First- and second-generation practical syntheses of chroman-4-one derivative: A key intermediate for the preparation of SERT/5-HT1A dual inhibitors

Article abstract of DOI:10.1021/op200357h

Two approaches to large-scale synthesis of the key intermediate 9, a precursor of novel dual inhibitors of SERT/5-HT_1A receptor, are described. These two approaches each feature a mild and efficient method for construction of the chroman-4-one

Full text of DOI:10.1021/op200357h

Article
pubs.acs.org/OPRD
First- and Second-Generation Practical Syntheses of Chroman-4-one
Derivative: A Key Intermediate for the Preparation of SERT/5-HT1A
Dual Inhibitors
Tomoaki Nishida,* Hidefumi Yoshinaga, and Tomohiro Toyoda
Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022,
Japan
Minoru Toshima
Process Chemistry Research and Development Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka,
Konohana-ku, Osaka 554-0022, Japan
S
* Supporting Information
ABSTRACT: Two approaches to large-scale synthesis of the key intermediate 9, a precursor of novel dual inhibitors of SERT/5-
HT1A receptor, are described. These two approaches each feature a mild and efficient method for construction of the chroman-4-
one scaffold, which can be used with substrates containing base-sensitive functionalities and enable synthesis on kilogram scale
without chromatographic purification. The first-generation synthesis enables quick delivery of a kilogram quantity of the key
intermediate 9 with only one slurry purification step. On the other hand, the highly practical second-generation synthesis is
suitable for the multikilogram campaign.
polyphosphoric acid (PPA) provided the ester 5 in 89%
yield. After protection of the ketone moiety of 5 as a ketal (6),
the methyl ester was reduced to alcohol 7 by treatment with
lithium aluminum hydride (LAH). Acidic deprotection of 7
gave compound 8, which was treated with tosyl chloride in
pyridine/CH2Cl2 to give the tosylate 9 as a crystalline solid.
The overall yield of this key intermediate 9 was less than 26%
in seven steps. N-Alkylation of the benzylpiperidine 10 with the
tosylate 9 and potassium carbonate in CH3CN gave the target
molecules 1 in excellent yield (>90%). Finally, treatment of the
crude 1 with conc. HCl in 2-propanol afforded the HCl salt of 1
as a solid. This synthesis enabled the supply of 1 for early-stage
evaluation.
INTRODUCTION
■
Depression is a disease that affects millions of people
worldwide. Although selective serotonin reuptake inhibitors
(SSRIs) have widely been used for the treatment of depression,
their slow onset action remains a problem. It has been reported
that combination of SSRIs with 5-HT1A antagonists can
accelerate SSRIs onset action.1 Accordingly, significant efforts
have been devoted to identification of 5-HT1A antagonists with
serotonin reuptake inhibitory activity. In our search for such
dual acting compounds, we have identified chroman-4-one
derivatives (1, Figure 1) as potent dual inhibitors of the
The aim of our medicinal chemistry work was to optimize
the structure, and indeed, the tosylate 9 prepared by the above
synthetic method was of great use in the preparation of various
derivatives of 1, since the tosylate 9 is chemically stable over
months of storage. However, assessment of this initial synthetic
route for large-scale synthesis of the common key intermediate
9 highlighted serious concerns in several reaction steps. A long
reaction time was needed to complete O-alkylation of the
commercially available 2, and this step was poorly reproducible.
In addition, production of the alcohol 3 was accompanied by
multiple byproducts. Moreover, the subsequent oxidation step
was conducted with the highly toxic PDC, giving a large
amount of metal waste. Finally, the chemical yield of this
alkylation−oxidation sequence was moderate, making this
synthesis inefficient from a cost perspective. Other drawbacks
Figure 1. Chemical structure of 1.
serotonin transporter (SERT) and 5-HT1A receptor.2 As these
derivatives were considered to have potential efficacy in the
treatment of depression, it was necessary to improve their
synthetic route to supply the required amounts for preclinical
pharmacology and safety studies.
The synthetic route of 1 for medicinal chemistry work is
shown in Scheme 1. A phenol moiety of the starting material 2
was alkylated with 3-bromo-1-propanol in the presence of
potassium carbonate to give the alcohol 3 in 65% yield.
Subsequent oxidation of this primary alcohol with pyridinium
dichromate (PDC) afforded the propanoic acid 4 in 66% yield.
The intramolecular Friedel−Crafts cyclization of 4 in
Received: December 8, 2011
Published: February 22, 2012
© 2012 American Chemical Society
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a
Scheme 1. Synthesis of 1 for medicinal chemistry work
a
Reagents and conditions: (i) 3-Bromo-1-propanol, K2CO3, CH3CN, reflux, 14 h; (ii) PDC, MS4A, DMF, rt, 20 h; (iii) PPA, 80 °C, 2 h; (iv)
trimethyl orthoformate, cat. TsOH-H2O, MeOH, rt, 13 h; (v) LAH, THF, rt, 1.5 h; (vi) 3 M HCl, acetone, rt, 1.5 h; (vii) TsCl, pyridine, CH2Cl2, 0
°C, 18 h; (viii) K2CO3, CH3CN, 60 °C, 15 h; then conc. HCl, 2-propanol.
Scheme 2. Reported approaches for construction of unsubstituted chroman-4-ones on aliphatic ring carbons
of the above synthetic route include the need for an excess
amount of PPA (20 w/w) as the reaction solvent to fully
convert the propanoic acid 4, which required laborious workup
process. Since the propanoic acid 4 did not dissolve in the
reaction mixture, standard HPLC analysis was unsuitable to
detect the remaining 4. Furthermore, most intermediates
except for 4 were obtained as oils, requiring purification by
silica gel chromatography in several steps. In order to solve
these problems, we focused our efforts on finding efficient and
scalable syntheses of 5.
Herein, we describe our successful establishment of two
methodologies toward construction of the chroman-4-one
scaffold, which can be used with substrates containing base-
sensitive functionalities. First-generation synthesis enables the
quick delivery of a kilogram quantity of the key intermediate 9,
while second-generation synthesis is suitable for a multikilo-
gram campaign.
graphic purification (Scheme 2).3 In addition, most of these
methodologies require the use of strong basic and/or acidic
conditions unsuitable for our substrate, since our starting
material 2 contains a base-sensitive active methylene group and
an ester functionality. Thus, it was necessary to establish a novel
methodology to construct the chroman-4-one scaffold under
mild conditions without chromatographic purification.
On the basis of the above, medicinal chemistry approach was
designed to avoid strong basic conditions and successfully
construct the chroman-4-one scaffold in 38% yield from the
starting material 2 in three steps (Scheme 1). As the reported
approaches were considered inappropriate for our purposes, we
examined optimization of our medicinal chemistry route. Since
transformation of 5 to the desired 9 was accomplished by
simple modifications, we focused on a scalable method for the
preparation of compound 5.
In order to improve product yield and purity in the O-
alkylation step of 2, the stoichiometries of the reagents and
reaction solvents were screened (Table 1). By the use of
CH3CN as a solvent, the starting material 2 was completely
consumed to give the alcohol 3 with 92% HPLC purity in 3 h
on 1-g scale (entry 1). We found that a reaction with less than 2
equiv of potassium carbonate did not reach completion, and
prolonged reaction time caused a decrease in product purity.
Reaction in acetone, 2-butanone or THF showed slow
RESULTS AND DISCUSSION
■
First-Generation Synthesis. Efforts related to synthesis of
the chroman-4-one scaffold have been widely reported in the
literature. However, there are relatively few accounts of
synthetic methods toward construction of unsubstituted
chroman-4-ones on the aliphatic ring carbons. These methods
produce low-to-moderate chemical yield and require chromato-
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Table 1. Solvent screening in the O-alkylation of 2
HPLC purity @ 3 h (%)
a
entry
solvent
temp., °C
3
2
11
12
1
2
3
4
5
6
CH3CN
acetone
reflux
reflux
reflux
reflux
80
92
55
79
12
61
54
75
83
94
96
93
95
−
41
17
82
17
25
17
0.43
0.32
−
3.9
1.4
−
1.8
0.49
0.91
2-butanone
THF
−
16
−
0.62
DMF
DMSO
CH3CN
80
13
1.4
b
,c
7
reflux
reflux
reflux
reflux
reflux
4.8
12
1.9
0.20
0.24
1.7
e
(crude)
b
b
8
9
0.5% (v/v) H2O/CH3CN
1.0% (v/v) H2O/CH3CN
2.0% (v/v) H2O/CH3CN
1.0% (v/v) H2O/CH3CN
1.2
1.7
b
b
10
11
−
−
0.46
0.66
2.4
,
d
reflux
b
0.44
e
a
c
d
Screening was performed on 1-g scale in freshly opened CH3CN. Freshly opened potassium carbonate was used. 50-g scale. 75-g scale. Refluxed
for 9 h.
Table 2. Screening of conditions for oxidation of 3
a
b
entry
oxidant (equiv)
catalyst (mol %)
none
yield (%)
1
2
3
4
5
PDC (3.5)
NaIO4 (4)
DAIB (2)
TCCA (2)
66
85
30
<5
98
RuCl3 (3)
TEMPO (10)
TEMPO (1)·NaBr (5)
TEMPO (7)·NaClO (2)
NaClO2 (2)
a
b
Chromatographic purified alcohol 3 was used. Isolated yield.
conversion rate and stalled at less than 80% conversion (entries
2−4). The use of an aprotic polar solvent such as DMF or
DMSO gave significant levels of impurities (entries 5, 6).
On the basis of these results, CH3CN was applied as a
solvent for 50-g-scale synthesis of 3. Unlike the result of entry
1, however, the reaction did not reach completion after 3 h, and
compound 2 was still remaining even after 9 h together with a
substantial amount of byproduct impurities (entry 7). Two of
these impurities were identified as carbonate 11 and diol 12.
The carbonate 11 was one of the major byproduct on this scale
which was caused by overreaction of the desired alcohol 3 with
3-bromo-1-propanol via potassium carbonate-promoted in-
sertion of carbon dioxide.4 On the other hand, the diol 12
was formed from 3 by a trans-esterification reaction. The
increasing levels of these impurities caused not only
degradation of product 3 but also lack of the reagent 3-
bromo-1-propanol itself. This resulted in delay of the reaction
completion and loss of product purity. Since the purification of
the alcohol 3 from the accompanied impurities was considered
difficult in light of the physical properties of 3, reproducible
conditions under which levels of impurities can be suppressed
should be identified.
Next, we examined the differences in experimental
conditions between entry 1 and entry 7. As potassium
carbonate from a freshly opened bottle was used for scale-up
in entry 7 but not in entry 1, we hypothesized that water
content in the reaction medium was a crucial factor for
suppression of side reactions. In order to confirm this
hypothesis, several conditions using CH3CN with various
amounts of water were screened. As shown in Table 1, addition
of water was very effective for rapid conversion to the desired
alcohol 3 and control of the generation of impurities (entries
8−10). In fact, generation of 11 was suppressed, depending on
water content in the reaction medium, whereas the opposite
was observed in the case of the diol 12. Thus, CH3CN
containing 1.0% (v/v) of water was selected as a suitable
solvent system for further scale-up studies. This condition
reproducibly gave the alcohol 3 with >95% HPLC purity on 75-
g scale (entry 11).5 The obtained alcohol 3 was used for the
next step without further purification.
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a
Scheme 3. First-generation practical synthesis
a
Calculated yield.
With improved conditions developed for the O-alkylation
step, our attention was directed toward optimization of the next
oxidation step. In order to avoid the use of PDC and improve
the chemical yield, we focused on finding a catalytic system that
can directly oxidize 3 to the propanoic acid 4 (Table 2). With
RuCl3·NaIO4 as a catalytic system, the oxidation of 3 proceeded
to completion in 5 h, and the desired product 4 was obtained in
85% yield without the use of a chlorinated cosolvent (entry 2).6
Encouraged by this result, we focused on metal-free catalytic
oxidation of 3 using 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO). Although the use of (diacetoxyiodo)benzene
(DAIB)7a or trichloroisocyanuric acid (TCCA)7b as oxidant
gave a mixture of multiple byproducts (entries 3 and 4),
utilizing NaClO2 under the TEMPO·NaClO catalytic system8
provided 4 in 98% yield (entry 5).
In spite of the excellent result described above (entry 5), this
experimental procedure was relatively complicated, as both
aqueous NaClO2 solution and diluted NaClO had to be
simultaneously added dropwise to the reaction mixture (mixing
of aqueous NaClO2 and diluted NaClO solutions prior to the
addition is not recommended since the mixture appears to be
unstable.8) We therefore started looking for a simpler and safer
experimental procedure that can be applied for the large-scale
preparation. Dropwise addition of diluted NaClO solution to a
solution of alcohol 3, TEMPO, and NaClO2 in
CH3CN·phosphate buffer (0.67 M, pH = 6.7) at 22 °C on 1-
g scale led to rapid oxidation into 4; however, the reaction
temperature rapidly increased to 42 °C within 10 min. This was
due to acute decrease of the pH in the reaction mixture as the
oxidation reaction progressed, and such a decrease of pH
accelerated the rate of oxidation with acute elevation of
temperature. Further investigation revealed that this elevation
of temperature can be controlled by modification of the
reaction conditions, namely a decrease in the phosphate buffer
concentration from 0.67 to 0.25 M and gradual addition of
aqueous NaClO2 solution (over 1 h) to a solution of alcohol 3,
TEMPO, and NaClO in CH3CN·phosphate buffer at 30−40
°C. Under these conditions, the oxidation successfully
progressed to completion in 1 h on 50-g and 1-kg scales, and
the reaction temperature could be controlled between 30 and
40 °C within jacket capabilities. When 0.10 M of phosphate
buffer was used, the rate of oxidation of alcohol 3 was
considerably slow, and the reaction did not reach completion
even after 5 h. On the basis of these findings, we concluded that
buffering capacity is important to control the reaction rate due
to the pH-dependent nature of this oxidation. Thus, we could
optimize the conditions for oxidation of alcohol 3 without using
the toxic and metal waste-producing PDC.
Our next aim was to replace PPA in the intramolecular
cyclization step, because its use would require not only a
laborious and time-consuming process in the addition of PPA
to the reaction vessel and the quench with water for workup
but also additional investigation of appropriate analytical
methods for detection of the remaining insoluble 4. With the
aim of avoiding the use of PPA, we tried to apply the traditional
intramolecular Friedel−Crafts cyclization conditions. Acid
chloride prepared from 4 with thionyl chloride and a catalytic
amount of DMF in toluene was cyclized with AlCl3 in CH2Cl2
at room temperature to give the desired 5 in 88% yield. This
alternative method could overcome the problems associated
with PPA. The unreacted acid chloride of 4 could be detected
as the corresponding methyl ester by quenching a portion of
the reaction mixture with methanol.
As described above, we established a robust synthetic route
to compound 5 from the commercially available 2. This
improved process enabled synthesis of the key intermediate 5
with 93.8% HPLC purity without chromatographic purification
on 50-g scale (Scheme 3). Effective purification of crude 5
proved to be difficult due to high solubility in various organic
solvents; however, we found that the use of crude 5 did not
cause major problems in the following reactions and could
afford the tosylate 9 with high purity.
For the purpose of large-scale production, the synthetic
method of the tosylate 9 from 5 was slightly modified.
Protection of the ketone moiety of 5 with trimethyl
orthoformate was effectively catalyzed by p-toluenesulfonic
acid at room temperature in methanol. NMR analysis was used
to determine the conversion rate instead of standard HPLC
analysis, because the ketal 6 was highly susceptible to hydrolysis
to ketone 5 even in neutral conditions.9 After the ester moiety
of the resulting ketal 6 was reduced to give alcohol 7 by LAH,
acidic workup enabled obtaining the deprotected ketone 8
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directly. Although tosylation of the hydroxyl group of 8 in
pyridine/CH2Cl2 required more than 10 h to reach completion,
a catalytic amount of trimethylamine hydrochloride
(Me3N·HCl) could highly accelerate this reaction to afford
crude 9 (85.7% HPLC purity) within 1 h.10 The crude 9 was
accompanying several byproducts obtained in previous steps
due to the lack of purifiable intermediate. These byproducts
were effectively removed by the slurry method, i.e. stirring in
toluene at 50 °C for 1 h, cooling to room temperature, and
collecting the resulting solid by filtration. Thus, the desired
tosylate 9 was prepared on 50-g scale with 98.5% HPLC purity.
As described above, we established a scalable and
reproducible process to construct the chroman-4-one scaffold
containing base-sensitive functionalities from starting material
2. This method enabled us to avoid the use of PDC and PPA,
and the overall yield was improved from 26% to 42% in seven
synthetic steps without chromatographic purification. As a
result of optimization in each step, the tosylate 9 was obtained
with only one slurry purification step. A scale-up by this
synthetic method afforded 1.6 kg of tosylate 9 in 49% yield with
98.5% HPLC purity, which was comparable to the result
obtained on 50-g scale. In conclusion, we have established a
synthetic method for supplying the common key intermediate 9
for preparation of the target compound 1 for preclinical studies.
Alternative Approaches to Synthesis of compound 5
without Oxidation. Although a kilogram of the tosylate 9
could be delivered by the first-generation synthesis described
above (Scheme 3), use of the oxidation reaction for further
scale-up synthesis was undesirable due to safety concerns.
Therefore, robust approaches for synthesis of compound 5
excluding any oxidation step were investigated. As shown in
Scheme 4, two methods were considered for the ring-closure
Scheme 5. C-Acylation of the starting material 2
accompanying byproducts have similar chemical properties. We
therefore discontinued further work on this route.
Next, we examined path B. O-Alkylation of 2 with 3-
bromopropanoic acid3c or β-propiolactone12 in basic conditions
(Cs2CO3 or KOtBu) resulted in a mixture of multiple
byproducts due to competing reactions at the active methylene
group. Michael addition of 2 with benzyl acrylate in the
presence of DBU as a mild base13 did not afford the desired
product but gave unknown decomposed byproducts. In
contrast, Michael addition of 2 with the benzyl propiolate 15
in the presence of N-methylmorpholine (NMM) afforded the
benzyl acrylate 16 in high yield.2c,14 Use of a catalytic amount
of NMM in CH3CN allowed the reaction to proceed to
completion within 1 h at room temperature to give 16 as a
mixture of stereoisomers in 95% yield (Scheme 6).15 16,
Scheme 6. Oxidation-free synthesis of 4
Scheme 4. Alternative approaches to synthesis of compound
5
purified by silica gel chromatography, was successfully hydro-
genated with Pd/C catalyst to give the propanoic acid 4 with
96.6% HPLC purity in 99% yield, achieving an efficient
oxidation-free synthesis of 4.16
Although the next cyclization of 4 with AlCl3 via the
corresponding acid chloride could overcome the resulting
problems from PPA and was applied for a kilogram-scale
synthesis, generation of a large amount of metal waste and
inefficient two-step cyclization via the isolation of the
corresponding acid chloride were still problems to be improved,
upon considering further scale-up synthesis. Screening of one-
step Friedel−Crafts cyclization conditions revealed that treat-
ment with trifluoroacetic anhydride (TFAA) can afford the
desired 5 from the carboxylic acid 4 via the corresponding
mixed anhydride generated in situ (Table 3).17 Addition of an
acid accelerated the reaction rate, and the use of a catalytic
amount of phosphoric acid gave excellent results in terms of
both reaction rate and product purity. As a result on this
improvement, the desired cyclized product 5 was obtained in
97% yield (entry 5).
reaction: O-alkylation with 3-chloropropionyl moiety (path A)
or intramolecular Friedel−Crafts cyclization as in the case of
first-generation synthesis (path B).
First, we focused on path A. Although treatment of 2 with 3-
chloropropionyl chloride in the presence of AlCl3 in refluxing
CH2Cl2 or chlorobenzen did not give any amount of the
expected meta-acylated 13 but afforded only undesired O-
acylated product 14,11 treatment of 2 with 3-chloropropionyl
chloride in TfOH afforded the desired 13 in 37% yield via Fries
rearrangement of the O-acylated product 14 (Scheme 5).
However, high concentration of TfOH was required for
complete conversion of 14, which resulted in a mixture of
multiple byproducts. In addition, isolation of 13 without
chromatographic purification was difficult, because 13 and the
Thus, we established a highly practical alternative route to
construct the chroman-4-one scaffold under oxidation-free and
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Table 3. Screening of one-step Friedel-Crafts cyclization of 4
entry
additive (equiv)
HPLC purity5/4 @ 1 h (%)
94.6/−
isolated yield (%)
a
1
−
none
88
−
−
−
97
b
2
3
4
5
6
2.72/95.2
TFA (3)
90.2/7.41
b
TFA (0.1)
H3PO4 (0.1)
AcOH (0.1)
7.14/90.8
98.1/−
5.12/92.9
b
−
a
b
Data obtained by the use of AlCl3 in first-generation synthesis. Reaction did not reach completion after 8 h.
a
Scheme 7. Alternative approach for synthesis of the tosylate 9
a
Reagents and conditions: (i) Benzyl bromide, K2CO3, DMF, 0 °C, 3 h; (ii) cat. NMM, CH3CN, 10 to 25 °C, 1.5 h; (iii) H2, Pd/C, THF, 25 °C, 3
h; then slurry in toluene, 25 °C, 1 h; (iv) TFAA, cat. H3PO4, 0 °C, 2 h; (v) K2CO3, MeOH, 25 °C, 1 h; (vi) TsCl, Et3N, Me3N·HCl, CH3CN, 0 °C, 1
h; then slurry in toluene, 50 °C, 1 h.
Scheme 8. Second-generation practical synthesis
mild conditions. Compound 5 was obtained from the phenol 2
in 91% yield, far exceeding the yield in first-generation synthesis
(73−78%). Each of the three steps reached completion within 1
h at room temperature; moreover, we could avoid the use of
the environmentally undesired AlCl3 and CH2Cl2.
Second-Generation Synthesis. From a cost perspective,
the 4-(2-hydroxyethyl)phenol 17 looks highly desired as an
alternative starting material.18 In addition, the use of this
compound can help avoid the reduction step of the ester
moiety and the treatment of the unstable intermediate 6 which
can readily be hydrolyzed to the ketone 5 with exposure to
moisture. Despite these advantages of compound 17, it was not
applied for the first-generation synthesis due to its primary
hydroxyl group which would be easily oxidized to carboxylic
acid in the second oxidation step. Selective protection of the
primary hydroxyl group of 17 over the phenol moiety was
considered difficult and inefficient; hence, efforts for the
synthesis of the tosylate 9 had been concentrated on using 2 as
the starting material. As the above Michael addition route
(Scheme 6) became available, however, the alternative
approach to 9 from 17 for the multikilogram campaign was
reconsidered.
Use of Michael addition enabled selective introduction of the
propanoic acid unit without protection of the primary hydroxyl
group to give the acrylate 18 (Scheme 7).2c Surprisingly, we
found that benzyl propiolate 15 was highly reactive to afford
the Michael adduct on the less active primary hydroxyl group as
well as on the desired phenol moiety, which resulted in the
generation of diacrylated byproduct. When 1.2 equiv of 15 was
used in this reaction at 25 °C, the obtained 18 was
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accompanying 27.7% (HPLC purity) of diacrylated byproduct.
The use of an equimolar amount of 15 at 10 °C successfully
suppressed this side reaction, and 18 was obtained with 93.5%
HPLC purity accompanying 3.22% (HPLC purity) of
diacrylated byproduct. The obtained acrylate 18 was hydro-
genated with Pd/C catalyst and then purified in toluene by
slurry method to give the propanoic acid 19 in 87% yield as a
sole product in three steps from propiolic acid. Treatment of 19
with TFAA and a catalytic amount of phosphoric acid gave 20
as the trifluoroacetate of the alcohol 8. Hydrolysis of 20 with
potassium carbonate in methanol afforded the alcohol 8, which
was led to the tosylate 9 in 58% yield. Thus, we identified an
alternative approach from desired starting material 17 in 50%
overall yield.
In order to improve this alternative synthesis, we considered
that hydrolysis of 20 could be avoided by transformation of the
primary hydroxyl group of 19 into a tosylate before Friedel−
Crafts cyclization. Although tosylation of 19 resulted in a
mixture of multiple side products, the acrylate 18 was
successfully tosylated in a one-pot reaction without isolation
after the Michael addition (Scheme 8). Subsequent hydro-
genation followed by recrystallization from toluene·THF (9:1)
afforded the penultimate 22 with 97.2% HPLC purity as an
isolated solid in 75% yield in four steps from propiolic acid. The
tosyl functionality was well tolerated in the Friedel−Crafts
cyclization step, and the resulting crude product was purified by
slurry method with 2-propanol·H2O (10:1) to give the tosylate
9 with 99.1% HPLC purity in 98% yield.
In this way, we have succeeded in developing a practical
second-generation synthesis for the tosylate 9. This synthetic
method allowed us to overcome the problems identified in the
first-generation synthesis. Using 17 as starting material, we
obtained 9 on 10-g scale with 99.1% HPLC purity in 74%
overall yield with five synthetic steps without having to use
chromatographic purification. As a consequence, we could
avoid the oxidation step, the unstable intermediate 6, and the
use of LAH and AlCl3 which would result in a large amount of
metal waste. We also obtained in this synthesis penultimate 22,
an appropriate intermediate that can be easily purified for
impurity control. Further optimization of this alternative route
for multikilogram campaign is currently under investigation.19
40 °C, UV detection at 220 nm. The purity listed is determined
by area %. Melting points were determined on an electro-
thermal apparatus without correction. NMR spectra were
recorded on a JEOL JNM-LA300 spectrometer. Chemical shifts
(δ) are given in parts per million, and tetramethylsilane was
used as the internal standard for spectra obtained in CDCl3 or
DMSO-d6. IR spectra were recorded on a JEOL JIR-SPX60
spectrometer as ATR. High-resolution MS spectra were
recorded on a Thermo Fisher Scientific LTQ orbitrap
Discovery MS equipment. Elemental analysis was performed
on a CE Instrument EA1110 and a Yokokawa analytical system
IC7000. Column chromatography was carried out using a
Yamazen W-prep system. All reactions were carried out under
nitrogen atmosphere unless otherwise mentioned. Reagents
and solvents were used as obtained from commercial suppliers
without further purification.
First-Generation Synthesis (Scheme 3). Methyl [4-(3-
Hydroxypropoxy)phenyl]acetate (3). To a solution of methyl
(4-hydroxyphenyl)acetate 2 (964 g, 5.80 mol) in CH3CN (15.2
kg) was added water (193 kg), and the mixture was stirred for
15 min at ambient temperature; then potassium carbonate
(1.76 kg, 12.8 mol, 2.2 equiv) and 3-bromo-1-propanol (1.05
kg, 7.55 mol, 1.3 equiv) were added. The mixture was refluxed
for 3 h and then allowed to cool to ambient temperature. The
precipitate was filtered off and washed with CH3CN (3.80 kg).
The combined filtrates were concentrated in vacuo. Then
toluene (8.34 kg) and water (4.82 kg) were added to the
residue, and the layers were separated. The aqueous layer was
extracted with toluene (3.58 kg). The combined organic layers
were washed with 0.5 M NaOH (1.93 kg) and 1% aqueous
KHSO4 solution (1.93 kg) and then concentrated in vacuo to
give 3 (1.27 kg) as a yellow oil. In total 2.09 kg of 3 was
prepared according to the above-described procedure. It was
1
used for the next step without further purification. H NMR
(300 MHz, CDCl3) δ 7.13 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6
Hz, 2H), 4.00 (t, J = 6.1 Hz, 2H), 3.72 (t, J = 5.9 Hz, 2H), 3.62
(s, 3H), 3.51 (s, 2H), 3.44 (br, 1H), 1.94 (t, J = 6.1 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 172.2, 157.6, 129.9, 125.6,
114.1, 64.6, 58.9, 51.6, 39.7, 31.6; IR (ATR) 3390, 1732, 1512
cm−1; HRMS (ESI) m/z calcd for C12H17O4 [M + H]+
225.1121, found 225.1117.
Methyl [4-(3-{[(3-Hydroxypropoxy)carbonyl]oxy}propoxy)-
phenyl]acetate (11). Analytically pure 11 was obtained by
silica gel chromatography. 1H NMR (300 MHz, CDCl3) δ 7.18
(d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 4.33 (t, J = 6.2 Hz,
2H), 4.27 (t, J = 6.2 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 3.73−
3.65 (m, 2H), 3.67 (s, 3H), 3.56 (s, 2H), 2.42 (br, 1H), 2.13
(quin, J = 6.1 Hz, 2H), 1.89 (quin, J = 6.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 172.3, 157.6, 155.2, 130.1, 126.0, 114.4,
64.8, 64.6, 63.7, 58.6, 51.9, 40.1, 31.4, 28.4; IR (ATR) 3446,
1736, 1512 cm−1; HRMS (ESI) m/z calcd for C16H23O7 [M +
H]+ 327.1438, found 327.1433.
CONCLUSION
■
We have successfully developed two approaches for large-scale
synthesis of the key intermediate 9, a precursor of novel dual
inhibitors of SERT/5-HT1A receptor. These two approaches
feature a mild and efficient method for construction of the
chroman-4-one scaffold, which can be used with substrates
containing base-sensitive functionalities, and enable synthesis
on kilogram scale without chromatographic purification.
Chroman-4-one derivatives are well-known not only as natural
products, but also as key building blocks with a ketone
functionality. Since our methodologies are applicable even in
the presence of labile functionalities, we anticipate the use of
these methods in the synthesis of various chroman-4-one
derivatives.
3-Hydroxypropyl [4-(3-Hydroxypropoxy)phenyl]acetate
(12). Analytically pure 12 was obtained by silica gel
1
chromatography. H NMR (300 MHz, CDCl3) δ 7.16 (d, J =
8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.20 (t, J = 6.2 Hz, 2H),
4.06 (t, J = 6.1 Hz, 2H), 3.79 (t, J = 5.4 Hz, 2H), 3.63−3.55 (m,
2H), 3.54 (s, 2H), 2.80−2.60 (m, 2H), 1.99 (quin, J = 6.1 Hz,
2H), 1.81 (quin, J = 6.2 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 172.3, 157.8, 130.1, 126.0, 114.5, 65.3, 61.8, 59.8, 58.8, 40.3,
31.8, 31.4; IR (ATR) 3358, 1718, 1512 cm−1; HRMS (ESI) m/
z calcd for C14H21O5 [M + H]+ 269.1384, found 269.1379.
EXPERIMENTAL SECTION
■
General. HPLC was performed on a Shimadzu UFLC
system; shim-pack XR-ODS column (3.0 mm i.d. × 100 mm);
gradient elution (0.05% TFA·H2O/0.05% TFA·CH3CN 90:10
to 10:90 over 6 min, hold 2 min); flow rate = 1.0 mL/min, T =
631
dx.doi.org/10.1021/op200357h | Org. Process Res. Dev. 2012, 16, 625−634

Organic Process Research & Development
Article
3-[4-(2-Methoxy-2-oxoethyl)phenoxy]propanoic Acid (4).
To a solution of KH2PO4 (319 g, 2.34 mol) and
Na2HPO4·12H2O (838 g, 2.34 mol) in water (18.1 kg) were
successively added 3 (1.27 kg, 5.65 mol) in CH3CN (14.7 kg),
TEMPO (111 g, 0.708 mol, 0.13 equiv), and NaClO (5%
solution) (169 g, 0.113 mol, 0.02 equiv). After the mixture was
heated to 30−40 °C (internal temperature), a solution of
NaClO2 (80%) (1.28 kg, 11.3 mol, 2 equiv) in water (5.63 kg)
was slowly added over 1 h. Then the mixture was kept at 30−40
°C for 2.5 h and cooled to 0−5 °C. A solution of 20% aqueous
NaHSO3 solution (9.38 kg) was added dropwise over 1 h,
keeping the temperature lower than 10 °C during the addition
(CAUTION: generated sulfur dioxide should be trapped by
aqueous NaOH solution.). The mixture was warmed to room
temperature, and then the biphasic system was separated. The
aqueous layer was extracted with EtOAc (8.46 kg), and the
combined organic layers were concentrated in vacuo. The
resultant precipitate was added to water (2.82 kg), collected by
filtration, washed with water (2 × 1.41 kg), and dried in vacuo
to give 4 (1.11 kg) as a white solid. In total 1.93 kg of 4 was
prepared according to the above-described procedure. It was
used for the next step without further purification. Mp 112 °C;
1H NMR (300 MHz, DMSO-d6) δ 12.39 (br, 1H), 7.17 (d, J =
8.4 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H),
3.60 (s, 3H), 3.60 (s, 2H), 2.69 (t, J = 6.1 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6) δ 172.4, 172.0, 157.3, 130.5, 126.5, 114.3,
63.6, 51.7, 39.3, 34.2; IR (ATR) 1734, 1691, 1514 cm−1;
HRMS (ESI) m/z calcd for C12H15O5 [M + H]+ 239.0914,
found 239.0910; Anal. Calcd for C12H14O5: C, 60.50; H, 5.92.
Found: C, 60.50; H, 5.83.
(8.50 kg) was cooled down to 0−10 °C, the reaction mixture
was added dropwise to that solution over 1 h. After the reaction
mixture was warmed to room temperature, toluene (7.36 kg)
was added, and then the layers were separated. The aqueous
layer was washed with toluene (4.42 kg), and the combined
organic layers were washed with water (3.40 kg) and then
concentrated in vacuo. Toluene (1.50 kg) was added to the
residue and concentrated in vacuo to give 6 (2.05 kg) as a
1
yellow oil. H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J = 2.2
Hz, 1H), 7.11 (dd, J = 8.4, 2.2 Hz, 1H), 6.75 (d, J = 8.4 Hz,
1H), 4.25 (t, J = 5.7 Hz, 2H), 3.61 (s, 2H), 3.59 (s, 3H), 3.17
(s, 6H), 2.09 (t, J = 5.8 Hz, 2H).
Obtained 6 (2.05 kg, 7.70 mol) in THF (3.64 kg) was added
dropwise over 40 min to a suspension of LAH (439 g, 11.6 mol,
1.5 equiv) in THF (23.7 kg) at such a rate that the reaction
temperature stayed in the range 20−30 °C. The mixture was
stirred for 2 h and cooled down to around 5 °C. Water (294 g)
in THF (145 g) and 3 M HCl (20.5 kg) were successively
added dropwise over 2.5 h, keeping the reaction temperature
lower than 15 °C during the addition. Toluene (17.7 kg) was
added to the reaction mixture, and the layers were separated.
The aqueous layer was washed with toluene (17.7 kg), and the
combined organic layers were washed with 3 M HCl (4.1 kg)
and water (8.2 kg) and then concentrated in vacuo to give 8
1
(1.39 kg) as a brown oil. H NMR (300 MHz, CDCl3) δ 7.70
(d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H), 6.90 (d, J =
8.4 Hz, 1H), 4.48 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 6.7 Hz, 2H),
2.86 (br, 1H), 2.81 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.5 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 192.1, 160.3, 136.9, 131.7,
126.6, 120.8, 117.8, 66.7, 63.0, 37.9, 37.5; IR (ATR) 3404,
1682, 1616 cm−1; HRMS (ESI) m/z calcd for C11H13O3 [M +
H]+ 193.0859, found 193.0856.
Methyl (4-Oxo-3,4-dihydro-2H-chromen-6-yl)acetate (5).
Thionyl chloride (1.16 kg, 9.74 mol, 1.2 equiv) was added
dropwise over 0.5 h to a suspension of 4 (1.93 kg, 8.11 mol) in
toluene (16.7 kg) and DMF (18.3 g). The mixture was stirred
at ambient temperature for 5 h and concentrated in vacuo.
Toluene (8.60 kg) was added to the residue, and the resultant
solution was concentrated in vacuo (twice) to give the
corresponding acid chloride (2.08 kg) as a yellow oil. The
residue was dissolved in CH2Cl2 (8.28 kg), and then added
dropwise over 1 h to a suspension of AlCl3 (2.16 kg, 16.2 mol, 2
equiv) in CH2Cl2 (19.3 kg) at ambient temperature. The
mixture was stirred for 1.5 h and added dropwise over 2 h to
cooled (0−5 °C) 2 M HCl (20.8 kg), keeping the temperature
lower than 20 °C during the addition. The mixture was warmed
to ambient temperature, and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (5.52 kg). The
combined organic layers were successively washed with water
(4.15 kg), 5% aqueous NaHCO3 solution (4.16 kg), and water
(4.16 kg), and then concentrated in vacuo. MeOH (3.28 kg)
was added to the residue, and the mixture was concentrated in
2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methyl-
benzenesulfonate (9). To a solution of 8 (1.39 kg, 7.21
mol) in CH3CN (10.9 kg) were added Me3N·HCl (68.9 g,
0.721 mol, 0.1 equiv) and triethylamine (1.46 kg, 14.4 mol, 2
equiv). The mixture was cooled down to around 5 °C, and then
tosyl chloride (1.65 kg, 8.64 mol, 1.2 equiv) in CH3CN (5.44
kg) was added dropwise over 1 h. The reaction mixture was
stirred for an additional 2 h, and then 5% aqueous NaHCO3
solution (10.4 kg) was added dropwise over 1 h. Toluene (8.98
kg) and water (6.92 kg) were added, and the layers were
separated. The aqueous layer was washed with toluene (8.98
kg), and the combined organic layers were washed with 1%
aqueous KHSO4 solution (10.4 kg) and 10% aqueous NaCl
solution (10.3 kg) and then were dried over MgSO4 (750 g).
The solid was filtered off and washed with toluene, and then
the filtrate was concentrated in vacuo to 7.2-fold volumes of
estimated quantity of 9 (slurry in 6.46 kg of toluene). The
suspension was then stirred at 50 °C for 1 h and cooled down
to 10 °C over 1 h, held for 2 h, and then filtered. The solid was
washed with cooled (5−10 °C) toluene (2 × 1.30 kg) and dried
in a vacuum oven at 50 °C. The target compound 9 (1.64 kg,
49% yield) was obtained as a pale-yellow solid (98.5% area
purity by HPLC). Mp 125 °C; 1H NMR (300 MHz, CDCl3) δ
7.70 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 2.2 Hz, 1H), 7.30 (d, J =
8.1 Hz, 2H), 7.25 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 (d, J = 8.4 Hz,
1H), 4.51 (t, J = 6.4 Hz, 2H), 4.18 (t, J = 6.9 Hz, 2H), 2.90 (t, J
= 6.9 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.44 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 191.5, 160.7, 144.7, 136.7, 132.7, 129.7,
129.2, 127.7, 126.8, 121.0, 118.1, 70.2, 66.9, 37.6, 34.2, 21.5; IR
(ATR) 1684, 1493, 1169 cm−1; HRMS (ESI) m/z calcd for
C18H19O5S [M + H]+ 347.0948, found 347.0938.
1
vacuo to give 5 (1.71 kg) as a yellow solid. H NMR (300
MHz, CDCl3) δ 7.77 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.5, 2.3
Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.52 (t, J = 6.5 Hz, 2H), 3.69
(s, 3H), 3.59 (s, 2H), 2.80 (t, J = 6.4 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 191.5, 171.6, 160.9, 136.9, 127.4, 127.0, 121.0,
118.1, 66.9, 52.0, 39.9, 37.5; IR (ATR) 1720, 1682, 1140 cm−1;
HRMS (ESI) m/z calcd for C12H13O4 [M + H]+ 221.0808,
found 221.0805.
6-(2-Hydroxyethyl)-2,3-dihydro-4H-chromen-4-one (8). To
a suspension of 5 (1.71 kg, 7.72 mol) in MeOH (4.03 kg) were
added trimethyl orthoformate (9.89 kg) and TsOH·H2O (146
g, 0.766 mol, 0.1 equiv), and the reaction mixture was stirred 15
h at room temperature. After 5% aqueous NaHCO3 solution
632
dx.doi.org/10.1021/op200357h | Org. Process Res. Dev. 2012, 16, 625−634

Organic Process Research & Development
Article
Alternative Approach for the Synthesis of 9 (Scheme
6). 3-[4-(2-Hydroxyethyl)phenoxy]propanoic Acid (19). To
a solution of 4-(2-hydroxyethyl)phenol 17 (2.00 g, 14.5 mmol)
in CH3CN (15 mL) were added NMM (159 μL, 1.45 mmol,
0.10 equiv) and a solution of 15 (2.32 g, 14.5 mmol, 1.0 equiv)
in CH3CN (5 mL) at 10 °C. This reaction mixture was stirred
for 1.5 h at 25 °C and then concentrated in vacuo. Toluene (20
mL) was added to the residue, and the resulting solution was
washed with 5% aqueous NaHCO3 solution (10 mL) and 5%
aqueous NaCl solution (10 mL) and then dried over Na2SO4.
After filtration, the solvent was removed in vacuo to give 18 as a
yellow oil.
reaction mixture was filtered through Celite, and the filtrate was
concentrated in vacuo. The resulting solid was purified by
recrystallization from toluene·THF (9:1) (300 mL) at 70 °C,
and cooled down to 0−5 °C over 2 h and held for 1 h. The
solid was filtered, washed with cooled (<5 °C) toluene, and
dried in vacuo to give 22 (19.8 g, 75% yield) as a white solid
1
(97.2% area purity by HPLC). Mp 119 °C; H NMR (300
MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.1 Hz,
2H), 7.01 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 4.21 (t,
J = 6.1 Hz, 2H), 4.16 (t, J = 7.1 Hz, 2H), 2.88 (t, J = 6.8 Hz,
2H), 2.84 (t, J = 6.1 Hz, 2H), 2.43 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 176.9, 157.3, 144.6, 132.9, 129.9, 129.7, 128.7,
127.8, 114.7, 70.8, 63.0, 34.4, 34.3, 21.6; IR (ATR) 1695, 1512,
1171 cm−1; HRMS (ESI) m/z calcd for C18H21O6S [M + H]+
365.1053, found 365.1045.
To a solution of obtained 18 in THF (40 mL) was added
10% Pd/C (50% wet) (802 mg), and the mixture was stirred
under hydrogen atmosphere (1 atm) at 25 °C for 3 h. The
reaction mixture was filtered through Celite, and the filtrate was
concentrated in vacuo. The residue was purified by slurry in
toluene (40 mL) at 25 °C for 1 h and filtered. The solid was
washed with cooled (0−5 °C) toluene (10 mL) and dried in
vacuo to give 19 (2.66 g, 87% yield) as a white solid. Mp 137
°C; 1H NMR (300 MHz, DMSO-d6) δ 12.35 (br, 1H), 7.11 (d,
J = 8.6 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.60 (br, 1H), 4.12 (t,
J = 6.1 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 6.1 Hz,
2H), 2.64 (t, J = 6.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
δ 172.3, 156.6, 131.6, 129.8, 114.1, 63.5, 62.5, 38.2, 34.2; IR
(ATR) 3385, 1722, 1043 cm−1; HRMS (ESI) m/z calcd for
C11H15O4 [M + H]+ 211.0965, found 211.0960; Anal. Calcd for
C11H14O4: C, 62.85; H, 6.71. Found: C, 62.95; H, 6.59.
Second-Generation Synthesis (Scheme 7). 3-[4-(2-
{[(4-Methylphenyl)sulfonyl]oxy}ethyl)phenoxy]propanoic
Acid (22). To a suspension of potassium carbonate (12.0 g, 86.9
mmol, 1.2 equiv) in DMF (40 mL) were added propiolic acid
(6.09 g, 86.9 mmol, 1.2 equiv) in DMF (20 mL) at 0−5 °C,
and the reaction mixture was stirred for 10 min. Benzyl
bromide (12.4 g, 72.4 mmol, 1.0 equiv) was added, and the
mixture was warmed to 25 °C and stirred for 2 h. Then water
(90 mL) was added to the residue at 0−5 °C. EtOAc·hexane
(1:1) (60 mL) was added to the residue at 25 °C, and the layers
were separated. The aqueous layer was extracted with
EtOAc·hexane (1:1) (30 mL). The combined organic layers
were washed with 5% aqueous NaCl solution (2 × 30 mL) and
dried over Na2SO4. After filtration, the solvent was removed in
vacuo to give 15 as a yellow oil.
2-(4-Oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methyl-
benzenesulfonate (9). To a solution of TFAA (26.8 mL)
and phosphoric acid (85%) (316 mg, 2.74 mmol, 0.10 equiv)
was added 22 (10.0 g, 27.4 mmol) at 0−5 °C, and the mixture
was stirred at 25 °C for 1 h. The reaction mixture was
concentrated in vacuo. Toluene·THF (2:1) (150 mL) and
water (100 mL) were added to the residue, and the layers were
separated. The aqueous layer was extracted with toluene (50
mL). The combined organic layers were washed with 5%
aqueous NaHCO3 solution (2 × 50 mL) and 5% aqueous NaCl
solution (50 mL) and dried over MgSO4. After filtration, the
solvent was removed in vacuo. To the resulting solid was added
2-propanol·H2O (10:1) (55 mL), and the suspension was
warmed to 45 °C and held for 1 h. After the mixture was cooled
to 25 °C, water (95 mL) was added and stirred at 25 °C for 1 h.
The mixture was cooled to 0−5 °C, held for 1 h, and then
filtered. The solid was washed with water (20 mL) and dried in
vacuo to give 9 (9.32 g, 98% yield) as a white solid (99.1% area
purity by HPLC). Obtained analytical data are in complete
accord with that of 9 obtained through first-generation
synthesis.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra of important intermediates in the first-
and second-generation synthesis. This material is available free
of charge via the Internet at http://pubs.acs.org.
To a solution of 4-(2-hydroxyethyl)phenol 17 (10.0 g, 72.4
mmol) in CH3CN (100 mL) were added NMM (796 μL, 7.24
mmol, 0.10 equiv) and a solution of obtained 15 in CH3CN
(20 mL) at 10 °C, and the reaction mixture was stirred for 1 h
at 25 °C. The mixture was cooled down to 0−5 °C, and then
triethylamine (20.1 mL, 145 mmol, 2.0 equiv), Me3N·HCl (346
mg, 3.62 mmol, 0.050 equiv), and tosyl chloride (16.6 g, 86.9
mmol, 1.2 equiv) were added. The reaction mixture was stirred
for additional 1 h at 0−5 °C, and then 3% aqueous NaHCO3
solution (100 mL) was added. The organic solvent was
removed in vacuo, toluene (100 mL) was added to the residue,
and the layers were then separated. The aqueous layer was
extracted with toluene (50 mL). The combined organic layers
were washed with 5% aqueous NaCl solution (50 mL), 5%
aqueous KHSO4 solution (50 mL), and 5% aqueous NaCl
solution (50 mL), and then dried over MgSO4. After filtration,
the solvent was removed in vacuo to give 21 as a yellow oil.
To a solution of obtained 21 in THF (300 mL) was added
10% Pd/C (50% wet) (6.00 g), and the mixture was stirred
under hydrogen atmosphere (1 atm) at 25 °C for 3 h. The
AUTHOR INFORMATION
■
Corresponding Author
*Telephone: +81-6-6466-5203. Fax: +81-6-6466-5484. E-mail:
tomoaki-nishida@ds-pharma.co.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We express our thanks to Ms. K. Bando for performing the
elemental analysis and to Ms. M. Honma for recording high-
resolution MS spectra.
REFERENCES
■
(1) (a) Artigas, F.; Perez, V.; Alvarez, E. Arch. Gen. Psychiatry 1994,
51, 248−251. (b) Zhou, D.; Stack, G. P.; Lo, J.; Failli, A. A.; Evrard, D.
A.; Harrison, B. L.; Hatzenbuhler, N. T.; Tran, M.; Croce, S.; Yi, S.;
Golembieski, J.; Hornby, G. A.; Lai, M.; Lin, Q.; Schechter, L. E.;
Smith, D. L.; Shilling, A. D.; Huselton, C.; Mitchell, P.; Beyer, C. E.;
Andree, T. H. J. Med. Chem. 2009, 52, 4955−4959.
633
dx.doi.org/10.1021/op200357h | Org. Process Res. Dev. 2012, 16, 625−634

Organic Process Research & Development
Article
(2) (a) Toyoda, T.; Yoshinaga, H. PCT Int. Appl. WO 2009/099087,
2009. (b) Toyoda, T.; Nishida, T; Yoshinaga, H. PCT Int. Appl. WO
2011/016468, 2011. (c) Kojima, M.; Nishida, T. Jpn. Kokai Tokkyo
Koho, JP 2010/150247, 2010.
(3) (a) Cohen, N.; Bizzarro, F. T.; May, W. P.; Toth, K.; Lee, F. K.;
Heslin, P. H.; Holland, G. W.; Kwoh, S. C.; Franco, L. S.; Simko, B. A.;
Yagaloff, K. A. Bioorg. Med. Chem. Lett. 1994, 4, 2883−2888. (b) Cube,
R. V.; Vernier, J. M.; Hutchinson, J. H.; Gardner, M. F.; James, J. K.;
Rowe, B. A.; Schaffhauser, H.; Daggett, L.; Pinkerton, A. B. Bioorg.
Med. Chem. Lett. 2005, 15, 2389−2393. (c) Vu, A. T.; Campbell, A. N.;
Harris, H. A.; Unwalla, R. J.; Manas, E. S.; Mewshaw, R. E. Bioorg. Med.
Chem. Lett. 2007, 17, 4053−4056. (d) Siddaiah, V.; Maheswara, M.;
Rao, C. V.; Venkateswarlu, S.; Subbaraju, G. V. Bioorg. Med. Chem. Lett.
2007, 17, 1288−1290.
(4) Cella, J. A.; Bacon, S. W. J. Org. Chem. 1984, 49, 1122−1125.
(5) The amounts of impurities 11 and 12 were different between
entries 9 and 11. Since water content in the reaction mixture and the
mixing conditions were similar between both experiments except for
the scale of the reaction, the reason for accounting this difference was
not identified.
(6) Kim, Y. J.; Wang, P.; Navarro-Villalobos, M.; Rohde, B. D.;
DerryBerry, J.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 11906−11915.
(7) (a) Rozners, E.; Liu, Y. J. Org. Chem. 2005, 70, 9841−9848.
(b) Luca, L. D.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem.
2003, 68, 4999−5001.
(8) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564−2566.
(9) NMR analysis was conducted in DMSO-d6, since ketal 6 was
gradually deprotected in CDCl3.
(10) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183−2192.
(11) Alagha, A.; Moman, E.; Adamo, M. F.; Nolan, K. B.; Chubb, A.
J. Bioorg. Med. Chem. Lett. 2009, 19, 4213−4216.
(12) Rassias, G.; Stevenson, N. G.; Curtis, N. R.; Northall, J. M.;
Gray, M.; Prodger, J. C.; Walker, A. J. Org. Process Res. Dev. 2010, 14,
92−98.
(13) Tatsuta, K.; Kasai, S.; Amano, Y.; Yamaguchi, T.; Seki, M.;
Hosokawa, S. Chem. Lett. 2007, 36, 10−11.
(14) Shinozuka, T.; Shimada, K.; Matsui, S.; Yamane, T.; Ama, M.;
Fukuda, T.; Taki, M.; Takeda, Y.; Otsuka, E.; Yamato, M.; Mochizuki,
S.; Ohhata, K.; Naito, S. Bioorg. Med. Chem. 2006, 14, 6789−6806.
(15) HPLC purity of the obtained 16 was 86.0% as a mixture of
stereoisomers.
(16) Although hydrogenation of some of 3-aryloxyacrylic acid
derivatives is reported to need no less than one week to reach
completion even under increased pressure, our substrates 16, 18, and
21 are readily hydrogenated in a few hours under ordinary pressure
(THF, 25 °C).
(17) (a) Kawasaki, M.; Kakuda, H.; Goto, M.; Kawabata, S.;
Kometani, T. Tetrahedron: Asymmetry 2003, 14, 1529−1534. (b) Galli,
C. Synthesis 1979, 4, 303−304.
(18) Catalogue prices from TCI-US: 4-(2-hydroxyethyl)phenol 17,
$176/500 g; methyl(4-hydroxyphenyl)acetate 2, $250/500 g.
(19) Subsequent work to identify the suitable salt of API 1 and
optimize a more suitable process for preparing 9 and the endgame will
be the subject of a future publication.
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dx.doi.org/10.1021/op200357h | Org. Process Res. Dev. 2012, 16, 625−634