Construction of a (3 aR,4 R,9 bR)-Hexahydropyrroloquinoline by Stereoselective Hydrogen-Mediated Domino Cyclization

Article abstract of DOI:10.1021/acs.oprd.8b00365

A novel practical asymmetric route to a chiral hexahydropyrroloquinoline derivative 2, a key fragment of TAK-480, is reported. The corresponding substrate, enamine 19, was directly transformed to a diastereopure and enantiopure (3aR,4R,9bR)-hexahydropyrroloquinoline 16 through a rhodium-catalyzed hydrogen-mediated domino cyclization consisting of four steps; (1) asymmetric hydrogenation of enamine, (2) hydrogenation of iminium olefin in a lactam, (3) dehydration and catalytic sulfonation, and (4) cis-selective intramolecular cyclization. A tuned asymmetric catalyst [Rh(cod){(2S,4S)-PTBP-SKEWPHOS}]OTf that we previously developed was found to promote improved reaction activity and be the most suitable catalyst for a multikilogram manufacturing for preclinical research. The resulting stereoselective domino cyclization drastically reduced several synthetic steps, and the resulting waste compared to the discovery route that required chiral preparative high-performance liquid chromatography and silica gel column separation.

Full text of DOI:10.1021/acs.oprd.8b00365

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Construction of a (3aR,4R,9bR)‑Hexahydropyrroloquinoline by
Stereoselective Hydrogen-Mediated Domino Cyclization
Masatoshi Yamada,*,†,‡ Hirotsugu Usutani,†,§ Tatsuya Ito,†,∥ and Mitsuhisa Yamano†,‡
†Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome,
Yodogawa-ku, Osaka, Japan
‡Chemical R&D Division, SPERA PHARMA, Inc., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka, Japan
§Consulting Division, Kyoto University Original Co., Ltd., Yoshida-Honmachi, Sakyo-ku, Kyoto, Japan
∥Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome Fujisawa,
Kanagawa, Japan
S
* Supporting Information
ABSTRACT: A novel practical asymmetric route to a chiral hexahydropyrroloquinoline derivative 2, a key fragment of TAK-
480, is reported. The corresponding substrate, enamine 19, was directly transformed to a diastereopure and enantiopure
(3aR,4R,9bR)-hexahydropyrroloquinoline 16 through a rhodium-catalyzed hydrogen-mediated domino cyclization consisting of
four steps; (1) asymmetric hydrogenation of enamine, (2) hydrogenation of iminium olefin in a lactam, (3) dehydration and
catalytic sulfonation, and (4) cis-selective intramolecular cyclization. A tuned asymmetric catalyst [Rh(cod){(2S,4S)-PTBP-
SKEWPHOS}]OTf that we previously developed was found to promote improved reaction activity and be the most suitable
catalyst for a multikilogram manufacturing for preclinical research. The resulting stereoselective domino cyclization drastically
reduced several synthetic steps, and the resulting waste compared to the discovery route that required chiral preparative high-
performance liquid chromatography and silica gel column separation.
KEYWORDS: asymmetric hydrogenation, domino reaction, hexahydropyrroloquinoline, Skewphos
ee and 98.7% de) at a multikilogram scale. The product was
converted to optically pure 3 through hydrolysis and
recrystallization.2
Most of our efforts were thus focused toward the synthesis
of 2, a hexahydropyrroloquinoline ring bearing three chiral
centers, and in this paper we describe details of a catalytic
asymmetric approach to its preparation.
INTRODUCTION
■
In 2006, Takeda Pharmaceutical Company disclosed 4-
(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxy-
methyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-
1-yl)carbonyl)cyclohexyl) benzamide (TAK-480, 1) as an
efficient antagonist for a tachykinin NK2 receptor (Scheme
1).1‑(a) TAK-480 shows potent binding affinity for human NK2
receptors with a marked species and a 10 000-fold selectivity
versus NK1 and NK3 receptors. The novel NK2 receptor
antagonist, TAK-480 improves visceral hypersensitivity and
accelerates defecation without causing constipation in
experimental animals. Furthermore, the potent functional
blockade of NK2 receptors in human colon has suggested the
potential effectiveness of TAK-480 in irritable bowel syndrome
(IBS) patients.1
Synthetically, TAK-480 possesses an extremely challenging
molecular structure consisting of five stereocenters. A simple
retrosynthetic analysis of 1 revealed that it can be disconnected
into two main building blocks: (3aS,4R,9bR)-4-(methoxy-
methyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
(2) and (1S,2R)-2-(4-(difluoromethoxy)benzamido)-
cyclohexane-1-carboxylic acid (3; Scheme 1). A synthesis of
3 was developed by our colleagues using an effective
asymmetric hydrogenation. A novel ruthenium catalyst,
[Ru(OAc)2 {(S)-2,2′-bis(bis(3,5-di-tert-butyl-4-
methoxyphenyl)phosphaneyl)-1,1′-binaphthalene}], was de-
veloped as a tuned catalyst to give the corresponding product
(ethyl (1S,2R)-2-(4-(difluoromethoxy)benzamido)-
cyclohexane-1-carboxylate) with high stereoselectivity (95.0%
EARLY DEVELOPMENT
■
Compound 2·2HCl had been originally prepared by medicinal
chemists at gram scale and was obtained after two column
separations: silica gel chromatography for separation of the two
diastereomers (rac-endo-5 and rac-exo-5) and chiral prepara-
tive high-performance liquid chromatography (HPLC) sepa-
ration of the two enantiomers (7 and ent-7) of a single
diastereomer (rac-endo-7; Scheme 2, discovery route).3
Besides the highly expensive and commercially unavailable
starting material 4, several issues were identified in this
synthesis from a standpoint of practicality for a manufacturing
process: (i) purification by silica gel and optical resolution by
chiral preparative HPLC; (ii) endo/exo selectivity in the aza-
Diels−Alder reaction; (iii) use of expensive reagents, for
example, Dy(OTf)3; (iv) no possibility for a purification step
Special Issue: Japanese Society for Process Chemistry
Received: November 21, 2018
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthetic Analysis of Clinical Candidate 1
Scheme 2. Discovery Route for Preparation of 2·2HCl
by crystallization, because all compounds from 4 to rac-endo-6
were oils.
with high enantioselectivity (97% ee).8 Although this synthetic
method was considered to be a useful direct route to the core
tetrahydroquinoline structure, it was deemed unsuitable for
large-scale supply because of complex industrial issues, such as
those encountered for a reaction needing the use of activated
molecular sieves at cryogenic temperature and a chiral catalyst
preparation using an expensive chiral source, as well as the
obtained diastereoselectivity being only moderate.
In 2008, Tatsuta and co-workers at Waseda University and
Kondo et al. at Takeda Pharmaceutical Company developed an
efficient asymmetric synthesis of 2 using asymmetric hydro-
genation of the enamine 12 and forward cis-stereoselective
intramolecular cyclization (Scheme 3, first-generation asym-
metric route of 2).11
The first-generation asymmetric route toward 2 started from
a commercially available and inexpensive material, pyrrolidine-
2-one 8, which was turned into the p-methoxybenzyl protected
pyrrolidine-2-one 9 and alkylated with methyl 2-methoxyace-
tate to furnish ketone 10 in good yield. The ketone was then
condensed with aniline to afford the Z form enamine 11 as a
crystalline powder. The asymmetric catalyst combination of
[Rh(cod)2]OTf and (S)-(R)-SL-J210-2 obtained from Solvias
was used for hydrogenation of the enamine 11 with syn-
selectivity (syn/anti = 94/6) and high enantioselectivity (91%
ee), affording the hydrogenation product syn-12 within 24 h
under a hydrogen pressure of 1 MPa at S/C = 25. The
As a part of our drug development program, a practical
asymmetric synthesis for multikilogram quantities of 2 for
clinical candidate 1 was required, to be applied at large scale
and with an increased overall yield. However, the diastereo-
and enantioselective synthesis of hexahydropyrroloquinoline
derivatives has not been well-studied. Many direct diaster-
eoselective syntheses of racemic hexahydropyrroloquinolines
have been reported for (+)-martineline and (−)-martinelic
acid, isolated from the roots of Martinella iquitosensis by
Witherup.4 Martineline or (−)-martinelic acid has been shown
to be a potent inhibitor for several G-protein coupled receptor
systems including bradykinin (BK), histaminergic, α-adrener-
gic, and muscarinic receptors, in spite of having a different
configuration to our target molecule.5 As an asymmetric
approach to prepare the hexahydropyrroloquinoline deriva-
tives, a few different methodologies have been reported, using
palladium-catalyzed intermolecular cyclization,6 conjugate
addition with a chiral building block,7 asymmetric Povarov
reaction catalyzed by chiral urea catalysts8 or chiral phosphoric
acid catalysts,9 and asymmetric tandem Michael-aldol reac-
tion.10 Among them, the asymmetric Povarov reaction by
Jacobsen and co-workers in 2010 provided 1-benzyl-4-ethyl
(3aR,4R,9bR)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]-
quinoline-1,4-dicarboxylate as an endo product (>20:1 dr)
B
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Scheme 3. First-Generation Asymmetric Route to 2
Scheme 4. Retrosynthesis of 2 for a Second-Generation Asymmetric Route
diastereopure and enantiopure syn-12 was obtained in 72%
yield with greater than 99% ee on recrystallization from a
mixture of isopropyl ether and hexane. After the protecting
group was changed from p-methoxybenzyl (PMB) to tert-
butyloxycarbonyl (Boc), the carbonyl on the pyrrolidine ring
was efficiently reduced at −78 °C with lithium triethyl
borohydride. The crude mixture was directly used in a cis-
selective intramolecular cyclization in the presence of
camphorsulfonic acid, followed by deprotection under acidic
conditions to obtain 2·2HCl. To improve the first-generation
asymmetric route, to give a practical manufacturing method,
we initiated an investigation according to the retrosynthetic
analysis shown in Scheme 4. The original aim was to replace
the protecting group PMB with carboxybenzyl (Cbz), since the
PMB-protected asymmetric hydrogenation product (syn-12)
could not be used in the subsequent carbonyl reduction step,
and Cbz protection is easy to track by HPLC. However, as an
unanticipated bonus it was surprisingly discovered that a novel
C
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Scheme 5. Operation Friendly Quenching Method for Acylation of 21
a
Table 1. Asymmetric Hydrogenation of 19
b
H2 pressure
(MPa)
16
HPLC area%
c
entry
L*
% ee
19
syn-18
ent-syn-18
16+ent-16
1
2
3
4
5
6
7
8
9
(S)-(R) SL-J210-2
(S,S)-SKEWPHOS
(S,S)-CHIRAPHOS
(S,S)-DIOP
(R)-(S)-JOSIPHOS
(R)-(S)-JOSIPHOS
(S,S)-SKEWPHOS
(S)-BINAP
1
1
1
1
1
5
5
5
5
5
n/a
n/a
n/a
n/a
n/a
n/a
60
n/a
n/a
71
70
46
84
84
52
43
4
88
85
28
4
16
1
2
2
2
11
1
2
24
2
5
0
1
12
6
4
1
1
8
0
7
0
0
8
25
49
0
0
16
(S)-PM-BINAP
(S,S)-Me-DUPHOS
10
a
b
Reactions were conducted for 16−18 h at 50 °C using 19 in MeOH containing a Ru complex. Assayed by chiral HPLC analysis condition B:
CHIRALPAK AS-RH column (5 μm, 150 × 4.6 mm), MeCN/aq K2HPO4 (0.02 M) 4/6, flow rate: 1.0 mL/min, oven temperature: 25 °C,
detection: 220 nm (UV), tR: 12.5 min (syn-18), tR: 15.3 min (ent-syn-18), tR: 22.3 min (16+ent-16), tR: 27.0 min (19). Assayed by chiral HPLC
c
analysis condition A: CHIRALPAK AD-H column (5 μm, 150 × 4.6 mm), hexane/2-propylalcohol 9/1, flow rate: 0.5 mL/min, oven temperature:
25 °C, detection: 220 nm (UV), tR: 29.9 min (ent-16), tR: 33.3 min (16). n/a indicates not applicable.
stereoselective hydrogen-mediated domino cyclization was able
loquinoline (16). After the catalysts were tuned, additives were
to directly convert the enamine (19) to the hexahydropyrro-
screened, and reaction conditions were optimized, a second-
D
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Figure 1. SKEWPHOS analogues used for ligand screening.
generation asymmetric route was established through asym-
metric process development for scale-up synthesis. Herein, we
disclose a highly efficient and robust synthetic method for a
diastereo- and enantiopure hexahydropyrroloquinoline with a
novel stereoselective hydrogen-mediated domino cyclization
and the scale-up result of the reaction in a multikilogram
manufacturing for preclinical research.
scale of 21, a moderate decrease in the yield (37%) was
observed, which was thought to be due to the large white
aggregated substances that formed in the reaction mixture and
inhibited mixing in the reactor during the reaction quenching
step with a HCl aqueous solution. To avoid the mixing issue in
scale-up manufacturing, the quenching method was examined
further, and it was found that no aggregated substance was
observed when AcOH (0.8 wt % to 21) was added into the
reaction mixture, although the isolated yield of 20·K decreased
from 56% to 34% because of workup issues (Scheme 5).
Benzyl (Z)-3-(2-methoxy-1-(phenylamino)-
ethylidene)-2-oxopyrrolidine-1-carboxylate 19 Synthe-
sis. Compound 20 free base was prepared by acidification of
20·K and 1 M aqueous (aq) HCl in toluene. Then the free
base of 20 in toluene was condensed with aniline in the
presence of p-toluensulfonic acid in cyclohexane while
removing water generated during reaction through an
azeotropic distillation, to give enamine 19 as a substrate for
asymmetric hydrogenation. The product 19 was purified by
activated carbon treatment to remove the substances of
inhibition for crystallization and crystallized from a mixture
of ethyl acetate/heptane. Starting from 183 kg of 20·K, 150 kg
of 19 was produced with a yield of 74% in the manufacturing
for preclinical research.
RESULTS AND DISCUSSION
■
Benzyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-car-
boxylate 20 Synthesis. Cbz-protected pyrrolidin-2-one 21
was prepared by protection with Cbz-Cl after deprotonation of
pyrrolidin-2-one 8. Deprotonation of 8 was performed using
sodium hydroxide in toluene at 110 °C while removing water
generated from the reaction through an azeotropic distillation
and then adding Cbz-Cl to the reaction mixture of
deprotonated pyrrolidine-2-one at 0−10 °C. On a 75 kg
scale of 8, the crude product 21, obtained in 94% yield, was
used directly in the next step as an easy-to-handle
tetrahydrofuran (THF) solution (209 kg with 87 wt %
concentration) without further purification.
The β-acylation of Boc-protected pyrrolidin-2-one with
chlorocarbonic acid methyl ester using lithium hexamethyldi-
silazide (LHMDS) as a base had been reported to proceed
with 85% yield.12 We confirmed that β-acylation of 21 with
methoxyacetyl chloride under the literature condition
proceeded with 68% yield. The acylation product 20 was
obtained as a potassium salt powder, 20·K, from potassium
carbonate in EtOAc, because 20 was an oil and unstable in air.
Unfortunately, although 20·K was obtained in 56% yield from
21 without any operation issues at a lab scale, the isolated yield
of 20·K was not reproducible at a larger scale. On an 88 kg
Benzyl (3aR, 4R,9bR)-4-(Methoxymethyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-
carboxylate 16 Synthesis by Novel Stereoselective
Hydrogen-Mediated Domino Cyclization. We first de-
signed a small focused screen to assess the feasibility of
asymmetric hydrogenation of enamine 19 to hydrogenation
product syn-18. The screen started with a relatively small set of
commercially available chiral bisphosphines (Table 1). [Rh-
E
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Scheme 6. Finalized Process for Stereoselective Hydrogen-Mediated Domino Cyclization
Scheme 7. Second-Generation Asymmetric Route to Hexahydropyrroloquinoline 2
(cod)2]OTf was used as a metal precursor because of its
demonstrated performance in the first-generation asymmetric
route. The experiments were performed in MeOH under 1 and
5 MPa of hydrogen pressure at 50 °C.
The first-generation asymmetric route condition, using a
[Rh(cod)2]OTf and (S)-(R)-SL-J210-2 combination, gave low
conversion (Table 1, entry 1), and other ligands such as
CHIRAPHOS, DIOP, and BINAP gave similar results (entries
3, 4, 8, and 9). However, it was found that the
hexahydropyrroloquinoline 16 could be slightly detected in
the reaction mixture on HPLC analysis when SKEWPHOS
and JOSIPHOS were used as the bisphosphine ligand under 1
MPa of hydrogen pressure (entries 2 and 5). Moreover, on
increasing the hydrogen pressure to 5 MPa, the amount of 16
increased when using both of those ligands and when using
Me-Duphos (entries 6, 7, and 10). The reaction proceeded
with perfect diastereoselectivity and moderate enantioselectiv-
ity (60% ee) when using SKEWPHOS.
The result of exploring additives showed that the addition of
cyanuric acid promoted the reaction, and 2,2-dimethoxypro-
pane was found to have a role to trap the water that is
generated as a byproduct in the reaction. After modifying
SKEWPHOS ligands, we adopted (2S,4S)-PTBP-SKEWPHOS
as the bisphosphine ligand because of the high conversion
obtained without decrease of enantioselectivity compared to
simple SKEWPHOS (Figure 1).
After optimization, the process for stereoselective hydrogen-
mediated domino cyclization of 19 was finalized as shown in
F
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Scheme 8. Plausible Mechanism for Novel Stereoselective Hydrogen-Mediated Domino Cyclization
Scheme 6. The enamine 19 was dissolved in 10 vol of acetone
and subjected to 1.66 mol % (substrate/catalyst ratio (s/c) 60)
catalyst loading under 5−6 MPa hydrogen at 45 °C. Acetone
was selected as the reaction solvent after the screening of
various solvents (Supporting Information, page S21).
The asymmetric catalytic reaction was scaled up without any
issues. Novel stereoselective hydrogen-mediated domino
cyclization of 19 (37.5 kg), under the conditions shown in
Scheme 6, gave 16 in good conversion (19/16 HPLC area
ratio = 2/98). Subsequent crystallization as a p-toluenesulfonic
acid salt allowed the isolation of 48.3 kg of 16·p-TsOH in 75%
ee. Thus, a practical synthetic method was developed,
including the manufacture of a novel chiral catalyst, [Rh(cod)-
{(2S,4S)-PTBP-SKEWPHOS}]OTf, at large scale for manu-
facturing 16.13
(3aS,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexa-
hydro-1H-pyrrolo[3,2-c]quinoline 2 Synthesis. Deprotec-
tion was accomplished by treatment of 16·p-TsOH with
hydrochloric acid in water at 80 °C for 2 h. To remove the
impurities, the reaction mixture was washed with toluene, and
2 was isolated by neutralization with aqueous sodium
hydroxide solution. On a 127 kg scale of 16·p-TsOH, the
manufacturing operation was implemented to give 46 kg of 2
without any scale-up issues. The enantiomeric excess of 2 was
slightly upgraded from 75% to 80% ee. To improve the
enantiomeric excess of 2, the diastereomeric salt formation in
EtOH was conducted with L-tartaric acid, which is inexpensive
and commercially available. As a result, 62 kg of 2·L-tartrate
was obtained with greater than 99% ee from 46 kg of 2 (80%
ee; Scheme 7). In addition, direct use of 2·L-tartrate for the
final amide bond formation with 3 successfully produced 1,
TAK-480 (API), and the isolated API satisfied the quality for
preclinical research.
result of exploring the first-generation asymmetric route for 7,
we considered the four steps leading to the product 16: (1)
rhodium-catalyzed asymmetric hydrogenation of enamine 19
(19 → syn-18), (2) rhodium-catalyzed hydrogenation of an
iminium ion from lactam (syn-18 → syn-17), (3) dehydration
and catalytic sulfonation (syn-17 → int-1), (4) cis-selective
intramolecular cyclization (int-1 → int-2). Our considerations
on the domino cyclization are shown below.
(1) Rhodium-catalyzed asymmetric hydrogenation of enam-
ine 19 (19 → syn-18).
We confirmed that the enantioselectivity of 16 is
decided in this step, and anti-18 was not detected in the
reaction mixture by HPLC analysis under the condition
in Table 1, entry 7. On the one hand, this suggests that
the asymmetric hydrogenation is perfectly syn-selective,
and enamine 19 was the predicted Z form.14 On the
other hand, when [Ru(Cp)(MeCN)3]PF6, [Cu-
(MeCN)4]PF6, [Pd2Cl2(allyl)2], and [Zn(OTf)2] were
used as the metal precursor, the reaction did not
proceed. Moreover, [Ir(cod)2]BF4 and [Rh(cod)Cl]2
(neutral complex) did not give 16 and gave only small
amounts of syn-18.
(2) Reduction of a carbonyl group in lactam (syn-18 → syn-
17).
We predicted that the hydrogenation of syn-18 would
not proceed in the absence of sulfonate anion, because
the hydrogenation of 19 using the neutral rhodium
complex ([Rh(cod)Cl]2) stopped at syn-18. Addition-
ally, it has been reported that N-methyl-2-pyrrolidine
can be isolated as an N-methyl-2-pyrrolidonium tosylate
salt.15 Therefore, on the one hand, we thought that the
iminium form of syn-18 generated by trifluoromethane-
sulfonic acid (formed from the trifluoromethanesulfo-
nate anion of [Rh(cod)2]OTf and a proton from
heterolytic cleavage of H2), could be easily hydrogenated
by the rhodium-bisphosphine catalyst in the reaction
mixture. On the other hand, the effect of protection
REACTION MECHANISM
■
A plausible mechanism for the novel stereoselective hydrogen-
mediated domino cyclization is depicted in Scheme 8. As a
G
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chloroformate (48.60 g, 0.285 mol, 1.00 equiv) was added
dropwise in 15 min and stirred for 1 h with the internal
temperature maintained below 10 °C. The reaction mixture
was quenched by addition of 121 mL of water in 5 min at 5−
10 °C. The phases were separated, and the organic layer was
washed with 121 mL of a 5% aqueous potassium hydrogen
sulfate solution, then with water (2 × 121 mL). The phases
were separated, and the organic layer was dried over
magnesium sulfate. The resulting mixtures were filtered to
remove insolubles, and the cake was washed with an
appropriate amount of toluene. The filtrate was evaporated
to dryness under reduced pressure and diluted with an
appropriate amount of tetrahydrofuran. The diluted solution
was evaporated to yield 21 as a colorless oil (60.00 g, 96%
yield, 83.9 area% HPLC purity). 1H NMR (500 MHz, CDCl3)
δ 7.31−7.36 (m, 2H), 7.20−7.30 (m, 3H), 5.17 (s, 2H), 3.70
(t, J = 7.25 Hz, 2H), 2.41 (t, J = 8.04 Hz, 2H), 1.90 (quin, J =
7.65 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 174.0, 151.4,
135.4, 128.6, 128.4, 128.2, 67.8, 46.4, 32.7, 17.5. HPLC: YMC-
Pack ODS-A A-302 column (5 μm, 150 × 4.6 mm), MeCN/aq
KH2PO4 (0.05 M) 2/3, flow rate: 1.0 mL/min, oven
temperature: 30 °C, detection: 220 nm (UV), tR: 5.2 min (21).
Lab-Scale Synthesis of Potassium 1-(1-((benzyloxy)-
carbonyl)-2-oxopyrrolidin-3-ylidene)-2-methoxyethan-1-
olate (20·K). All reactions were performed under a positive
pressure of nitrogen. To a four-necked round-bottom flask
were charged bis(trimethylsilyl)amine (32.39 g, 0.200 mol,
2.19 equiv) and tetrahydrofuran (80 mL, 4 vol). The solution
was cooled to −80 °C, and n-butyllithium (125 mL of a 1.6 M
solution in hexane, 0.200 mol, 2.19 equiv) was added dropwise
in 20 min with the internal temperature maintained below −60
°C. The solution was stirred at −80 °C for 1 h. To this
solution was added a solution of 21 (20.00 g, 0.091 mol, 1.0
equiv) in tetrahydrofuran (20 mL), with the internal
temperature maintained below −60 °C. The solution was
stirred at −80 °C for 1 h, and then a solution of 2-methoxy
acetyl chloride (14.84 g, 0.137 mol, 1.51 equiv) in
tetrahydrofuran (20 mL) was added, with the internal
temperature maintained below −60 °C. This solution was
stirred at −80 °C for 2 h, and the reaction was quenched by
addition of a 6 M aqueous hydrogen chloride solution (50 mL)
with the internal temperature maintained below −20 °C.
Water (25 mL) and toluene (100 mL) were added, and the
mixture was warmed to room temperature. The phases were
separated, and the organic layer was washed with water (2 ×
75 mL) and evaporated to dryness under reduced pressure.
The oil was then diluted with ethyl alcohol (140 mL, 5 vol),
and a 40% aqueous potassium carbonate solution (94.50 g, 30
equiv) was added. The suspension was stirred at room
temperature overnight. Water (94.5 mL) was added to the
suspension to dissolve the slurry, and ethyl acetate (168 mL)
was added. The phases were separated, and the organic layer
was evaporated to 32.71 g of concentrates under reduced
pressure. The concentrates were then diluted with ethyl
alcohol (28 mL, 1.4 vol) and ethyl acetate (280 mL, 14 vol).
The suspension was stirred at room temperature for 2 h. The
solid was collected by filtration, and the cake was washed with
ethyl acetate and dried under vacuum at 60 °C to yield 20·K as
a pale yellow solid (13.46 g, 45% yield, 87.7 area% HPLC
purity). 1H NMR (500 MHz, CD3OD) δ 7.24−7.41 (m, 5H),
5.18 (s, 2H), 4.52−4.59 (m, 2H), 3.66 (t, J = 8.04 Hz, 2H),
3.35 (s, 3H), 2.60 (t, J = 8.04 Hz, 2H). 13C NMR (126 MHz,
CD3OD) δ 182.3, 169.9, 152.9, 136.6, 128.1, 127.8, 127.5,
group was contributed to facilitate this step, because
PMB-protected 19 did not proceed in this step. We
predicted the impact of electronic effect by protecting
group.
(3) Dehydration and catalytic sulfonation (syn-17 → int-1).
The fact that 10-camphorsulfonic acid (( )-CSA)
catalyzed a facile one-pot synthesis of 1,3,4-oxadiazoles
has been reported,16 and Cu(OTf)2 instead of ( )-CSA
also gave the same reaction. With reference to the
mechanism for the synthesis of 1,3,4-oxadiazoles in the
report, the domino cyclization can be described as
follows: syn-17 is protonated in the presence of
trifluoromethanesulfonic acid, generated from the
trifluoromethanesulfonate anion of [Rh(cod)2]OTf and
a proton from heterolytic cleavage of H2. In turn, the
protonated syn-17 eliminates a water molecule and
forms a sulfonate complex int-1.
(4) cis-Selective intramolecular cyclization (int-1 → int-2).
The aniline moiety of int-1 only promotes the
elimination of trifluoromethanesulfonic acid when it
approaches from the α face of the pyrrolidine ring (cis-
selective intramolecular cyclization). No suitable intra-
molecular overlap for bond formation is attained by
approaching from the β face of the pyrrolidine ring.
CONCLUSION
■
In this study, a novel stereoselective hydrogen-mediated
domino cyclization of carbamate-protected enamines facili-
tated by a cationic rhodium catalyst has been discovered. The
reaction allows a novel short-cut method for the synthesis of
16, which helps to drastically reduce the number of synthetic
steps and waste associated with the process in comparison to
the first-generation asymmetric route to 2. This second-
generation asymmetric route to construct the hexahydropyrro-
loquinoline derivative 2 has been successfully applied for
multikilogram scale production. Further optimization of this
process should focus on reduction of the catalyst loading and
yield improvement for the β-acylation step of Cbz-protected
pyrrolidine-2-one 21.
EXPERIMENTAL SECTION
■
General Remarks. All reagents and solvents were
purchased commercially and used without further purification.
HPLC analysis was performed on HITACHI 7400 instruments
1
or SHIMADZU LC-10ADvp instruments. H NMR and 13C
NMR spectra were measured in CDCl3, CD3OD, or D2O
solutions at 500 and 126 MHz, respectively, using a Bruker
Avance-III spectrometer for analysis of 21, 20·K, 19, syn-18,
16·p-TsOH, 2, and 2·L-tartrate. IR spectrum was measured
using a SHIMADZU IR Prestige-21. High-resolution mass
spectrometry (HRMS) spectra were measured using a
SHIMADZU LCMS-IT-TOF, and melting points were
measured using a SIBATA B-545 apparatus. Specific rotations
were measured using a JASCO P-1030.
Lab-Scale Synthesis of Benzyl 2-oxopyrrolidine-1-carbox-
ylate (21). To a four-necked round-bottom flask with an
attached Dean−Stark trap were charged pyrrolidin-2-one
(24.20 g, 0.284 mol, 1.0 equiv), powder sodium hydroxide
(11.40 g, 0.285 mol, 1.00 equiv), and toluene (480 mL, 20
vol). The suspension was heated to reflux (110 °C) and stirred
for 18 h while removing the water (removed water: ca. 4.8
mL). The reaction mixture was cooled to −5 °C, and benzyl
H
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94.3, 73.1, 66.3, 57.3, 43.0, 21.2. HRMS (m/z, electrospray
ionization (ESI)+) for C15H17NO5 as a free base (M+H)+ calcd
292.1179, measured 292.1186. HPLC: YMC-Pack ODS-A A-
302 column (5 μm, 150 × 4.6 mm), MeCN/aq KH2PO4 (0.05
M) 2/3, flow rate: 1.0 mL/min, oven temperature: 30 °C,
detection: 220 nm (UV), tR: 5.9 min (20).
stainless steel autoclave. The used Schlenk tube was washed
with dehydrated acetone (10 mL) three times, and the
combined washings were added to the autoclave. Hydrogen
was initially introduced into the autoclave at a pressure of 0.1
MPa, before being reduced to atmospheric pressure by
carefully releasing the stop valve. After this procedure was
repeated 10 times, the hydrogen pressure was introduced at 6
MPa, and the solution was stirred at 50 °C for 10 h. The
solution was cooled to room temperature, and hydrogen gas
was then carefully vented. After evaporation of the solvent, the
residue (syn-18/anti-18 = 4/1) was purified by silica gel
chromatography, eluted with 1:2 hexane−ethyl acetate to give
the pure hydrogenation product syn-18 (1.14 g, 57% yield,
Lab-Scale Synthesis of Benzyl 3-(2-methoxy-1-
(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate
(19). To a separatory funnel were charged 20·K (100.00 g,
0.304 mol, 1.0 equiv), 1 M aqueous hydrogen chloride solution
(500 mL, 0.500 mol, 1.50 equiv), and toluene (1 L, 10 vol).
After they were mixed, the phases were separated, and the
organic layer was washed with water (5 L). To a four-necked
round-bottom flask with an attached Dean−Stark trap were
charged this organic layer, aniline (25.45 g, 0.273 mol, 0.90
equiv), and p-toluenesulfonic acid monohydrate (0.58 g, 0.003
mol, 0.01 equiv). The suspension was heated to reflux (93 °C)
and stirred for 2 h while removing the water. Then the reaction
mixture was cooled to room temperature, before 500 mL of a 5
w/v% aqueous acetic acid solution was added. The phases
were separated, and the organic layer was washed with 500 mL
of a 5w/v% aqueous potassium bicarbonate solution, followed
by water (2 × 500 mL). The organic layer was evaporated to
87.34 g of concentrates under reduced pressure. The
concentrates were dissolved in methyl alcohol (10 L), and
activated carbon (Shirasagi-A, 10.00 g) was added. The
suspension was stirred at room temperature for 30 min and
filtered. The filter cake was rinsed with methyl alcohol (100
mL), and the filtrates were evaporated to dryness under
reduced pressure. The crude oil was dissolved with 500 mL of
ethyl acetate and evaporated to dryness under reduced
pressure. The crude oil was dissolved in 50 mL of ethyl
acetate and cooled to −10 °C. A seed crystal of 19 was added,
and heptane (400 mL) was added dropwise over 1 h at 0 °C.
The resulting suspension was then warmed to room temper-
ature and aged for 1 h. The solid was collected by filtration,
and the cake was washed with 150 mL of a 10/1 v/v heptane−
ethyl acetate solution and dried at 50 °C under vacuum to
yield 19 as a pale yellow solid (67.31 g, 60% yield, 95.1 area%
HPLC purity). 1H NMR (500 MHz, CDCl3) δ 10.57 (s, 1H),
7.46 (d, J = 7.88 Hz, 2H), 7.35−7.40 (m, 2H), 7.32 (d, J =
7.88 Hz, 3H), 7.10−7.15 (m, 3H), 5.32 (s, 2H), 4.04 (s, 2H),
3.83 (t, J = 7.72 Hz, 2H), 3.36 (s, 3H), 2.80 (t, J = 7.88 Hz,
2H). 13C NMR (126 MHz, CDCl3) δ 170.0, 152.3, 150.6,
139.3, 135.9, 129.2, 128.6, 128.2, 128.1, 124.4, 122.8, 98.7,
68.0, 67.6, 58.5, 43.6, 21.0. Anal. Calcd for C21H12N2O4: C,
68.84; H, 6.05; N, 7.65. Found: C, 68.63; H, 6.02; N, 7.72%.
HPLC: YMC-Pack ODS-A A-302 column (5 μm, 150 × 4.6
mm), MeCN/aq KH2PO4 (0.05 M, adjusted to pH 7 by 10%
aq KOH) 55/45, flow rate: 1.0 mL/min, oven temperature: 30
°C, detection: 220 nm (UV), tR: 11.2 min (19).
1
99.0 area% HPLC purity, 24.4% ee). H NMR (500 MHz,
CDCl3) δ 7.40−7.75 (m, 2H), 7.31−7.40 (m, 3H), 7.17 (t, J =
7.72 Hz, 2H), 6.69−6.76 (m, 3H), 5.22−5.33 (m, 2H), 4.11−
4.31 (m, 1H), 3.92−4.07 (m, 1H), 3.77−3.87 (m, 1H), 3.60−
3.69 (m, 2H), 3.54 (dd, J = 9.46, 5.04 Hz, 1H), 3.34 (s, 3H),
2.94 (td, J = 9.54, 4.26 Hz, 1H), 2.13−2.22 (m, 1H), 2.03−
2.13 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 174.8, 151.5,
147.0, 135.4, 129.4, 128.6, 128.4, 128.2, 118.3, 114.3, 73.4,
68.0, 59.1, 53.3, 45.8, 44.8, 20.8. Anal. Calcd for C21H24N2O4:
C, 68.46; H, 6.57; N, 7.60. Found: C, 68.55; H, 6.48; N,
7.63%. Liquid chromatography−mass spectrometry (LC-MS)
(ESI): tR = 7.27 min (97.9 area%); m/z 368, tR = 7.71 min (1.4
area%); m/z 368 as an anti-18. HPLC: YMC-Pack ODS-A A-
302 column (5 μm, 150 × 4.6 mm), MeCN/aq KH2PO4 (0.05
M, adjusted to pH 7 by 10% aq KOH) 55/45, flow rate: 1.0
mL/min, oven temperature: 30 °C, detection: 220 nm (UV),
tR: 7.2 min (rac-syn-18), tR: 7.6 min (rac-anti-18). Chiral
HPLC: CHIRALPAK AS-RH column (5 μm, 150 × 4.6 mm),
MeCN/aq K2HPO4 (0.05 M) 45/55, flow rate: 1.0 mL/min,
oven temperature: 25 °C, detection: 220 nm (UV), tR: 7.6 min
(syn-18), tR: 9.6 min (ent-syn-18).
Lab-Scale Synthesis of Benzyl (3aR,4R,9bR)-4-(methox-
ymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]-
quinoline-1-carboxylate para-toluenesulfonate (16·p-
TsOH). To a 120 mL stainless steel autoclave equipped with
a Teflon-coated stirring bar were added 19 (4.00 g, 10.92
mmol, 1.0 equiv) and cyanuric acid (1.41 g, 10.92 mmol, 1.00
equiv). The atmosphere was evacuated and filled with argon
gas seven times. To a 50 mL Schlenk tube were added
[Rh(cod)2]OTf (102.3 mg, 0.218 mmol, 0.020 equiv = s/c 50)
and (2S,4S)-PTBP-SKEWPHOS (174.2 mg, 0.262 mmol,
0.024 equiv). The atmosphere was evacuated and filled with
argon gas seven times, and this was followed by the addition of
dehydrated acetone (20 mL). The mixture was stirred at room
temperature for 1 h and then added to the above mixture of 19
and cyanuric acid. The used Schlenk tube was washed with
dehydrated acetone (60 mL) and 2,2-dimethoxypropane (3.90
mL, 32.75 mmol, 3.00 equiv), and the washings were added to
the autoclave. Hydrogen was initially introduced into the
autoclave at a pressure of 0.1 MPa, before being reduced to
atmospheric pressure by carefully releasing the stop valve. After
this procedure was repeated 10 times, the hydrogen pressure
was introduced at 6 MPa, and the solution was stirred at 50 °C
for 20 h. The solution was cooled to room temperature, and
hydrogen gas was then carefully vented. After evaporation of
the solvent, the residue (1% assay yield of 19, 5% assay yield of
syn-18 (anti-18 was not detected), and 92% assay yield of 16
with 64% ee) was evaporated to dryness. The residue was
diluted with ethyl acetate (40 mL) and evaporated to dryness.
The residue was diluted with ethyl acetate (40 mL) and
Authentic Sample Synthesis of Benzyl (R)-3-((R)-2-
methoxy-1-(phenylamino)ethyl)-2-oxopyrrolidine-1-carbox-
ylate (syn-18). To a 120 mL stainless steel autoclave equipped
with a Teflon-coated stirring bar was added 19 (2.00 g, 5.46
mmol, 1.0 equiv). The atmosphere was evacuated and filled
with argon gas seven times. To a 50 mL Schlenk tube were
added [Rh(cod)Cl]2 (134.6 mg, 0.273 mmol, 0.05 equiv) and
(2S,4S)-SKEWPHOS (264.6 mg, 0.601 mmol, 0.11 equiv).
The atmosphere was evacuated and filled with argon gas seven
times, and this was followed by the addition of dehydrated
acetone (10 mL). The mixture was stirred at room
temperature for 1 h and then added to 19 in a 120 mL
I
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filtered, and the filter cake was rinsed with ethyl acetate (10
mL). The seed crystal of 16·p-TsOH was inoculated to the
filtrate, and p-toluenesulfonic acid (2.07 g, 10.88 mmol, 1.00
equiv) was added at room temperature. The resulting
suspension was aged for 1 h. The solid was collected by
filtration, and the cake was washed with ethyl acetate (15 mL)
before being dried at 50 °C under vacuum to yield 16·p-TsOH
as a colorless solid (4.75 g, 83% yield, 95.7 area% HPLC
were charged L-tartaric acid (6.19 g, 41.24 mmol, 1.00 equiv)
and ethyl alcohol (248 mL, 27.6 vol). The suspension was
heated to 50 °C to dissolve all solids. The seed crystal of 2·L-
tartrate was inoculated, and 2 (9.00 g, 41.22 mmol, 1.0 equiv)
was added at 50 °C. The resulting suspension was aged at 50
°C for 30 min and cooled to room temperature. The solid was
aged for 1 h and collected by filtration, and then the cake was
washed with ethyl alcohol (54 mL) and dried at 50 °C under
vacuum to yield 2·L-tartrate as a colorless solid (11.75 g, 77%
1
purity, 63.1% ee). H NMR (500 MHz, CDCl3) δ 7.18−7.93
1
(m, 11H), 7.05 (d, J = 7.88 Hz, 2H), 5.13−5.38 (m, 3H),
3.89−4.10 (m, 2H), 3.71−3.88 (m, 1H), 3.19−3.40 (m, 4H),
2.71−2.89 (m, 1H), 2.30 (s, 3H), 1.82−2.09 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 156.6, 155.0, 141.2, 140.5, 136.6,
131.4, 131.0, 130.0, 129.5, 129.4, 129.0, 128.9, 128.8, 128.7,
128.6, 128.3, 128.1, 127.8, 125.9, 123.7, 123.6, 70.2, 70.1, 67.5,
67.3, 59.3, 55.4, 55.2, 53.1, 52.8, 45.5, 36.9, 36.1, 22.9, 21.9,
21.3. Anal. Calcd for C28H32N2O6S: C, 64.10; H, 6.15; N, 5.34;
S, 6.11. Found: C, 63.82; H, 6.29; N, 5.33; S, 6.12%. HPLC:
YMC-Pack ODS-A A-302 column (5 μm, 150 × 4.6 mm),
MeCN/aq KH2PO4 (0.05 M, adjusted to pH 7 by 10% aq
KOH) 55/45, flow rate: 1.0 mL/min, oven temperature: 30
°C, detection: 220 nm (UV), tR: 10.2 min (16). Chiral HPLC:
CHIRALPAK AD-H column (5 μm, 150 × 4.6 mm), hexane/
2-propylalcohol 9/1, flow rate: 1.0 mL/min, oven temperature:
25 °C, detection: 220 nm (UV), tR: 12.0 min (ent-16), tR: 13.2
min (16).
yield, 99.1 area% HPLC purity, 97.9% ee). H NMR (500
MHz, D2O) δ 7.12−7.25 (m, 2H), 6.80−6.90 (m, 1H), 6.73−
6.78 (m, 1H), 5.02 (d, J = 10.0 Hz, 1H), 4.42 (s, 2H), 3.42−
3.59 (m, 3H), 3.34 (s, 3H), 3.12−3.28 (m, 2H), 2.73−2.88
(m, 1H), 1.85−2.11 (m, 2H). 13C NMR (126 MHz, D2O) δ
176.4, 145.8, 130.2, 129.6, 120.2, 116.8, 116.5, 73.5, 72.8, 58.5,
57.8, 51.2, 44.7, 38.7, 22.7.
Authentic Sample Synthesis of (3aS,4R,9bR)-4-(methox-
ymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]-
quinoline L-tartrate (2·L-tartrate). To a four-necked round-
bottom flask were charged L-tartaric acid (3.00 g, 20.0 mmol,
1.00 equiv) and ethyl alcohol (15 mL, 3.4 vol). The suspension
was heated to 70 °C to dissolve all solids, before 2 (4.37 g, 20.0
mmol, 1.0 equiv, >99.9% ee) and ethyl acetate (30 mL, 6.9
vol) were added at 70 °C. The resulting suspension was aged
at 70 °C for 30 min and cooled to room temperature. The
solid was aged overnight and collected by filtration, and then
the cake was washed with a 1/2 v/v ethyl alcohol−ethyl
acetate solution and dried at 50 °C under vacuum to yield 2·L-
tartrate as a colorless solid (7.19 g, 98% yield, 98.8 area%
HPLC purity, >99.9% ee). mp 175 °C; [α]20D −16.3° (c =
1.0, H2O); IR (KBr): 3385, 3319, 3275, 3051, 2870, 2843,
2737, 2515, 2453, 1701, 1611, 1553, 1491, 1408, 1373, 1308,
Lab-Scale Synthesis of (3aS,4R,9bR)-4-(Methoxymethyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (2). To
a four-necked round-bottom flask were charged 16·p-TsOH
(47.37 g, 90.29 mmol, 1.0 equiv) and a 6 M aqueous hydrogen
chloride solution (237 mL, 0.142 mol, 15.75 equiv). This
suspension was heated to 80 °C and stirred for 2 h. The
reaction mixture was cooled to 25 °C, and toluene (237 mL)
was added. The phases were separated, and activated carbon
(Shirasagi-A, 3.16 g) was added to the aqueous layer. The
suspension was stirred at room temperature for 30 min and
filtered, and then the filter cake was rinsed with water (119
mL). An 8 M aqueous sodium hydroxide solution (288 mL)
was added dropwise to the filtrate with the internal
temperature maintained below 30 °C. The resulting
suspension was stirred at room temperature for 1 h. The
solid was collected by filtration, and the cake was washed with
water (95 mL) and dried at 60 °C under vacuum to yield 2 as a
colorless solid (16.88 g, 86% yield, 94.7 area% HPLC purity,
1
1263, 1136, and 877 cm−1. H NMR (500 MHz, D2O) δ
7.07−7.21 (m, 2H), 6.81 (t, J = 7.57 Hz, 1H), 6.72 (d, J = 8.20
Hz, 1H), 4.98 (d, J = 9.14 Hz, 1H), 4.39 (s, 2H), 3.38−3.56
(m, 3H), 3.31 (s, 3H), 3.08−3.24 (m, 2H), 2.70−2.84 (m,
1H), 1.82−2.04 (m, 2H). 13C NMR (126 MHz, D2O) δ 176.4,
145.8, 130.1, 129.5, 120.2, 116.8, 116.5, 73.5, 72.8, 58.5, 57.7,
51.2, 44.7, 38.6, 22.7. Anal. Calcd for C17H24N2O7: C, 55.43;
H, 6.57; N, 7.60. Found: C, 55.38; H, 6.69; N, 7.52%. HRMS
(m/z, ESI+) for C12H18N2O as a free base (M+H)+ calcd
219.1492, measd 219.1463.
Manufacturing for Preclinical Research. Kilogram-Scale
Synthesis of Benzyl 2-oxopyrrolidine-1-carboxylate (21). To
a reactor were charged sodium hydroxide (35.6 kg, 0.890 kmol,
1.00 equiv), pyrrolidin-2-one (75.0 kg, 0.881 kmol, 1.0 equiv),
and toluene (1297.5 kg). This suspension was heated to 110
°C for 12 h, while azeotropic dehydration by toluene
distillation was performed. Fresh toluene (total 6487.5 kg)
was used to replace the toluene removed by azeotropic
dehydration. The reaction mixture was cooled to 0 °C, and to
the suspension was added benzyl chloroformate (151.8 kg,
0.890 kmol, 1.00 equiv) over 2 h with the internal temperature
maintained below 10 °C. The reaction mixture was stirred at 5
°C for 1 h, and the reaction was quenched by addition of water
(375 L) over 15 min with the internal temperature maintained
below 10 °C. The mixture was warmed to 23 °C. The phases
were separated, and the organic layer was washed with 387.4
kg of a 5% aqueous potassium hydrogen sulfate solution, then
with water (2 × 375 L). The phases were separated, and
magnesium sulfite (30.0 kg) was added to the organic layer.
The mixture was filtered, and the cake was washed with
toluene (64.9 kg). The filtrate was concentrated under reduced
1
70.2% ee). H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 7.57
Hz, 1H), 7.02 (t, J = 7.57 Hz, 1H), 6.75 (t, J = 7.41 Hz, 1H),
6.57 (d, J = 7.88 Hz, 1H), 4.42 (d, J = 7.88 Hz, 1H), 4.09 (s,
1H), 3.61−3.68 (m, 1H), 3.46−3.51 (m, 1H), 3.41 (s, 3H),
3.37−3.41 (m, 1H), 2.88−2.96 (m, 1H), 2.80−2.88 (m, 1H),
2.37−2.47 (m, 1H), 1.97 (br s, 1H), 1.75−1.84 (m, 1H),
1.64−1.73 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 144.8,
129.0, 127.5, 125.4, 119.0, 114.9, 75.5, 59.0, 57.7, 52.5, 45.6,
41.0, 24.9. HPLC: YMC-Pack ODS-A A-302 column (5 μm,
150 × 4.6 mm), MeCN/aq KH2PO4 (0.05 M, adjusted to pH
7 by 10% aq KOH) 55/45, flow rate: 1.0 mL/min, oven
temperature: 30 °C, detection: 220 nm (UV), tR: 2.2 min (2).
Chiral HPLC: CHIRALCEL OD-RH column (5 μm, 150 ×
4.6 mm), MeCN/aq KPF6 (0.10 M) 15/85, flow rate: 1.0 mL/
min, oven temperature: 25 °C, detection: 254 nm (UV), tR:
16.0 min (ent-2), tR: 17.7 min (2).
Lab-Scale Synthesis of (3aS,4R,9bR)-4-(Methoxymethyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline L-tar-
trate (2·L-tartrate). To a four-necked round-bottom flask
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pressure to the extent possible. Tetrahydrofuran (333.4 kg)
was added, and the mixture was concentrated under reduced
pressure to the extent possible. The concentrates were diluted
with tetrahydrofuran (26.7 kg), and the resulting solution
containing 21 (181.80 kg of 21 in 209.05 kg solution, 86.9 w/
w% assay, 94.1% yield) was used directly in the next step.
HPLC analysis of a sample evaporated to dryness matched the
analysis of one from the lab-scale synthesis.
(19). To a reactor were charged 1 M aqueous hydrogen
chloride solution (978 kg, 0.978 kmol, 1.76 equiv), 20·K(183.4
kg, 0.557 kmol, 1.0 equiv), and toluene (1586.4 kg, 10.0 vol).
The reaction mixture was stirred for 10 min at 25 °C. The
phases were separated, and the organic layer was washed with
water (917.0 kg, 5 vol). Aniline (49.3 kg, 0.529 mol, 0.95
equiv), p-toluenesulfonic acid monohydrate (1.06 kg, 5.572
mol, 0.01 equiv), cyclohexane (1912.3 kg, 13.5 vol), and
toluene (888.4 kg, 5.6 vol) were added to the organic layer.
The reaction mixture was heated to 96 °C for 2 h to allow
azeotropic dehydration of the organic solvent (2580 L of 6/4
v/v a cyclohexane−toluene mixture was used to replace the
solvent removed by azeotropic dehydration). The reaction
mixture was then cooled to 0 °C, and a 5% aqueous acetic acid
solution (922.1 kg, 1.38 equiv) was added at 3 °C followed by
stirring for 10 min. The phases were separated, and the organic
layer was washed with a 5% aqueous sodium hydrogen
carbonate solution (950.5 kg). The organic layer was washed
with water (2 × 917.0 kg) and concentrated under reduced
pressure to the extent possible. The concentrates were then
diluted with methyl alcohol (1305.6 kg, 9 vol). Activated
carbon (18.3 kg) was added to the methyl alcohol solution,
and the suspension was stirred for 0.5 h at 23 °C. The mixture
was filtered, and the cake was washed with methyl alcohol
(145.1 kg). The filtrate was concentrated under reduced
pressure to the extent possible. Ethyl acetate (827.3 kg) was
added, and the mixture was concentrated under reduced
pressure to the extent possible. The concentrates were diluted
with ethyl acetate (82.7 kg) and cooled to 6 °C. A seed of 19
(69.0 g) was added, and heptane (504.7 kg, 4.0 vol) was added
to promote the crystallization over 2 h with the internal
temperature maintained below 15 °C. The suspension was
warmed to 25 °C and aged for 9 h. The solid was collected by
filtration, and the cake was washed with 555 L of a 4/1 v/v
heptane−ethyl acetate solution and dried under vacuum at 40
°C to yield 19 as a pale yellow solid (150.1 kg, 74% yield).
HPLC analysis of a sample matched that of one from the lab-
scale synthesis.
Kilogram-Scale Synthesis of Benzyl (3aR,4R,9bR)-4-
(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-
c]quinoline-1-carboxylate para-toluenesulfonate (16·p-
TsOH). A 500 L pressure reactor was charged with 19 (37.5
kg, 0.102 kmol, 1.0 equiv), cyanuric acid (13.2 kg, 0.102 kmol,
1.00 equiv), and [Rh(cod){(2S,4S)-ptbp-skewphos}]OTf
(1741.5 g, 1.70 mol, 0.0167 equiv, s/c 60). The reactor was
evacuated to −0.09 MPa and then filled with nitrogen to 0.10
MPa. This operation was repeated five times. To the reactor
were added 2,2-dimethoxypropane (16.0 kg, 0.154 kmol, 1.51
equiv) and anhydrous acetone (375 L, 10 vol) by nitrogen gas
feed. The reactor was pressurized with nitrogen (0.60 MPa),
vented three times, and then pressurized with hydrogen (0.60
MPa) and vented three times. The hydrogen pressure was set
to 3.0 MPa, and heating was started. After a reaction
temperature of 45 °C was reached, the pressure was adjusted
to 5.5 MPa. The reaction mixture was stirred with the
hydrogen pressure maintained within the range of 5.0−6.0
MPa at 40−50 °C (set point 45 °C) for 48 h. The reactor was
cooled below 30 °C, and the hydrogen was carefully vented.
The reactor was pressurized with nitrogen (0.60 MPa) and
vented six times. The reaction mixture was concentrated under
reduced pressure to the extent possible. Ethyl acetate (187.5 L,
5 vol) was added, and the mixture was concentrated under
reduced pressure to the extent possible. The concentrates were
Kilogram-Scale Synthesis of Potassium 1-(1-((Benzyloxy)-
carbonyl)-2-oxopyrrolidin-3-ylidene)-2-methoxyethan-1-
olate (20·K). All reactions were performed under a positive
pressure of nitrogen. To a reactor A were charged bis-
(trimethylsilyl)amine (116.5 kg, 0.722 kmol, 1.81 equiv) and
tetrahydrofuran (304.8 kg, 4 vol). The solution was cooled to
−80 °C, and n-butyllithium (309.1 kg of a 1.6 M solution in
hexane, 0.755 kmol, 1.88 equiv) was added dropwise over 6 h
with the internal temperature maintained below −55 °C. The
charging line was washed with tetrahydrofuran (7.9 kg), and
the resulting solution was stirred with the internal temperature
maintained below −55 °C for 1 h. To this solution was added a
solution of 21 (87.9 kg, 0.401 kmol, 1.0 equiv) in
tetrahydrofuran (70.3 kg) over 1.5 h, with the internal
temperature maintained below −60 °C. The charging line
was washed with tetrahydrofuran (7.8 kg), and the resulting
solution was stirred with the internal temperature maintained
below −60 °C for 1 h. To this solution was added a solution of
2-methoxy acetyl chloride (47.9 kg, 0.441 kmol, 1.10 equiv) in
tetrahydrofuran (70.3 kg), with the internal temperature
maintained below −60 °C over 3 h. The charging line was
washed with tetrahydrofuran (7.8 kg), and the resulting
solution was stirred for 1.5 h with the internal temperature
maintained below −60 °C. Then the mixture was warmed to 5
°C, and the reaction was quenched by addition of acetic acid
(69.2 kg) over 40 min with the internal temperature
maintained below 15 °C, and toluene (380.2 kg) was added
with the internal temperature maintained below 10 °C. To 4 M
aqueous hydrogen chloride solution (374.7 kg) in a reactor B
was added the reaction mixture from reactor A over 0.5 h, and
the mixture was then stirred for 10 min. The phases were
separated, and the organic layer was washed with an 8%
sodium hydrogen carbonate solution (3 × 439.2 kg) and water
(440.0 kg). The organic layer was concentrated under reduced
pressure to the extent possible. The oil was then diluted with
ethyl alcohol (461.0 kg, 6.6 vol), and a 40% aqueous potassium
carbonate solution (415.3 kg, 3.00 equiv) was added. The
resulting suspension was stirred at 25 °C for 10 h. Water
(416.0 kg) was added to the suspension to dissolve the slurry,
and then ethyl acetate (631.9 kg) was added. The phases were
separated, and the organic layer was concentrated under
reduced pressure to the extent possible. The concentrates were
then diluted with ethyl alcohol (347.4 kg, 5 vol) and
concentrated under reduced pressure to remove the organics
(ca. 260 L). Ethyl alcohol (347.4 kg, 5 vol) was added, and the
reaction mixture was concentrated under reduced pressure to
remove the organics (ca. 435 L). Ethyl acetate (1506.9 kg, 21.6
vol) was added, and the suspension was stirred at 25 °C for 3
h. The solid was collected by filtration, and the cake was
washed with 143 L of a 10/1 v/v ethyl acetate−ethyl alcohol
solution and dried under vacuum at 60 °C to yield 20·K as a
pale yellow solid (44.6 kg, 34% yield). HPLC analysis of a
sample matched that of a sample from a lab-scale synthesis.
Kilogram-Scale Synthesis of Benzyl 3-(2-methoxy-1-
(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate
K
DOI: 10.1021/acs.oprd.8b00365
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
diluted with ethyl acetate (375.0 L, 10 vol) and stirred at 25 °C
for 1 h. The insolubles were removed by filtration and washed
with ethyl acetate (93.8 L, 2.5 vol). p-Toluenesulfonic acid
(19.5 kg, 0.103 kmol, 1.00 equiv) was added to the filtrate, and
the mixture was stirred at 25 °C for 1 h. The solid was
collected by filtration, and the cake was washed with ethyl
acetate (350 L, 10 vol) before being dried at 50 °C under
vacuum to yield 16·p-TsOH as a colorless solid (48.3 kg, 90%
yield, 75.0% ee). HPLC analysis of a sample matched that of
one from the lab-scale synthesis.
Kilogram-Scale Synthesis of (3aS,4R,9bR)-4-(Methoxy-
methyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
(2). To a reactor were charged 16·p-TsOH (127.1 kg, 0.243
kmol, 1.0 equiv) and a 6 M aqueous hydrogen chloride
solution (686.3 kg, 4.12 kmol, 16.95 equiv). The resulting
suspension was heated to 80 °C, stirred for 2 h, and then
cooled to 25 °C before adding toluene (635.5 L, 5 vol). After
they were stirred for 15 min, the phases were separated, and
activated carbon (Shirasagi-A, 8.6 kg) was added to the
aqueous layer. The suspension was stirred at 25 °C for 30 min
and filtered, and the filter cake was rinsed with water (127 L, 1
vol). An 8 M aqueous sodium hydroxide solution (762.6 L, 6
vol) was added dropwise to the filtrate with the internal
temperature maintained below 30 °C. The resulting
suspension was stirred at room temperature for 2 h. The
solid was collected by filtration, and the cake was washed with
water (254.2 L, 2 vol) before being dried at 50 °C under
vacuum to yield 2 as a colorless solid (46.4 kg, 88% yield,
80.0% ee). HPLC analysis of a sample matched that of one
from the lab-scale synthesis.
Kilogram-Scale Synthesis of (3aS,4R,9bR)-4-(Methoxy-
methyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
L-tartrate (2·L-tartrate). To a four-necked round-bottom flask
were charged L-tartaric acid (31.9 kg, 0.213 kmol, 1.00 equiv)
and ethyl alcohol (1300 L, 28 vol). The suspension was heated
to 50 °C to dissolve the solid, and then a seed crystal of 2·L-
tartrate (5 g) was inoculated, and 2 (46.4 kg, 0.213 kmol, 1.0
equiv) was added at 50 °C. The resulting suspension was aged
at 50 °C for 30 min and cooled to 25 °C. The solid was aged
for 2 h before being collected by filtration, and then the cake
was washed with ethyl alcohol (278.4 L, 6 vol) and dried at 50
°C under vacuum to yield 2·L-tartrate as a colorless solid
(62.0 kg, 79% yield, >99.9% ee). HPLC analysis of a sample
matched that of one from the lab-scale synthesis.
ACKNOWLEDGMENTS
■
We thank our industrial partners Hamari Chemicals, Ltd., for
the manufacturing operation of the stereoselective hydrogen-
mediated domino cyclization, and FUJIFILM Wako Pure
Chemical Corporation for catalyst preparation. Also, we thank
TAKEDA colleagues T. Ishida, M. Kajino, and Y. Kondo and
SPERA colleagues H. Mizufune and T. Fujitani for their
helpful discussion to this project.
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ASSOCIATED CONTENT
* Supporting Information
This material is available free of charge via Internet at The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.oprd.8b00365.
■
S
General analytical methods and copies of HPLC
chromatogram, 1H NMR and 13C NMR for compounds
21, 20·K, 19, syn-18, 16·p-TsOH, 2, and 2·L-tartrate
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: masatoshi.yamada@spera-pharma.co.jp.
■
ORCID
Masatoshi Yamada: 0000-0002-8390-6021
Notes
The authors declare no competing financial interest.
L
DOI: 10.1021/acs.oprd.8b00365
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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