Development of a Multigram synthesis of URB937, a peripherally restricted FAAH inhibitor

Article abstract of DOI:10.1021/op300301u

A new synthetic approach to URB937 was developed starting from the inexpensive and widely available 4-benzyloxyphenol. A reproducible four-step procedure, requiring no chromatographic purifications, was optimized that allowed the preparation of 100 g of URB937 in 45% overall yield.

Full text of DOI:10.1021/op300301u

Article
pubs.acs.org/OPRD
Development of a Multigram Synthesis of URB937, a Peripherally
Restricted FAAH Inhibitor
Claudio Fiorelli,*,† Rita Scarpelli,† Daniele Piomelli,†,‡ and Tiziano Bandiera*,†
†Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, I-16163 Genova, Italy
‡Department of Anatomy and Neurobiology, University of California, Irvine, California 92697-4625, United States
S
* Supporting Information
ABSTRACT: A new synthetic approach to URB937 was developed starting from the inexpensive and widely available 4-
benzyloxyphenol. A reproducible four-step procedure, requiring no chromatographic purifications, was optimized that allowed
the preparation of 100 g of URB937 in 45% overall yield.
rodent models of nociceptive and inflammatory pain8,10 and
therefore represents the prototype of new analgesic agents
devoid of central side effects. To investigate in detail the
1. INTRODUCTION
Fatty-acid amide hydrolase (FAAH) is an intracellular
membrane-bound serine hydrolase that catalyzes the hydrolysis
pharmacology of URB937, multigram amounts of compound
are required.
of the endocannabinoid signaling molecule anandamide and of
other noncannabinoid fatty-acid ethanolamides such as
oleoylethanolamide and palmitoylethanolamide.1,2 Natural
FAAH substrates, such as anandamide, play important
physiological roles and have been implicated in several disease
conditions, which might be caused in part by deficits in their
normal function.3 Inhibition of FAAH activity may reduce such
deficits and, therefore, is of considerable pharmaceutical
interest. Among the different chemical classes of FAAH
inhibitors disclosed so far,4 the O-aryl carbamates5 and the
piperidine/piperazine ureas6 have been shown to have favorable
profiles with respect to both selectivity and pharmacological
activity in vivo. The O-aryl carbamates comprise N-cyclo-
hexylcarbamic acid O-aryl ester derivatives such as URB597 (1,
Figure 1), which demonstrated in animals an interesting
The previously described synthesis of URB9378,10 starting
from the commercially available 3-bromo-4-hydroxybenzalde-
hyde 3 is depicted in Scheme 1.
Scheme 1. Medicinal Chemistry Route to URB937
(a) BnCl (1.1 equiv), Cs2CO3 (1.1 equiv), DMF, 23 °C, 3 h; (b) m-
CPBA (3.0 equiv), CH2Cl2, 23 °C, 4 h; (c) 1 M NaOH, MeOH, 23
°C, 18 h; (d) 3-carbamoylphenylboronic acid (1.2 equiv), 5%
Pd(PPh3)4, Na2CO3 (5 equiv), toluene/H2O, reflux, 18 h; (e) c-
hexNCO (1.2 equiv), Et3N (0.15 equiv), EtOH/MeCN, reflux, 4 h; (f)
H2 (4 atm.) 10% Pd/C, EtOAc/EtOH, 50 °C, 4 h.
Figure 1. O-aryl carbamate FAAH inhibitors.
combination of anxiolytic, antidepressant, and analgesic proper-
ties.7 URB937, [3-(3-carbamoylphenyl)-4-hydroxyphenyl]-N-
cyclohexylcarbamate (2, Figure 1), a close analogue of
URB597, is a potent inhibitor of FAAH (rat FAAH IC50:
26.8 nM) and is unique among the O-arylcarbamate FAAH
inhibitors because it is actively extruded from the central
nervous system (CNS) thus increasing anandamide levels
exclusively in peripheral tissues.8 Recent studies have suggested
that ABCG2 is the major transporter responsible for extrusion
of URB937 from the CNS.9 Despite its peripherally restricted
distribution, URB937 exhibited marked analgesic properties in
This versatile six-step procedure allowed a quick exploration
of the structure−activity relationships of URB937 close
analogues. In fact, different carbamate residues and distal
phenyl rings can be introduced late in the synthesis, thus
making possible a time-efficient preparation of an array of
differently substituted derivatives for the investigation of the
impact of structural modifications on the inhibition of FAAH
Received: October 24, 2012
Published: February 5, 2013
© 2013 American Chemical Society
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Article
activity. However, this route suffers from suboptimal yield in
several steps, and required chromatographic purifications in
order to isolate the intermediates and the final compound in
pure form. When this synthetic procedure was scaled up to
prepare 1 g of URB937, a 5% overall yield was obtained, thus
making this synthesis unsuitable for the preparation of large
quantities of the compound.
Herein, we report the results of our studies which led to a
more efficient, higher-yielding, and robust route for the
preparation of URB937 in up to 100 g amount.
Table 1. Experimental Conditions and Conversion of
Halogenation Reactions of Compound 9
T
t
conversion
(%)
a
entry
reagents
equiv
solvent
(°C) (h)
1
2
3
4
5
6
Br2/NaOAc
NaBr/Oxone
NBS
1.4/1.4
AcOH
MeOH
DMF
22
22
22
22
75
60
48
96
96
96
16
6
100
b
1.1/1.1
46
1
1
83
80
NBS
AcOH
DMF
c
NBS
1.4
100
I2/HIO3/
H2SO4
1.25/2/1
AcOH
100
2. RESULTS AND DISCUSSION
Our retrosynthetic plan (Scheme 2) envisaged the formation of
the biphenyl system by a Suzuki coupling reaction on the aryl
d
7
I2/HIO3/
H2SO4
1.25/2/1
DMF
60
6
100
a
b
% conversion of compound 9 as measured by UPLC/MS analysis. 9
c
d
was poorly soluble in the reaction mixture. 88% isolated yield. 64%
isolated yield.
Scheme 2. New Retrosynthetic Approach to URB937
safe method for the bromination of electron-rich aromatic
rings.11 When this procedure was applied to our substrate, the
reaction was exceedingly slow with only 46% conversion of
compound 9 observed after 96 h (entry 2), most likely because
of the limited solubility of 9 in MeOH.
The bromination reaction with NBS was run under various
experimental conditions (entries 3−5). Incomplete conversion
of the starting material after 96 h was observed when the
reaction was conducted at room temperature with either DMF
(entry 3) or AcOH (entry 4) as the solvent. Increasing the
temperature to 75 °C (entry 5) led to complete conversion of 9
into 10a after 18 h.
The iodo-derivative 10b was prepared as an alternative
reactant in the Suzuki coupling reaction (see Supporting
Information). Iodination of compound 9 with the I2/HIO3
system12 in the presence of H2SO4 in either AcOH (entry 6) or
DMF (entry 7) provided compound 10b in moderate yield
(64% isolated yield, entry 7). The optimization of the synthesis
of compound 10b was not pursued, as in initial experiments the
Suzuki coupling reaction of 10b with 3-carbamoylphenyl
boronic acid failed to produce the desired intermediate 7
(see section 2.2).
halides 10a−b obtained by regioselective halogenation of the
O-aryl carbamate 9, which in turn can be prepared by
carbamoylation of the cheap and widely available 4-benzylox-
yphenol 8.
2.1. Synthesis of Aryl Halides 10a and 10b. The
synthesis of the carbamate 9 was easily accomplished by
reaction of 8 with c-hexylisocyanate in the presence of Et3N
(Scheme 3). The use of a 1:1 mixture of absolute EtOH and
Scheme 3. Synthesis of Intermediates 9, 10a, and 10b
For our synthetic purposes, NBS was preferred to bromine
due to its easier and safer handling. Bromination reactions of up
to 53g of 9 were performed with 1.4 equivalents of NBS in
DMF at 75 °C for 16 h. Bromination occurred at the ortho
position to the benzyloxy group13 with >99:1 selectivity, as
determined by 1H NMR analysis of the crude material.14
Compound 10a was easily isolated by precipitation with an
aqueous sodium thiosulfate solution. After filtration and
recrystallization from EtOH, 10a was obtained in 88% yield
as small white needles. This step was repeated several times and
proved to have good reproducibility. The high yield of both the
carbamoylation and the bromination reactions, coupled with
their easy workup, allowed us to prepare more than 300 g of
10a using common medicinal chemistry laboratory equipment
and labware.
2.2. Synthesis of Intermediate 7. The Suzuki coupling
reaction15 on the O-arylcarbamates 10a and 10b was expected
to be a challenging synthetic step due to the base-sensitivity of
the carbamate functionality of both the starting material (10a
or 10b) and the product (7). In fact, under the basic conditions
required for the reaction, compounds 10a, 10b, and 7 could
hydrolyze to the corresponding phenols 5, 12, and 6,
respectively (Table 2).
(a) c-hexNCO (1.2 equiv), Et3N (0.6 equiv), EtOH/MeCN, r.t., 16 h;
(b) NBS (1.4 equiv), DMF, 75 °C, 16 h; (c) I2 (1.25 equiv), HIO3 (2
equiv), H2SO4 (1 equiv), DMF, 60 °C, 6 h.
MeCN as the solvent resulted in compound 9 crystallizing out
from the reaction mixture. A simple filtration allowed the
isolation of 9 in 85% yield. This step was repeated several times
employing up to 50 g of 8, and proved to be reproducible.
Different reaction conditions for the bromination and
iodination of 9 were then studied: the results are summarized
in Table 1.
Bromination reactions were conducted with Br2 in AcOH,
NaBr/Oxone, and N-bromosuccinimide (NBS), while iodina-
tion was performed with I2/HIO3/H2SO4 in AcOH or DMF.
Br2 in AcOH led to complete conversion of the starting
material after 48 h at room temperature (entry 1). The use of
NaBr/Oxone in MeOH has been reported as an efficient and
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Table 2. Experimental Conditions and Outcome of Suzuki Coupling Reactions of Compounds 10a and 10b with 3-Carbamoyl
a
Phenylboronic Acid 11
b
b
b
b
entry
aryl halide
catalyst
base
10 (%)
5 (or 12) (%)
6 (%)
7 (%)
1
2
3
10a
10a
10a
10a
10a
10a
10a
10a
10b
10b
A
A
A
A
A
A
A
B
B
A
KOAc
Na2CO3
CsF
88
90
100
19
40
85
38
31
66
72
2
1
0
0
10
9
0
0
0
c
4
CsF
14
60
2
17
0
50
0
d
5
CsF
e
6
c
KOAc
KOAc
CsOAc
CsOAc
KOAc
1
12
47
57
0
7
11
5
4
8
9
7
34
28
0
c
10
0
0
a
b
General conditions: 1.5 equiv of 11, 2.5 equiv of base, 5% catalyst in anhydrous dioxane, 80 °C, 120 min; A: Pd(PPh3)4; B: PdCl2dppf. % of
c
compound remaining (10a or 10b) or formed (5, 12, 6, and 7) as measured by UPLC/MS analysis after 120 min. Addition of 50 equiv of H2O.
d
e
Toluene/H2O 1:1. Addition of 10 equiv of H2O.
This consideration prompted us to first investigate the
as observed also with KOAc as the base (entries 6 and 7).
Several attempts were made to adjust the amount of water in
order to obtain a more favorable ratio between the conversion
of the starting material and the amount of desired product.
Difficulties encountered in obtaining reproducible results led us
to abandon this approach.
We then turned our attention to the PdCl2dppf/CsOAc
system, which has been recently employed with success in a
Suzuki coupling reaction under anhydrous conditions on
h y d r o l y t i c a l l y l a b i l e s y s t e m s s u c h a s [ 3 -
(trifluoromethylsulfonyloxy)phenyl]acetate.19 When PdCl2dppf
was used as the catalyst and CsOAc as the base (entry 8), the
desired compound 7 was the major component (57%) of the
reaction mixture, with the combined hydrolysis products 5 and
6 accounting for only 12%.
The aryl iodide 10b did not lead to the desired compound 7
when reacted under the reaction conditions (entries 9 and 10)
which gave the best results with the bromide 10a. This is in
sharp contrast with literature reports on Suzuki reactions on
dialkoxyaryl iodides, where high yields were observed in several
cases.20
Encouraged by the good result obtained by reacting 10a with
PdCl2dppf and CsOAc in refluxing dioxane (entry 8), we
directed our efforts to the identification of a suitable 3-
carbamoyl phenylboronic acid derivative with higher solubility
in our experimental conditions. We focused our attention on
boronic acid esters 13−15 (Scheme 4). The pinacol ester 13 is
commercially available, while esters 14 and 15 were synthesized
in situ by heating 11 with the corresponding diol (see
Supporting Information).
stability of 10a under different experimental conditions
commonly used in Suzuki coupling reactions. Various
combinations of solvents and bases were tried. As expected, a
fast hydrolysis (t1/2 < 20 min as measured by UPLC/MS
analysis) occurred upon heating compound 10a at 80 °C in
polar solvents like DMF or MeCN, even employing weak bases
such as KOAc or CsF. On the contrary, under the same
conditions the stability of compound 10a was acceptable16
when the polar solvents were replaced with THF, dioxane, and
toluene. With these data in hand, we started the optimization of
the Suzuki coupling reaction: the results are summarized in
Table 2.
The bromide 10a was initially reacted with 3-carbamoyl
phenylboronic acid 11 in dioxane at 80 °C using Pd(PPh3)4 as
the catalyst and KOAc or Na2CO3 as the base. Under these
reaction conditions, compound 10a was stable, even on
prolonged heating, but a maximum of 10% conversion was
observed (entries 1 and 2).
In order to verify whether a different base could accelerate
the reaction, compound 10a was reacted in the presence of
CsF, which was successfully used in Suzuki coupling reactions
on labile systems, such as aryl trifluoroacetamides17 and
nitroaryl esters.18 Under our experimental conditions, CsF
was ineffective (entry 3): no formation of the desired product 7
was observed after 2 h. Interestingly, adding a small amount of
water greatly improved the conversion of the starting material
(entry 4), while a biphasic toluene/water system led exclusively
to the formation of the hydrolysis product 5 (entry 5).
The observed increase in the amount of compound 7 when
water was added to the reaction mixture led us to speculate that
the low conversion of 10a (entries 1, 2, and 3) could be due, at
least in part, to the poor solubility of 3-carbamoyl phenyl-
boronic acid 11 in dioxane. Unfortunately, the higher reaction
rate in the presence of water was accompanied, as expected, by
an increase in the formation of the hydrolysis products 5 and 6,
Pinacol-derived boronic esters are commonly used in Suzuki
coupling reactions due to their exceptional stability while
maintaining good reactivity, and many are commercially
available, such as 13. Catechol-derived boronic esters have
not received as much attention as their pinacol counterparts
due to their easy hydrolysis. For this reason, they have been
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A first attempt of Suzuki coupling reaction was conducted
with the pinacol ester 13, 5% PdCl2dppf, and CsOAc as the
base in dioxane (entry 1). The reaction proceeded slowly, and
significant amounts of the hydrolysis products 5 and 6 were
observed. We then tested the ethylene glycol ester 14 (entry 2).
Under the previous experimental conditions, the reaction was
faster, with only 13% of unreacted starting material 10a left
after 120 min, and the combined hydrolysis products 5 and 6
accounting for only 8% of the reaction mixture.24 The catechol-
derived boronic ester 15 showed comparable reactivity with
respect to 14: almost complete consumption of 10a was
observed after 120 min at 80 °C (entry 3), but the combined
hydrolysis products 5 and 6 accounted for 12% of the reaction
mixture. Replacement of CsOAc with CsF, KOAc, or K2CO3
coupled with the boronic acid ethylene glycol ester 14 resulted
in low conversion (entries 4, 5, and 6). Compound 10a was
instead quite reactive in the presence of K3PO4, even if
hydrolysis to 6 still remained an issue, the latter compound
accounting for 23% of the reaction mixture (entry 7).
Interestingly, weak bases like K2HPO4 and KHCO3 (entries 8
and 9) resulted in very low percentage of the hydrolysis
products 5 and 6, but ca. 40% of the starting material was still
present after 120 min. Addition of base and/or catalyst did not
Scheme 4. Preparation of Boronic Acid Esters 14 and 15
used more as protective group of the boronic acid moiety21
than as reagents for C−C bond formation.22 Boronic esters
derived from ethylene glycol have found more widespread use,
particularly in the asymmetric synthesis of chirotropic biaryls,
where the steric hindrance of the reagents can affect the
enantiomeric excess of the final product.23 The results obtained
in the reaction of compound 10a with boronic acid esters are
reported in Table 3.
Table 3. Experimental Conditions and Outcome of Suzuki Coupling Reactions of 10a or 10b with Boronic Acid Esters 13, 14,
a
and 15
b
b
b
b
entry
ArX
ArB(OR)2
catalyst
base
T (°C)
10 (%)
5 or 12 (%)
6
(%)
19
7
(%)
38
1
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10b
13
14
15
14
14
14
14
14
14
14
14
14
14
15
14
14
14
14
14
14
14
14
B
B
B
B
B
B
B
B
B
B
B
B
B
B
A
C
D
D
B
B
B
B
CsOAc
CsOAc
CsOAc
CsF
80
80
80
80
80
80
80
80
80
80
80
60
100
60
80
80
80
80
80
80
80
80
25
13
7
18
2
2
6
6
79
81
46
69
42
68
58
55
29
0
3
6
4
46
22
52
6
6
2
5
KOAc
4
5
6
K2CO3
K3PO4
K2HPO4
KHCO3
Et3N
3
3
7
3
23
1
8
40
42
67
0
1
9
1
2
10
11
12
13
14
15
16
17
18
2
2
DBU
70
10
7
30
3
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
K2CO3
CsOAc
CsOAc
CsOAc
CsOAc
30
3
57
41
46
0
49
6
42
65
9
6
35
4
0
25
18
4
62
44
47
58
64
46
0
20
47
30
19
21
69
18
2
c
19
5
7
d
20
7
10
15
0
e
21
18
31
22
a
General conditions: 1.5 equiv of pre-formed boronic ester, 2.5 equiv of base, 5% catalyst in anhydrous dioxane at the reported temperature, 120
b
min; A: Pd(PPh3)4; B: PdCl2dppf; C: 10% SPhos/5% Pd(OAc)2; D: PEPPSI-Ipr. % of compound remaining (10a or 10b) or formed (5, 12, 6, and
7) as measured by UPLC/MS analysis after 120 min. Toluene as solvent. 2Me-THF as solvent. 2.5% of PdCl2dppf.
c
d
e
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improve the conversion of the starting material. Soluble organic
bases25 were also tried. While Et3N resulted in low conversion
(entry 10), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) led
exclusively to the formation of hydrolysis products (entry 11).
The effect of the temperature was also investigated. When
the reaction of 10a with 14 was run using PdCl2dppf as the
catalyst and CsOAc as the base, the best results were observed
at 80 °C (entry 2). At 60 °C the reaction proceeded much
more slowly (entry 12), while raising the temperature to 100
°C led to an increase in the reaction rate, along with an
extensive hydrolysis of compound 7 to 6 (entry 13). A decrease
in the conversion of compound 10a with a decrease in the
reaction temperature was also observed with the boronic ester
15 (entry 14).
(see Supporting Information, Table 1). Therefore, a reaction
time of 100 min was selected for the reaction’s scale-up.
In conclusion, the scale-up of the Suzuki coupling reaction of
10a with the boronic acid esters 14 was conducted in dioxane
at 80 °C, for 100 min, using 5% PdCl2dppf as the catalyst and
CsOAc as the base. Compound 7 was isolated in 66% yield
after aqueous workup, extraction with EtOAc, evaporation of
the solvent to small volume, precipitation with MeCN, and
recrystallization from the same solvent. This step was repeated
several times starting from up to 33 g of 10a, and showed good
reproducibility.
2.3. Debenzylation of 7 to 2 (URB937). The final step of
the synthesis consisted of the removal of the O-benzyl group
from intermediate 7. This reaction was previously performed
on a 2 g scale by catalytic hydrogenation with H2 (4 atm), 10%
Pd/C in a mixture of EtOAc and MeOH as solvent. As the high
pressure apparatus required for scaling up this reaction was not
available in our laboratories, we decided to run a transfer
hydrogenation reaction.
To ascertain how the catalyst could affect the reaction
outcome, we first reacted compound 10a with 14 in the
presence of Pd(PPh3)4 and CsOAc (entry 15); under these
conditions, only the hydrolysis product 5 was observed. The
26
Buchwald’s catalyst Sphos/Pd(OAc)2 (entry 16) showed a
The different solubility of the starting material 7 and of 2 in
the solvents commonly used in hydrogenation reactions,
prompted us to carefully verify the compounds’ solubility in
order to avoid the formation of precipitate during the reaction.
Alcohols like MeOH, EtOH, or iPrOH solubilize 2 well, while
the starting material 7 is sparingly soluble in these solvents.
Ethereal solvents like THF or dioxane solubilize both 7 and 2.
Dioxane was selected for its higher boiling point that allows for
a safer and faster reaction.
comparable reactivity to PdCl2dppf (entry 2). Finally, we tested
the PEPPSI-Ipr catalyst, which was reported to be a general and
effective system for various palladium catalyzed reactions.27
However, in our hands this catalyst did not perform as well as
PdCl2dppf (entry 2), and a high percentage of the hydrolysis
compounds 5 and 6 was observed (entry 17). When the
reaction was run with K2CO3 as the base (entry 18), the
conversion of the starting material was comparable to that
observed with PdCl2dppf as the catalyst (entry 6) but lower
than the one observed with the PdCl2dppf/CsOAc system
(entry 2).
Many common reducing agents28 were tested and the results
are summarized in Table 4. Cyclohexene29 gave a fast and
The influence of the solvent was briefly investigated by
reacting compound 10a under the reaction conditions of entry
2. Replacement of dioxane with toluene resulted in a lower
conversion (entry 19), probably due to the low solubility of
CsOAc in this solvent. 2-Methyl-THF was tested as a greener
alternative to dioxane; the conversion was higher than in
toluene (entry 20), but lower than in dioxane (entry 2).
Finally, an attempt was made to reduce the amount of
palladium catalyst to 2.5% (entry 21). Unfortunately, this
resulted in a decrease in the conversion of 10a and the
formation of much higher percentage of the hydrolysis products
5 and 6.
A further attempt was made to replace the aryl bromide 10a
with the iodide 10b as the substrate in the Suzuki coupling
reaction. When 10b was reacted with the boronic ester 14 in
the presence of PdCl2dppf and CsOAc in dioxane (entry 22),
the hydrolysis compound 12 was the only product observed
after 120 min at 80 °C, in keeping with the result obtained in
the reaction with 3-carbamoylphenyl boronic acid.
From the previous work, the best results in the Suzuki
coupling reaction were obtained using Wang-Sun’s conditions
(5% PdCl2dppf, CsOAc in dioxane at 80 °C) with the boronic
acid esters 14 and 15. As the boronic acid ester 15 leads to the
formation of catechol, which was difficult to separate from the
final product, the ester 14 was selected for further scale-up of
the reaction. Starting from these experimental conditions, a
final optimization effort was undertaken to identify the reaction
time that simultaneously maximized the conversion of bromide
10a into compound 7 and reduced the formation of the
hydrolysis products 5 and 6. We found that after 100 min
compound 7 and the combined hydrolysis products 5 and 6
accounted for 80% and 7%, respectively, of the reaction mixture
Table 4. Experimental Conditions and Conversion of
Transfer Hydrogenation Reactions of Intermediate 7
a
T
t
conversion
(%)
entry reducing agent
solvent equiv (°C) (min)
1
2
3
4
5
6
7
cyclohexene
cyclohexene
cyclohexene
γ-terpinene
dioxane
dioxane
THF
10
−
−
10
10
10
−
80
80
65
80
80
80
80
180
60
/
b
b
100
100
100
23
150
60
dioxane
α-phellandrene dioxane
60
PMHS
dioxane
60
100
74
HCO H/
2 c
−
300
Et3N
a
% conversion of compound 7 as measured by UPLC/MS analysis.
Cyclohexene/solvent 1:3 (v/v). Used as solvent.
b
c
efficient conversion of the starting material only when used as
cosolvent (Table 4, entries 1−3). The more reactive γ-
terpinene allowed reducing the amount of reducing agent to
10 equiv (entry 4). Surprisingly, its conjugated diene isomer, α-
phellandrene, performed poorly, with only 23% conversion of
the starting material observed under the same reaction
conditions (entry 5). Transfer hydrogenation reaction with
poly(methylhydroxysiloxane) (PMHS)30 in dioxane ran to
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completion in 60 min (entry 6), but the removal of excess
polymeric reagent made the work-up difficult. The use of
HCOOH as reducing agent in Et3N as the solvent31 led to
incomplete conversion of the starting material even after 300
min (entry 7). On the basis of these results, cyclohexene was
selected due to its low boiling point, that allows easy removal,
and low cost. This reaction was repeated several times starting
from up to 32 g of 7.
species, and reaction time. Although a relatively high catalyst
loading was required for optimal yield, the palladium content in
the final product was in the sub-ppm range. This four-step
procedure proved to be robust and reproducible, required no
chromatographic purifications, and provided URB937 in 45%
overall yield.
4. EXPERIMENTAL SECTION
After debenzylation, compound 2 was obtained as white
foam after filtration of the catalyst and removal of the solvents.
Treatment with MeCN led to the formation of a white powder
consisting of a 1:1 mixture of compound 2 and MeCN, as
determined by NMR analysis. Several prolonged drying
procedures failed to remove MeCN, thus suggesting that a
solvate was likely formed. According to the ICH Q3C
guidelines,32 MeCN is a class 2 solvent, and therefore its
content in pharmaceutical products should be limited because
of inherent toxicity. To remove MeCN, the solid was dissolved
in absolute EtOH and then precipitated with H2O as a free-
flowing white powder in 91% yield. The compound showed
>99% purity by UPLC/MS analysis, >98% purity by
quantitative NMR (1.5% EtOH was the only impurity observed
in the spectrum). The high percentage of the metal catalyst in
the Suzuki coupling reaction raised the concern for the
palladium content in the final product. Therefore, compound 2
was subjected to inductively coupled plasma−mass spectrom-
etry (ICP-MS) analysis: gratifyingly, the palladium content33
was found to be ≤0.1 ppm, well below the 10 ppm limit set for
drug substances.34
Solvents and reagents were obtained from commercial suppliers
and were used without further purification. Anhydrous dioxane
was purchased from Sigma Aldrich. For simplicity, solvents and
reagents were indicated as follows: acetic acid (AcOH),
acetonitrile (MeCN), Celite (diatomaceous earth), cesium
acetate (CsOAc), dimethylsulfoxide (DMSO), ethanol
(EtOH), ethylacetate (EtOAc), N-bromosuccinimmide
(NBS), nitrogen (N2), N,N-dimethylformamide (DMF),
palladium on carbon (Pd/C), triethylamine (Et3N), and
water (H2O). Melting points are uncorrected. NMR experi-
ments were run on a Bruker Avance III 400 system (400.13
1
MHz for H, and 100.62 MHz for 13C), equipped with a BBI
probe and Z-gradients. Spectra were acquired at 300 K, using
deuterated dimethylsulfoxide (DMSO-d6) or deuterated chloro-
1
form (CDCl3) as solvents. Chemical shifts for H and 13C
spectra were recorded in parts per million using the residual
nondeuterated solvent as the internal standard (for CDCl3:
1
1
7.26 ppm, H; 77.16 ppm, 13C; for DMSO-d6: 2.50 ppm, H;
39.52 ppm, 13C). All compounds except 15 were characterized
1
1
1
by H NMR, 13C NMR, H−1H-MQF-COSY, and H−13C-
HSQC. Structure of compounds 10a and 10b was determined
by 1H-NOESY experiments. UPLC/MS analyses were run on a
Waters ACQUITY UPLC/MS system consisting of a SQD
(single quadropole detector) Mass Spectrometer (MS)
equipped with an electrospray ionization (ESI) interface and
a photodiode array detector. PDA range was 210−400 nm.
Chromatographic analyses were performed on an ACQUITY
UPLC HSS T3 C18 column (50 × 2.1 mmID, particle size 1.8
μm) with a VanGuard HSS T3 C18 precolumn (5 × 2.1 mmID,
particle size 1.8 μm). The mobile phase was: (A) 10 mM
NH4OAc in H2O, pH 5, and (B) 10 mM NH4OAc in MeCN/
H2O (95:5) pH 5, gradient 5% to 95% B over 3 min, flow rate
0.5 mL/min, temperature 40 °C. Accurate mass measurement
was performed on a Synapt G2 Quadrupole-Tof Instrument
(Waters, USA), equipped with an ESI ion source; compounds
were diluted to 10 μM in H2O/MeCN and analyzed. Leucine
Enkephalin (2 ng/mL) was used as lock mass reference
compound for spectra calibration.
In conclusion, a total of 100 g of URB937 was prepared in
45% overall yield via a four-step synthesis. The optimized
synthesis is summarized in Scheme 5.
Scheme 5. Optimized Synthesis of URB937
(4-Benzyloxyphenyl)-N-cyclohexylcarbamate (9). To a
suspension of 4-benzyloxyphenol 8 (50 g, 0.250 mol, 1 equiv)
in absolute EtOH (220 mL) in a three-necked 1 L round-
bottomed flask, equipped with a 50 mm magnetic stirrer bar, a
thermometer, and a 100 mL dropping funnel, was added
MeCN (220 mL) under stirring to give a clear brown solution.
The addition of MeCN was endothermic and the temperature
dropped to +6 °C. Et3N (20.77 mL, 0.150 mol, 0.6 equiv) was
then added in one portion with no observable changes. To this
mixture, cyclohexylisocyanate (38.3 mL, 0.300 mol, 1.2 equiv)
was added dropwise under stirring over a period of 30 min. The
reaction mixture was slowly allowed to reach +22 °C. After 15
min, a precipitate began to form and its quantity increased
rapidly. The mixture was stirred at room temperature for 16 h.
Absolute EtOH (120 mL) was added and the mixture was
cooled to +4 °C with an ice−water bath for 1.5 h, then filtered
on a Buchner funnel and washed with cold absolute EtOH (130
(a) c-hexNCO (1.2 equiv), Et3N (0.6 equiv), EtOH/MeCN, 22 °C, 16
h; (b) NBS (1.4 equiv), DMF, 75 °C, 16 h; (c) 15 (1.5 equiv), 5%
PdCl2dppf, CsOAc (2.5 equiv), dioxane, 80 °C, 100 min; (d) 10% Pd/
C, cyclohexene/dioxane 3:10, 80 °C, 120 min.
3. CONCLUSIONS
We developed a new synthetic route to the O-arylcarbamate
URB937 that allowed the preparation of this compound on a
multigram scale. The key step of the synthesis is the
construction of the biphenyl core of URB937 by a Suzuki
coupling reaction. We optimized the reaction conditions by
investigating the influence of solvent, base, catalyst, aryl boronic
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Organic Process Research & Development
Article
mL). The filter cake was dried in vacuo at 45 °C until stable
L) and EtOAc (500 mL), in a 5 L bottle, kept under vigorous
stirring. The resulting mixture was stirred for 2 h, the content
was transferred into a 3 L separatory funnel, and the two phases
separated. The organic phase was concentrated to yield a brown
oil which upon treatment with MeCN (700 mL) led to the
formation of a precipitate. The suspension was stirred at room
temperature for 16 h and then filtered through a Buchner
funnel and washed with MeCN (100 mL). In a 2 L one-neck
round-bottomed flask, the crude was suspended in MeCN (1.6
L) and the mixture was heated at reflux to obtain a clear
solution, which was maintained at the same temperature for 15
min. The solution was then allowed to cool to room
temperature in about 60 min and the compound rapidly
crystallized out. The solid was filtered through a Buchner
funnel and dried in vacuo at 45 °C until stable weight. Light
grey solid; 32.3 g, 55% yield. Concentration of the mother
liquor (150 mL) allowed the production of a second crop of
product. Total amount: 38.7 g, 66% yield. 1H NMR (400 MHz,
DMSO-d6) δ 8.05 (m, 1H), 8.01 (bs, 1H), 7.83 (d, J = 7.8 Hz,
1H), 7.71 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.48 (t,
J = 7.7 Hz, 1H), 7.43−7.25 (m, 5H), 7.18 (d, J = 8.9 Hz, 1H),
7.09 (m, 2H), 5.13 (s, 2H), 3.29 (m, 1H), 1.46−2.0 (m, 5H),
1.41−1.00 (m, 5H). 13C NMR (101 MHz, DMSO-d6) δ 168.3,
154.2, 152.6, 145.3, 137.7, 137.5, 134.8, 132.5, 130.5, 128.8,
128.3, 128.1, 127.7, 126.8, 124.2, 122.4, 114.3, 70.6, 50.2, 33.0,
25.6, 25.0. UPLC/MS analysis: Rt 2.76 min. MS (ESI): 445 (M
+H)+. HRMS: C27H28N2O4 [M+H]+: calculated 445.2127,
measured 445.2136; Δppm 2.0. Mp: 187−189 °C.
[3-(3-Carbamoylphenyl)-4-hydroxyphenyl]-N-cyclo-
hexylcarbamate (2, URB937). To a suspension of [4-
benzyloxy-3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarba-
mate 7 (32.3 g, 0.073 mol, 1.0 equiv) in dioxane (1L) in a 2
L three-necked round-bottomed flask, equipped with a
magnetic stirrer bar, cyclohexene (300 mL) was added under
a static N2 atmosphere. The suspension was heated at 50 °C for
15 min in order to ensure complete dissolution. The mixture
was allowed to cool to +22 °C and then 10% wet Pd/C (10g)
was carefully added and the reaction mixture was heated at 80
°C for 120 min. Activated charcoal (7 g) was added and the
mixture was allowed to cool to +22 °C. The mixture was
filtered through a small pad of Celite and washed with dioxane
(200 mL). The clear, colorless solution was concentrated to
dryness to afford a white foam, which was treated with MeCN
(200 mL) in one portion and under stirring leading to the
formation of a white solid. The mixture was stored at +5 °C for
16 h, and then filtered on a Buchner funnel. The white solid
was washed with cold MeCN (100 mL) and then dried under
vacuum at 45 °C until stable weight. The solid was suspended
in absolute EtOH (450 mL) in a 2 L round-bottomed flask, and
the suspension heated at 80 °C until a clear colorless solution
was obtained (10 min). After cooling to +22 °C, H2O (1.2 L)
was added dropwise over 30 min. A white precipitate rapidly
formed. The stirring was maintained for 60 min, then the solid
was filtered through a Buchner funnel, using Whatman grade 6
filtering paper, washed with H2O (200 mL), and dried in vacuo
at 30 °C until stable weight. White powder; 23.44 g, 91% yield.
1H NMR (400 MHz, DMSO-d6) δ 8.02 (m, 2H), 7.80 (d, J =
7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H),
7.48 (t, J = 7.7 Hz, 1H), 7.35 (bs, 1H), 7.04 (m, 1H), 6.92 (m,
2H), 3.32 (m, 1H), 1.48−2.0 (m, 5H), 1.00−1.41 (m, 5H). 13C
NMR (101 MHz, DMSO-d6) δ 168.5, 154.5, 151.8, 144.1,
138.3, 134.7, 132.4, 128.5, 128.3, 127.7, 126.4, 123.8, 122.4,
116.7, 50.2, 33.1, 25.6, 25.1. UPLC/MS analysis: Rt 2.14 min.
1
weight. Light pink solid; 69 g, 85% yield. H NMR (400 MHz,
DMSO-d6) δ 7.61 (d, J = 11.2 Hz, 1H), 7.48−7.29 (m, 5H),
6.99 (m, 2H), 5.09 (s, 2H), 3.29 (m, 1H), 1.95−1.47 (m, 5H),
1.40−1.00 (m, 5H). 13C NMR (101 MHz, DMSO-d6) δ 155.7,
154.3, 145.2, 137.6, 128.9, 128.3, 128.1, 123.1, 115.6, 70.0, 50.2,
33.0, 25.6, 25.0. UPLC/MS analysis: Rt 3.01 min. MS (ESI):
326 (M+H)+; 324 (M-H)−. HRMS C20H23NO3 [M+H]+:
calculated 326.1756, measured 326.1763; Δppm 2.1. Mp: 144−
146 °C.
(4-Benzyloxy-3-bromophenyl)-N-cyclohexylcarba-
mate (10a). To a solution of (4-benzyloxyphenyl) N-
cyclohexylcarbamate 9 (53 g, 0.163 mol, 1 equiv) in DMF
(580 mL) in a 2 L three-necked round-bottomed flask, NBS
(40.64 g, 0.228 mol, 1.4 equiv) was rapidly added under
vigorous stirring and the resulting clear orange solution was
heated at 75 °C for 16 h. The reaction mixture was then cooled
to +22 °C, transferred in 3 L bottle and cooled to +4 °C with
an ice−water bath. Under vigorous stirring, an aqueous solution
of sodium thiosulfate pentahydrate (0.3 M, 200 mL) was added
over a period of 75 min. A precipitate formed and the mixture
was stirred for additional 2 h. The yellow solid was filtered
through a Buchner funnel and washed with H2O (500 mL).
The yellow cake was dried in vacuo at 45 °C until stable weight
and then transferred in a 2 L one-neck round-bottomed flask
and suspended in absolute EtOH (600 mL). The suspension
was heated at reflux until a clear yellow solution was obtained.
The mixture was maintained at the same temperature for
additional 10 min and then allowed to reach +22 °C in about 1
h. A white solid rapidly crystallized out. The flask was cooled at
+5 °C for 16 h; the solid was filtered through a Buchner funnel
and dried in vacuo at 45 °C until stable weight. Small white
1
needles; 57.6 g, 88% yield. H NMR (400 MHz, DMSO-d6) δ
7.61 (d, J = 11.2 Hz, 1H), 7.51−7.46 (m, 2H), 7.46−7.29 (m,
4H), 7.18 (d, J = 9.0 Hz, 1H), 7.08 (dd, J = 9.0, 2.7 Hz, 1H),
5.20 (s, 2H), 3.29 (m, 1H), 2.0−1.46 (m, 5H), 1.41−1.00 (m,
5H). 13C NMR (101 MHz, DMSO-d6) δ 153.9, 152.2, 145.3,
137.1, 128.9, 128.4, 127.8, 126.9, 122.4, 114.6, 111.1, 70.9, 50.3,
32.9, 25.6, 25.0. UPLC/MS analysis: Rt 3.20 min. MS (ESI):
404 (M+H)+, 406 (M+H)+; 402 (M-H)−, 404 (M-H)−.
HRMS: C20H22NO3Br [M+H]+: calculated 404.0861, measured
404.0862; Δppm 0.2. Mp: 136−138 °C.
[4-Benzyloxy-3-(3-carbamoylphenyl)phenyl]-N-cyclo-
hexylcarbamate (7). To a solution of 3-carbamoylbenzene-
boronic acid 11 (32.7 g, 0.198 mol, 1.5 equiv) in anhydrous
dioxane (700 mL) in a three-necked 2 L round-bottomed flask,
equipped with a mechanical stirrer and a reflux condenser,
ethylene glycol (14.9 mL, 0.264 mol, 2 equiv) was added in one
portion under stirring and under a static N2 atmosphere, and
the funnel washed with anhydrous dioxane (100 mL). The
reaction mixture was heated at 80 °C to give a slightly turbid
1
solution. The conversion of 11 to 14 was monitored by H
NMR analysis. (4-Benzyloxy-3-bromophenyl)-N-cyclohexylcar-
bamate 10a (53.4 g, 0.132 mol, 1 equiv) was then added
portionwise, washing the funnel with anhydrous dioxane (200
mL), followed by the addition of CsOAc (63.5 g, 0.330 mol, 2.5
e q u i v ) i n o n e p o r t i o n a n d , a f t e r
5
m i n ,
PdCl2diphenylphosphinoferrocene (4.8 g, 6.61 mmol, 0.05
equiv). The mixture turned rapidly from red to a dark brown
color. Heating was continued for 100 min at 80 °C, then the
mixture was allowed to cool to +22 °C and EtOAc (800 mL)
was added. The reaction mixture was transferred through a
cannula into a mixture of a 3% aqueous solution of citric acid (2
365
dx.doi.org/10.1021/op300301u | Org. Process Res. Dev. 2013, 17, 359−367

Organic Process Research & Development
Article
MS (ESI): 355 (M+H)+; 353 (M-H)−. HRMS: C20H22N2O4
[M+H]+: calculated 355.1658, measured 355.1669; Δppm 3.1.
Mp: 193−195 °C.
(9) Moreno-Sanz, G.; Barrera, B.; Guijarro, A.; d’Elia, I.; Otero, J. A.;
Alvarez, A. I.; Bandiera, T.; Merino, G.; Piomelli, D. Pharmacol. Res.
2011, 64, 359.
(10) Sasso, O.; Bertorelli, R.; Bandiera, T.; Scarpelli, R.; Colombano,
G.; Armirotti, A.; Moreno-Sanz, G.; Reggiani, A.; Piomelli, D.
Pharmacol. Res. 2012, 65, 553.
(11) Narender, N.; Srinivasu, P.; Ramakrishna Prasad, M.; Kulkarni,
S. J.; Raghavan, K. V. N. Synth. Commun. 2002, 32, 2313.
(12) Hoger, S. Liebigs Ann./Recueil 1997, 273.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedures for the preparation of compounds 10b, 14, and 15,
copies of NMR spectra of compounds 2, 7, 9, 10a-b, 14, and
15, and reaction time course of the Suzuki coupling reaction of
compound 14 with 10a. This material is available free of charge
via Internet at http://pubs.acs.org.
(13) The regiochemistry of the reaction is in accordance with a
literature report on the bromination of (4-methoxyphenyl) acetate
leading to (2-bromo-4-methoxy-phenyl) acetate as the major product:
see Roughley, S., Walls, S., Hart, T., Parsons, R., Brough, P., Graham,
C., Macias, A. U.S. Patent Appl. 2012/028953, 2012. Direct
bromination of 8 is reported to give 4-benzyloxy-2-bromophenol:
see Epple, R., Cow, C., Azimiora, M., Russo, R., Reid, S. W. PCT Int.
Appl. WO 2007/056496, 2007.
AUTHOR INFORMATION
Corresponding Author
*E-mail: claudio.fiorelli@iit.it; tiziano.bandiera@iit.it.
■
1
Notes
(14) Regioisomeric ratio was determined by comparison of the H
The authors declare no competing financial interest.
NMR spectrum of the crude material with that of an authentic sample
of (4-benzyloxy-2-bromophenyl)-N-cyclohexylcarbamate (see Sup-
porting Information). Integration of the signals of the benzylic
protons in the crude material gave a >99:1 ratio between compound
10a and its regioisomer.
(15) General reviews on the Suzuki reaction: Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457. Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633. Suzuki, A. Angew. Chem., Int. Ed. 2011, 50,
2.
(16) As an example, the phenol 5 accounted for only 8% of the
reaction mixture when 10a (1 equiv) and 11 (1.5 equiv) were heated
at 80 °C in dioxane in the presence of KOAc (2.5 equiv) for 3 h.
Under the same experimental conditions, but using DMF as the
solvent, the phenol 5 accounted for 94% of the reaction mixture after
only 30 min.
ACKNOWLEDGMENTS
■
We thank Andrea Armirotti for high resolution mass experi-
ments, Luca Goldoni for NMR support, Sine Mandrup Bertozzi
for analytical support, and REDOX S.n.c., Monza (Italy) for
ICP-MS analysis.
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NOTE ADDED AFTER ASAP PUBLICATION
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This article was published ASAP on February 27, 2013.
Changes have been made to the footnotes of Schemes 1 and 5.
The corrected version was reposted on March 1, 2013.
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