A safe and practical procedure for the difluoromethylation of methyl 4-hydroxy-3-iodobenzoate

Article abstract of DOI:10.1021/op200052z

The difluoromethylation of methyl 4-hydroxy-3-iodobenzoate has been demonstrated on multikilogram scale. Prior to execution, several issues had to be addressed. First, the difluorocarbene source had to be explored to avoid using highly toxic gases such as

Full text of DOI:10.1021/op200052z

TECHNICAL NOTE
pubs.acs.org/OPRD
A Safe and Practical Procedure for the Difluoromethylation
of Methyl 4-Hydroxy-3-iodobenzoate
Jeffrey B. Sperry*,† and Karen Sutherland‡
Wyeth Research, Department of Chemical and Pharmaceutical Development, 401 North Middletown Road, Pearl River,
New York 10965, United States
S Supporting Information
b
ABSTRACT: The difluoromethylation of methyl 4-hydroxy-3-iodobenzoate has been demonstrated on multikilogram scale. Prior
to execution, several issues had to be addressed. First, the difluorocarbene source had to be explored to avoid using highly toxic gases
such as chlorodifluoromethane. After choosing sodium chlorodifluoroacetate as the difluororcarbene precursor and potassium
carbonate as the base, a safety evaluation had to be performed to ensure this transformation could be carried out safely on
multikilogram scale. Herein, we report a safe and practical difluoromethylation protocol of methyl 4-hydroxy-3-iodobenzoate. This
procedure was successfully implemented on 7 kg scale to produce (6) in 99% yield and 99% purity after crystallization.
Scheme 1. Byproduct formation in the difluoromethylation
’ INTRODUCTION
of phenols
Aryl difluoromethyl ethers are becoming increasingly preva-
lent in the pharmaceutical,1 agrochemical,2 and materials3 in-
dustries. Recently, this functional group has been incorporated in
selective phosphodiesterase-4 inhibitors,4 PPAR-δ agonists,5
treatments for cardiac arrhythmias,6 and HCV inhibitors.7 Dur-
ing the course of a cGMP campaign for a compound entering
development, we required the conversion of an o-iodo phenol to
the corresponding difluoromethyl ether. The original medicinal
chemistry route utilized chlorodifluoromethane,8 a highly toxic
chlorofluorocarbon (CFC) gas, as the source of the difluorocar-
bene intermediate. This reagent could not be used on scale.
Other reagents used for the difluoromethylation of phenols
include those derived from chlorodifluoroacetic acid,9 including
the sodium salt and alkyl esters. These bench-stable solids are
readily available in bulk and easier to handle than chlorodifluor-
omethane, however, the reactions must be carried out at elevated
temperature, release an equimolar amount of carbon dioxide, and
produce unwanted byproduct such as double-addition and triple-
addition adducts. Alternative reagents do exist10 for converting
phenols to the corresponding difluoromethyl ether, but their lack
of commercial availability, characteristically high toxicity, and/or
inadequate efficiency limit their use in the pharmaceutical
industry. Examination of the literature also suggests that difluor-
omethylation reactions are often plagued by low yields and/or
limited scope.9,10 We now report our efforts for the safe and
efficient difluoromethylation of methyl 4-hydroxy-3-iodobenzo-
ate carried out on multikilogram scale.
acidic hydrolysis to the parent free phenol, which can be extracted
into aqueous base. Specifically, treatment with aqueous acid to
hydrolyze (3) and (4) with partitioning into an organic solvent is
followed by a phase split. Washing the organic layer with aqueous
base to remove the parent phenol provides the desired product as a
solution in organic solvent. It quickly became apparent that the
ability to control, if not eliminate, the formation of (3) and (4)
would greatly simplify the execution of this reaction on scale.
In addition to these impurities, the use of reagents derived
from chlorodifluoroacetic acid also generate an equivalent of car-
bon dioxide. The ability to control the release of carbon dioxide
from the reaction was another critical safety parameter which
’ RESULTS AND DISCUSSION
The difluoromethylation of the free phenol moiety in 1 is first
expected to provide the desired difluoromethyl ether (2). This
product can be consumed by remaining phenol (1) to provide
the double-addition adduct (3). This adduct can further react
with free phenol (1) to generate a triple-addition adduct (4) (see
Scheme 1). The easiest way to remove these impurities is via
Received: February 28, 2011
Published: April 10, 2011
r
2011 American Chemical Society
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TECHNICAL NOTE
Table 1. Carbonate base screen for the difluoromethylation of 5a
base
5 (LC A%)
6 (LC A%)
7 (LC A%)
8 (LC A%)
Na2CO3
K2CO3
40
0.5
39
32
88
52
19
10
5
7
ND
ND
Cs2CO3
a These reactions were carried out with 2.0 equiv of sodium chlorodifluoroacetate and 1.5 equiv of carbonate base in 6 volumes of DMF in standard batch
mode on a 1 g scale of 5.
Table 2. Results of difluoromethylation of 5
Table 3. Thermal stability study of 6a
time after
5
6
7
other impuritiesb
(LC A %)
entry addition (min) (LC A %) (LC A %) (LC A %)
scale
addition time age time
6
7
isolated yield
(g of 1)
(min)
(min) (LC A %) (LC A %) (%)
1
2
3
4
15
90
1.5
86
88
88
88
9.5
8.9
8.9
9.1
3.0
3.1
3.1
2.9
NDc
NDc
NDc
126
247
60
60
15
15
15
15
98
97
1.8
1
92a
92b
94a
99a
180
330
1000
7040c
40
96
3.5
0.3
a This study was performed on 10 g scale with rapid addition of the
reactive reagents to intentionally produce 7 and other impurities. b This
includes 8 and other unknown baseline impurities. c ND = not detected.
240
>99
a After crystallization from aq DMF. b After recrystallization from aq
MeOH. All isolated yields adjusted for potency of product. c 2.0 equiv of
SCDA used.
the formation of dimer and trimer (as well as HF formation). On
the other hand, the issue of carbon dioxide release also had to be
addressed before large-scale production could begin. Our pro-
posed 7 kg scale-up batch would produce 1,500 L12 of CO2, thus
vent capacity and off-gas rate needed to be evaluated and safely
controlled. Adding a solution of SCDA (2.0 to 2.5 equivalents)
and 5 in DMF (3 volumes) to a hot (95 °C) suspension of
potassium carbonate and DMF (2 volumes) addressed both of
these requirements. By controlling the addition rate of the
solution of SCDA and 5, the rate of CO2 release was effectively
managed and the concentration of SCDA (and the proposed
difluorocarbene intermediate) was kept higher than the concen-
tration of 5 throughout the course of the reaction.
As seen in Table 2, this process proved highly efficient and was
essentially complete once addition of the SCDA/ 5 solution was
finished. In addition, the formation of 7 was minimized, typically
<4% by area. The final entry in Table 2 shows the kilo-lab run.
With a slow addition of the SCDA/ 5 solution, the formation of 7
(and all other impurities) was minimized and provided the
desired product in near quantitative yield and 99% HPLC purity
needed to be addressed. The primary development goal was to
develop a safe, simple, and reliable process that greatly minimized
the generation of 3 and 4.
The reagent of choice for the difluoromethylation reaction was
sodium chlorodifluoroacetate (SCDA) due to its stability and
availability in bulk. The reaction is typically run in a polar aprotic
solvent such as DMF with sodium, potassium, or cesium
carbonate as the base. A recent report suggested that water
may be an important additive.11 In our case, any additional water
resulted in hydrolysis of the methyl ester in our substrate. A
limited screen indicated potassium carbonate to be superior to
sodium and cesium carbonate (see Table 1). Potassium carbo-
nate was the only base that promoted near full consumption of
starting material with formation of a small (∼10%) amount of 7.
With the knowledge that the difluoromethylation reaction was
both fast and high-yielding, it was hypothesized that keeping the
concentration of the SCDA higher than the concentration of 5
throughout the course of the entire experiment would minimize
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TECHNICAL NOTE
Figure 1. TSu evaluation of a solution of 5 and SCDA in DMF.
crude DMF product mixture resulted in crystallization. Although
this direct method simplified the workup, the direct crystal-
lization resulted in significantly slower filtration rates, which we
presumed was due to residual potassium carbonate present as a
fine powder. Once filtered, the cake could be washed with water
until the pH of the filtrate was neutral. This facilitates removal of
residual DMF and potassium carbonate. As 6 is insoluble in
water, no product loss was observed in the water washes. Mother
liquor losses from the direct crystallization procedure were
typically e1%.
Safety Evaluation. With our slow-addition protocol in hand,
we hoped the issues associated with CO2 off-gassing and heat
generation would be well controlled; however, all aspects of the
procedure had to be examined by Process Safety before begin-
ning. Since a solution of 5 and SCDA was being added to a hot
suspension of potassium carbonate in DMF, the thermal stability
of this mixture was first examined by a thermal screening unit
(TSu) to determine if the solution of 5 and SCDA would be safe
to prepare and store at ambient temperature. TSu data showed a
very strong exotherm beginning at about 96 °C, corresponding to
a maximum dT/dt of 23 °C/min at 170 °C (Figure1). The
increase in temperature was also followed by an initial increase in
pressure to 80 bar, a second increase to 115 bar at oven
temperatures above 150 °C, and a maximum dP/dt of 68 bar/
min at 160 °C. A residual pressure of 75 bar was also observed
(Figure1). This TSu suggested that preparing and storing a
solution of 5 and SCDA at ambient temperature would not result
in an unwanted thermal event. Upon reaction completion, the
crude DMF solution of (6) displayed no significant exotherm or
increase in pressure (see Supporting Information for graphs).
We also evaluated the “worst case scenario” (all reactants
added together) by the advanced reactive system screening tool
(ARSST). The reaction mixture exhibited a large exotherm at
84 °C, eventually rising to 180 °C (Figure 2). In addition, this
Figure 2. ARSST data (time versus temperature) for the reaction
suspension.
To examine the thermal stability of both 6 and 7 during the
difluoromethylation reaction, an experiment was conducted that
intentionally formed a traceable amount of dimer and held the
mixture at 95 °C for an extended period of time (Table 3). In this
case, the solution of SCDA/ 5 was added over 3 min (10 g scale)
and formed ∼10 area % of the dimer. No change was observed in
the formation of dimer or impurities after holding the contents of
the reactor at 95 °C for 5.5 h. This gave us confidence that our
upcoming kilo-lab run, which would involve a 4-h addition of the
SCDA and iodophenol could be completed without significant
thermal degradation of our product (6) (Table 2).
Crystallization and Isolation. The isolation of 6 proved
relatively straightforward as solubility studies indicated that
crystallization from water was the best option. Compound 6 is
soluble (>200 mg/mL) in almost every common organic solvent
but is insoluble in water. Initially, the crude DMF product solu-
tion was partitioned between MTBE and water. After extraction,
the MTBE was switched to methanol, and the product was
readily crystallized from a methanol/water mixture. Later, it was
discovered that the direct addition of water (8 volumes) to the
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TECHNICAL NOTE
Also, RC1 data showed that the dose-controlled addition of the
reactive reagents can minimize the thermal hazards associated
with this reaction.
’ EXPERIMENTAL SECTION
General Methods. Reaction progress and chemical purity
were evaluated by HPLC analysis using an Agilent Eclipse XDB-
C18 column (4.6 mm ꢁ 250 mm) with mobile phases A (25 mM
NH4OAc in water) and B (acetonitrile). Dual detection was at
210 and 254 nm, flow was set at 1.5 mL/min, and the tempera-
ture was 30 °C. Gradient: 0 min: A = 10%; B = 90%; 10 min:
A = 90%; B = 10%; 12 min A = 90%; B = 10%. Retention time of
5: 6.83 min. Retention time of 6: 9.09 min.
Figure 3. ARSST data (time versus pressure) for the reaction suspension.
Large-Scale Difluoromethylation Procedure. A solution of
sodium chlorodifluoroacetate (9.6 kg, 63 mmol, 2.0 equiv) and
methyl 4-hydroxy-3-iodobenzoate (5) (7.0 kg, 31 mmol, 1.0 equiv)
in DMF (22.1 kg) was added in two portionsa over a period of
4 h to a 95 °C suspension of potassium carbonate (5.2 kg, 47 mmol,
1.5 equiv) in DMF (13.2 kg). The addition was controlled to
maintain an internal temperature range of 93ꢀ98 °C. After
complete addition, the suspension was stirred for 15 min and
cooled to 30 °C. Water (17.5 kg) was added, and the contents of
the reactor were transferred to a 180 L reactor for further pro-
cessing. The remaining 52.5 kg of water was added, and the batch
was cooled to 10ꢀ15 °C. After stirring at this temperature for 1 h,
the suspension was filtered on a N€utsche filter. The crystals were
washed with water (3 ꢁ 22.4 kg) and dried under nitrogen.
4-Difluoromethoxy-3-iodobenzoic acid methyl ester (6).
Isolated as a white solid (mp = 56 °C) 99.6% pure by LC analysis.
1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J = 2.0 Hz, 1H), 7.81
(dd, J = 8.5, 2.0 Hz, 1H), 6.96 (dt, J = 8.5, 1.0 Hz, 1H), 6.39 (t, J =
72.6 Hz, 1H), 3.93 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
δ 164.6, 154.7, 140.85, 131.4, 128.0, 117.8, 116.5 (t, J = 260 Hz),
88.8, 52.8. HRMS calculated for C9H8O3F2I: 328.94807
[M þ H]; found: 328.94768.
Figure 4. RC1 study of controlled addition process.
exotherm was also accompanied by an increase in pressure from
314 psig to 360 psig (Figure 3). Taken together, the dT/dt of
426 °C/min and dP/dt of 546 psi/min highlight the safety
concerns associated with this reaction (see Supporting Informa-
tion for graphs). Although the difluoromethylation reaction
would never be carried out in this way, the ARSST studies
provide additional data to support our initial safety concerns.
Safety assessment of the controlled addition process was also
evaluated via RC1 calorimetry (see Figure 4). As expected, the
difluoromethylation reaction exhibited a short incubation period
of less than 5 min. In addition, the exotherm stayed constant
during the course of the experiment, which is consistent with a
fast reaction rate. Once the dose-controlled addition of the
reactive materials was complete, heat generation ceased after
less than 5 min, indicating a complete reaction. Utilizing the RC1
also allowed for the determination of both the ΔTad and ΔH for
the process. The thermal profile observed during the course of
the reaction resulted in a net output of ꢀ159 kJ/mol with a ΔTad
of 193 K. Although a significant and potentially dangerous
amount of heat and CO2 are generated during the course of
the reaction, proper dose control allowed for successful imple-
mentation of this process on the 7 kg scale.
’ ASSOCIATED CONTENT
S
Supporting Information. Additional ARSST and TSu
b
data for the reaction described. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
E-mail: Jeffrey.Sperry@Pfizer.com.
Present Addresses
†Research-API, Pharmaceutical Sciences, Pfizer Global Research
and Development, 558 Eastern Point Road, Groton, Connec-
ticut 06340
‡Development-API, Pharmaceutical Sciences, Pfizer Global Re-
search and Development, 558 Eastern Point Road, Groton,
Connecticut 06340
’ CONCLUSIONS
A scalable procedure for the difluoromethylation of methyl
4-hydroxy-3-iodobenzoate (5) has been developed, and the
major safety issues that accompany this type of reaction have
been evaluated. The dosing of a solution of SCDA and 5 in DMF
to a 95 °C suspension of potassium carbonate in DMF allowed
for the careful control of both the exotherm and the release of
carbon dioxide. TSu and ARSST data show that performing
this reaction under standard batch conditions is not advisible.
’ ACKNOWLEDGMENT
We are grateful to our colleagues Dr. Roger Farr and
Dr. Richard Heid for helpful discussions and to Dr. Eric Hansen
for his assistance with obtaining RC1 data. We acknowledge
Dr. Richard Kwasny and Susan Hollywood for evaluating
the safety of this process. We also thank the Pearl River
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TECHNICAL NOTE
kilo-laboratory personnel for their assistance in the scale-up
efforts. Finally, we thank the Analytical and Quality Services
department for their expertise and Victor Soliman in the Pfizer
Structural Elucidation Group for help with high-resolution mass
spectrometry.
’ ADDITIONAL NOTE
a The large-scale addition of the SCDA/5 solution was charged
through a pressure can. Due to the limited capacity of the
pressure can, two batches of SCDA and 5 in DMF were
generated and added consecutively. Once the first charge was
complete, the second batch was dissolved and charged to the
same pressure can. The time between the completion of the first
charge and the beginning of the second charge was about 10 min.
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