Process research on a phenoxybutyric acid LTB4 receptor antagonist. Efficient kilogram-scale synthesis of a 3,5-bisarylphenol core

Article abstract of DOI:10.1021/op300302s

An improved, kilogram-scale synthesis of a LTB4 receptor antagonist is reported. The title compound was prepared in four linear steps (seven steps total) and 54% overall yield. The 3,5-bisarylphenol core was obtained in nearly quantitative yield by the condensation of 1-benzotriazol-1-ylpropan-2-one with a chalcone. Although all the intermediates were oils, no chromatography purification was required.

Full text of DOI:10.1021/op300302s

Article
pubs.acs.org/OPRD
Process Research on a Phenoxybutyric Acid LTB4 Receptor
Antagonist. Efficient Kilogram-Scale Synthesis of a 3,5-Bisarylphenol
Core
Lianhe Shu,†,* Ping Wang,† Roumen Radinov,† Romyr Dominique,‡ James Wright,† Lady Mae Alabanza,†
and Yan Dong†
‡
†Process Research and Synthesis, Discovery Chemistry, Pharma Research and Early Development (pRED), Hoffmann-La Roche
Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States
ABSTRACT: An improved, kilogram-scale synthesis of a LTB4 receptor antagonist is reported. The title compound was
prepared in four linear steps (seven steps total) and 54% overall yield. The 3,5-bisarylphenol core was obtained in nearly
quantitative yield by the condensation of 1-benzotriazol-1-ylpropan-2-one with a chalcone. Although all the intermediates were
oils, no chromatography purification was required.
benzyl bromide 7 (Scheme 2). While this synthesis is
straightforward, several limitations prevented its use for large-
scale production. First, except for the API, none of the
intermediates was crystalline, and chromatographic purifica-
tions were required at almost every step. Second, the one-pot
Suzuki coupling reactions of 4 with 5 and 6 produced 1
together with two symmetric Suzuki coupling products. The
isolation of 1 from the reaction mixture was found to be
tedious, and multiple chromatographic purifications were
required to obtain 1 in reasonable purity. The synthesis of 2
was lengthy, and the bromination of 11 using carbon
tetrabromide was undesirable due to poor atom economy.
Herein, we report an efficient, kilogram-scale synthesis of 3 in
54% overall yield from bromide 7 without chromatography.
INTRODUCTION
■
Leukotriene B4 (LTB4) is an important mediator of acute and
chronic inflammatory diseases. Elevated levels of LTB4 are
observed in pulmonary tissues of patients suffering from a
variety of pulmonary diseases, such as asthma, chronic
obstructive pulmonary disease (COPD), and acute lung
injury/acute respiratory distress syndrome (ALI/ARDS). It
was hypothesized that blockade of LTB4 receptors could
potentially provide a treatment for these diseases.1 At Roche,
RO5101576 (3) was identified as a potent LTB4 receptor
antagonist.2 In order to support the planned toxicology studies,
process research was initiated to secure active pharmaceutical
ingredient (API) supply on a kilogram scale.
In the original synthesis developed by the Discovery
Chemistry group, 3 was prepared in two steps from 3,5-
bisarylphenol 1 and bromide 2 in good yield (Scheme 1).2b
The phenol, 1, was initially prepared by one-pot Suzuki
coupling of 3,5-dibromophenol (4) with boronic acids 5 and 6.
Bromide 2 was obtained in four steps from custom-synthesized
RESULTS AND DISCUSSION
■
Preparation of the 3,5-Bisarylphenol Core, 1. The
original Suzuki coupling of compounds 4, 5, and 6 in one pot
gave 1 in only 37% yield due to the lack of coupling selectivity.
A sequential approach that proceeds via a Kumada coupling,
followed by a Suzuki coupling, was thus investigated (Scheme
3). Compound 13 was prepared in 93% yield from 12 as
described in the literature.3 Treatment of 13 with isopropyl
magnesium chloride (1.06 equiv) generated the corresponding
mono-Grignard reagent, which upon reaction with iodide 14
gave the PMB-protected phenol 15, a crystalline intermediate,
in 53−70% yield. Deprotection of 15 by treatment with
ethanolic HCl then afforded phenol 16, and Suzuki coupling of
16 with 5 produced the desired product 1 as an oil in 98%
purity. While this new process eliminated the chromatographic
purification of 1, the overall yield from 12 was still in the
suboptimal 31−41% range.
Scheme 1. Assembly of 3
Alternatively, the Suzuki coupling of 15 with 5 gave 17 as an
oil in 95% yield. However, the subsequent deprotection of 17
was found to be problematic. No reaction was observed under
Received: October 24, 2012
Published: November 30, 2012
© 2012 American Chemical Society
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Scheme 2. Original synthesis of building blocks 1 and 2
Scheme 3. Preparation of 1 by sequential Kumada and Suzuki couplings
hydrogenolysis conditions using Pd/C or Pd(OH)2/C as
catalyst. When 17 was treated with TFA in CH2Cl2, LC−MS
analysis indicated formation of a 1:2:2 mixture of 1 plus two
other peaks with a molecular weight of 416, possibly isomers of
17.4 The addition of a cation scavenger, anisole, as a cosolvent
did not alter the product ratio.
Meanwhile, an alternative approach for the synthesis of 3,5-
bisarylphenols, reported by Katritzky et al.,5 was found to give
very promising results. The condensation of chalcone 20 with
1-benzotriazolylacetone (22) afforded 1 in 83% yield after
chromatographic purification (Scheme 4). This route was
selected for further optimization.
While numerous conditions for Claisen−Schmidt condensa-
tion have been reported in the literature,6 lithium hydroxide-
catalyzed reaction described by Bhagat et al.7 was found to give
the desired product efficiently under very mild conditions. A
suspension of ketone 19 in ethanol was treated with LiOH
powder (0.1 equiv) for 5−10 min, and then aldehyde 18 was
added. After the mixture was stirred at room temperature
overnight and aqueous work-up, compound 20 was collected by
filtration as a white solid in nearly quantitative yield and
>99.9% purity.
Compound 22 was initially prepared in 53% yield by the
reaction of benzotriazole with bromoacetone, according to the
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although pure 1 was isolated in up to 83% yield, column
chromatography purification was required. Since 1 is an oil, it is
necessary to improve the reaction so that the crude product
could be directly used in the next step. The reaction was first
tested in THF using DBU or KOtBu as the base. Under both
these conditions, the reaction stopped at the intermediate 24,
without further elimination of the benzotriazole. A much
cleaner and complete conversion was subsequently achieved
when the reaction was carried out in ethanol under anhydrous
conditions, using KOtBu as the base. Thus, to a suspension of
20 and 22 in ethanol was added KOtBu (4 equiv) portionwise
over 5−10 min. On a 100 g-scale reaction, an exotherm raised
the temperature of the reaction mixture from 22 to 60 °C,10
and HPLC analysis indicated the formation of 1, along with
intermediate 24. A complete reaction was achieved after the
mixture was heated to reflux for an additional 30 min. Upon
aqueous wash and extractive work-up, compound 1 was
obtained as a red oil in quantitative yield and >98% purity.
Material of this quality could be used directly in the next step.
The major impurity (∼0.5%), with a molecular weight of 413,
was presumed to be 25, which is derived from the oxidation of
24.
Scheme 4. Preparation of 1 via condensation of 20 and 22
reported procedure.5 As bromoacetone is about 20 times more
expensive than chloroacetone (21), the reaction of the latter
was examined. Thus, a mixture of 21, benzotriazole,8 DIPEA,
and toluene was heated to 90−100 °C.9 HPLC analysis
indicated the formation of 22 along with a byproduct with
molecular weight of 231, possibly bis-adduct 23. After aqueous
workup, compound 22 was isolated by filtration as a white solid
in 65% yield. Slow addition of DIPEA, or using potassium
carbonate as the base, did not offer any advantage. No reaction
occurred when sodium bicarbonate was used. While this
process still requires development, it was deemed suitable for
use at this early stage of development.
The condensation of 20 with 22 was successfully carried out
at the scale of 848 g of 20. The exotherm was well controlled by
adding KOtBu in portions over 30 min. Although both KOEt
and NaOEt can be used in place of KOtBu, the latter was
preferred as it could be obtained in consistent quality from
multiple commercial sources.
Since pyridinium salt 26 is commercially available and is
known to undergo essentially the same chemistry to give 3,5-
bisarylphenols,11 its reaction with 20 was also briefly examined.
Upon addition of KOtBu to a mixture of 26 and 20 (1 g scale)
in ethanol, a strong exotherm immediately ensued that brought
the reaction mixture to reflux; HPLC analysis indicated
complete reaction. While 1 was the major product, the reaction
was not as clean as that of 22.12
Preparation of Bromide 2. The four-step synthesis of 2
from benzyl bromide 7 presented a major challenge as all the
intermediates were oils. Except for 11, chromatographic
purification was required for all intermediates. Originally, the
five-carbon aliphatic chain was introduced via Wittig reaction of
the TBS protected aldehyde 8 (Scheme 2). While a shorter
synthesis of 2 was desired, it was also important to ensure that
According to the literature procedure,5 condensation of 22
with chalcones was accomplished in ethanol at reflux using
aqueous sodium hydroxide as the base. Under these conditions,
Scheme 5. Improved synthesis of 2
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each individual step resulted in a crude product that could be
used directly in the subsequent downstream processing.
The Wittig reaction of commercially available and inex-
pensive 2-hydroxytetrahydropyran (28)13 was initially evaluated
in an attempt to eliminate the TBS protection in 9 (Scheme 5).
This reaction worked well on a gram scale under certain
conditions but was not consistent on scale-up primarily due to
competitive decomposition of the phosphonium salt 27 to give
byproduct 29.14 In addition, the extractive removal of
triphenylphosphine oxide from the reaction mixture was more
difficult because of the increased solubility of 10 in the aqueous
methanol phase as compared to that of 9.
In order to eliminate the undesirable bromination of 11 in
the original sequence, and to avoid the isolation issue
encountered with 10, the use of 5-bromopentanal (30), instead
of the 5-hydroxypentanal derivative, was considered.
The phosphonium salt 27 was formed by heating a mixture
of 7 and triphenylphosphine (1.1 equiv) in acetonitrile to reflux
for 1 h. Treatment of 27 with a base (Table 1, entries 2−8)
in the absence of base and overall gave the best result (Table 1,
entry 1). These conditions were thus used for the first scale-up
batches.
Due to the safety concern of the use of large quantities of
1,2-epoxybutane,15 the Wittig reaction was revisited after the
first scale-up campaign was complete. A significant improve-
ment was realized when cesium carbonate was used, which
allowed the reaction to be run more concentrated and to be
completed within a shorter time (Table 1, entry 9). The yield
and purity of 31 were also improved. This improved process
was expected to replace the initial scale-up procedure using 1,2-
epoxybutane.
In the hydrogenation step, triphenylphosphine carried over
from the Wittig reaction is a catalyst poison. Thus, it was
necessary to oxidize any residual material completely to
triphenylphosphine oxide. The reaction mixture from the
16
Wittig reaction was treated with 30% H2O2 at reflux, until
HPLC analysis confirmed the absence of triphenylphosphine.
After extractive work up to remove triphenylphosphine oxide,
crude 31 was used directly in the subsequent hydrogenation
step. With such treatment, the hydrogenation of 31 proceeded
smoothly with 10% Pd/C (2 mol % Pd) under 500−550 psi of
hydrogen pressure over 20 h. The crude product 2, obtained as
an oil, was used directly in the next step. On the contrary, when
the H2O2 treatment was omitted, the hydrogenation was
considerably slower, and only the double bond located in the 6-
bromohexenyl chain could be reduced.
Coupling and Hydrolysis to the Final Product (3). A
mixture of phenol 1 and potassium carbonate in DMF was
heated to 45 °C to generate the potassium salt of 1; then
bromide 2 was added and the mixture was heated to 67 °C
(Scheme 6). The reaction was complete in 24 h as compared to
40 h when acetone was used as solvent in the original synthesis.
Upon extractive workup and treatment with charcoal, crude 32
was obtained as an oil. Ester hydrolysis was accomplished by
treating a THF/ethanol mixture of 32 with 2 M NaOH. The
resulting solution was extracted with methyl tert-butyl ether to
remove nonpolar impurities. The aqueous phase was then
acidified with hydrochloric acid and extracted with ethyl
acetate. After an aqueous wash and solvent exchange to
acetonitrile, 3 precipitated and was isolated by filtration. A
recrystallization in acetonitrile afforded 3 in 98% purity and
54% overall yield from 7.
Table 1. Wittig reaction of 7 with 30
HPLC result
(area %)
ylides formation conditions
time
(h)
yield
(%)
entry
base
temp (°C)
31
29
a
1
2
3
4
5
6
7
8
9
none
reflux
−5 to rt
−5 to rt
−5
18
1
95.2
94.0
92.1
95.2
81.0
66.4
66.6
90.9
96.5
1.5
3.7
5.6
2.6
6.3
−
16.7
8.3
1.0
79.4
73.5
81.8
71.3
−
−
−
85.6
NaOMe
NaOEt
1
NaOEt
0.08
0.25
1
NaOEt
−35 to −15
−30
LHMDS
DBU
30
1
BuLi/DMSO
Cs2CO3
−20 to rt
reflux
0.25
1.2
89.2
a
Phosphonium salt 27 was used directly in the presence of an acid
scavenger, 1,2-epoxybutane.
generated the ylide, which reacted with aldehyde 30 to afford
31. Strong bases promoted the decomposition of the
phosphonium salt 27 to 29 (Table 1, entries 3−5, 7, 8), or
gave a messy mixture (Table 1, entry 6). On the other hand,
when the acid scavenger 1,2-epoxybutane was used, the
olefination reaction between 27 and 30 proceeded smoothly
Scheme 6. Final coupling and hydrolysis to 3
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wash were combined in an extractor and washed with 2 M HCl
(8.4 L), followed by water (8.9 L). The organic phase was then
concentrated at 50 °C/75 mmHg to give 12b (1.95 kg, >99%
yield) as a brown oil in 98% purity.
CONCLUSION
■
We have developed an efficient synthesis of LTB4 receptor
antagonist 3 in four linear steps (seven steps in total). The key
building block, 3,5-bisarylphenol 1, was prepared in high yield
from readily available starting materials. A streamlined
preparation of the requisite bromide 2 was also developed.
Although all the intermediates were oils, the title compound
was prepared in 54% overall yield and 98% purity without any
chromatographic purifications. While safety evaluations were
required for further development, this process was successfully
utilized for the preparation of the initial 1.26 kg of 3 for the
toxicology studies.
5-Bromopentanal (30). A 12 L round-bottom flask was
charged with sodium hypochlorite (10−13%, 7.0 L) and
potassium carbonate (675 g). The mixture was stirred for 15
min and then filtered to give the solution of bleach used below.
Two flasks were each charged with 5-bromopentanol (879 g,
4.99 mol), KBr (133 g), Bu4NHSO4 (94.4 g), water (1.8 L),
CH2Cl2 (4.0 L), and TEMPO (8.88 g, 56.3 mmol). The
reaction mixtures were cooled to 0 °C, and to each flask was
added the bleach solution (3.3 L) from above at 1 °C over 1.5
h. After GC analysis indicated complete reaction (∼3.5%
starting material remaining),18 the contents of the two flasks
were combined in an extractor, and diluted with hexane (17.8
L). The organic layer was separated and washed successively
with 1 M NaOH (5.3 L) and water (2 × 6.7 L) and then dried
over sodium sulfate (700 g). The mixture was filtered and the
filtrate was concentrated at 35 °C/10 mmHg to give 3019 (1.71
kg, 86% GC purity, 84% yield) as a red oil, which was used
directly in the next step.
EXPERIMENTAL SECTION
■
General. HPLC analysis was performed on Cadenza CD-
C18 (100 × 3 mm, 3 μm) column with 50−100% CH3CN/
H2O (+0.1% HCO2H) as mobile phase at flow rate of 0.5 mL/
min over 10 min, and held for 7 min. Compound 7 was
prepared by a contract supplier following a previously reported
synthesis.2b
(E)-1-Benzo[1,3]dioxol-5-yl-3-thiophen-3-ylprope-
none (20). A mixture of 19 (1.89 kg, 11.5 mol), ethanol (11.3
L), and anhydrous LiOH (28.0 g, pre-ground) was stirred at
room temperature for 10 min, and then 18 (1.29 kg, 11.5 mol)
was added in one portion. The resulting yellow suspension was
stirred at room temperature overnight and then diluted with
water (6 L) and filtered. The collected solid was washed with
ethanol−water (1:1, v/v, 6 L) and water (11.3 L), then dried in
a vacuum oven at 40 °C/120 mmHg to give 2017 (2.93 kg, 99%
yield) as a white solid in >99.9% purity.
1-Benzotriazol-1-ylpropan-2-one (22). A mixture of 21
(1.02 kg, 11.0 mol), benzotriazole (1.33 kg, 11.2 mol)
(CAUTION: Benzotriazole is explosive under certain con-
ditionsdo not repeat this experiment without sufficient safety
awareness and precautions.), and toluene (5.1 L) was heated to
80 °C; DIPEA (2.31 L) was then added at 80−90 °C over 70
min. The reaction mixture was stirred at 90−95 °C for 1.5 h,
then cooled to 60 °C, and diluted with water (5 L). After the
mixture was cooled to room temperature, the resulting
suspension was filtered, and the filter cake was washed with
water (3 × 5.1 L) and toluene (3 × 3.5 L). The resulting wet
cake was reslurried in toluene (5 L) at room temperature for 30
min. The solid was filtered, washed with toluene (2 × 1 L), and
dried to give 225 (1.25 kg, 65% yield) as a white solid in 99%
purity.
3-Benzo[1,3]dioxol-5-yl-5-thiophen-3-ylphenol (1).
Two 22-L flasks were each charged with 20 (848 g, 3.28
mol), 22 (575 g, 3.28 mol), and ethanol (8.4 L). To each of the
resulting suspensions was added, portionwise, potassium tert-
butoxide (1.55 kg, 13.8 mol) over 30 min. (CAUTION:
Beware of the exotherm if addition is too fast.) An exotherm
ensued that increased the batch temperature from 22 to 66 °C.
The resulting solutions were heated to reflux for 30 min. After
cooling to room temperature, conc. HCl (1.64 L) was added to
each flask at ≤25 °C. The resulting suspensions were combined
and filtered. The solid cake was then washed with MTBE (2 ×
3.3 L). The filtrate and washes were combined and
concentrated. The resulting brown oil was redissolved in
MTBE (12 L) and diluted with heptane (6 L). After stirring at
room temperature for 20 min, the resulting solid was removed
by filtration, and the collected solids were washed with a
mixture of MTBE/heptane (2:1, v/v, 3 L). The filtrate and
4-[3-(6-Bromohex-1-enyl)-2-(2-ethoxycarbonylvinyl)-
phenoxy]butyric Acid Ethyl Ester (31). (Important Note:
The procedure described in this step was used for the initial
scale-up at early stage of development. Although no problems
occurred over multiple runs, this procedure should not be used
for large-scale preparation without sufficient safety evaluation.
The Cs2CO3-promoted Wittig reaction which is safe and more
efficient should be used instead.) Two flasks were each charged
with 7 (651 g, 1.63 mol), triphenylphosphine (477 g, 1.82
mol), and acetonitrile (5.4 L). The mixtures were stirred at
reflux for 1 h. After the mixtures cooled to 40 °C, 30 (296 g,
1.79 mol) and 1,2-epoxybutane15 (8.2 L, 95.2 mol) were added
to each flask. The dark solutions were heated to reflux for 18 h,
16
and then H2O2 (272 mL, 30 wt %) was added to each flask
over 10 min. The reaction mixtures were heated to reflux for an
additional 2.5 h while maintaining a N2 flow. After cooling to
room temperature, the contents of the two flasks were
combined and concentrated at 35 °C/10 mmHg. (CAUTION:
The reaction mixture should be tested to be free of residual
H2O2 before concentration.) The residual suspension was
diluted with n-heptane/EtOAc (3:1, v/v, 15.0 L) and washed
with MeOH/H2O (2:1, v/v, 7.1 L). The aqueous bottom layer
was separated and back extracted with n-heptane/EtOAc (3:1,
v/v, 2 × 3.5 L). The combined organic layers were washed with
MeOH/H2O (2:1, v/v, 2 × 7.0 L) and then with H2O (7.3 L);
this mixture was concentrated at 40 °C/10 mmHg to give 3120
(1.28 kg, 84% yield) as an orange oil, which was used directly in
the next step.
4-[3-(6-Bromohexyl)-2-(2-ethoxycarbonylethyl)-
phenoxy]butyric Acid Ethyl Ester (2). A 20-L autoclave was
charged with 31 (1.67 kg, 3.57 mol), 10% Pd/C (166 g, 53%
water wet, 73.3 mmol), and EtOAc (5.0 L). The mixture was
stirred at 40 °C under 550 psi of hydrogen for 20 h until LC−
MS analysis indicated complete reaction. The reaction mixture
was then filtered through a thin layer of Celite, and the Celite
pad was washed with EtOAc (3 × 100 mL). The combined
filtrate and washes were concentrated at 40 °C/10 mmHg to
give crude 22b (overweight, 3.57 mol in theory) as a light-
yellow oil, which was used directly in the next step.
4-[3-[6-(3-Benzo[1,3]dioxol-5-yl-5-thiophen-3-
ylphenoxy)hexyl]-2-(2-ethoxycarbonylethyl)phenoxy]-
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Fotouhi, N.; Tilley, J.; Cohen, N.; Choudhry, S.; Cavallo, G.; Tannu, S.
A.; Ventre, J. D.; Lavelle, D.; Tare, N. S.; Oh, H.; Lamb, M.; Kurylko,
G.; Hamid, R.; Wright, M. B.; Pamidimukkala, A.; Egan, T.; Gubler,
U.; Hoffmann, A. F.; Wei, X.; Li, Y. L.; O’Neil, J.; Marcano, R.;
Pozzani, K.; Molinaro, T.; Santiago, J.; Singer, L.; Hargaden, M.;
Moore, D.; Catala, A. R.; Chao, L. C. F.; Hermann, G.; Venkat, R.;
Mancebo, H.; Renzetti, L. M. J. Med. Chem. 2010, 53, 3502.
(c) Dominique, R.; Fotouhi, N.; Gillespie, P.; Goodnow, R. A. Jr.;
Kowalczyk, A.; Qiao, Q.; Sidduri, A. PCT Int. Appl. WO/2009/
024492, February, 26, 2009; Chem. Abstr. 2009, 150, 282682.
(3) Davidson, J. P.; Sarma, K.; Fishlock, D.; Welch, M. H.;
Sukhtankar, S.; Lee, G. M.; Martin, M.; Cooper, G. F. Org. Process
Res. Dev. 2010, 14, 477.
butyric Acid Ethyl Ester (32). A mixture of 1 (1.03 kg, 3.47
mol), DMF (3.2 L) and K2CO3 (1.08 kg, 7.81 mol) was heated
to 45 °C and stirred for 20 min; then a solution of 2 (crude oil,
containing 3.57 mol of 2 in theory) in DMF (2.0 L) was added.
The mixture was stirred at 65−67 °C for 24 h and then diluted
with H2O (16 L), MTBE (24 L), and heptane (2.4 L). The
organic phase was separated and washed with aqueous K2CO3
(1.2 wt %, 2 × 8 L). Charcoal (350 g) was added, and the
resulting mixture was stirred for 20 min and then filtered
through a pad of Celite (750 g); the Celite pad was then
washed with MTBE (4.0 L). The combined filtrate and wash
were concentrated to give 322b (2.47 kg, 3.47 mol in theory) as
an oily foam which was used directly in the next step.
(4) For an example of acidic rearrangement of benzyl phenyl ethers,
see Sagrera, G.; Seoane, G. Synthesis 2009, 4190.
4-[3-[6-(3-Benzo[1,3]dioxol-5-yl-5-thiophen-3-
ylphenoxy)hexyl]-2-(2-carboxyethyl)phen-oxy]butyric
Acid (3). Two flasks were each charged with 32 (1.11 kg of oil,
containing 1.56 mol of 32 in theory), THF (4.5 L), and ethanol
(2.0 L). To each solution was added 2 M NaOH (3.25 L, 6.50
mol). The mixtures were stirred at 19−23 °C for 16 h to obtain
clear, brownish solutions. The contents of the two flasks were
combined and concentrated at 40 °C/10 mmHg to remove
THF. The residue was diluted with water (14 L) and MTBE
(18 L). The aqueous layer was separated and acidified with 4 M
HCl (3.0 L) to pH ∼1.2, while cooling with an ice−water bath.
The mixture was then diluted with EtOAc (16 L). The organic
layer was separated, washed with water (4 × 10 L), and
concentrated at 35 °C/10 mmHg. The residual oil was diluted
with CH3CN (7.5 L) and further concentrated to near dryness.
The resulting oil was diluted with CH3CN (8.5 L) and stirred
at 19−23 °C for 3 h. The precipitated solid was isolated by
filtration to give crude 3 (1.53 kg) as an off-white solid.
Crude 3 (1.53 kg) and CH3CN (4.0 L) were heated to reflux
to obtain a light-brown solution. This solution was gradually
cooled to room temperature with stirring to complete the
crystallization. The resulting solid was isolated by filtration,
washed with CH3CN (2 × 1 L), and dried to give 32b (1.26 kg,
64% yield from 31) as a white solid in 98% purity.
(5) Katritzky, A. R.; Belyakov, S. A.; Henderson, S. A.; Steel, P. J. J.
Org. Chem. 1997, 62, 8215.
(6) For examples of Claisen−Schmidt condensations, see (a) Kohler,
E. P.; Chadwell, H. M. Org. Synth. 1922, 2, 1. (b) Breslow, D. S.;
Hauser, C. R. J. Am. Chem. Soc. 1940, 62, 2385 and references cited in
ref 7.
(7) Bhagat, S.; Sharma, R.; Sawant, D. M.; Sharma, L.; Chakraborti,
A. K. J. Mol. Catal. A: Chem. 2006, 244, 20.
(8) Benzotriazole is stable at the reaction temperature. For thermal
stability of benzotriazole, see Katrizky, A. R.; Wang, Z.; Tsikolia, M.;
Hall, C. D.; Carman, M. Tetrahedron Lett. 2006, 47, 7653.
(9) Thermal hazard analysis was not conducted due to the
termination of the project.
(10) The exotherm was primarily caused by mixing KOtBu with
ethanol. When KOEt or NaOEt was used, only a mild exotherm was
observed.
(11) Eichinger, K.; Nussbaumer, P.; Balkan, S.; Schulz, G. Synthesis
1987, 1061.
(12) This approach was not further investigated due to the
termination of the project.
(13) For an example of Wittig reaction of 28, see Ohloff, G.; Vial, C.;
Naf, F.; Pawlak, M. Helv. Chim. Acta 1977, 60, 1161.
̈
(14) For an example of the decomposition of phosphonium salt, see
Grayson, M.; Keough, P. T. J. Am. Chem. Soc. 1960, 82, 3919.
(15) 1,2-Epoxybutane is highly flammable, and it could polymerize
and generate heat under certain conditions. Although it has been
widely used in Wittig reactions as acid scavenger and solvent, it is not
recommended for use at large scale.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lshu@verizon.net.
■
(16) Oxidation using H2O2 in flammable solvent is potentially
hazardous. It is important to maintain a constant flow of inert gas to
prevent oxygen from building up in the reaction vessel. For safe scale-
up of oxidation by H2O2 in flammable solvents, see Astbury, G. R. Org.
Process Res. Dev. 2002, 6, 893.
Notes
The authors declare no competing financial interest.
(17) The 1HNMR of 20 was in agreement with that of the structure.
(18) A complete conversion is not desired as it resulted in the
formation of a high level of a high-boiling impurity.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Masami Okabe for helpful discussions.
We thank Rui Yu, Bojana Nedjic, Aaron Obdens, and Joseph
Degasperi for analytic support.
́
(19) Miesch, M.; Miesch, L.; Horvatovich, P.; Burnouf, D.; Delincee,
H.; Hartwig, A.; Raul, F.; Werner, D.; Marchioni, E. Radiat. Phys.
Chem. 2002, 65, 233.
(20) Compound 31, a mixture of E/Z (2:1) isomers, was directly
used in the next step without characterization.
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