves and full
conversion with good enantioselectivity was achieved, although
under prolonged reaction times. The use of 60 °C/20 bar
(Table 3, entries 1 and 4) gave higher enantioselectivity than
the combination of 65 °C/10 bar (entries 2 and 5). Full
conversion with consistent ee (∼95% ee) was obtained at
catalyst loading as low as S/C 2125/1 (entry 8). One reaction
was run in the presence of (S)-BINAP (entry 6) and confirmed
that the [Ir(COD)Cl]2-(S)-BINAP had very similar activity to
[Ir(COD)Cl]2-(S)-P-Phos but gave lower enantioselectivity
(87% ee). The reactions with the [Ir(COD)Cl]2-(S)-P-Phos
system were repeated in a similar 100 mL autoclave on 3.10 to
3.75 g scale at S/C 850/1 (entry 9) and at S/C 1275/1 (entry
10). The reactions gave full conversion but some starting
material was found unreacted on the top of the vessel,
EXPERIMENTAL SECTION
■
Synthesis of N-Phenethylbenzamide. Phenethylamine
(3.86 mmol, 468 g, 486 mL) and CH2Cl2 (2.25 L) were
charged into a 10 L reaction vessel and cooled to 0 − 5 °C.
Benzoyl chloride (3.88 mmol, 545 g, 450 mL) was added slowly
over 2 h. NEt3 (4.46 mmol, 451 h, 621 mL) was added to the
white reaction suspension over 1 h at 0−5 °C. The reaction
mixture was heated to reflux for 5 h and then cooled to room
temperature overnight, under stirring. Purified water (3 L) was
added, and the phases were separated. The organic phase was
washed with water (1.5 L) and dried over Na2SO4 (50 g). The
E
dx.doi.org/10.1021/op3000543 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
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solvent was evaporated to give N-phenethylbenzamide (525 g,
60% yield) as a white to yellow crystalline powder. H NMR
(400 MHz, DMSO-d6): δ (ppm) 2.82 (t, J = 7 Hz, 2H, CH2-
Ph), 3.45 (t, J = 7 Hz, CH2-N), 7.16−7.28 (m, 5H), 7.28−7.45
(m, 3H), 7.78 (d, J = 7 Hz, 2H), 8.5 (sb, 1H, NH). 13C NMR
(400 MHz, DMSO-d6): δ (ppm) 35.5, 41.3, 126.5, 127.5, 128.7,
128.8, 129.1, 131.5, 135.0, 140.0, 166.6.
25% ammonium hydroxide (to constant pH 8/9). The layers
were separated, and the aqueous layer was further extracted
with CH2Cl2 (4 × 100 mL). The organic layers were combined,
dried over Na2SO4, and filtered, and the filter cake was washed
with more CH2Cl2 (2 × 75 mL). The CH2Cl2 solution was
evaporated under reduced pressure to give an off-white solid
(>99% amine 3, 94.5% ee, 13.8 g). At this stage, the isolated
yield was not established.23
1
Synthesis of 1-Phenyl-3,4-dihydroisoquinoline (2). N-
phenethylbenzamide obtained in the previous step (1.15 mmol,
260 g) and 2 L of xylene were added into a 10 L reaction vessel.
To this mixture POCl3 (3.62 mmol, 556 g, 338 mL), P2O5
(2.34 mmol, 332 g), and additional 1.12 L of xylene were
added. The reaction mixture was heated to 140 °C (temper-
ature of the reactor jacket). The reaction was cooled after 5 h to
room temperature, and 1.5 kg of ice was slowly added to the
reaction mixture (the order of addition was determined by the
fact that the product was obtained as a melted residue on the
bottom of the reactor, which precluded isolation by adding it to
ice). An exothermic reaction occurred. Additional 2 L of
purified water was added, and the reaction mixture was stirred
overnight at room temperature. The two phases were separated,
the water layer was transferred into a 10 L reactor, and the pH
was adjusted to 10−11 using a 20% solution of NaOH (6 L). It
was washed with 2 × 1.95 L of CH2Cl2. The organic phases
were combined, the solvent was evaporated, and 211 g of an
oily product (88% yield if 2) was obtained. The crude product
was used directly in the next step.
Recrystallization. Amine 3 (13.1 g) from the previous step
was placed in a 250 mL round-bottomed flask equipped with an
air condenser. Water (50 mL) and i-PrOH (50 mL) were
added, and the reaction was heated to 90 °C (oil bath, external
temperature) to obtain a clear-yellow solution. The reaction
was allowed to cool to room temperature to give a thick, white
suspension that was diluted with 50 mL water and collected by
filtration. The off-white solid was allowed to dry on the filter for
two days and then was further dried under reduced pressure
(13.1 g, 88% yield). HPLC analysis showed >99% purity of 1-
(S)-phenyl-1,2,3,4-tetrahydroisoquinoline, 3, with 94.5% ee. 1H
NMR (400 MHz, CDCl3): δ (ppm) 2.19 (s, 1H, NH), 2.75 (m,
1H), 3.00 (m, 2H), 3.20 (m, 1H), 5.02 (s, 1H), 6.67 (d, J = 9
Hz, 1H), 6.95 (m, 1H), 7.08 (d, J = 4 Hz, 2H), 7.16−7.27 (m,
5H). 13C NMR (100 MHz, CDCl3): δ (ppm) 31.4, 43.9, 63.7,
127.3, 128.0, 129.1, 129.8, 130.1, 130.69, 130.72, 137.1, 139.9,
146.5.
HPLC Method. Both conversion and enantioselectivity were
determined using a CHIRALPAK AD-H, 0.46 cm× 25 cm;
eluent: isocratic, hexane/EtOH, 98.5:1.5 + 0.1% Et2NH; flow: 1
mL/min; temperature: 30 °C; detection: 220 nm. Imine 2
eluted at 7.5 min; (S)-3 enantiomer at 9 min and (R)-3
enantiomer at 12 min.
Hydrogenation of 2·HCl on 202 g Scale in 10 L Biazzi
Reactor (S/C 1060/1, entry 14, Table 3). Hydrogenation.
Imine 2·HCl (202.5 g, 0.8308 mol), 103 mL of 85% H3PO4,
[Ir(COD)Cl]2 (0.39 mmol, 0.263 g), (S)-P-Phos (0.9 mmol,
0.579 g), and 2.15 L of THF, were added to the reactor. The
reaction mixture was purged with nitrogen and hydrogen,
pressurized with hydrogen (20 bar), heated to 60 °C, and
stirred. After 47 h HPLC analysis of the crude reaction mixture
showed 97% HPLC purity of 3 and 97% ee. The walls of the
reactor were washed with 100 mL of THF, and 1.11 L of
MeOH was added to the reaction mixture. The solvent was
evaporated, and an oily residue (418 g) was obtained. HPLC
analysis showed 97.8% HPLC purity, 97% ee and 41.8% HPLC
assay of 3 (quantitative yield).
Workup. Crude product (390 g) of the from the previous
step was charged into the reactor; 3.75 L of AcOEt and 3.75 L
of KOH 4 M aqueous solution were added, and the mixture
was stirred for one hour at room temperature. The phases were
separated, the water phase was extracted with 3.75 L of AcOEt,
the organic phases were combined, and the solvent was
evaporated. A quantity of 170 g of light-yellow crystalline
product was obtained. HPLC analysis showed 98% HPLC
purity and 95.6% HPLC assay of 3 (quantitative yield).
Recrystallization. Crystalline product 3 (169 g) of from the
previous step was charged in a 10 L reactor; 1.69 L of i-PrOH
was added, and the mixture was heated to 83 °C until the
solution was clear. The mixture was cooled to 0−5 °C over 2 h,
5.07 L of water was added, and the mixture was stirred for 30
min. The product was filtered off, washed with 0.27 L of water,
and dried until loss on drying (LOD) was stable. HPLC
analysis showed 99.2% purity and 97.8% ee (153 g of
crystallized 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline, (S)-3,
Synthesis of 1-Phenyl-3,4-dihydroisoquinoline·HCl
(2·HCl). 1-Phenyl-3,4-dihydroisoquinoline 1 (190 g) from the
previous step was dissolved in TBME (190 mL). A solution of
126 g HCl g in 2.5 L of TMBE was added to give a suspension
that was stirred for one hour. The product was collected by
1
filtration to give 208 g of 2·HCl (93% yield). H NMR (400
MHz, DMSO-d6): δ (ppm) 3.22 (t, J = 8 Hz, 2H, CH2-Ph),
3.98 (t, J = 8 Hz, CH2-N), 7.40 (m, 1H), 7.50 (m, 1H), 7.63
(m, 1H), 7.68 (m, 2H), 7.84 (m, 4H), 14 (sb, 1H). 13C NMR
(400 MHz, DMSO-d6): δ (ppm) 24.6, 41.0, 125.6, 127.8, 128.7,
128.8, 129.6, 130.8, 132.9, 133.6, 136.5, 139.5, 172.6. Cl
analysis; calculated for C15H14NCl: 14.55, found: 14.44. Mp:
218−222 °C.25
Hydrogenation of 2·HCl on 15.5 g Scale in 600 mL
Autoclave (S/C 850/1, entry 12, Table 3). Hydrogenation.
[Ir(COD)Cl]2 (0.0375 mmol, 25 mg), (S)-P-Phos (0.086
mmol, 1.15 equiv to Ir, 55.5 mg) and imine 2·HCl (63.7 mmol,
15.52 g) were placed in a stainless steel 600 mL Parr autoclave.
The autoclave was sealed and placed under nitrogen. THF (165
mL) and H3PO4 (85% in water, 7.9 mL, 115 mmol) were
premixed and then added to the solid in the autoclave using a
50 mL syringe through the autoclave injection port. The
autoclave was sealed and then purged with nitrogen five times
by pressurizing to 3 bar under stirring and then releasing
pressure. The reaction was then purged with hydrogen five
times. The pressure was set to 20 bar, and the reaction was
heated to 60 °C over ∼30 min (pressure increased to about 22
bar). The reaction was stirred at maximum stirring speed
(1200−1500 rpm) for 65 h, then it was cooled to 45 °C and
opened to find a clear, thick yellow/green solution that was
sampled. HPLC analysis showed full conversion to amine 3 and
94% ee (S)-enantiomer.
Workup. The reaction was diluted with MeOH (∼200 mL),
transferred to a round-bottomed flask, and concentrated under
reduced pressure to obtain a clear-yellow/-green oil. CH2Cl2
(100 mL) was added, followed by 50 mL of water and 60 mL of
F
dx.doi.org/10.1021/op3000543 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
95% isolated yield). 1H NMR (400 MHz, DMSO-d6): δ (ppm)
2.46 (s, 1H, NH), 2.69 (m, 1H), 2.88 (m, 2H), 3.06 (m, 1H),
4.97 (s, 1H), 6.59 (d, J = 4 Hz, 1H), 6.96 (m, 1H), 7.06 (m,
2H), 7.2−7.3 (m, 5H). 13C NMR (100 MHz, DMSO-d6):
29.55, 42.0, 61.5, 125.7, 126.3, 127.4, 128.0, 128.5, 129.3, 129.4,
135.8, 139.1, 145.5. CHN analysis; calculated for C15H15N: C
86.08, H 7.22, N 6.69; found: C 85.83, H 7.26, N 6.68. Mp:
86.5 °C,3,26 [α]D = +4.0° (c = 1, MeOH, T = 20 °C).
(g) Canivet, J.; Suss-Fink, G. Green Chem. 2007, 9, 391. (h) Werner,
F.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 3911. (i) Czarnocki,
S. J.; Wojtasiewicz, K.; Jozwiak, A. P.; Maurin, J. K.; Czarnocki, Z.;
́
́
Drabowicz, J. Tetrahedron 2008, 64, 3176. (j) Martins, J. E. D.;
Clarkson, G. J.; Wills, M. Org. Lett. 2009, 11, 847. (l) Martins, J. E. D.;
Redondo, M. A.; Wills, M. Tetrahedron: Asymmetry 2010, 21, 2258.
(8) Recent examples of hydrogenation (and references therein):
(a) Li, C.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 13208. (b) Jackson, M.;
Lennon, I. Tetrahedron Lett. 2007, 48, 1831. (c) Guiu, E.; Claver, C.;
̈
HPLC Analytical Methods. The reactions were analyzed for
conversion using an Ascentis Express C8 column, 2.7 μm
particles, 100 mm × 4.6 mm i.d., Detection: 210 nm; Flow: 0.7
mL/min, 25 °C; Eluent A: 0.02 M Na2HPO4 adjusted to pH
2.5 by addition of H3PO4; Eluent B: acetonitrile. 85:15 A/B for
3 min, then gradient to 40:60 A/B for 10 min. The reactions
were analyzed for enantioselectivity using a CHIRALPAK IB
column, 250 mm × 4.6 mm, 5 μm, 0.46 cm × 25 cm; eluent:
isocratic hexane/EtOH/MeOH, 90:4:6 + 0.2% TFA; flow: 1
mL/min; temperature: 25 °C; detection: 220 nm. (S)-3
enantiomer at 7.9 min and (R)-3 enantiomer at 10.7 min.
Benet-Buchholz, J.; Castillon
3365.
́
, S. Tetrahedron: Asymmetry 2004, 15,
(9) Transfer hydrogenation catalysts were employed only at high
catalyst loadings: (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (b) Mao, J.; Baker, D. C.
Org. Lett. 1999, 1, 841. (c) Vedejs, E.; Trapencieris, P.; Suna, E. J. Org.
Chem. 1999, 64, 6724.
(10) During the preparation of the manuscript a report was published
on the same topic of asymmetric hydrogenation of 2 en route to
solifenacin, using the iodine-bridged dimeric catalyst [{Ir(H)[(S,S)-
(f)-binaphane]}2(μ-I)3]+I− (up to S/C = 10,000/1) in the presence of
iodine with 95% enantioselectivity: Chang, M.; Li, W.; Zhang, X.
Angew. Chem., Int. Ed. 2011, 50, 10679. In our catalyst screen a similar
catalyst, [Ir(COD)Cl]2-binaphane, gave a comparable ee but low
activity under unoptimized conditions.
(11) (a) Lantos, I.; Bhattacharjee, D.; Eggleston, D. S. J. Org. Chem.
1986, 51, 4147. (b) Buesing, A.; Fortte, R.; Stoessel, P.; Vestweber, H.;
Heil, H.; Parham, A. U.S. Patent 20090048415, 2009. (c) Nagubandi,
S.; Fodor, G J. Heterocycl. Chem. 1980, 17, 1457. (d) Whaley, W. M.;
Hartung, W. H. J. Org. Chem. 1949, 14, 650. (e) Brodrick, C. I.; Short,
W. F. J. Chem. Soc. 1949, 2587. (f) Decker, H.; Kropp, W.; Hoyer, H.;
Becker, P. Justus Liebigs Ann. Chem. 1913, 395, 299. (g) Pictet, A.; Kay,
F. W. Ber. Dtsch. Chem. Ges. 1909, 42, 1973.
(12) Reviews: (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry
1999, 10, 2045. (b) Wang, C.; Wu, X.; Xiao, J. Chem. Asian J. 2008, 3,
1750. (c) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300.
(d) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (e) Ikariya,
T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (f) Ito, M.;
Ikariya, T. Chem. Commun. 2007, 5134.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full results of the catalyst screen and small-scale optimization
reaction, HPLC analytical methods, representative NMR
spectra and HPLC chromatograms. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*milos.ruzic@krka.biz (M.R.); antonio.zanotti-gerosa@
matthey.com (A.Z.-G.).
■
Notes
The authors declare no competing financial interest.
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(17) We also tested an alternative procedure where the catalyst was
preformed by stirring [Ir(COD)Cl]2 and (S)-BINAP for 30 min under
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procedure in which the catalyst was formed in the presence of the
substrate was not only experimentally easier but also more
reproducible. This procedure was therefore applied throughout the
project.
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counterion BArF were tested in three solvents (DCE, THF, and i-
PrOH) using (S)-BINAP as the ligand; however, they showed no
advantage over the much more easily available [Ir(COD)Cl]2. BArF
complexes are widely used with P∧N-iridium catalysts: Smidt, S. P.;
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(19) Nomenclature, references, and commercial sources of the
ligands are reported in the Supporting Information.
̌
̌ ̌ ̌
N. WO/2008/019055A2, 2008. (g) Ruzic, M.; Prudic, D.; Pecavar, A.;
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G
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(21) Once reaction conditions had been optimized, [Ir(COD)Cl]2-
Tol-BINAP and Tol-P-Phos catalysts were tested again but provided
no advantage over the use of [Ir(COD)Cl]2-BINAP and P-Phos
catalysts (see Supporting Information).
(22) An example of hydrogenation of the phosphate salt of a 3,4-
dihydroisoquinoline: McGarrity, J. F.; Brieden, W.; Fuchs, R.; Mettler,
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Weinheim, 2003; pp 283.
(23) 1H NMR analysis of the reaction mixtures in 600 mL autoclaves
after workup highlighted the presence of variable amounts of a side
product that was not detected by HPLC analysis. On the basis of
analysis of 1H NMR signals, it was tentatively assigned as a compound
derived from degradation of THF and structurally unrelated to
products 2 and 3. This compound was completely removed during the
crystallization process (see Supporting Information).
(24) The amount of iridium residues (the theoretical amount of
iridium in the product, assuming quantitative yield, 860 ppm) was little
affected by the aqueous workup and was reduced to 380 ppm by the
crystallization process.
(25) (a) Pictet, K. Chem. Ber. 1909, 42, 1977. (b) Nagubandi, S.;
Fodor, G. J. Heteroat. Chem. 1980, 17, 1457.
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Tetrahedron 1990, 46, 5909. (b) Wanner, K. T.; Beer, H.; Hoefner, G.;
Ludwig, M. Eur. J. Org. Chem. 1998, 2019.
H
dx.doi.org/10.1021/op3000543 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX