Practical synthesis of PGI2 agonist: Resolution-inversion- recycle approach of its chiral intermediate

Article abstract of DOI:10.1021/op3003085

Practical synthesis of ((2R)-5-benzyloxy-2-hydroxy-1,2,3,4- tetrahydronaphth-2-yl)methanol ((R)-7b), a key chiral intermediate for the synthesis of the novel PGI₂ agonist, (R)-[6-[(diphenylcarbamoyloxy) methyl]-6-hydroxy-5,6,7,8-tetrahydronapht

Full text of DOI:10.1021/op3003085

Article
pubs.acs.org/OPRD
Practical Synthesis of PGI2 Agonist: Resolution−Inversion−Recycle
Approach of Its Chiral Intermediate
Atsushi Ohigashi,* Atsushi Kanda, Shigeru Moriki, Yukihisa Baba, Norio Hashimoto, and Minoru Okada
Process Chemistry Labs, Astellas Pharma Inc., 160-2, Akahama, Takahagi-shi, Ibaraki 318-0001, Japan
ABSTRACT: Practical synthesis of ((2R)-5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol ((R)-7b), a key chiral
intermediate for the synthesis of the novel PGI2 agonist, (R)-[6-[(diphenylcarbamoyloxy)methyl]-6-hydroxy-5,6,7,8-tetrahydronaph-
thalen-1-yloxy]acetic acid (1), was achieved via optical resolution by diastereoselective crystallization of ester derivative 18 of racemic
(5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol (7b) with (1S,4R)-(−)-camphanic acid ((−)-CpOH) followed by
saponification. Starting from commercially available 5-hydroxy-1-tetralone (2), this process features recycling of the undesired
enantiomer (S)-7b via inversion of the C2 hydroxyl group by acid-catalyzed hydrolysis of its epoxide derivative (S)-11. Performing
this resolution−inversion−recycle approach provided a 44% overall yield of (R)-7b (>99% ee) from racemic 7b. The enantiopure
(R)-7b synthesized by this approach was then used to prepare 1. This robust, reproducible, and scalable synthesis of 1 was successfully
demonstrated on a pilot scale.
a
Scheme 1. Medicinal chemistry route to 1
INTRODUCTION
■
Prostacyclin (PGI2) is a potent vasorelaxant and inhibitor of
human platelet aggregation that acts at a specific G protein-
coupled receptor: the IP receptor.1 Despite being imbued with a
number of fascinating pharmacological properties, the inherent
instability and side effects of PGI2 limit its therapeutic applicability.
Recently, the medicinal chemistry groups at Astellas Pharma Inc.
discovered that non-PG structural compound 1 exhibited highly
potent PGI2 agonistic activity with good selectivity for the IP
receptor, improved solubility, and good bioavailability.2 The key
structural feature of 1 is a tetrahydronaphthalene backbone with a
chiral tertiary hydroxyl group of (R)-configuration (Figure 1).
Figure 1. Chemical structure of 1.
Here, in order to supply sufficient quantities required for
further preclinical and clinical studies, we conducted a practical scale-
up synthesis of 1. Our efforts were focused on the development of an
efficient synthesis of the chiral tetrahydronaphthalene core. The
medicinal chemistry route2 to 1 involved the Sharpless asymmetric
dihydroxylation reaction3 of α,β-unsaturated ester 5 with AD-mix-α4
to construct the key chiral intermediate (R)-7a (Scheme 1).
However, this route was deemed unlikely to be ideal for large-
scale production, due to the potential for contamination of
both the toxic osmium and cyanide wastes from this reaction in
the drug substance. Use of AD-mix-α also introduced toxic waste
handling and disposal problems. Further, this process suffered
from the following drawbacks associated with the preparation
of 1: (1) step 2 gave 4 with 29% of the over-reduced alcohol
Imp A; (2) step 4 gave inconsistent results with a mixture of
6 and 17% of the overoxidized ketone Imp B; (3) step 5 gave
a
Reagents: (a) TBDPSCl, imidazole; (b) (EtO)2CO, NaH; (c) NaBH4;
(d) KHSO4; (e) AD-mix-α; (f) CBr4, PPh3; (g) LiAlH4; (h) ClCONPh2,
pyridine; (i) TBAF; (j) BrCH2CO2Et, K2CO3; (k) recrystallization from
diethyl ether/n-hexane; (l) aq NaOH.
Received: October 30, 2012
Published: February 26, 2013
© 2013 American Chemical Society
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incomplete reduction to (R)-7a by LiAlH4 due to residual CBr4
in the brominated intermediate; (4) step 6 used recrystallization of
8 with an unacceptable level of mother liquor loss while upgrading
the ee of 1. In addition, this route included several tedious, time-
consuming, and inefficient silica gel chromatographic separation
steps.
During the development of the medicinal chemistry route,
the medicinal chemistry group also investigated the Katsuki−
Sharpless asymmetric epoxidation5 of 9 as an alternative route
(Scheme 2); however, both the ee and yield were disappointingly
RESULTS AND DISCUSSION
■
Synthesis of Racemic Diol 7b via 2-Tetralone 16. We
sought an efficient method of synthesizing 7b from commercially
available 2 via 2-tetralone 16 (Scheme 4). While synthetic methods
a
Scheme 4. Synthesis of 7b via 2-tetralone 16
a
Scheme 2. Alternative asymmetric route to (R)-7a
a
Reagents: (a) DlBALH; (b) Ti(Oi-Pr)4, t-BuOOH, (−)-diethyl
tartrate; (c) H2, Pd/C.
low (71% ee and 31% isolated yield based on 5). Therefore, these
asymmetric approaches did not encourage further investigation
into the practical synthesis of 1.
a
Reagents: (a) BnCl, K2CO3, DMF; (b) NaBH4, EtOH, toluene;
Large numbers of elaborate asymmetric syntheses are
developed for use in preparing chiral compounds, while efficient
separation processes such as crystallization-based chiral reso-
lution are widely applicable to a broad spectrum of substances.
With that in mind, we considered a synthetic route for the chiral
key intermediate (R)-7b starting from commercially available
5-hydroxy-1-tetralone (2), as well as a medicinal chemistry route,
using a diastereomeric resolution approach. However, this res-
olution approach theoretically suffered from the disadvantage of
low yields caused by the loss of at least 50% of the undesired
enantiomer (S)-7b. Consequently, an efficient recycling process
where such loss was minimized was required to use the diaste-
reomeric resolution process more effectively. To overcome this
problem, we developed a process to recycle (S)-7b, utilizing the
inversion of the C2 hydroxy group by acid-catalyzed hydrolysis of
its epoxide derivative (S)-11 (Scheme 3).
(c) cat. KHSO4, toluene; (d) m-CPBA, toluene; (e) cat. TsOH, toluene;
(f) M3SOI, t-BuOK, toluene; (g) γ-alumina; (h) cat. TsOH, aq. THF;
(i) recrystallization from toluene.
for conversion of 1-tetralones to 2-tetralones have been reported, a
publication by Hauser and Prasanna appeared to be the most
attractive route for large-scale synthesis of 16 due to the relatively
mild conditions needed for this transposition;6 however, their
method was unsuitable for large-scale synthesis because of the use
of toxic osmium tetraoxide, carcinogenic benzene solvent, and silica
gel chromatographic separation steps. To address these issues,
we developed a synthetic route to 7b via 16 based on several
modifications to Hauser and Prasanna’s route and procedure.
The benzyl group was selected as a protecting group for the
hydroxyl function of 2 due to the stability of benzyl ether to both
acidic and basic conditions and its ease of removal under mild
conditions by catalytic hydrogenation. Benzyl-protected com-
pound 12 was obtained quantitatively after treatment of 2 with
BnCl in the presence of K2CO3. Benzyl-protected 12 was con-
verted into 15 by reduction with NaBH4, dehydration with
KHSO4, followed by epoxidation with m-CPBA.7
Scheme 3. Process chemistry route to (R)-7b based on the
diastereomeric resolution approach with recycling of the
undesired (S)-7b
Two synthetic approaches to prepare 16 from 15 were investi-
gated. First, we attempted to obtain 16 via diol 17. Treatment
of 15 with KOH in 60% aqueous DMSO solution followed by
TsOH in toluene gave 16, but the results were disappointing,
with low yield and complicated impurities (48% isolated yield
based on 15). Second, a more direct approach was tried by
Meinwald rearrangement8 of 15 in the presence of various acid
catalysts such as HCO2H, TFA, MsOH, TsOH, and BF3 (Table 1).
The use of 0.5 equiv of HCO2H or TFA resulted in complex
impurities with mostly unchanged 15, while 0.1 equiv of MsOH or
TsOH gave relatively good yields (69% and 72%, respectively),
and TsOH afforded somewhat better results. In case of BF3, a
disappointing 34% yield with complex impurities was obtained.
While a Corey−Chaykovsky epoxidation reaction9 of 16 with
Me3SI and t-BuOK in dimethoxyethane (DME) did not occur,
epoxidation with Me3SOI delivered 11 in 74% yield. Subsequent
We report here the practical synthesis of enantiomerically
pure, key intermediate (R)-7b via a diastereomeric resolution
approach incorporating recycling of the undesired enantiomer
(S)-7b and describe its application for the synthesis of 1.
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Table 1. Effect of acid catalysts in Meinwald rearrangement of
15 to 16
Table 3. Recrystallization of 18 from alcohols
a
a
entry
solvent
isolated yield (%)
ratio (R)-18/(S)-18
entry
acid (equiv)
reaction conditions
yield (%)
1
2
3
4
MeOH
EtOH
35
31
40
73
96:4
b
1
2
3
4
5
HCO2H (0.5)
TFA (0.5)
90 °C, 4.0 h
90 °C, 1.5 h
90 °C, 1.0 h
90 °C, 0.5 h
5 °C, 1.5 h
−
−
93:7
b
EtOH
89:11
60:40
MsOH (0.1)
TsOH (0.1)
BF3 (0.3)
69
72
34
i-PrOH
a
40 volumes in entries 1 and 3, and 60 volumes in entries 2 and 4.
a
Twelve volumes of toluene were used as the solvent in all entries.
Reacted very slowly and formed unacceptable amounts of impurities.
oil out (entry 1). Diastereomeric 18 was recrystallized from EtOH
(60 volumes) to give (R)-18 with good diastereomeric purity but
poor yield (entry 2). To improve the yield, we investigated the
implementation of volume reduction of EtOH for the recrystalliza-
tion. Reduced volume of EtOH (40 volumes) led to improved
yield and acceptable diastereomeric purity of (R)-18 (entry 3). In
contrast, recrystallization from i-PrOH resulted in disappointing
diastereomeric purity (entry 4). According to these results,
recrystallization of 18 twice from EtOH (40 volumes) successfully
provided 34% isolated yield of diastereomerically pure (R)-18
(>99% de). After the hydrolysis of (R)-18 in aqueous NaOH
solution, 91% isolated yield of enantiopure (R)-7b (>99% ee) was
obtained. Thus, racemic 7b was successfully resolved into (R)-7b
(>99% ee, 30% overall yield) via optical resolution of diastereomeric
derivative 18.
b
treatment of 11 with a catalytic amount of TsOH in aqueous
THF solution resulted in 73% yield of 7b, while NaOH in
aqueous i-PrOH solution required harsh reaction conditions and
produced a worse yield (52% yield, Table 2).
Table 2. Hydrolysis of 11 to 7b
a
entry
acid or base (equiv)
TsOH (0.1)
reaction conditions
.yield (%)
1
2
rt, 6 h
73
52
b
aq NaOH (6.0)
80 °C, 17 h
a
Aqueous THF 77% (26 volumes) and i-PrOH (8 volumes) were used
b
as the solvent in entries 1 and 2, respectively. Aqueous NaOH solution
24% (w/v) was used.
However, the combined mother liquor from the two EtOH
recrystallizations still contained as much as 50% of the
diastereomerically enriched undesired (S)-18 based on 18. To
recover the diastereomerically enriched undesired (S)-18 from
the mother liquors, the combined liquors were concentrated
under reduced pressure, and the resulting residue was then
crystallized from n-heptane to produce the diastereomerically
enriched undesired (S)-18 in 52% isolated yield based on 18.
This compound was then hydrolyzed by treatment with aqueous
NaOH solution to give enantiomerically enriched (S)-7b (R/S =
31:69) in 92% isolated yield. Further, we were able to quantitatively
recover relatively expensive (−)-CpOH from the mother liquor
after hydrolysis (see Experimental Section).
We next tested two synthetic strategies to recycle the undesired
(S)-7b to the desired (R)-7b (Scheme 6). The first strategy was
the more effective and practical of the two and involved the
inversion of the C2 hydroxyl group of (S)-7b by hydrolysis of its
epoxide derivative (S)-11, while the second involved the oxidative
cleavage of diol (S)-7b to 2-tetralone 16 using NaIO4.
On establishing large-scale synthesis of 7b, we subsequently
focused on making the process more efficient and productive. As
a result of toluene-based solvent unification and minimal solvent
switches, an easier process of 7b synthesis was achieved with a
25% isolated yield based on 2 (see Experimental Section).
Diastereomeric Resolution of Racemic Diol 7b into the
Desired (R)-7b and Recycle of the Undesired (S)-7b. To
determine the optical resolution of 7b, wefirst examined crystallinity
of the diastereomeric ester derivatives of 7b with three chiral acids:
(−)-menthoxyacetic acid, (1R)-(−)-camphorsulfonic acid, and
(1S,4R)-(−)-camphanic acid ((−)-CpOH).10 Of the acids
tested, only 18 formed from 7b and (−)-CpOH was found to
crystallize; as such, we attempted to diastereomerically resolve
18 by recrystallization (Scheme 5). Racemic diol 7b reacted with
(−)-CpOH in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride (EDC·HCl), and a catalytic amount of
N,N-dimethyl-4-aminopyridine (DMAP) to give 18 in 96% isolated
yield. Among the compounds investigated for diastereomeric reso-
lution (MeOH, EtOH, and i-PrOH; Table 3), the use of MeOH
gave (R)-18 of the best diastereomeric purity, but (R)-18 tended to
We investigated the inversion of the C2 hydroxyl group of (S)-7b
via epoxide (S)-11. Treatment of the enantiomerically enriched
(S)-7b with MsCl and N-methylmorpholine (NMM) followed
Scheme 5. Optical resolution of 7b into (R)-7b via diastereomeric ester 18 and recovery of the undesired (S)-7b
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Scheme 6. Recycling the undesired (S)-7b
by t-BuOK gave its epoxide derivative (S)-11 quantitatively.
Acid hydrolysis of (S)-11 to (R)-7b in aqueous DME solution pro-
ceeded smoothly at room temperature, causing inversion with a
slight loss of stereochemistry (Table 4). Although almost the same
Scheme 7. Synthesis of 1
Table 4. Acid-catalyzed hydrolysis of the enantiomerically
a
enriched (S)-11
entry
acid (equiv)
aq DME (vol) enantiomer ratio R/S yield (%)
1
2
3
4
TsOH (0.1)
MsOH (0.1)
MsOH (0.1)
MsOH (0.3)
61% (31)
61% (31)
50% (14)
50% (14)
65:35
65:35
64:36
65:35
74
76
77
76
a
Epoxide (S)-11 derived from (S)-7b (R/S = 31:69) was treated with
HCO2NH4 and Pd/C in 95% isolated yield (Scheme 7). In the
medicinal chemistry route, ester compound 8 was isolated at
the next O-alkylation step of 21, although both the finished
drug substance 1 as well as intermediate 8 cause significant
vasorelaxation at low concentrations (Scheme 1). Consequently,
we attempted to combine the O-alkylation step and the sub-
sequent hydrolysis step to alleviate safety concerns related to
the large-scale synthesis of 1. As a result, treatment of 21 with
ethyl bromoacetate and K2CO3 in DMF and addition of NaOH
in aqueous THF solution after completion of the O-alkylation
reaction produced 1 (>99% ee) in 91% isolated yield in a one-pot
fashion.
acid in aqueous DME solution at room temperature for 2 h.
results were obtained for all cases, the combination of 0.1 equiv
of MsOH and 14 volumes of 50% aqueous DME solution (entry 3)
was determined to be the best choice on the basis of reduction of
solvent and reagent and was selected for use in our subsequent
studies. After fine-tuning the synthetic procedure, the enantiomeri-
cally enriched (R)-7b (R/S = 67:33) was obtained from (S)-7b
(R/S = 31:69) via its epoxide derivative in 66% isolated yield
(see Experimental Section).
We also investigated the oxidative cleavage of diol (S)-7b to
2-tetralone 16 by NaIO4. Treatment of the enantiomerically
enriched (S)-7b with NaIO4 in the presence of a catalytic amount
of n-Bu4NSO4 in a toluene−water biphasic system gave 16, and
the subsequent Corey−Chaykovsky epoxidation reaction of 16
with Me3SOI and t-BuOK followed by acid-catalyzed hydrolysis
with MsOH in aqueous DME solution delivered the racemic 7b
in 49% isolated yield based on the enantiomerically enriched
(S)-7b. Because of the higher yield and more favorable enantiomeric
ratio of 66% isolated yield (R/S = 67:33) vs 49% isolated yield
(R/S = 50:50), we selected the route of inversion of the C2
hydroxyl group of (S)-7b via epoxide (S)-11 in our manufacturing
process. Following the aforementioned diastereomeric resolution
approach with some modifications, the enantiomerically pure (R)-
7b (>99% ee) was obtained from the enantiomerically enriched
(R)-7b in 47% isolated yield (see Experimental Section). Thus,
performing this resolution−inversion−recycle approach provided
44% overall yield of (R)-7b (>99% ee) from racemic 7b.
CONCLUSIONS
■
Here, we have described a practical and scalable method of syn-
thesizing ((2R)-5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydro-
naphth-2-yl)methanol ((R)-7b), a key chiral intermediate for
the synthesis of PGI2 agonist 1. The enantiomerically pure
(R)-7b was obtained with >99% ee and 44% overall yield from
racemic 7b by the combination via diastereoselective crystal-
lization of ester derivative 18 of 7b and recycling of the undesired
enantiomer (S)-7b. Advantages over the original methods are
avoidance of the troublesome AD-mix-α and several inefficient
silica gel chromatographic separation steps. Further, the syn-
thesized (R)-7b can be used to prepare 1. This highly efficient and
scalable process was successfully demonstrated in the large-scale
synthesis of 1.
EXPERIMENTAL SECTION
■
Synthesis of 1. Enantiomerically pure (R)-7b was converted
into 21 by carbamoylation with diphenyl carbamoyl chloride and
pyridine in 94% isolated yield, followed by debenzylation with
All reagents and solvents were commercially available and used
without further purification. All reactions were performed under
an atmosphere of nitrogen. 1H NMR spectra were recorded with
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TMS as an internal standard. HPLC was performed using Shimazu
LC-10AT systems. HPLC conditions are described below.
HPLC conditions A: column: YMC-ODS-AM-120-S5 4.6 mm
× 150 mm, eluent: phosphate buffer (KH2PO4 [2.00 g],
Na2HPO4·12H2O [8.00 g], and H2O [1200 mL])/acetonitrile
(40:60), flow rate: 1.0 mL/min, column temperature: 35 °C, UV
detection at 254 nm: 16, 6.65 min; 11, 9.81 min.
HPLC conditions B: column: CHIRALPAK AD 4.6 mm ×
250 mm, eluent: n-hexane/i-PrOH (70:30), flow rate: 1.0 mL/
min, column temperature: 30 °C, UV detection at 254 nm:
(R)-18, 9.44 min; (S)-18, 11.4 min; (R)-7b, 5.80 min; (S)-7b,
6.64 min.
HPLC conditions C: column: CHIRAL AGP 4.0 mm ×
100 mm, eluent: 0.02 M NaH2PO4 buffer adjusted to pH 6.0 with
2 mM Na2HPO4/acetonitrile (100:8), flow rate: 0.8 mL/min,
column temperature: 25 °C, UV detection at 240 nm: 1, 6.86 min;
(S)-enantiomer of 1, 9.23 min.
TsOH·H2O (2.93 kg) was added at 85−90 °C. The reaction mix-
ture was stirred at the same temperature for 1 h and then cooled to
<10 °C. Insoluble impurities were removed by filtration and then
washed with toluene (25 L). The combined filtrates were washed
sequentially with aqueous NaHCO3 solution (NaHCO3 [6.25 kg]
and H2O [125 L]), H2O (125 L), and aqueous NaCl solution
(NaCl [25.0 kg] and H2O [125 L]). The resulting organic layer
was dried over MgSO4 (25.0 kg) and filtered, and the MgSO4 cake
was washed with toluene (25 L) to give 19.8 kg (assay yield) of
5-benzyloxy-1,2,3,4-tetrahydro-2-oxonaphthalene (16) as a solution
in 51% yield based on 2. To this stirred solution, trimethylsulfoxo-
nium iodide (20.7 kg) and t-BuOK (10.6 kg) were added at 20−
30 °C, and the reaction mixture was stirred at 75−80 °C for 2 h.
After the mixture was cooled to below 15 °C, the mixture was
washed sequentially with H2O (119 L) and aqueous NaCl solution
(NaCl [23.8 kg] and H2O [119 L]). The resulting organic layer
was dried over MgSO4 (19.8 kg) and filtered, and the MgSO4 cake
was washed with toluene (20 L). The combined filtrates were con-
centrated under reduced pressure, and the residue was dissolved in
AcOEt (36 L). Insoluble impurities were removed by filtration and
then washed with AcOEt (12 L). The combined filtrates were
subjected to column chromatography on γ-alumina (119 kg) using
AcOEt (238 L) to give 17.8 kg (assay yield) of 5-benzyloxy-1,2,3,4-
tetrahydrospiro[naphthalene-2,2′-oxirane] (11) as a solution in
85% yield based on 16. This solution was concentrated under
reduced pressure, and the resulting residue was dissolved in
aqueous THF solution [THF (356 L) and H2O (107 L)].
TsOH·H2O (1.27 kg) was added to the mixture at 20−30 °C.
The reaction mixture was stirred at 30−35 °C for 3 h, cooled to
15 °C, and then neutralized with addition of 13.6 kg of aqueous
NaHCO3 solution (NaHCO3 [1.00 kg] and H2O [19 L]). The
resulting mixture was concentrated until most of THF was
removed. The residue was extracted with AcOEt (267 L) and
washed with aqueous NaCl solution (NaCl [17.8 kg] and H2O
[89 L]). The resulting organic layer was dried over MgSO4
(17.8 kg) and filtered, and the MgSO4 cake was washed with
AcOEt (18 L). The combined filtrates were concentrated under
reduced pressure. Toluene (18 L) was added, and then the
concentration was continued under reduced pressure. The
resulting residue was dissolved in a mixture of toluene (107 L)
and n-heptane (71 L) at 75−80 °C, cooled to 0 °C over 1 h, and
stirred at 0−5 °C for 1 h. The resulting slurry was filtered and
washed with a mixture of toluene (21 L) and n-heptane (14 L).
The wet crystal was dried under vacuum at 40−45 °C to give
12.2 kg of crude 7b as a crystalline solid. A stirred mixture of crude
7b (12.2 kg) and toluene (122 L) was dissolved at 65−70 °C,
cooled, and then maintained at 23−27 °C for 3 h. The resulting
slurry was filtered, and washed with toluene (37 L). The wet
crystal was dried under vacuum at 40−45 °C to give 10.9 kg of 7b
as a crystalline solid (25% isolated yield based on 2).
(5-Benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphtho-
2-yl)methanol (7b). To a stirred mixture of 5-hydroxy-1-
tetralone (2) (25.0 kg), powdered K2CO3 (21.3 kg), and DMF
(125 L) was added benzyl chloride (19.6 kg) at 20−30 °C. The
reaction mixture was stirred at 85−90 °C for 5 h. After the mix-
ture cooled to −5 °C, H2O (250 L) and toluene (200 L) were
added to the reaction mixture at <10 °C. The layers were then
separated, and the aqueous layer was re-extracted with toluene
(125 L). The combined organic extracts were washed
sequentially with aqueous NaOH solution (48% [w/v] aqueous
NaOH solution [11.0 kg] and H2O [119 L]), H2O (125 L), and
aqueous NaCl solution (NaCl [25.0 kg] and H2O [125 L]). The
resulting organic layer was dried over MgSO4 (25.0 kg) and
filtered, and the MgSO4 cake was washed with toluene (25 L) to
give 5-benzyloxy-1,2,3,4-tetrahydro-1-oxonaphthalene (12) as a
solution. EtOH (125 L) and NaBH4 (5.83 kg) were sequentially
added to this stirred solution at 5−30 °C. The mixture was
refluxed for 1 h and then cooled to <10 °C. Aqueous citric acid
solution (citric acid [12.5 kg] and H2O [125 L]) was then added
to the reaction mixture dropwise at <20 °C. The organic layer
was separated and washed sequentially with aqueous NaHCO3
solution (NaHCO3 [6.25 kg] and H2O [125 L]) and aqueous
NaCl solution (NaCl [25.0 kg] and H2O [125 L]). The resulting
organic layer was dried over MgSO4 (25.0 kg) and filtered, and
the MgSO4 cake was washed with toluene (25 L) to give 5-benzyloxy-
1,2,3,4-tetrahydro-1-naphthol (13) as a solution. KHSO4 (10.5 kg)
was added to this stirred solution at 5−30 °C. The reaction mixture
was concentrated under atmosphere until the temperature exceeded
110 °C, and was then refluxed for 1 h. After cooling to <10 °C, the
mixture was washed twice with aqueous NaHCO3 solution 2×
(NaHCO3 [6.25 kg] and H2O [125L]) and then with aqueous NaCl
solution (NaCl [25.0 kg] and H2O [125L]). The resulting organic
layer was dried over MgSO4 (25.0 kg) and filtered, and the MgSO4
cake was washed with toluene (25 L) to give 5-benzyloxy-3,4-
dihydronaphthalene (14)asasolution. Thissolutionwasthencooled
to <5 °C, and 70% (w/w) m-chloroperbenzoic acid (38.0 kg) was
added at <20 °C. The reaction mixture was stirred at 25−30 °C for
1.5 h and then allowed to cool to <10 °C. The mixture was washed
twice with alkaline Na2S2O3 solution 2× (Na2S2O3·5H2O [37.7 kg],
48% [w/v] aqueous NaOH solution [14.9 kg], and H2O [225 L]),
with aqueous NaCl solution (NaCl [12.5 kg] and H2O [125 L]),
and then with aqueous NaCl solution (NaCl [25.0 kg] and H2O
[125 L]). The resulting organic layer was dried over MgSO4 (25.0 kg)
and filtered, and the MgSO4 cake was washed with toluene (25 L)
to give 4-benzyloxy-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirane (15)
as a solution. This solution was stirred and heated to 85 °C, and
1H NMR (200 MHz, CDCl3) δ 7.47−7.25 (m, 5H), 7.09
(t, J = 7.9 Hz, 1H), 6.76−6.69 (m, 2H), 5.06 (s, 2H), 3.56
(s, 2H), 2.90−2.84 (m, 4H), 2.04 (br, 2H), 1.99−1.69 (m, 2H);
MS (ESI+, m/z): 307 [M + Na]+. Assay yields were analyzed for
16 and 11 via HPLC (HPLC conditions A).
Analytically pure 12, 13, 14, 15, 16, and 11 were obtained via
silica gel chromatography. 5-Benzyloxy-1,2,3,4-tetrahydro-
1
1-oxonaphthalene (12): H NMR (200 MHz, CDCl3) δ 7.67
(m, 1H), 7.46−7.20 (m, 6H), 7.07 (m, 1H), 5.09 (s, 2H), 2.96
(t, J = 6.1 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.17−2.04 (m, 2H); MS
(ESI+, m/z): 275 [M + Na]+. 5-Benzyloxy-1,2,3,4-tetrahydro-
1
1-naphthol (13): H NMR (200 MHz, CDCl3) δ 7.45−7.03
(m, 7H), 6.78 (m, 1H), 5.04 (s, 2H), 4.73 (br, 1H), 2.91−2.54
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(m, 2H), 2.04−1.67 (m, 4H); MS (ESI+, m/z): 277 [M + Na]+.
5-Benzyloxy-3,4-dihydronaphthalene (14): 1H NMR (200
MHz, CDCl3) δ 7.45−7.20 (m, 5H), 7.08 (m, 1H), 6.79 (d, J =
8.3 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 6.43 (m, 1H), 6.07−5.98
(m, 1H), 5.05 (s, 2H), 2.86 (t, J = 8.7 Hz, 2H), 2.34−2.23 (m,
2H). 4-Benzyloxy-1a,2,3,7b-tetrahydronaphth[1,2-b]oxirane
(15): 1H NMR (200 MHz, CDCl3) δ 7.41−7.03 (m, 7H), 6.92
(d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 3.84 (d, J = 4.2 Hz, 1H), 3.73
(m, 1H), 3.13−3.05 (m, 1H), 2.44−2.28 (m, 2H), 1.79−1.55
(m, 1H); MS (ESI+, m/z): 275 [M + Na]+. 5-Benzyloxy-1,2,3,4-
tetrahydro-2-oxonaphthalene (16): 1H NMR (200 MHz,
CDCl3) δ 7.46−7.13 (m, 6H), 6.85 (d, J = 8.2 Hz, 1H), 6.75
(d, J = 7.6 Hz, 1H), 5.09 (s, 2H), 3.58 (s, 2H), 3.15 (t, J = 6.6 Hz,
2H), 2.52 (t, J = 7.0 Hz, 2H); MS (ESI+, m/z): 275 [M + Na]+.
5-Benzyloxy-1,2,3,4-tetrahydrospiro[naphthalene-2,2′-oxir-
ane] (11): 1H NMR (200 MHz, CDCl3) δ 7.47−7.25 (m, 5H),
7.10 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 8.7 Hz, 2H), 5.08 (s, 2H),
3.14−2.93 (m, 4H), 2.76 (s, 2H), 1.88 (t, J = 6.7 Hz, 2H); MS
(ESI+, m/z): 289 [M + Na]+.
with n-heptane (76 L). The wet crystal was dried under vacuum at
40−45 °C to give 14.8 kg of 18 as a crystalline solid (96% isolated
yield).
1H NMR (200 MHz, CDCl3) δ 7.46−7.26 (m, 5H), 7.10 (t, J =
8.0 Hz, 1H), 6.77−6.68 (m, 2H), 5.07 (s, 2H), 4.24 (m, 2H),
2.90−2.86 (m, 4H), 2.54−1.64 (m, 7H), 1.13 (s, 3H), 1.08
(s, 3H), 1.00 (s, 3H); MS (ESI+, m/z): 487 [M + Na]+.
(−)-(1S,4R)-Camphanic Acid-[((2R)-5-Benzyloxy-2-hy-
droxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]ester ((R)-18).
After diastereomeric ester 18 (14.7 kg) was dissolved in EtOH
(588 L) at >65 °C, the solution was cooled to 50−55 °C, and
seed crystals (5.6 g) were added at the same temperature. The
solution was maintained at 50−55 °C for 0.5 h, cooled, and held
at 15−20 °C for 1 h. The resulting slurry was filtered and washed
with EtOH (118 L). The wet crystal was dried under vacuum at
40−45 °C to give 5.93 kg of diastereomerically enriched crude
(R)-18 (78% de) as a crystalline solid. The obtained compound
(5.93 kg) was dissolved in EtOH (237 L) at 75−80 °C, and then
the solution was cooled to 25 °C for 2.5 h and held there for 1 h.
The resulting slurry was filtered and washed with EtOH (47 L).
The combined filtrates from the isolation of crude (R)-18 and
(R)-18 were kept for recovering the diastereomerically enriched
(S)-18 (filtrate A). The wet crystal was dried under vacuum at
40−45 °C to give 5.05 kg of (R)-18 (>99% de) as a crystalline
solid (34% isolated yield based on 18).
(−)-(1S,4R)-Camphanic Acid ((−)-CpOH). (+)-(1R,3S)-
Camphoric acid (25.0 kg) was added to a stirred phosphorus
oxychloride (50 L) cooled to 0−5 °C. Phosphorus pentachloride
(91.0 kg) was added to the mixture, maintaining the temperature
at 0−15 °C. The reaction mixture was stirred at reflux temperature
for 9 h and then cooled to 25−30 °C. The resulting mixture was
added to a stirred aqueous H2SO4 solution (H2SO4 [1.15 kg] and
H2O [225 L]), heated, and maintained at 70−90 °C. The reaction
mixture was stirred at reflux temperature for 8 h. After the mix-
ture cooled to <10 °C, dichloromethane (200 L) was added to
the reaction mixture at <20 °C. The layers were then separated,
and the aqueous layer was re-extracted twice with dichloro-
methane (2 × 125 L). The combined organic extracts were washed
twice with aqueous NaCl solution 2× (NaCl [25.0 kg] and H2O
[125 L]). The resulting organic layer was then dried over MgSO4
and filtered, and the MgSO4 cake was washed with dichloro-
methane (25 L). The combined filtrates were concentrated under
reduced pressure. Toluene (25 L) was then added, and the con-
centration was continued under reduced pressure. The resulting
residue was dissolved in toluene (50 L) at reflux temperature,
cooled to 0 °C over 30 min, and stirred at 0−5 °C for 1 h. The
resulting slurry was filtered and washed with toluene (25 L). The
wet crystal was dried under vacuum at 40−45 °C to give 9.80 kg of
(−)-CpOH as a crystalline solid (40% isolated yield).
1H NMR (200 MHz, CDCl3) δ 7.46−7.26 (m, 5H), 7.10 (t, J =
7.9 Hz, 1H), 6.78−6.68 (m, 2H), 5.07 (s, 2H), 4.24 (s, 2H), 2.90−
2.84 (m, 4H), 2.54−1.62 (m, 6H), 1.13 (s, 3H), 1.08 (s, 3H), 1.00
(s, 3H); MS (ESI+, m/z): 487 [M + Na]+. Diastereomeric excess
for crude (R)-18 and (R)-18 were determined via chiral assay
(HPLC condition B).
((2R)-5-Benzyloxy-2-hydroxy-1,2,3,4-tetrahydro-
naphth-2-yl)methanol ((R)-7b). To a mixture of (R)-18 (5.05
kg), THF (51 L), and MeOH (51 L) were added H2O (5.7 L)
and 48% (w/v) aqueous NaOH solution (2.9 kg) at 20−25 °C.
The reaction mixture was stirred at the same temperature for 1 h,
and then H2O (51 L) was added. The mixture was neutralized
with addition of aqueous HCl solution (35% [w/v] aqueous HCl
solution [2.1 kg] and H2O [25 L]) and then concentrated until
approximately 30 L (total volume) was obtained. Aqueous NaHCO3
solution (NaHCO3 [2.5 kg] and H2O [51 L]) was added to the
mixture at 20−25 °C. The resulting slurry was stirred at 20−25 °C
for 1 h, filtered, and washed with H2O (51 L). The filtrate from the
isolation of (R)-7b was kept for recovering (−)-CpOH (filtrate B).
The wet crystal was dried under vacuum at 40−45 °C to give 2.81 kg
of (R)-7b (>99% ee) as a crystalline solid (91% isolated yield).
1H NMR (200 MHz, CDCl3) δ 7.46−7.25 (m, 5H), 7.10 (t, J =
7.9 Hz, 1H), 6.76−6.70 (m, 2H), 5.06 (s, 2H), 3.57 (s, 2H),
2.91−2.85 (m, 4H), 1.97−1.70 (m, 4H); MS (ESI+, m/z): 307
[M + Na]+. The ee for (R)-7b was determined via chiral assay
(HPLC conditions B).
Recycle of Diastereomerically Enriched (−)-(1S,4R)-
Camphanic Acid-[((2S)-5-Benzyloxy-2-hydroxy-1,2,3,4-
tetrahydronaphth-2-yl)methyl]ester ((S)-18) to [(2R)-5-
Benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-
methanol ((R)-7b): Recovery of the Diastereomerically
Enriched (−)-(1S,4R)-Camphanic Acid-[((2S)-5-Benzyl-
oxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-
ester ((S)-18). The above combined filtrates from the isolation
of crude (R)-18 and (R)-18 (filtrate A) were concentrated under
reduced pressure until approximately 50 L (total volume) was
obtained. n-Heptane (100 L) was added to the solution at 23−27 °C
for 0.5 h, and the resulting slurry was stirred at the same temperature
1H NMR (200 MHz, CDCl3) δ 2.55−2.41 (m, 1H), 2.10−1.90
(m, 2H), 1.68−1.54 (m, 1H), 1.09 (s, 6H), 0.94 (s, 3H); MS
(ESI+, m/z): 221 [M + Na]+.
(−)-(1S,4R)-Camphanic Acid-[(5-Benzyloxy-2-hydroxy-
1,2,3,4-tetrahydronaphth-2-yl)methyl]ester (18). 1-Ethyl-
3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.0 kg)
was added to a stirred solution of 7b (9.44 kg), (−)-CpOH
(11.8 kg) N,N-dimethyl-4-aminopyridine (1.22 kg), and DMF
(47 L) at 5−10 °C. The reaction mixture was stirred at 5−10 °C
for 2 h. The resulting reaction mixture, cooled to <10 °C, was
added to a stirred mixture of AcOEt (472 L) and H2O (94 L).
The organic layer was then separated and washed twice with
aqueous NaHCO3 solution 2× (NaHCO3 [4.72 kg] and H2O
[94 L]) and aqueous NaCl solution (NaCl [18.9 kg] and H2O
[94 L]). The resulting organic layer was concentrated under
reduced pressure. n-Heptane (189 L) was added to the result-
ing residue, and the mixture was concentrated under reduced
pressure until approximately 142 L (total volume) was obtained.
After n-heptane (47 L) was added, the mixture was stirred at
20−25 °C for 1.5 h. The resulting slurry was filtered and washed
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for 1 h, filtered, and washed with n-heptane (30 L). The wet crystal
was dried under vacuum at 40−45 °C to give 7.70 kg of the
diastereomerically enriched (S)-18 as a crystalline solid (52% isolated
yield based on 18).
enantiomerically enriched crude (R)-7b as a crystalline solid. The
obtained crude compound (9.38 kg) was dissolved in toluene (94 L)
at 65−70 °C. The solution was cooled to 23−27 °C for 2.5 h and
held there for 1 h. The resulting slurry was filtered and washed with
toluene (28 L). The wet crystal was dried under vacuum at
40−45 °C to give 8.64 kg of the enantiomerically enriched (R)-7b
as a crystalline solid (66% isolated yield based on the enantiomeri-
cally enriched (S)-7b). HPLC analysis of the mixture of
enantiomers (R)-7b and (S)-7b (HPLC conditions B) showed a
67:33 ratio of (R)-7b/(S)-7b.
Diastereomerically Enriched (−)-(1S,4R)-Camphanic
Acid-[((2R)-5-Benzyloxy-2-hydroxy-1,2,3,4-tetrahydro-
naphth-2-yl)methyl]ester ((R)-18). Enantiomerically en-
riched (R)-7b (8.64 kg) was converted into diastereomerically
enriched (R)-18 (14.1 kg) as a crystalline solid according to the
above method (100% isolated yield). HPLC analysis of the
mixture of diastereomers (R)-18 and (S)-18 (HPLC conditions
B) showed a 65:35 ratio of (R)-18/(S)-18.
(−)-(1S,4R)-Camphanic Acid-[((2R)-5-Benzyloxy-2-hy-
droxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]ester ((R)-18).
Diastereomerically enriched (R)-18 (14.1 kg) was dissolved in
MeOH (494 L) at reflux temperature. The solution was cooled to
23−27 °C for over 0.5 h and then maintained at the same
temperature for 1 h. The resulting slurry was filtered and washed
with MeOH (71 L), and the wet crystal was dried under vacuum
at 40−45 °C to give 7.84 kg of diastereomerically enriched crude
(R)-18 as a crystalline solid (96% de). The obtained compound
(7.84 kg) was dissolved in a mixture of MeOH (237 L) and
i-PrOH (118 L) at 68−69 °C. The solution was cooled to 23−
27 °C for over 0.5 h and then maintained at the same temperature
for 1 h. The resulting slurry was filtered and washed with MeOH
(39 L). The wet crystal was dried under vacuum at 40−45 °C to
give 6.76 kg of the diastereomerically pure (R)-18 (>99% de) as a
crystalline solid (48% isolated yield based on diastereomerically
enriched (R)-18). Diastereomeric excesses for crude (R)-18 and
(R)-18 were determined via chiral assay (HPLC conditions B).
((2R)-5-Benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaph-
tho-2-yl)methanol ((R)-7b). Diastereomerically pure (R)-18
(6.76 kg) was converted into (R)-7b (4.06 kg, >99% ee) as a
crystalline solid in accordance with the above method (98%
isolated yield). The filtrate from the isolation of (R)-7b was kept
for recovering (−)-CpOH (filtrate C). The ee for (R)-7b was
determined via chiral assay (HPLC conditions B).
Recovery of (−)-(1S,4R)-Camphanic acid ((−)-CpOH).
AcOEt (117 L) was added to the above filtrate (filtrate B) from
the isolation of (R)-7b. The aqueous layer was separated and was
adjusted to pH 2.0 using 37.4 kg of aqueous HCl solution (35%
[w/v] aqueous HCl solution [18 L] and H2O [18 L]). The
resulting aqueous layer was extracted twice with 2 × 235 L and
once with 117 L of AcOEt, and the combined organic layers were
then concentrated under reduced pressure. Toluene (23 L) was
added, and the slurry was reconcentrated under reduced
pressure. More toluene (47 L) was then added, and the mixture
was stirred at 10−15 °C for 12 h. The resulting slurry was filtered
and washed with toluene (12 L). The wet crystal was dried under
vacuum at 40−45 °C to give 10.2 kg of (−)-CpOH as a
crystalline solid (100% isolated yield based on the enantiomeri-
cally enriched (S)-18). (−)-CpOH can also be recovered from
filtrate C by the same procedure.
Enantiomerically Enriched [(2S)-5-Benzyloxy-2-hy-
droxy-1,2,3,4-tetrahydronaphth-2-yl]methanol ((S)-7b).
H2O (18 L) and 24% (w/v) aqueous NaOH solution (18 L)
were sequentially added to a mixture of the diastereomerically
enriched (S)-18 (23.5 kg), THF (118 L), and MeOH (118 L) at
20−30 °C. The reaction mixture was stirred at the same tem-
perature for 2 h, and then H2O (235 L) was added. The mixture
was neutralized with addition of 53.4 kg of aqueous HCl solution
(35% [w/v] aqueous HCl solution [5.9 L] and H2O [64 L]), and
then aqueous NaHCO3 solution (NaHCO3 [11.8 kg] and H2O
[235 L]) was added at 20−30 °C. The mixture was stirred at
the same temperature for 1 h, and then at 0−10 °C for 17 h.
The resulting slurry was filtered and washed with H2O (118 L).
The combined filtrates from the isolation of the enantiomerically
enriched (S)-7b were kept for recovering (−)-CpOH (filtrate
C). The wet crystal was dried under vacuum at 40−45 °C to give
13.2 kg of the enantiomerically enriched (S)-7b as a crystalline
solid (92% isolated yield). HPLC analysis of the mixture of
enantiomers (R)-7b and (S)-7b (HPLC conditions B) showed a
31:69 ratio of (R)-7b/(S)-7b.
Enantiomerically Enriched [(2R)-5-Benzyloxy-2-hy-
droxy-1,2,3,4-tetrahydronaphth-2-yl]methanol ((R)-7b).
MsCl (7.92 kg) was added to a stirred solution of the
enantiomerically enriched (S)-7b (13.1 kg), N-methylmorpho-
line (9.32 kg), and THF (262 L) at below 30 °C. The reac-
tion mixture was stirred at 20−30 °C for 1 h, and H2O (262 L) and
AcOEt (262 L) were sequentially added. The organic layer was
washed with aqueous citric acid solution (citric acid [26.2 kg] and
H2O [262 L]), aqueous NaHCO3 solution (NaHCO3 [13.1 kg]
and H2O [262 L]), and aqueous NaCl solution (NaCl [26.2 kg] and
H2O [131 L]). The resulting organic layer was dried over MgSO4
(6.55 kg) and filtered, and the MgSO4 cake was washed with AcOEt
(26 L). The filtrates were combined and concentrated under
reduced pressure. Dimethoxyethane (66 L) was then added, and
the solution was concentrated under reduced pressure. This pro-
cedure was repeated, and the resulting residue was dissolved in
dimethoxyethane (262 L) to give an enantiomerically enriched
methanesulfonic acid-[((2S)-5-benzyloxy-2-hydroxy-1,2,3,4-tetra-
hydronaphth-2-yl)methyl]ester (19) as a solution. t-BuOK (5.65 kg)
at −10 to −5 °C was added to the stirred solution cooled to <−5
°C. The reaction mixture was stirred at the same temperature for
1 h and then warmed to 20−30 °C, with H2O (262 L) and AcOEt
(210 L) added to the resulting mixture. The organic layer was
separated and then washed with aqueous NaCl solution (NaCl
[26.2 kg] and H2O [131 L]). The organic layer was concentrated
under reduced pressure, and the resulting residue was dissolved
in a mixture of dimethoxyethane (92 L) and H2O (92 L) to give
an enantiomerically enriched (2S)-5-benzyloxy-1,2,3,4-tetra-
hydrospiro[naphthalene-2,2′-oxirane] ((S)-11) as a solution.
MsOH (0.44 kg) was added to the stirred solution at 20−30 °C.
The reaction mixture was stirred at the same temperature for
3.5 h, and then AcOEt (131 L) was added. The organic layer was
separated and then washed with aqueous NaCl solution (NaCl
[13.1 kg] and H2O [66 L]). The resulting organic layer was under
reduced pressure, and toluene (52 L) and n-heptane (39 L) were
sequentially added to the residue. The slurry was stirred at 20−
30 °C for 0.5 h, and then at 0−5 °C for 1 h. The resulting slurry
was filtered and washed with n-heptane (13 L). The wet crystal
was dried under vacuum at 40−45 °C to give 9.38 kg of the
Diphenylcarbamic Acid-[((2R)-5-Benzyloxy-2-hy-
droxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]ester (20).
Diphenyl carbamoyl chloride (9.95 kg) was added to a stirred
mixture of (R)-7b (4.07 kg) and pyridine (20 L) at 15−25 °C.
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The reaction mixture was stirred at 97−102 °C for 4.5 h. After
the mixture cooled to 55 °C, MeOH (41 L) was added dropwise
at 55−60 °C for 0.5 h, and then H2O (20 L) was added dropwise
at the same temperature and for the same length of time. The
resulting slurry was stirred for 25−30 °C for 1 h, filtered, and
washed with a mixture of MeOH (41 L) and H2O (20 L). The
wet crystal was dried under vacuum at 40−45 °C to give 6.24 kg
of 20 as a crystalline solid (91% isolated yield).
crystalline solid (91% isolated yield). The ee for 1 was determined
via chiral assay (HPLC condition C).
1H NMR (600 MHz, CDCl3) δ 7.35 (m, 4H), 7.29 (m, 4H), 7.23
(m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 6.60 (d, J =
7.9 Hz, 1H), 4.11 (d, J = 11.0 Hz, 1H), 4.08 (d, J = 11.0 Hz, 1H),
2.82−2.71 (m, 2H), 2.72 (d, J = 16.7 Hz, 1H), 2.61 (d, J = 16.7 Hz,
1H), 1.72 (dt, J = 13.3, 6.1 Hz, 1H), 1.65 (dt, J = 13.3, 7.1 Hz, 1H);
IR: 3510, 3460, 1750, 1708, 1242, 1121, 762, 696 cm−1; MS (ESI+,
m/z): 446 [M − H]−. Anal. Calcd for C26H25N1O6: C, 69.79; H,
5.63; N, 3.13. Found: C, 69.62; H, 5.66; N, 2.91.
1H NMR (200 MHz, CDCl3) δ 7.42−7.19 (m, 15H), 7.08
(t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 7.7 Hz,
1H), 5.05 (s, 2H), 4.15 (s, 2H), 2.91−2.74 (m, 4H), 2.11 (s, 1H),
1.88−1.65 (m, 2H); MS (ESI+, m/z): 502 [M + Na]+.
AUTHOR INFORMATION
Corresponding Author
*Telephone: +81-293-23-4413, E-mail: atsushi.oohigashi@
astellas.com.
■
Diphenylcarbamic Acid-((2R)-2,5-Dihydroxy-1,2,3,4-
tetrahydronaphth-2-yl)methyl Ester (21). Aqueous
HCO2NH4 solution (HCO2NH4 [2.46 kg] and H2O [19 L]) and
10% Pd/C (50% [w/w], 0.37 kg) suspended in H2O (12 L) were
addedto a stirred mixture of20 (6.24 kg), THF (187 L), and MeOH
(62 L) at 20−30 °C. The reaction mixture was stirred at 25−30 °C
for 3.5 h and then filtered. The catalyst was washed with aqueous
MeOH solution (MeOH [25 L] and H2O [25 L]). The combined
filtrates were concentrated under reduced pressure until approx-
imately a 40 L total volume was obtained, and then AcOEt (125 L)
was added to the resulting mixture. The organic layer was separated,
washed twice with aqueous NaCl solution 2× (NaCl [6.24 kg] and
H2O [31 L]), and concentrated under reduced pressure. Toluene
(62 L) was added to the residue, and the mixture was warmed to
60−65 °C. n-Heptane (62 L) was added dropwise at the same tem-
perature for 1 h, and then the slurry was stirred for 0−5 °C for 14.5 h.
The resulting slurry was filtered and washed with n-heptane (62 L).
The wet crystal was dried under vacuum at 40−45 °C to give 4.81 kg
of 21 as a crystalline solid (95% isolated yield).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. K. Hattori for helpful discussions about
the medicinal synthetic route to 1. Additionally, we thank Mr.
H. Tsuboi and Mr. S. Mizobata for their assistance in developing
the manufacturing process.
REFERENCES
■
(1) (a) Bley, K. R.; Hunter, J. C.; Eglen, R. M.; Smith, J. A. M. Trends
Pharmacol. Sci. 1998, 19, 141. (b) Vane, J. R.; O’Grady, J. Therapeutic
Applications of Prostaglandins; Edward Arnold: London, 1993.
(c) Dusting, G. J.; MacDonald, P. S. Pharmacol. Ther. 1990, 48, 323.
(2) (a) Hattori, K. J. Synth. Org. Chem., Jpn. 2006, 64, 33. (b) Hattori,
K.; Tanaka, A.; Okitsu, O.; Tabuchi, S.; Taniguchi, K.; Nishio, M.;
Koyama, S.; Higaki, M.; Seki, J.; Sakane, K. Bioorg. Med. Chem. Lett.
2005, 15, 3091.
1H NMR (200 MHz, CDCl3) δ 7.40−7.19 (m, 10H), 6.89
(t, J = 7.8 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.46 (d, J = 7.5 Hz,
1H), 4.09 (d, J = 1.5 Hz, 2H), 2.75−2.52 (m, 4H), 1.27−1.19
(m, 2H); MS (ESI+, m/z): 412 [M + Na]+.
(3) (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.;
Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(c) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.
(d) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968.
(4) AD-mix-α (containing K2OsO2(OH)4 as an osmium source and
K3Fe(CN)6 as a co-oxidant) was purchased from Sigma-Aldrich Japan.
(5) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (c) Hanson, R. M.;
Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(6) Hauser, F. M.; Prasanna, S. Synth. Commun. 1980, 10, 621.
(7) We also reported the epoxidation of 14 using Oxone as a safer and
less hazardous alternative to m-CPBA, see: Hashimoto, N.; Kanda, A.
Org. Process Res. Dev. 2002, 6, 405.
(8) Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963,
85, 582.
(R)-[6-[(Diphenylcarbamoyloxy)methyl]-6-hydroxy-
5,6,7,8-tetrahydronaphthalen-1-yloxy]acetic Acid (1).
Caution: special care should be taken to prevent contact with 1
and its intermediate 8, since minute quantities of both compounds
cause significant vasorelaxation. Powdered K2CO3 (2.32 kg) was
added to a stirred solution of 21 (3.85 kg) and DMF (19 L). After
the mixture was stirred at 20−30 °C for 0.5 h, ethyl bromoacetate
(1.98 kg) was added. The reaction mixture was stirred at 20−
30 °C for 22.5 h, and then THF (58 L) was added. After the
mixture cooled to 0−10 °C, aqueous NaOH solution (NaOH
[1.11 kg] and H2O [28 L]) was added dropwise at the same
temperature for 0.5 h. The reaction mixture was stirred at 0−10 °C
for 1.5 h, and then AcOH (2.20 kg) was added at the same tem-
perature. The mixture was concentrated under reduced pressure
until approximately 50 L (total volume) was obtained. AcOEt
(96 L) and aqueous HCl solution (35% [w/v] aqueous HCl solu-
tion [5.0 L] and H2O [26 L]) were then sequentially added to the
residue at 20−30 °C. The organic layer was separated, and then
washed twice with aqueous NaCl solution 2× (NaCl [3.85 kg] and
H2O [39 L]). The resulting organic layer was clarified by filtration
through a pharmaceutical-grade sterilizing filter and then washed
with AcOEt (12 L). The combined filtrates were concentrated
under reduced pressure until approximately 19 L (total volume)
was obtained. Isopropyl ether (39 L) was added dropwise to the
residue at 20−25 °C for 0.5 h, and then the mixture was stirred at
the same temperature for 1 h. The resulting slurry was filtered and
washed with isopropyl ether (19 L). The wet crystal was dried
under vacuum at 40−45 °C to give 4.01 kg of 1 (>99% ee) as a
(9) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867;
(b) 1965, 87, 1353.
(10) Resolving reagent (−)-CpOH was not readily available in bulk.
While Gerlach et al. reported the synthesis of (−)-CpOH starting from
commercially available (+)-(1R,3S)-camphoric acid in multikilogram
quantities,11 there are some drawbacks from the viewpoint of large-scale
synthesis. Therefore, we prepared (−)-CpOH in one-pot fashion by
some modifications of the reported method, which offered several
advantages over the original synthesis, such as suitability for large-scale
preparation and high productivity (see Experimental Section).
(11) (a) Gerlach, H.; Kappes, D.; Boeckman, R. K.; Maw, B. N. Organic
Syntheses; Wiley & Sons: New York, 1998; Collect. Vol. 9, p 151. Org.
Synth. 1993, 71, 48.
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dx.doi.org/10.1021/op3003085 | Org. Process Res. Dev. 2013, 17, 658−665