Synthesis of a TRPV1 receptor antagonist

Article abstract of DOI:10.1021/jo901943s

(Chemical Equation Presented) A five-step synthesis of a TRPV1 receptor antagonist 1 is described. The key step involves a novel palladium-catalyzed amidation reaction of 4-chloro-1-methylindazole 8 with the benzyl urea 9 to form the unsymmetrically subst

Full text of DOI:10.1021/jo901943s

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constructed from the couplings of amines with isocyanates,
Synthesis of a TRPV1 Receptor Antagonist
activated esters, or carbamates. An initial synthesis of 1
employed the treatment of aniline, 4, with N,N-disuccinimi-
dyl carbonate to form an activated carbamate that was
condensed with amine 7 to give the unsymmetrically sub-
stituted urea 1 (Scheme 1). A drawback found with this route
was the instability of aminoindazole 4. In addition, synthesis
of 4 proved tedious due to the need to separate the amino-
indazole 4 from the benzophenone byproduct. Thus, a more
robust synthesis was needed to support the development of 1.
Su Yu,* Anthony Haight, Brian Kotecki, Lei Wang,
Kirill Lukin, and David R. Hill
Abbott Laboratories, GPRD Process Research and
Development, Dept. R450, Bldg. R8, 1401 Sheridan Road,
North Chicago, Illinois 60064
su.yu@abbott.com
Received September 10, 2009
Even though C-N cross-couplings have become common
in the synthetic repertoire,5 few examples of N-arylation of
ureas have been reported and even fewer have described the
couplings of chloro-arenes in this transformation.6 Recently,
our laboratory reported a new method for the preparation of
unsymmetrically substituted ureas utilizing palladium-cata-
lyzed amidation7 employing a Pd/bippyphos8 catalytic sys-
tem. We report here the application of this methodology in a
concise synthesis of compound 1 utilizing the novel coupling
reaction between 4-chloro-1-methylindazole, 8, and benzyl
urea, 9 (Scheme 2).
A five-step synthesis of a TRPV1 receptor antagonist 1 is
described. The key step involves a novel palladium-cata-
lyzed amidation reaction of 4-chloro-1-methylindazole 8
with the benzyl urea 9 to form the unsymmetrically
substituted urea 1.
Chloroindazole 8 was prepared from readily available
2-chloro-6-fluorobenzaldehyde 10 by treatment of 10 with
excess methyl hydrazine to afford chloroindazole 8 in one
step (Scheme 3). However, about 5% of the regioisomer 14
was observed in the product.
To gain insight into the formation of regioisomer 14, we
monitored the reaction by NMR. The addition of methylhy-
drazine to a slurry of potassium carbonate and 10 in DMSO
caused a large and immediate exotherm (1120 J/g of 10).9 1H
NMR analysis suggested rapid formation of a ∼2:1 mixture
of aminals at ambient temperature which were tentatively
assigned as 11a and 11b (Figure 1). The aminals converged
TRPV1 receptor antagonists represent a non-NSAID,
nonopiate approach for pain management1 with reduced
potential for substance abuse.2 Compound 1 is a novel,
potent, and selective TRPV1 receptor antagonist.3
Retrosynthetically, compound 1 can readily be discon-
nected at the urea moiety. Ureas, and in particular, N-aryl
and N-heteroaryl ureas, have found a ubiquitous position in
a number of biologically active targets.4 They are usually
(1) (a) Jara-Oseguera, A.; Simon, S. A.; Rosenbaum, T. Curr. Mol.
Pharmacol. 2008, 1 (3), 255–269. (b) Jancso, G.; Dux, M.; Oszlacs, O.;
Santha, P. Br. J. Pharmacol. 2008, 155 (8), 1139–1141. (c) Wang, Y.
Neurochem. Res. 2008, 33 (10), 2008–2012.
(2) (a) Gomtsyan, A.; Bayburt, E. K.; Koenig, J. R.; Lee, C.-H. U.S. Pat. Appl.
US 2004254188. (b) Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Surowy, C. S.;
Honore, P.; Marsh, K. C.; Hannick, S. M.; McDonald, H. A.; Wetter, J. M.;
Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R.; Lee, C.-H. J. Med. Chem. 2008, 51
(3), 392–395. (c) Gomtsyan, A.; Bayburt, E. K.; Lee, C-H.; Koenig, J. R.; Schmidt,
R.; Lukin, K.; Chambournier, G.; Hsu, M.; Leanna, M. R.; Cink, R. D. PCT Int.
Appl. WO 2004111009.
(5) (a) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In Chemistry
of Anilines; Rapporport, Z., Ed.; Wiley-Interscience: New York, 2007; Vol. 1,
p 455. (b) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2004.
(6) (a) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron
Lett. 2001, 42, 4381. (b) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P.
(3) Lee, C.-H.; Brown, B. S.; Perner, R. J.; Darbyshire, J. PCT Int. Appl.
ꢀ
~
WO 2008024945.
Tetrahedron Lett. 2003, 44, 4719. (c) Abad, A.; Agullo, C.; Cunat, A. C.;
Vilanova, C. Synthesis 2005, 6, 915. (d) McLaughlin, M.; Palucki, M.;
Davies, I. W. Org. Lett. 2006, 8, 3311. (e) Willis, M. C.; Snell, R. H.; Fletcher,
A. J.; Woodward, R. L. Org. Lett. 2006, 8, 5089.
(7) Kotecki, B.; Fernando, D.; Haight, T.; Lukin, K. Org. Lett. 2009,
11 (4), 947.
(4) For examples see: (a) Gallou, I. Org. Prep. Proced. Int. 2007, 4, 355.
(b) Looker, A. R.; Littler, B. J.; Blythe, T. A.; Snoonian, J. R.; Ansell, G. K.;
Jones, A. D.; Nyce, P.; Chen, M.; Neubert, B. J. Org. Process Res. Dev. 2008,
12 (4), 666–673. (c) Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.;
Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.;
Harris, C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.;
Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease, L. J.;
Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D. R.; Davidsen,
S. K.; Michaelides, M. R. J. Med. Chem. 2007, 50 (7), 1584–1597.
(8) Singer, R. A.; Dore, M.; Sieser, J. E.; Berliner, M. Tetrahedron Lett.
2006, 47, 3727.
(9) The reaction was monitored in an Omincal super chemical reactivity
calorimeter.
DOI: 10.1021/jo901943s
r
Published on Web 11/23/2009
J. Org. Chem. 2009, 74, 9539–9542 9539
2009 American Chemical Society

Yu et al.
JOCNote
SCHEME 1. First Generation Synthesis of 1
FIGURE 1. NMR of 10, MeNHNH2 (3 equiv), and DMSO-d6 at
25 °C/100 min.
SCHEME 4. New Synthesis of 1 with a Novel Urea Coupling
Reaction
SCHEME 2. Retrosynthetic Analysis of 1
The ratio of compounds 8 vs. 14 was not significantly
affected by equivalents of methylhydrazine either. DMSO
proved optimal of the solvents screened (NMP, DME,
toluene, DMAC, DMF) in terms of conversion.
SCHEME 3. Synthesis of Chloroindazole 8
Benzyl urea 9 was prepared via a three-step sequence from
3-chloro-4-cyanobenzotrifluoride, 15 (Scheme 4).11 Sonoga-
shira coupling of aryl chloride 15 with 3,3-dimethylbut-1-yne
is accomplished by using Davephos ligand12 in triethylamine
at 65 °C. Deactivated aryl chlorides are typically not compe-
tent substrates for Sonogashira couplings;13 however, the use
of the hindered ligand combined with triethylamine as a
solvent proved capable of providing the substituted alkyne in
>95% yield. It was noted that using THF as a cosolvent
decreased the reaction rate. With copper iodide the reaction
rates were slightly higher. Slow addition of 3,3-dimethylbut-
1-yne minimized oligomerization of the acetylene.
Hydrogenation of 16 was carried out with Ra-Ni under
basic conditions at 50 °C. Reduction of the nitrile and alkyne
was observed to be rapid while the final alkene reduction
proceeded over the course of several hours.14 The final
into hydrazone 12 with little to no formation of indazoles 8 and
14. The formation of the indazoles presumably involves sub-
stitution of the aryl fluoride with another molecule of methyl
hydrazine, followed by cyclization of 13a and 13b10 (Scheme3).
(11) Lukin, K. A.; Hsu, M. C.; Fernando, D. P.; Kotecki, B. J.; Leanna,
M. R. U.S. Pat. Appl. US2007244178.
(12) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722. (b) An initial screen of a series of hindered ligands resulted in
Davephose as the best ligand for the reaction.
(13) (a) Lee, D.-H.; Qiu, H.; Cho, M.-H.; Lee, I-M.; Jin, M.-J. Syn. Lett.
2008, 11, 1657. (b) Huang, H.; Liu, H.; Jiang, H.; Chen, K. J. Org. Chem.
2008, 73, 6037. (c) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003,
42, 5993.
(14) The reaction was monitored by HPLC. Aliquots were taken out to
identify the reaction intermediates.
(10) Exposure of 12 to the reaction conditions without excess MeN2H3
resulted in complex product mixtures while heating 12 with excess MeN2H3
cleanly gave 8 and 13 mixtures. See also: Lukin, K.; Hsu, M. C.; Fernando,
D.; Leannna, M. R. J. Org. Chem. 2006, 71, 8166.
9540 J. Org. Chem. Vol. 74, No. 24, 2009

Yu et al.
JOCNote
benzylic amine 17 is isolated as the succinate salt providing a
purification point without the need of chromatography.
Benzyl urea 9 was formed by reacting the benzylic amine
17 with phenyl carbamate (1.07 equiv) and N,N-diisopropy-
lethylamine (2 equiv) in 2-methyl-THF.
To determine the preferred conditions for the coupling
between benzyl urea 9 with chloroindazole 8, we screened
ligands and catalyst first. Two ligands, 10-binaphthyl-2-di-
tert-butylphosphine and Bippyphos8 18, provided high con-
versions for the coupling when complexed with a palladium
source. Bippyphos precomplexed with Pd2(dba)3 with 2:1
ratio in DME provided an optimal rate for the reaction. The
complete conversion was achieved with 0.5 mol % of the
catalyst.
(910 mL). The combined organics were washed with 10% citric
acid (125 mL) and water (125 mL) and concentrated to oil. To
the oil was added water (125 mL). The resulting solid was
filtered, washed with water, and dried at 30 °C to yield 27.4 g
of crude 8.
Water (40 mL) was added to a solution of crude 8 (27.4 g) in
methanol (40 mL) at 0 °C. The resulting solid was filtered and
washed with 33% methanol/67% water (150 mL total) followed
by water. A yield of 24.5 g of off-white solid were obtained after
drying under vacuum at 30 °C. Yield: 73%. Purity of the solid
1
was 98.5% with 1.34A% of N-2 isomer. H NMR (400 MHz,
DMSO) δ 4.06 (s, 3H), 7.19 (dd, J = 0.5, 7.5 Hz, 1 H), 7.37 (dd,
J = 7.3, 8.5 Hz, 1H), 7.62 (td, J = 0.8, 8.5 Hz, 1H), 8.07 (d, J = 4
Hz, 1H); 13C NMR (101 MHz, DMSO) δ 35.8, 108.6, 119.5,
121.8, 124.2, 126.4, 129.9, 140.0; HRMS (ESI) calcd for
C8H8ClN2 m/z 167.03705 [M þ H], found m/z 167.03697.
3-(3,3-Dimethylbut-1-ynyl)-4-cyanobenzotrifluoride 16. To a
flask was added Pd2dba3 (0.405 g, 0.44 mmol), DavePhos
(0.6884 g, 1.75 mmol), and CuI (0.1655 g, 0.87 mmol). It was
then purged with nitrogen and degassed triethylamine (100 mL)
was added. To this was added 3-chloro-4-cyanobenzotrifluoride
15 (36.2 g, 176 mmol). The mixture was heated to 65 °C and 3,3-
dimethylbutyne (23.7 g, 288 mmol) was then slowly added over
2 h. The mixture was heated for an additional 2 h. The mixture
was diluted with isopropyl acetate (150 mL). Then it was washed
twice with water (150 mL) and twice with 10% aqueous citric
acid (150 mL). The organics were diluted with methanol (40 mL)
and the volume reduced in vacuo to 60 mL. This was repeated
twice with 190 mL of methanol and the residual material was
diluted to 250 g with methanol and used in the next step as a
solution. Assay yield was 95% with 97% HPLC purity. A solid
sample was obtained by removing all of the solvent for the
analyses. 1H NMR (400 MHz, DMSO) δ 1.32 (s, 9H), 7.86 (d,
J = 8.2 Hz, 1H), 7.91 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H); 13C
NMR (101 MHz, DMSO) δ 28.0, 30.1, 74.7, 106.8, 115.9, 117.7,
124.7, 127.1, 127.9, 132.3, 132.6,133.6; HRMS (ESI) calcd for
C14H13F3N m/z 252.09946 [M þ H], found m/z 252.09944.
4-Aminomethyl-3-(3,3-dimethylbutyl)benzotrifluoride Succi-
nate Salt 17. To a flask containing Raney Nickel (19 g)
was added 3-(3,3-dimethylbut-1-ynyl)-4-cyanobenzotrifluoride
16 in methanol (134 g, 14.9 wt % 16), potassium hydroxide
(0.23 g, 4.1 mmol)), and additional methanol (44.3 g). The
mixture was pressurized with hydrogen and agitated for 42 h.
The solution was filtered and the cake washed with methanol
(20 g). To the solution was added succinic acid (10.65 g, 90
mmol). The solution was reduced in vacuo to 100 mL and
diluted with isopropanol (100 mL) and concentrated again to
100 mL. The slurry was filtered and the wetcake washed with
isopropanol (120 mL). The cake was dried under vacuum at
35 °C to give a white solid with 91% yield as the monosuccinate
salt in >97A% purity.17 1H NMR (400 MHz, DMSO) δ 0.96 (s,
9H), 1.35-1.39 (m, 2 H), 2.30 (s, 4H), 2.62-2.67 (m, 2H), 3.99 (s,
2H), 7.51 (s, 1H); 13C NMR (101 MHz, DMSO) δ 27.2, 29.0,
30.5, 31.2, 39.9, 44.8, 122.1, 125.0, 127.5, 127.8, 128.3, 139.7,
141.7, 174.1; HRMS (ESI) calcd for C14H21F3N m/z 260.16206
[M þ H], found m/z 260.16273.
Milled potassium phosphate tribasic was found to be the
most efficient base for the reaction with more reactive sur-
face. The catalyst was preformed by mixing the benzyl urea,
Pd2(dba)3, BippyPhos, K3PO4, and DME separately for
30 min at 50 °C. The aryl chloride was then added and the
mixture heated to 80 °C for 15 to 20 h. This protocol gave
consistent rates and yields.7
Purification entailed an aqueous workup followed by
sequential exposure of an ethyl acetate solution of the
product to a thiourea bound resin and activated carbon.
The thiourea resin and the carbon proved necessary to
remove residual levels of palladium from the product prior
to crystallization from aqueous isopropanol.15 The product
was obtained in >99.5% purity after crystallization with 5%
product loss in the mother liquor.
In summary, we have developed a concise, robust, and
scalable synthesis for the TRPV1 receptor antagonist 1. The
synthesis involves a novel coupling reaction between benzyl
urea and chloroindazole with readily available16 nonpro-
prietary Bipyphos as the ligand as well as a high-yielding
Sonogashira coupling of an aryl chloride. Compound 1 was
delivered by this process to support development efforts.
Experimental Section
4-Chloro-1-methyl-1H-indazole 8. Methyl hydrazine (47.3 g,
1.03 mol, 5 equiv) was added to a slurry of potassium carbonate
(55.0 g, 0.4 mol), 2-chloro-6-fluorobenzaldehyde 10 (32.1 g,
0.2 mol), and DMSO (317 g) at ambient temperature. The
mixture was then heated at 70 °C for 7 days. The mixture was
cooled to ambient and diluted with water (250 mL) and methyl
tert-butyl ether (950 mL). The upper organics were separated
and the lower layer was re-extracted with methyl-tert-butyl ether
1-(2-(3,3-Dimethylbutyl)-4-(trifluoromethyl)benzyl)urea 9. To
a solution of 4-aminomethyl-3-(3,3-dimethylbutyl)benzotri-
fluoride succinate salt 17 (14 g, 37 mmol) in toluene (150 mL)
was added 70 mL of 5% NaOH. Then it was mixed and layers
were separated. The organic layer was washed twice with 5%
NaHCO3 (50 mL) followed by 20% brine (50 mL). It was then
(15) The initial levels of Pd were >2000 ppm, yet after treatment with
thiourea capped resin and carbon, the levels could be brought down to less
than 35 ppm with less than 1% of the product lost in the treatments. The Pd
level was further dropped with the final crystallization.
(16) It is commercially available in variant quantities from Aldrich and
Digital Special Chemicals.
(17) HPLC method: Zorbax RX-C8; 5 um (4.6 mm ꢀ 250 mm); 1.0 mL/
min; 90:10 H2O (0.1% H3PO4):CH3CN then to 1:99 in 15 min, held at 1:99 for
10 min, and then to 90:10 in 1 min and held for 4 min; 220 nm wavelength. The
reaction mixture is dissolved in 50:50 H2O (0.1% H3PO4):CH3CN at 1.0 mg/
mL at 5 uL for injection. Retention time for 16 is 10.5 min
J. Org. Chem. Vol. 74, No. 24, 2009 9541

Yu et al.
JOCNote
concentrated and chased with 2-methyl-THF to give benzyl-
amine free base in 99.8% yield. To a slurry of phenyl carbamate
(5.12 g, 37 mmol) in 2-methyl-THF (25 mL) was added N,N-
diisopropylethylamine (8.77 g, 68 mmol) and benzylamine/2-
methyl-THF solution (total solvent ca. 50 mL). The mixture was
stirred at 45 °C overnight and cooled to 20 °C. Isopropyl acetate
(55 mL) was added and the organic layer was then washed twice
with 5% NaOH (50 mL each) followed by three times with 20%
NaCl (50 mL each). The organic layer was concentrated and
chased with methanol to ca. 30 mL. To the residue was added 40
mL of methanol. The resulting mixture was heated to 50-60 °C
and water (80 mL) was slowly added. The slurry was cooled to
20 °C, filtered, and washed with 50% aqueous methanol fol-
lowed by water. The wet cake was dried at 55 °C to give 18.8 g of
urea 9 as a white solid in 98% yield with 99.6% HPLC purity.18
1H NMR (400 MHz, DMSO) δ 0.96 (s, 9H), 1.37-1.41 (m, 2 H),
2.61-2.65 (m, 2H), 4.25 (d, J = 8 Hz, 2H), 5.57 (s, 2H), 6.40 (t,
J = 8 Hz, 1H), 7.39-7.51 (m, 3H); 13C NMR (101 MHz,
DMSO) δ 27.0, 29.1, 30.5, 39.9, 44.7, 121.9, 124.8, 126.7,
127.0, 127.4, 141.1, 142.4, 157.8. HRMS (ESI) calcd for
C15H22F3N2O m/z 303.16787 [M þ H], found m/z 303.16796.
1-[2-(3,3-Dimethylbutyl)-4-trifluoromethylbenzyl]-3-(1-meth-
yl-1H-indazol-4-yl)urea 1. To a flask was added urea 9 (20 g, 66.2
mmol), potassium carbonate (21.04 g, 99.2 mmol), Pd2dba3 (606
mg, 0.66 mmol), and bippyphos 18 (1.34 g, 2.65 mmol). After
being purged with nitrogen, the mixture was diluted with
sparged dimethoxyethane (DME, 260 mL). The mixture was
heated to 50 °C for 30 min. Indazole 8 (13.23 g, 79.4 mmol) in 40
mL of sparged DME was added to the catalyst mixture at 50 °C.
The mixture was heated to 80 °C for 18 h. The mixture was
cooled to ambient, filtered, and concentrated to approximately
150 g. The residue was chased twice with isopropanol (2 ꢀ 500
mL). The remaining material was diluted to ca. 230 g with
isopropanol and heated to 65 °C. Water (182 g) was slowly
added at 65 °C and the solution cooled to 0 °C. The slurry was
stirred at 0 °C for 1 h and filtered, then the cake was washed with
45% water/methanol (100 mL). The solids were dried at 40 °C to
give 24.0 g of product 1 as a white solid in 84% yield. 1H NMR
(400 MHz, DMSO) δ 0.96 (s, 9H), 1.42-1.46 (m, 2 H),
2.67-2.71 (m, 2H), 3.98 (s, 3H), 4.44 (d, J = 8 Hz, 2H), 6.79
(t, J = 5.8 Hz, 1H), 7.13 (d, J = 8 Hz, 1H), 7.24 (t, J = 8 Hz,
1H), 7.50-7.55 (m, 3H), 7.63 (d, J = 7.3 Hz, 1H), 8.03 (s, 1H),
8.81 (s, 1H); 13C NMR (101 MHz, DMSO) δ 27.2, 29.1, 30.5,
35.4, 40.0, 44.9, 102.1, 106.9, 114.9, 122.1, 125.0, 126.6, 127.1,
127.4, 127.8, 129.1, 132.4, 139.9, 141.5, 141.6, 154.1. HRMS
(ESI) calcd for C23H28F3N4O m/z 433.22097 [M þ H], found m/
z 433.22083.
Acknowledgment. We would like to thank Dr. Timothy
Robbins for preparing Bippyphos, Christopher Ling for
HRMS analysis of all compounds, and Dr. Zhe Wang for
the reaction heat analysis.
(18) HPLC condition: Zorbax C8 column; 4.6 ꢀ 250 mm; 205 nm
detection; run time 38 min; injection volume 5 uL; flow rate 1 mL/min; oven
temperature 30 °C; gradient elution 20% acetonitrile/80% (0.1% aq H3PO4)
to 80% acetonitrile/20% (0.1% aq H3PO4) in 7 min, hold 23 min then back to
20% acetonitrile/80% (0.1% aq H3PO4) in 5 min, hold for 3 min. Retention
time for 16 is 7.3 min and for 9 is 10.1 min.
1
Supporting Information Available: Copies of H and 13C
NMR spectra of compounds 8, 9, 16, 17, and 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
9542 J. Org. Chem. Vol. 74, No. 24, 2009