Development of a Robust Protocol for the Synthesis of 6-Hydroxybenzofuran-3-carboxylic Acid

Article abstract of DOI:10.1021/acs.oprd.9b00546

Benzofuran scaffolds are fundamental moieties found in a variety of biologically active natural products and synthetic drugs. In the course of one of our development programs, we needed to develop a practical and cost-effective manufacturing approach to such a benzofuran scaffold. Here we report a highly robust four-step, one-pot process that provides access to a 6-hydroxybenzofuran-3-carboxylic acid structure. An 1H NMR monitoring study allowed a better understanding of the overall sequence of events and the nature of the detected intermediates. After six steps, including the optimized tandem process, the desired hydroxylated benzofuran was obtained in 40% yield with a purity above 99%.

Full text of DOI:10.1021/acs.oprd.9b00546

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Communication
Development of a robust protocol for the synthesis
of 6-hydroxybenzofuran-3-carboxylic acid
Isabelle Gallou, Bernhard Erb, Michael Marti, Gianluca Nuzzo, Andreas Jager, Manuela
Seeger, Pierre Chassagne, Jonas Aronow, Margery Cortes-Clerget, and Fabrice Gallou
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00546 • Publication Date (Web): 28 Jan 2020
Downloaded from pubs.acs.org on January 30, 2020
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Development of a robust protocol for the synthesis of 6-hydroxybenzofuran-3-carboxylic
acid
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Gallou, Isabelle; Erb, Bernhard ; Marti, Michael; Nuzzo, Gian-Luca; Jager, Andreas;
Seeger, Manuela; Chassagne, Pierre; Aronow, Jonas; Cortes-Clerget, Margery, Gallou,
Fabrice *
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Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel
fabrice.gallou@novartis.com
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Abstract. Benzofuran scaffolds are fundamental moieties found in a variety of biologically active
natural products and synthetic drugs. In the course of one of our development programs, we
needed to develop a practical and cost-effective manufacturing approach to such a benzofuran
scaffold. Here, a 4-step 1-pot process is reported, allowing the access to a 6-hydroxybenzofuran-
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1
3-carboxylic acid structure as highly robust. A H NMR monitoring study allowed a better
understanding of the overall sequence of event and the nature of the detected intermediates. After
6 steps, including the optimized tandem process, the desired hydroxylated benzofuran was
obtained with 40% yield and a purity above 99%.
Keywords: benzofuran, manufacturing process, robustness, streamlining
Both monocyte chemoattractant protein-1 (MCP-1) and its chemokine receptor-2 (CCR2) have
been recognized to play a major role in the pathogenesis of inflammatory diseases, atherosclerosis
and cancers.1 By binding to CCR-2, MCP-1 initiates a cascade of events including an innate
immunity response by recruiting monocytes into the sites of inflammation, leading to inflammation
and inflammation-related diseases.2,3 Many studies suggest that interfering with the MCP-1/CCR-
2 interaction reduces the CCR-2-mediated inflammatory syndrome or diseases such as psoriasis,4
rheumatoid arthritis,5 multiple sclerosis6 or asthma.7 In the course of one of our development
programs, Compound A was identified as a selective antagonist for CCR-2 and CCR-5.
To synthesize the drug candidate depicted in Figure 1, a viable route to access the 6-
hydroxybenzofuran-3-carboxylic acid central moiety (highlighted in blue), was required. Thus, a
long-term manufacturing approach taking into consideration cost, safety and environmental
aspects is reported. While many obvious and relatively standard cross-coupling approaches relying
on an ortho-halophenol can be envisioned, the potential for persistent dioxin they could form
constitute a real no-go within our organization.
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OH
O
OH
N
O
O
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O
N
H
NH
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A
compound
Figure 1: antagonist for CCR-2 and CCR-5 drug candidate
The benzofuran scaffold is widely present in naturally occurring and biologically active
compounds, which can display various pharmacological activities.8–11 For this reason,
considerable efforts have been devoted to the development of efficient methods for their
preparation.12 Several reports describe the preparation of 3-substituted benzofurans. The most
common approaches proceed via:
(a): dehydrative cyclization of -(phenoxy)-alkyl ketones under acidic conditions.13,14
(b): dehydration of 2-hydroxybenzyl ketones under acidic conditions15 or catalyzed by copper.16
(c): decarboxylation of 2-acylphenoxyacetic acids or esters on treatment with a base.17,18
(d): Pd0 catalyzed cyclization of aryl acetylenes.19,20
R6
R6
R5
R4
O
O
R1
R2
R5
R4
OH
R2
(a)
(b)
O
acid
acid
R1
R3
R3
R6
R5
R4
O
R1
R2
R3
R1
COOR
R2
R6
R6
R5
R4
R5
R4
O
OH
(c)
base
(d)
Pd0, R2-X
R1
R3
R3
O
Scheme 1: Commonly employed strategies for the synthesis of the benzofuran moiety
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The dehydrative cyclization pathway provided an attractive alternative to the use of ortho-
halophenol as starting material, and thus, eliminated the risk of dioxin formation. It was also a
viable route from an economic perspective, as O-methylated resorcinol was a cheap feedstock
material to start with. All the other catalytic approaches were prohibitively expensive. We
therefore revisited this original approach and decided to optimize one of the very early routes.
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The benzofuran fragment 5 was originally prepared in 5 steps from the cheap and readily available
O-methylated resorcinol 1 (Figure 2). First, a ketodiester intermediate 2 was prepared in a two-
step process by reaction of 1 with ethyl chloroacetate under basic conditions, followed, in a second
step, by base-promoted acylation with diethyloxalate. The key dehydrative cyclization step was
originally performed with 6 M sulfuric acid at −15 °C, thus avoiding decomposition of the ester
groups. Intermediate 3 was then selectively decarboxylated using Krapcho’s21 conditions (NaCl in
DMSO, 160 °C). Overall, the isolated yield for this sequence was not only low but also
inconsistent.
COOEt
COOEt
OH
COOEt
O
O
cyclization
COOEt
O
MeO
MeO
MeO
1
2
3
O
O
COOEt
COOH
decarboxylation
MeO
MeO
4
5
Figure 2: dehydrative cyclization step under strong acidic conditions
Despite a fast and simple set up, this approach lacked of robustness and the scale-up led to
inconsistent results, with an overall yield comprised between 6 and 25%. The reproducibility issue
happened during the cyclization step and the subsequent decarboxylation due to the harsh
conditions needed.
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The breakthrough came by re-imagining a controlled process in a tandem 4-step, 1-pot fashion
transformation, that consisted in a net dehydrative cyclization-selective hydrolysis-
decarboxylation-hydrolysis. We started our study by generating all intermediates along the
sequence, along with such others as the various mono-acid-mono-esters. The ester derivative was
preferred over the alternative methyl ester as the resulting side-product was slightly easier to
handle technically from a waster stream standpoint (methyl halide vs ethyl halide of slightly lesser
volatility). The initial thought was that, by performing the dehydrative cyclization under acidic
conditions, which would allow for the ester hydrolysis and the decarboxylation of the 2-carboxylic
acid, the substituted benzofuran 6 (Figure 3) could be obtained in a much more efficient manner.
We had indeed observed a few key aspects that would constitute in our mind enablers for a
controlled process:
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-
-
Dehydrative cyclization would occur onto the diester leading to benzofuran 3;
Hydrolysis occurred preferentially and selectively first on the acid bared by C3 of the
newly formed benzofuran, thus leading to 8;
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Decarboxylation would occur more readily from the 6-methoxybenzofuran-2,3-
dicarboxylic acid 9 compared to 3-(ethoxycarbonyl)-6-methoxybenzofuran-2-carboxylic
acid 9* (see figure 3);
Demethylation of the methyl ether would occur ultimately and result into the final product
7.
COOH
COOH
O
FAST
O
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O
SLOW
COOH
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COOEt
MeO
MeO
MeO
MeO
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9*
6
high yielding
9
Figure 3: qualitative assessment of the decarboxylation of benzofurans 3 and 3*
Several acids that could be used for future, industrially relevant large-scale applications, especially
in terms of costs and safety, were evaluated (Table 1). The reactions were set up with various acids,
all in large excess (30 equiv), at temperatures varying from 60 to 100 °C, on ca. 1 gram scale
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experiments. After 3 days (unless otherwise noted), numerous intermediates were detected by 1H
NMR. Depending on the conditions, the ratio between those intermediates varied greatly. In
accordance with these NMR results, the presumed sequence has been postulated (Scheme 2).
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COOEt
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COOEt
H
COOEt
COOEt
COOEt
O
O
O
O
O
COOEt
OH
COOEt
COOH
MeO
MeO
MeO
MeO
2
not observed
O
3
8
COOH
O
O
COOH
COOH
COOH
HO
MeO
MeO
7
6
9
Scheme 2: presumed sequence for the 4-step 1-pot transformation
Table 1: screening of various acidic conditions
Yield of 7
Yield of 8
(%)
Yield of 9
(%)
Yield of 6
Entry
Conditions
Purity (%)1
(%)
(%)
1
2
3
4
5
6
7
8
9
HCl 37%, 60 °C
HCl 37%, 80 °C
HCl 37%, 100 °C
HBr 48%, 60 °C
HBr 48%, 80 °C
HBr 48%, 80 °C2
HBr 48%, 100 °C2
H2SO4 48%, 60 °C
H2SO4 48%, 80 °C
H2SO4 48%, 100
°C2
5.2
63.9
30.8
71.5
9.1
46.1
58.5
28.3
80.6
50.2
44.8
46.1
47.9
46.1
54.4
20.0
20.0
61.4
10
11
28.0
Mixture of
3 and 8
only
AcOH
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1 determined by NMR assay; 2 reaction stirred overnight
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Hydrobromic acid was found to be the most suitable acid, giving rise to satisfactory yields22 of the
desired benzofuran 7 (entries 5-7), although with mediocre purity. Neither hydrochloric nor
sulfuric acid led to the final product 7; instead, while treatment with sulfuric acid at 100 °C led to
reasonable amounts of intermediate 6, the reaction with hydrochloric acid only gave mixtures of
di- and mono-acids 9 and 6. In the course of these experiments, we were able to find out that
temperature ≥ 80 °C were required to allow for the decarboxylation.
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Reducing the amount of hydrobromic acid was detrimental for the overall efficiency of the
reaction, as only 8% isolated yield was obtained when going from a concentration of 6.4 M to 4.1
M. For the sake of comparison, the initial experiment with 6.4 M of HBr resulted in a 47.9%
isolated yield of the desired benzofuran 7, although, with mediocre purity.
Nevertheless, multiple runs leading to disparate results, the remaining challenge was to address
the observed lack of robustness and reproducibility of the experiment. As the formation of a crust
was sometimes observed on the side of the reactor, for the most part comprising of decomposition
by-products, the hypothesis was that the stirring speed had a significant impact on the outcome of
the sequence.
In order to assess the importance of this phenomenon, we evaluated different stirring rates. Three
different stirring rates were evaluated on a tube-like, 0.5 L reactor so as to increase the extent of
crusting, on ca. 20 g scale.
Table 2: impact of the rate stirring on the yield and the purity
Entry
1
Conditions
HBr 48% 30 equiv 80 °C
3 days
Yield (9) (%)
Purity (NMR Assay)
75.0
44.8
500 rpm
HBr 48% 30 equiv 80 °C
3 days
2
26.7
28.3
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150 rpm
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HBr 48% 30 equiv 80 °C
3
3 days
53.1
16.3
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50 rpm
A significant difference was noticed on purity by increasing the stirring rate. Indeed, the highest
purity (75%) was observed for a high speed (500 rpm) whereas low speed stirring (50 rpm) led to
decomposition of the material by overheating. An hypothesis is that an increase of the stirring rate
would minimize the extent of crust at the surface of the reaction mixture, in comparison with a
gently stirred reaction. Such observations intuitively make sense with easier accumulation of
organic components on the edges of the bulk medium with limited stirring, hence ensuing drying,
local exotherms and decomposition.
The conditions screening also highlighted that shortening the reaction time to an overnight stirring
also improved significantly the purity of the isolated product (Table 1- entry 6) as an increase of
approximately 50% purity was reached (up to 80%). In the final tuning of the reaction, the
significant differences in kinetics observed during scale-up was addressed. Indeed, using the
following optimized conditions, i.e. 48% aqueous HBr, 30 equivalents, 80 °C, with vigorous
stirring (300 rpm), a very slow decarboxylation was observed (more than a day to reach full
decarboxylation). The use of acetic acid as co-solvent to allow for a homogeneous reaction mixture
throughout the whole sequence and gentle sub-surface bubbling with nitrogen dramatically
increased the rate of the decarboxylation, thus allowing for completion of the reaction within
roughly 12 hours, compared to 3-4 days as previously observed on scale.
In order to better understand the overall sequence, a NMR study was conducted to unambiguously
identify the intermediates and gain knowledge on the kinetics of the transformation. The reaction
was performed in deuterated acetic acid, using DBr 48% in D2O as reagent. Four intermediates
were identified by 1H and 13C NMR along the sequence and are presented in Figure 3. The tandem
reaction has been carefully monitored by 1H NMR to follow the disappearance and formation of
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various intermediates over time. The results are presented in Scheme 3. The overall reaction time
here differed significantly compared to that of the large scale experiments, most likely due to
mixing. A total of almost 48 h was required to reach completion from the NMR tube experiment,
instead of 12 h in a standard reactor.
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time (h)
starting material (2)
cyclized di-acid (9)
cyclized di-ester (3)
cyclized mono-ester (8)
final product (7)
cyclized mono-acid (6)
Scheme 3: profile of the 1-pot sequence to access product 9
This experiment demonstrated that the cyclization happened rapidly, followed by two sequential
and fast selective ester hydrolyses. The subsequent decarboxylation proceeded at a slower rate,
concomitantly with a slow demethylation event to access the final product 7, representing
relatively 95% of the medium composition after 48 h.
In conclusion, the desired benzofuran building block was further functionalized and prepared in 6
steps, including a 4-step in 1-pot sequence, from the cheap and readily available O-methylated
resorcinol. The sequence has been optimized for large-scale application and streamlined to result
in the desired benzofuran in an overall 40% yield, and excellent purity (above 99.0%).
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Experimental section
1H or 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker spectrometer in
a suitable deuterated solvent. The used solvent as well as the respective measurement frequency
are indicated for each experiment. The signal of the residual deuterated solvent relative to
tetramethylsilane was used as the internal reference. All spectra are reported as follows: chemical
shift  in ppm (multiplicity, coupling constant J in Hz, number of protons). The resonance
multiplicity is described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of
doublets (dd), doublet of triplets (dt), triplet of doublets (td). Purities were determined by 1H NMR
assay using dimethylfumarate as internal integration standard and are given in molar percentage.
Analytical thin-layer chromatography (TLC) was performed on Merck Silica gel 60 F254 plates.
Visualization was accomplished by irradiation with UV light (254 or 366 nm).
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Preparation of 2.23 3-methoxyphenol 7 (5 kg, 40.3 mol) was dissolved in 45 L acetone. Potassium
carbonate (13.92 kg, 100.7 mol, 2.5 equiv), potassium iodide (0.134 kg, 0.8 mol, 0.02 equiv) and
o
1.448 kg water were added. The resulting suspension was heated to reflux (63 C mantel
temperature). A solution of ethyl chloroacetate 8 (6.42 kg, 52.4 mol, 1.3 equiv) in 37 L acetone
was added over 1 h. No exotherm was observed. The reaction mixture was then stirred for 4 h.
After 7 h under refluxing conditions, the mixture was cooled to rt and stirred at this temperature
overnight (13 h). The reaction mixture was filtered (slow filtration) and the cake was washed with
14 L acetone. The filtrate was concentrated under reduced pressure (50 oC, 100 mbar). The residue
was taken up in 8.5 L xylenes and concentrated again under reduced pressure. The residue was
taken up in 3 L isopropanol and concentrated under reduced pressure (3×). The desired product 9
was isolated in 94% yield (7.93 kg) and 98.4 A% GC purity.
To an inerted (3×) reactor was introduced 33 L MTBE. The reactor was re- inerted (3×) and sodium
ethoxide (3.1 kg, 45.3 mmol, 1.2 equiv) was added. The reactor was re-inerted again and diethyl
oxalate 10 (6.1 kg, 41.5 mmol, 1.1 equiv) was added to the orange suspension at room temperature
(20 oC). A slight exotherm was observed (IT 30 oC). The previously prepared intermediate 9 (7.93
kg, 37.7 mol) was dissolved in 37 L MTBE and was added to the above mixture. The reaction
mixture was heated to reflux and stirred at that temperature for 4 h. The mixture was cooled to rt,
poured onto 35 L water and 42 L of aq HCl (2 M) solution was added. The layers were separated,
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and the organic layer was washed with brine (35 L). The organic layer was concentrated under
o
reduced pressure (40 C, 200 mbar) and the residue was taken up twice in 2 L toluene and
concentrated again under reduced pressure. The product 2 was isolated in 98% yield (11.54 kg)
and 94.6 A% GC purity. 1H NMR (300 MHz, CDCl3) δ = 7.25-7.15 (m, 1H), 6.6 – 6.5 (m, 3H),
4.5-4.1 (m, 5H), 3.78 (s, 3H), 1.6-1.1 (m, 6H); HRMS (CI) m/z calcd for C15H18O7 [M]+:310.1;
found:310.3.
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Preparation of 7.24 The previously prepared compound 2 (5.47 kg, 17.64 mol) was dissolved in
21.9 kg L AcOH. HBr 48% in water (29.56 kg, 176.4 mol, 10 equiv.) was added at room
o
temperature and the mixture was heated to reflux (IT 100 C) for 3 h. The internal temperature
(IT) was then lowered to 85 oC and the mixture was stirred at that temperature overnight (because
of a defective absorber). The reaction mixture was cooled to rt and a TLC (unreliable HPLC
method) showed a mixture of product and unprotected methyl ether. 12.11 kg HBr 63% in water
(149.65 mmol, 8.5 equiv) was added and the mixture was heated to reflux for 1 h. TLC analysis
still showed the same mixture. The reaction mixture was cooled to rt, 20 L water were added and
the mixture was stirred at that temperature overnight. The product precipitated overnight. Due to
a very slow filtration, the product was collected via centrifuge (30 minutes). The cake was washed
o
with 10 L water and dried in a vacuum oven (60 C, 15 mbar) overnight. 1.5 kg of a mixture of
product and unprotected methyl ether were isolated as a dark brown solid. 1.3 kg of this mixture
were taken up in a mixture of 1.7 L AcOH, HBr 48% in water (8.6 kg, 51 mol, ca. 8 equiv) and
HBr 33% in AcOH (3.12 kg, 12.7 mol, ca. 2 equiv). The mixture was heated to reflux (IT 100 oC)
for 5 h then cooled to 5 oC over a period of 1.5 h and stirred at this temperature for 30 minutes.
The fine suspension was filtered (fast filtration). The cake was washed twice with 1 L ice-cold
water and dried in a vacuum oven overnight (55 oC, 15 mbar). A total of 888 g (33% yield) of 12
was isolated as a dark brown solid. 1H-NMR (300 MHz, DMSO-d6): δ (ppm) 9.8 (br s, 1 H), 8.42
13
(s, 1H), 7.71 (s, 1H), 6.90-6.80 (m, 2H). C-NMR (DMSO-d6): δ (ppm) 164.3, 156.2, 156.2, ,
150.5, 139.6, 121.6, 116.4, 114.5, 113.6. MH+ (CI) m/z calcd for C9H6O4 [M+H]+:179.0;
found:179.1.
ASSOCIATED CONTENT
Supporting information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/
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Includes: NMR spectra of 2 and 7
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AUTHOR INFORMATION
Corresponding Authors
Gallou, Fabrice — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Other Authors
Gallou, Isabelle — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Erb, B — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Marti, M — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Nuzzo, G.-L — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Jager, A — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Seeger-Weibel, M — Chemical & Analytical Development, Novartis Pharma AG, CH-4056
Basel.
Chassagne, P — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Aronow, J — Chemical & Analytical Development, Novartis Pharma AG, CH-4056 Basel.
Cortes-Clerget, Margery — Chemical & Analytical Development, Novartis Pharma AG, CH-
4056 Basel. https://orcid.org/0000-0002-8358-1925
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