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