Direct synthesis of a pde4 inhibitor by using pd-cu-catalyzed c-h/c-br coupling of benzoxazole with a heteroaryl bromide

Article abstract of DOI:10.1021/acs.oprd.6b00106

A short and practical synthetic route of a PDE4 inhibitor (1) was established by using Pd-Cu-catalyzed C-H/ C-Br coupling of benzoxazole with a heteroaryl bromide. The combination of Pd(OAc)₂-Cu(OTf)₂-PPh₃ was found to be

Full text of DOI:10.1021/acs.oprd.6b00106

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Full Paper
Direct Synthesis of a PDE 4 inhibitor by using Pd-Cu-Catalyzed
C-H/C-Br Coupling of Benzoxazole with A Heteroaryl Bromide
Kiichi Kuroda, Shinjiro Tsuyumine, and Tomohiro Kodama
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00106 • Publication Date (Web): 10 May 2016
Downloaded from http://pubs.acs.org on May 11, 2016
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Direct Synthesis of a PDE 4 inhibitor by using
Pd-Cu-Catalyzed C-H/C-Br Coupling of
Benzoxazole with A Heteroaryl Bromide
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Kiichi Kuroda †*, Shinjiro Tsuyumine †, Tomohiro Kodama#
†Process Chemistry Research and Development Laboratories, Technology Research &
Development Division, Sumitomo Dainippon Pharma Co., Ltd., 3ꢀ1ꢀ98 Kasugadeꢀnaka,
Konohanaꢀku, Osaka 554ꢀ0022, Japan
#DSP Cancer Institute, Sumitomo Dainippon Pharma Co., Ltd., 3ꢀ1ꢀ98 Kasugadeꢀnaka,
Konohanaꢀku, Osaka 554ꢀ0022, Japan
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ABSTRACT : A short and practical synthetic route of a PDE4 inhibitor (1) was established by
using PdꢀCuꢀcatalyzed CꢀH/CꢀBr coupling of benzoxazole with a heteroaryl bromide. The
combination of Pd(OAc)2ꢀCu(OTf)2ꢀPPh3 was found to be effective for this key step.
Furthermore, telescoping methods were adopted to improve the yield and manufacturing time,
and twoꢀstep synthesis of 1 was accomplished in 71% overall yield.
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Keywords: CꢀH/CꢀBr Coupling, CꢀH activation, benzoxazole, telescoping
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INTRODUCTION:
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by
cognitive decline, memory loss, and dementia. Although Donepezil, Rivastigmine, Galanꢀ
thamine, and Memantine are marketed as Alzheimerꢀtype dementia, all of these compounds are
used as symptomatic therapy and have not high satisfaction with treatment. Therefore, there are
strong unmet medical needs in the development of AD therapy. 1 is PDE4 inhibitor and
expected to improve memory impairment. In addition to the mechanism of action, 1 enhances
BDNF signal transduction and induces NXF, a brain specific transcription factor, in the
presence of low concentrations of BDNF. NXF induction is expected to lead to nerve
regeneration and neuroprotective efficacy.
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O
N
CH3
O
N
N
•1/2
CO2H
HO2C
1
Figure 1. Chemical structure of 1.
In this article, we would like to describe two synthetic methods of 1 developed for scale up.
The Firstꢀgeneration synthesis was based on the medicinal chemistry route and successfully
scaled up to produce 14 kg of active pharmaceutical ingredient (API) for early clinical trials.
The Secondꢀgeneration synthesis was devised that enables direct coupling of benzoxazole with
a heteroaryl bromide, and confirmed by 300 g synthesis for scale up feasibility.
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RESULTS AND DISCUSSION
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First-generation synthesis: The initial medicinal chemistry route to 1 is shown in Scheme 1.1
This route was capable for preparation of the small amounts of API needed for early toxicology
studies, but it was not suitable for largeꢀscale production due to the following issues: (i) the
operational problem such as evaporation to dryness to obtain 4, (ii) the use of possibly
carcinogenic solvent 1,4ꢀdioxane and a mutagenic 2ꢀaminophenol, and (iii) the requirement for
high temperature (240ꢀ250 ºC)2 and chromatographic purification for the synthesis of 7.
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Scheme 1. Medicinal chemistry route
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O
O
8
9
4-aminotetrahydro-2H-pyran・HCl
F
H2, Pd/C
Et3N
NH
NH
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THF/MeOH
rt, 4.5 h
EtOH, 78℃, 10.5 h
HO2C
NO2
HO2C
3（96.5%）
NO2
HO2C
4（quant.）
NH2
2
O
O
AcCl
1) 2-aminophenol, EDC・HCl, THF, rt
N
N
OH
N
N
H
CH3
1,4-dioxane
reflux, 6.5 h
2) aq. NaHCO3
CH3
N
HO2C
O
HCl
・
5（93.3%）
6（80.5%）
O
N
B(OH)3
fumaric acid
CH3
crude-1（91.9%）
O
diethylene glycol dibutyl ether
N
MeOH
240-250℃, 4 h
803g
N
column chromatography
overall yield: 47%
7（69.9%）
Since we need to provide API in a short period for early clinical trial, the firstꢀgeneration
synthesis was adopted by addressing the problems of medicinal chemistry route (Scheme 2). The
improved results are shown as follows: (i) The solution of 4 was used in the next step without
evaporation (Telescoping). (ii) 1, 4ꢀDioxane was switched to THF/MeOH which were used in
the previous step. Acetyl chloride was also changed to acetic anhydride because the starting
material 4 was not completely consumed in the use of acetyl chloride due to formation of
hydrochloride of 4. Furthermore, EDC・HCl was replaced with an inexpensive SOCl2. (iii)
Cyclization reaction of 6 was accomplished at 130 ºC under azeotropic dehydration by the use of
methanesulfonic acid, and chromatographic purification of 7 was avoided by crystallizing 1
directly as fumarate of 7. And the quality of 1 was controlled by recrystallization.
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This firstꢀgeneration synthesis was applied to 14 kg campaign for early clinical trial without a
problem accompanying scaleꢀup.
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Scheme 2. First-Generation Synthesis.
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Second-generation synthesis: After the manufacture by the firstꢀgeneration route, we
examined more efficient synthetic route of 1 for future material supply. In order to reduce the
number of manufacturing steps, we planned to synthesize the API skelton 7, by direct coupling
of benzoxazole with an aryl bromide 8 (Scheme 3). The advantage of this method is not only
to shorten a number of manufacturing steps, but also to avoid using 2ꢀaminophenol, which is
known to be mutagenic.
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Scheme 3. New approach for the synthesis of 7 by C-H/C-Br coupling
Heterobiaryl compounds are very important motifs in biologically active natural products and
pharmaceuticals.3 These moieties has been synthesized by cross coupling of arylꢀmetal
compounds with aryl halides (CꢀM/CꢀX coupling, M = metal).4 On the other hand, recent
advances in the metal mediated direct CꢀH arylations of aryl compounds with aryl halides (Cꢀ
H/CꢀX coupling) provide an efficient and ideal access to the target molecules because it can
avoid the need to prepare stoichiometric amounts of arylꢀmetal reagent.5 Although the direct Cꢀ
H arylations of arylazole with aryl halides have also been extensively studied to date, Miura and
coꢀworkers made a breakthrough in this area in 1998 by finding the catalyst system of
Pd(OAc)2/PPh3/Cs2CO3 that is effective for the arylation of azole including (benzo)thiazoles
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and (benz)oxazoles.6,7 It was noted that the reaction was significantly accelerated by the
addition of CuI (Scheme 4).
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Scheme 4. Arylation of azole reported by Miura and co-workers
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Table 1. Effects of the addition of copper salts
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O
O
Pd(OAc)2 (10 mol%)
CuX (20 mol%)
PPh3 (24 mol%)
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O
N
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N
N
N
N
H
CH3
CH3
Cs2CO3 (2.0 equiv.)
NMP, 100°C, 8 h
O
Br
N
(1.0 equiv.)
(2.0 equiv.)
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7
Entry
CuX(I)
Yield(%)a
Entry
CuX(II)
Yield(%)a
1
2
None
CuI
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Cu(OAc)2
CuO
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CuBr
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CuBr2
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4
CuCI
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87
9
Cu(OTf)2
Cu(OTf)2
87
5b
CuOTf
10
N.D.c
aReaction yields were quantified by HPLC.
b(CuOTf)2•toluene complex was used.
cThe reaction was carried out in the absence of Pd(OAc)2.
Firstly, we applied the Miura’s conditions to the coupling reaction of 88 with benzoxazole in
the absence of a copper salt, and obtained the desired product 7 in 73% yield (Table 1, Entry 1).
The addition of CuI was not effective for this reaction and the yield was lowered to 29% (Entry
2). Next, the effects of the other copper salts were examined (Entries 3⁃9). When CuBr or CuCl
was used, the yields of 7 were low while the reaction was significantly accelerated by the
addition of CuOTf, and the yield of 7 increased up to 87% (Entries 3⁃5). The yield by addition
of Cu(OAc)2 was slightly improved compared to the no copper salt conditions (Entry 6). On the
other hand, the reaction with copper (II) salts such as CuO, CuBr2 and Cu(OTf)2 afforded 7 in
high yields as in the case in CuOTf (Entries 7⁃9). These results indicate that the higher Lewis
acidities of copper salts increase the reactivity, probably due to the activation of benzoxazole.
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When Cu(OTf)2 was used without Pd(OAc)2, 7 was not formed (Entry 10)9,10. In view of
reactivity, cost and availability, Cu(OTf)2 was selected as additive. To the best of our
knowledge, this is the first example of the combination of Pd(OAc)2 with Cu(OTf)2 for CꢀH
arylations of arylazole.11
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In addition to above results, the solvent could be changed from NMP to toluene which was
used for later crystallization. The amount of Pd(OAc)2 could be reduced to 5 mol%.
Although the effects of various ligands were examined next (Table 2), PPh3 gave the best
result (Entry 1). This reaction did not proceed without ligand (Entry 2), and the other ligands
were not effective except for PtBu (Entries 3⁃8)12. As a result, readily available PPh3 was
chosen a ligand.
Since the conditions of copper salt and ligand were identified, the molar ratio of PPh3/ Pd in
coupling reaction was examined. It was found that the formation of unknown impurities was
most suppressed in the case of the ratio of PPh3/Pd 2.5 without depressing reactivity. Then, the
reaction yield increased up to 94% under optimized conditions at 10 g scale.
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Table 2. Effects of the ligandsa
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Entry
1
Ligand
PPh3
Time (h)
6
Residual ratio of 8 (LC area%)b
<1
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2
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none
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97
95
P(o-Tol)3
4
PtBu3
cataCXium® A
XPhos type
dppf
8
5
5
5
6
<1
70
42
22
67
5
6
7
8c
PEPPI-IPr
aThe reaction was carried out by using Pd(OAc)2 (5 mol%), Cu(OTf)2 (20mol%),
ligand (15 mol%), and Cs2CO3 (2.0 equiv.) in toluene at 100°C.
bResidual ratio of 8 is 8 / (8 + 7)
cThe reaction was carried out in the absence of Pd(OAc)2, Cu(OTf)2 and PPh3.
iPr
iPr
iPr
N
N
P
iPr
Cl Pd Cl
iPr
PCy2
iPr
N
cataCXium® A
XPhos type
Cl
PEPPI - IPr
Lastly, the efficient telescoping synthesis of 11 was also studied (Scheme 5). The initial
approach to 11 required the isolation of intermediate 10 to remove triethylamine hydrochloride.
It could be omitted by switching the base from triethylamine to potassium carbonate which was
easily removed by filtration, and then the solution of 10 was directly used in the next step. In the
hydrogenation of the nitro group of 10, the use of platinum, sulfide, on carbon instead of
palladium on carbon controlled the produce of a debromo compound completely. Only THF was
used as a solvent in the telescoping method of 11 from 9.
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In addition, the telescoping was also incorporated into the coupling reaction and salt formation.
For this purpose, it was need to skip of isolation of 8 and 7. When toluene/THF was used instead
of methanol, 8 could be extracted into the organic layer. After evaporation of THF, the solution
of 8 was used in the coupling reaction. After the work up of coupling reaction, 7 was treated with
fumaric acid and 1 was directly crystallized in a manner similar to the firstꢀgeneration method.
Therefore, crudeꢀ1 was synthesized in twoꢀstep from 9. We demonstrated this secondꢀgeneration
route in multiꢀhundred grams scale manufacturing. In the demonstration, 330 g of 11 was
synthesized from 9 in 71% over yield.
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Scheme 5. Second-Generation Synthesis.
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CONCLUSION
We have successfully developed two scalable synthetic methods of a PDE4 inhibitor 1. Although
firstꢀgeneration synthesis based on the medicinal chemistry route was developed for early
clinical trial use, the construction of a benzoxazole unit was not efficient and a mutagenic 2ꢀ
aminophenol was used. In order to solve these problems, direct CꢀH arylation of benzoxazol was
introduced to secondꢀgeneration synthesis. It was found that the combination of Pd(OAc)2ꢀ
Cu(OTf)2ꢀPPh3 is effective for CꢀH/CꢀBr coupling of benzoxazole with heteroaryl bromide.
Furthermore, telescoping methods were adopted to improve the overall yield and operational
efficiency, and twoꢀstep synthesis of 1 was accomplished in 71% over yield.
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EXPERIMENTAL SECTION
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General. 1H and 13C NMR spectra were recorded on a Bruker Ultrashield 400 Plus spectrometer
at 400 and 100.6 MHz, respectively. Chemical shifts (δ) are given in parts per million, and
tetramethylsilane was used as the internal standard for spectra obtained in DMSOꢀd6 and D2O.
Mass spectra were recorded on JEOL JMSꢀT100GC “AccuTOF GC” mass spectrometer with EI
resource. HPLC was performed on a Agilent 1100 system; XBridge C18 column (4.6 mm i.d. ×
100 mm, 5μm); elutent: (a) 0.01 mol/L phosphate buffer (pH 6.8), (b) MeOH ; flow rate = 1.0
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mL/min, Temperature: 40°C, UV detection at 220 nm, Gradient: (b/a) 10/90 (0 min) − 70/30
(0−30 min) −70/30 (30−35 min) −25/75 (35.1 min) −10/90 (35.1−40 min). The purity listed is
determined by area %. Metal analysis was performed using ICPꢀMS analysis (PerkinElmer
ELAN DRC II). All reactions were carried out under nitrogen or argon atmosphere unless
otherwise mentioned. Reagents and solvents were used as obtained from commercial suppliers
without further purification.
First-Generation Synthesis (Scheme 2).
3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)benzoic acid (3). To the solution of 4ꢀfluoroꢀ3ꢀ
nitrobenzoic acid (15.97 kg, 86.27 mol) in water (95.8 kg) was added triethylamine (21.82 kg,
215.68 mol) and 4ꢀaminotetrahydroꢀ2Hꢀpyran (9.60 kg, 94.90 mol) at 65−72°C. The reaction
mixture was stirred at 70°C for 7 h and then allowed to cool to 47°C. Acetic acid (12.95 kg,
215.68 mol) was added to the mixture at 47−52°C and the resulting slurry was stirred at 50°C for
0.5 h. After cooling to 25°C over 2 h, the slurry was filtered. The wet cake was washed with
water (24.0 kg) and isopropyl alcohol (24.0 kg), and dried at 50 °C under vacuum to a constant
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weight to give 3 (21.82 kg, 94.9%) as a yellow solid. Spectral data are consistent with those of
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the literature.1
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1H NMR (400 MHz, DMSOꢀd6): δ 12.91 (br, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 7.7 Hz,
1H), 7.96 (d, J = 9.3, 2.1 Hz, 1H), 7.28 (d, J = 9.3 Hz, 1H), 3.46 (dt, J = 11.5, 2.1 Hz, 3H), 1.95
(dd, J = 2.4, 2.0 Hz, 2H), 1.67−1.58 (m, 2H).
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13C NMR (100 MHz, DMSOꢀd6): δ 165.81, 146.15, 136.04, 130.49, 128.53, 117.35, 114.96,
65.56, 48.29, 32.03.
2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazole-5-carboxylic acid hydrochloride
(5). To the solution of 3 (21.75 kg, 81.69 mol) in MeOH (108.8 kg) and THF (217.5 kg) was
added 10% Pd/C (50% wet), and the mixture was stirred under hydrogen atmosphere (0.02 MPa)
at 26 °C for 2 h. Acetic anhydride (9.17 kg, 89.86 mol) was added, and the mixture was stirred
at 25−27 °C for 2 h. The mixture was filtered and washed with MeOH (10.88 kg). Aqueous HCl
(35%, 8.51 kg, 81.69 mol) was added, and the mixture was stirred at 40°C for 4 h. The mixture
was filtered and washed two times with MeOH (32.63 kg × 2), and dried at 50 °C under vacuum
to a constant weight to give 5 (20.66 kg, 85.3%) as a yellow solid. Spectral data are consistent
with those of the literature.1
1H NMR (400 MHz, DMSOꢀd6): δ 8.27 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.05 (d, J
= 8.8, 1.3 Hz, 1H), 4.86 (m, 1H), 4.06 (dd, J = 11.4, 4.2 Hz, 2H), 3.56 (t, J = 11.4, 2H), 2.94 (s,
3H), 2.42 (m, 2H), 1.99 (dd, J = 12.4, 2.6 Hz, 2H).
13C NMR (100 MHz, DMSOꢀd6): δ 166.49, 153.61, 133.32, 131.59, 127.56, 125.69, 115.83,
114.13, 66.13, 54.35, 30.00, 12.89.
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N-(2-hydroxyphenyl)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzoimidazole-5-
carboxamide (6). To the solution of 5 (18.07 kg, 60.89 mol) in toluene (306.0 kg) and DMF
(8.87 kg) was added SOCl2 (14.48 kg, 121.71 mol) at 75 °C. The reaction mixture was stirred at
75 °C for 7 h and then allowed to cool to 45°C. Toluene (108.0 kg × 2) was added to the mixture
and concentrated below 50 °C until the amount of distillate was 108.0 kg. The mixture was
cooling to 25 °C and the solution of 2ꢀaminophenol (7.28 kg, 66.71 mol) in pyridine (10.57 kg,
133.62 mol) and NMP (90.1 kg) was added to the mixture, and was stirred at 27°C for 24 h.
Aqueous NaOH (24%, 22.26kg, 133.56 mol) was added to the mixture at 27−31 °C over 1h and
warmed up to 50°C. The water (180.0 kg) was added to the mixture at 51−53 °C over 1 h, and
the slurry was stirred at 50 °C for 1 h and was cooling to 25 °C over 1.5 h. After stirring at 25 °C
for 19 h, the slurry was filtered. The wet cake was washed with the mixture of NMP (9.00 kg)
and water (18.0 kg), and acetone (27.0 kg × 2), and dried at 48 °C under vacuum to a constant
weight to give 6 (19.78 kg, 92.5%) as a gray solid. Spectral data are consistent with those of the
literature.1
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1H NMR (400 MHz, DMSOꢀd6): δ 9.76 (s, 1H), 9.54 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.82 (dd,
J = 8.6, 7.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.06−7.01 (m, 1H),
6.93 (dd, J = 8.0, 1.4 Hz, 1H), 6.84 (td, J = 7.6, 1.4 Hz, 1H), 4.67−4.60 (m, 1H), 4.05 (dd, J = 7.6,
11.3, 4.3 Hz, 2H), 3.57 (dd, J = 11.3, 10 Hz, 2H), 2.65 (s, 3H), 2.45−2.35 (m, 2H), 1.88−1.84 (m,
2H).
13C NMR (100 MHz, DMSOꢀd6): δ 165.73, 153.52, 149.07, 142.45, 135.97, 127.22, 126.28,
125.40, 123.76, 121.20, 119.08, 118.12, 116.16, 111.33, 66.51, 52.60, 30.68, 14.65.
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2-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole
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hemifumarate (1). To the solution of 6 (16.50 kg, 46.96 mol) in NMP (49.4 kg) and Toluene
(25.1 kg) and DMF was added methanesulfonic acid (22.56 kg, 234.78 mol) at 23−56 °C. The
mixture was heated to 125−129 °C and stirred for 8h under azeotropic dehydration. The mixture
was cooled to 25°C, and toluene (256.0 kg) and aqueous NaOH (24%, 46.96 kg, 281.76 mol)
was added. The aqueous layer was removed and the organic layer was washed two times with
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20% aqueous NaCl (65.8 kg
× 2). The organic layer was concentrated under reduced pressure
bellow 50 °C to distill off 78.8 kg. Residue was adjusted to ca. 231.0 kg with additional toluene
(1.2 kg) and heated to 69°C. Fumaric acid (0.16 kg, 1.41 mol) in NMP (1.7 kg) and seed crystal
(17g) was added and stirred for 0.5 h. Additional fumaric acid (3.11 kg, 26.76 mol) in NMP (31.3
kg) was added dropwise over 0.5 h at 69°C and stirred for 0.5 h. Heptane (100.4 kg) was added
dropwise over 0.5 h and stirred for 0.5h. The slurry was cooled to ꢀ1 °C over 11 h and filtered.
The wet cake was washed two times with acetone (16.5 kg × 2), and dried at 48 °C under
vacuum to a constant weight to give crudeꢀ1 (15.36 kg, 83.6%, HPLC area 99.9%) as a pale
brown solid.
The solution of crudeꢀ16 (15.14 kg, 38.68 mol) in EtOH (230.6 kg) and water (57.6 kg) was
filtered at 78 °C, and washed with the mixture of EtOH (12.13 kg) and water (3.03 kg). Filtrate
was concentrated bellow 80 °C to distill off 91.3 kg and water (106.1 kg) was added. After
stirring at 75−82°C for 1 h, the solution was cooled to 65°C and seed crystal (15g) was added
and stirred at 60−62°C for 1 h. Water (197.2 kg) was added dropwise over 1 h at 58−50°C and
stirred for 0.5 h. The slurry was cooled to 3 °C over 6.5 h and filtered. The wet cake was washed
two times with acetone (15.2 kg × 2), and dried at 48 °C under vacuum to a constant weight to
give 1 (14.1 kg, 93.1% , HPLC area >99.9%) as a pale brown solid. Spectral data are consistent
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1H NMR (400 MHz, DMSOꢀd6): δ 13.1 (br, 1H), 8.33 (d, J = 1.5 HZ, 1H), 8.06 (dd, J = 5.1,
1.6 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.82−7.76 (m, 2H), 7.43−7.38 (m, 2H), 6.64 (s, 1H),
4.71−4.62 (m, 1H), 4.06 (dd, J = 11.4, 4.3 Hz, 2H), 3.58 (dd, J = 11.7, 11.4 Hz, 2H), 2.67 (s, 3H),
2.47−2.36 (m, 2H) , 1.90−1.86 (m, 2H).
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13C NMR (100 MHz, DMSOꢀd6): δ 165.92, 163.26, 153.94, 150.20, 142.94, 141.75, 136.21,
133.93, 124.94, 124.67, 120.89, 119.40, 117.70, 112.44, 110.72, 66.50, 52.67, 30.70, 14.62.
Second-Generation Synthesis (Scheme 5).
5-bromo-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazole hydrochloride (11). The
reaction of 4ꢀbromoꢀ1ꢀfluoroꢀ2ꢀnitrobenzene (9) with 4ꢀaminotetrahydroꢀ2Hꢀpyran and
hydrogenation process of 10 was carried out in two batches at the same scale. To the solution of
K2CO3 (109.3 g, 0.79 mol) and 4ꢀaminotetrahydroꢀ2Hꢀpyran (73.3 g, 0.73 mol) in THF (507.5
kg) was added 9 (145.0 g, 0.66 mol) in THF (73.0 g) at 63−66 °C over 0.5 h. After stirring under
reflux for 5h, the mixture cooled to room temperature, and THF (290.0 g) and 3% PtꢀS/C (14.5
g) were added. The mixture was stirred under hydrogen atmosphere at 25 °C for 5 h and THF
(290.0 g) was added. The mixture was filtered and washed two times with THF (290.0 g × 2).
After filtrates (two batches) were combined into one batch, THF (870.0 g) was added at room
temperature and heated to 40 °C. Acetic anhydride (67.29 g, 0.66 mol) was added dropwise over
0.5 h and seed crystal (1.5g) was added and stirred at 42°C for 20 min. Additional acetic
anhydride (134.6 g, 1.32 mol) was added dropwise over 1 h and stirred for 3.5 h. Aqueous HCl
(35%, 164.1 g, 1.58 mol) was added dropwise over 0.5 h at 40°C and the mixture was stirred for
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5 h. After cooling to 0 °C, the mixture was filtered and washed two times with acetone (435.0 g
× 2) , and dried at 40 °C under vacuum to a constant weight to give 11 (401.3 g, 91.8%) as a
white solid.
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1H NMR (400 MHz, D2O): δ 7.84 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.60 (dd, J =
9.0, 1.8 Hz, 1H), 4.86−4.80 (m, 1H), 4.14 (dd, J = 11.8, 4.7 Hz, 2H), 3.65 (td, J = 12.1, 1.9 Hz,
2H ), 2.55−2.45 (m, 2H), 2.01−1.96 (m, 2H).
13C NMR (100 MHz, D2O): δ 151.60, 131.49, 129.54, 128.59, 118.54, 117.00, 115.46, 66.71,
54.69, 29.68, 11.97.
HRMS (EI) exact mass calcd for C13H15BrN2O (M − HCl) 294.0368, found: 294.03711.
2-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole
hemifumarate (1). Spectral data are consistent with those of the first generation synthesis. To
the solution of 11 (359.5 g, 1.08 mol) in Toluene (3200 g), THF (3200 g), and water (640.0 g)
was added aqueous NaOH (27%, 176.7 g, 1.19 mol) and heated to 37 °C. The aqueous layer was
removed and the organic layer was washed with water (960.0 g). After removing the aqueous
layer, the organic layer was concentrated under reduced pressure bellow 50 °C to distill off 4302
g. Toluene (4554 g) was added and the organic layer was concentrated to distill off 4942 g.
Additional toluene (4604 g) was added and the organic layer was concentrated to distill off 4877
g. After analyzing water and THF content in toluene solution (173 ppm and 0.01%, respectively),
the solution was adjusted to 2528 g with additional toluene (388.0 g). To the solution of 8 was
added PPh3 (35.5 g, 0.136 mol), Cs2CO3 (706.4 g, 2.168 mol), Cu(OTf)2 (706.4 g, 0.217 mol),
Pd(OAc)2 (12.2 g, 0.054 mol), benzoxazole (258.3 g, 2.168 mol) and toluene (32.0 g) under
nitrogen flow. Additional nitrogen substitution was performed with vacuum deairing (three
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times). After analyzing oxygen concentration (0.1%), the mixture was heated to 100 °C and
stirred for 1 h. After additional heating to 110 °C, the mixture was stirred for 2 h. Toluene (4800
g) was added, and the mixture was filtered at 80 °C and washed two times with toluene (480.0 g
× 2). Activated carbon (32.0 g) was added ant stirred for 1 h. ISOLUTE® SiꢀThiol (32.0 g) was
added as metal scavenger and stirred for 3 h. The mixture was filtered at 80 °C and washed two
times with toluene (160.0 g × 2). The filtrate was concentrated to distill off 2129 g was adjusted
to 6080 g with additional toluene (187.0 g). PPh3 (14.2 g, 0.054 mol) was added at 80 °C ant
stirred for 0.5 h. Fumaric acid (3.8 g, 0.033 mol) in NMP (32.0 g) and seed crystal (0.35 g) was
added and stirred for 0.5 h. Additional fumaric acid (71.7 g, 0.618 mol) in NMP (608 g) was
added dropwise over 1.5 h at 80 °C and stirred for 0.5 h. Heptane (1440 g) was added dropwise
over 0.5 h and stirred for 0.5h. The slurry was cooled to 0 °C over 5 h and stirring was performed
for another 14 h. The slurry was filtered and the wet cake was washed two times with acetone
(640.0 g × 2), and dried at 50 °C under vacuum to a constant weight to give crudeꢀ1 (329.8 g,
77.7%, HPLC area 99.5%) as a pale brown solid. The content of Pd and Cu was 18 and 0.8 ppm,
respectively.
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To the solution of crudeꢀ16 (20.0 g, 51.00 mmol) in EtOH (304.0 g) and water (76.0 g) was
added ISOLUTE® SiꢀThiol (0.2 g) at 78 °C. After stirring 2 h, the mixture was filtered and
washed with the mixture of Ethanol (16.0 g) and water (4.0 g). Filtrate was concentrated under
reduced pressure to distill off 120.0 g and water (140.0 g) was added. After heating to 78 °C, the
solution was cooled to 59°C and seed crystal (2.0 g) was added and stirred for 1.5 h. Water
(260.0 g) was added dropwise over 1 h at 59 °C and cooled to 2 °C over 4 h. Stirring was
performed for another 15 h and filtered. The wet cake was washed two times with acetone (20.0
g × 2), and dried at 40 °C under vacuum to a constant weight to give 1 (19.1 kg, 95.5% , HPLC
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area 99.9%) as a white to pale yellow solid. The content of Pd and Cu was 0.3 and 0.1 ppm,
respectively.
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ASSOCIATED CONTENT
Supporting Information
NMR spectra for compounds (PDF)
AUTHOR INFORMATION
*Corresponding Author
kiichiꢀkuroda@dsꢀpharma.co.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Dr. Yuji Fujiwara for proofreading of the manuscript.
REFERENCE
(1) (a) Ishikawa, J.; Saito, K.; Ohe, N.; Kobayashi, K. PCT int. Appl. WO2010/137349 A1. (b)
Patent pending
(2) For an example of synthesis of benzoxazole by using B(OH)3, see: Kauffman, J. M.; Moyna,
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G. J. Heterocyclic. Chem. 2002, 39, 981.
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9
(3) For review, see: a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995. b) Nicolaou, K. C.; Bulger, P.
G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. c) Carey, J. S.; Laffan, D.; Thomson,
C.; Williams, M. T.; Org. Biomol. Chem. 2006, 4, 2337.
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(4) MetalꢀCatalyzed CrossꢀCoupling Reactions, 2nd ed.; de Meijere A., Diederich, F.; Eds.;
WileyꢀVCH, Weinheim, 2004. (b) CrossꢀCoupling Reactions: A Practical Guide; Miyaura,
N.; Ed.; Topics in Current Chemistry, Vol. 219, Springer, Berlin, 2002.
(5) For recent review, see: a) Miura, M.; Satoh, T.; Hirano, K. Bull. Chem. Soc. Jpn. 2014, 87,
751. b) Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamagushi, J.; Itami, K.
Chem. Eur. J. 2011, 17, 10113. c) Rossi, R.; Belina, F.; Lessi, M.; Manzini, C.; Adv. Synth.
Catal. 2014, 356, 17. d) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2,
20.
(6) PivsaꢀArt, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998,
71, 467.
(7) The first CꢀH arylations of (benz)oxazole was reported by reported by Ohta and coworkers,
see: Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Komatsu,
J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma, R.; Akita, Y.; Ohta, A. Heterocycoles 1992,
33, 257.
(8) The compound 8 was prepared from commercially available 9 in a manner similar to a firstꢀ
generation approach.
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(9) For examples of Cu catalyzed CꢀH arylation of azoles, see: a) Kim, D.; Yoo, K.; Kim, S. E.;
Cho, H. J.; Lee. J.; Kim, Y.; Kim, M. J. Org. Chem. 2015, 80, 3670. b) Nishino, M.; Hirano,
K.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2013, 52, 4457. c) Zhang, W.; Zeng, Q.;
Zhang, X.; Tian, Y.; Yue, Y.; Guo, Y.; Wang, Z. J. Org. Chem. 2011, 76, 4741.
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(10) For examples of Cu(OTf)2 catalyzed synthesis of benzoxazole from benzanilides, see: a)
Ueda, S.; Nagasawa, H. Angew. Chem. Int. Ed. 2008, 47, 6411. b) Ueda, S.; Nagasawa, H. J.
Org. Chem. 2009, 74, 4272.
(11) For examples of PdꢀCu catalytic system for CꢀH arylation of heteroarenes, see: a) Huang,
J.; Chan, J.; Chen. Y.; Borths, C. J.; Baucom. K. D.; Larsen. R. D.; Faul. M. M. J. Am. Chem.
Soc. 2010, 132, 3674. b) Yan, X.ꢀM.; Mao, X.ꢀR.; Huang, Z.ꢀZ. Heterocycles 2011, 83, 1371.
c) Alagille, D.; Baldwin, R. M.; Tamagnan, G. D. Tetrahedron Lett. 2005, 46, 1349.
(12) For an example of NHCꢀPd complex catalyzed CꢀH arylation of (benz)oxazole, see:
Shen, X.ꢀB.; Zhang, Y.; Chen, W.ꢀX.; Xio, Z.ꢀK.; Hu, T.ꢀT.; Shao, L.ꢀX. Org. Lett. 2014, 16,
1984.
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