A practical synthesis of 2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2- (piperidin-4-yl)-1H-imidazol-1-yl}- N, N -dimethylethanamine

Article abstract of DOI:10.1055/s-0031-1290371

A practical synthesis of the title compound was accomplished by hydrogenation of 2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-(pyridin-4-yl)-1H- imidazol-1-yl}-N,N-dimethylethanamine. The latter was obtained by N-alkylation of 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Treatment of N-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl} isonicotinamide hydrochloride with ammonium acetate in acetic acid provided 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Coupling of 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone 4-methylbenzene sulfonate with pyridine 4-carboxylic acid using either T₃P or EDCI-HOBt provided N-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl} isonicotinamide hydrochloride. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290371

PAPER
▌2231
paper
A Practical Synthesis of 2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(piperi-
din-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine
Practical Synthesis of a Substituted Imidazole Derivative
Radhe K. Vaid,*a Jeremy Spitler,a Sathish Boini,a Kenneth Henry,b Xu Jiansheng,c Baitao Gao,c Xiaoquan Luc
a
Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
b
Discovery Chemistry Research and Technologies, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
c
Shanghai PharmaExplorer, Shanghai 20120, P. R. of China
Fax +1(317)2764507; E-mail: vaid_radhe_k@lilly.com
Received: 16.03.2012; Accepted after revision: 26.04.2012
Substituted imidazoles are important heteroaromatic com-
Abstract: A practical synthesis of the title compound was accom-
pounds, which not only exhibit a broad range of biological
plished by hydrogenation of 2-{4-[4-fluoro-3-(trifluoromethyl)phe-
activities such as antifungal properties,1–10 analgesic ac-
nyl]-2-(pyridin-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine.
The latter was obtained by N-alkylation of 4-{4-[4-fluoro-3-(triflu-
tivity,2,3 anti-inflammatory activity inhibiting the p38
oromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Treatment of N-{2- MAP kinase or cytokine release,4,5 and antiallergic activi-
ty,6 but also are important building blocks found in natu-
[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}isonicotinamide
hydrochloride with ammonium acetate in acetic acid provided 4-{4-
rally occurring compounds.7–10 Therefore, we were
[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine.
interested in a robust synthesis of 2-{4-[4-fluoro-3-(trifluo-
Coupling of 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]etha-
romethyl)phenyl]-2-(piperidin-4-yl)-1H-imidazol-1-yl}-
none 4-methylbenzene sulfonate with pyridine 4-carboxylic acid
using either T3P or EDCI-HOBt provided N-{2-[4-fluoro-3-(trifluo-
romethyl)phenyl]-2-oxoethyl}isonicotinamide hydrochloride.
N,N-dimethylethanamine. A survey of literature revealed
that synthesis of the title compound can be accomplished
in six steps from 2-bromo-1-[4-fluoro-3-(trifluorometh-
yl)phenyl]ethanone (1) (Scheme 1).11
Key words: imidazole, EDCI, T3P, ammonium acetate, hydrogena-
tion
The existing synthetic approach to 5, while well docu-
mented, resulted in poor isolated yield of 5 because of
oligomerization of the starting material 4 under reaction
O
O
O
TsOH•H2O
EtOH, 4 h
Br
NH2
–
Br
•TsOH
+
HMTA
N
F
F
F
N
N
CF3
CF3
CF3
N
3
1
CO2H
2
THF, 0–5 °C
EDCI, HOBt
N
CF3
Boc
AcONH4
i-BuOH
N
F
O
F
110 °C, 24 h
55%
N
N
H
F3C
NBoc
O
NBoc
5
4
•HCl
DMSO
40–50 °C
Me2N
NaOH
Cl
NMe2
NBoc
NMe2
N
EtOH–HCl
N
•3HCl
F
F
N
N
F3C
F3C
NH
7
6
Scheme 1 Literature synthesis of compound 7
SYNTHESIS 2012, 44, 2231–2236
Advanced online publication: 13.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290371; Art ID: SS-2012-M0276-OP
© Georg Thieme Verlag Stuttgart · New York

2232
R. K. Vaid et al.
PAPER
NH
NH
F
H2N
+
N
+
N
F3C
F3C
NH
NBoc
NH4OAc
i-BuOH
9
8
4
+
5
polymer
+
heat
N
N
N
N
N
CF3
HN
F
CF3
10
Scheme 2 Impurities formed during scale-up of 5
conditions due to its condensation with 9 derived by the
thermal deprotection of Boc group. Thus, in addition to
the formation of desired 5, deprotected product 9, and sig-
nificant quantities of aniline analogue 8 along with dimer
10 were observed (Scheme 2). These additional impurities
generated in this process along with the specific need for
protected imidazole 5 posed challenges during scale-up
with respect to reproducibility and purification. Further,
N-alkylation of 5 in DMSO at 100 kg scale also resulted
in the formation of undesired impurities at significantly
high level (8–12%, Figure 1), which made the purification
of 6 very difficult resulting in a poor isolated yield.
O
Me2N
N
F3C
NBoc
N
NMe2
11
F
N
F3C
NBoc
N
12
In order to avoid the above mentioned issues, we were in-
terested in developing a robust synthesis of title com-
pound 18 from 3. Herein, we report a practical synthesis
of title compound as shown in Scheme 3.
Figure 1 Impurities 11 and 12 observed during synthesis of 6
Imidazole ring construction from ketoamides using am-
monium acetate has been known in literature.12 Thus,
keeping the literature methods in view, synthesis of 15
was explored in various solvents with excess of ammoni-
um acetate (Table 2). As determined by HPLC, the forma-
tion of 15 was successful in acetic acid, propanoic acid,
and toluene. However, azeotropic removal of water was
required in the synthesis of 15 using toluene as a solvent
system. Based upon the yield data, we preferred acetic
Thus, synthesis of 3 was accomplished following the lit-
erature procedure.11 Coupling of acid chloride of 13 with
3 resulted in poor conversion. However, synthesis of 14
was successfully achieved in good yield and purity via ac-
tivation of acid 13 either by using T3P (2,4,6-tripropyl-
1,2,3,2,4,6-trioxatriphosphorinane-2,4,6-trioxide)
EDCI-HOBt (Table 1).
or
•HCl
O
CF3
N
NH4OAc (18 equiv)
N
F
toluene (10 vol)
O
OH
F
110 °C, 24 h
13
N
3
N
H
or
T3P, Et3N
THF, 0–5 °C
or
F3C
•AcOH
15
NH4OAc (36 equiv)
AcOH (10 vol)
140 °C, 16 h
N
O
N
HCl
14
EDCI, HOBt
KOH
THF (10 vol)
60 °C, 16 h
•HCl
Cl
Me2N
16
NMe2
NMe2
NH
N
PtO2 (2.5% wt)
EtOH–HCl
N
F
F
N
N
H2; 50 °C,
17 h
F3C
F3C
N
17
18
Scheme 3 Synthesis of compound 18
Synthesis 2012, 44, 2231–2236
© Georg Thieme Verlag Stuttgart · New York

PAPER
Practical Synthesis of a Substituted Imidazole Derivative
2233
Table 1 A Solvent and Acid Activating Agents Screening Study in the Synthesis of 14
Entry
Substrate
Acid activating reagent Solvent
Basea
Temp (°C)
Yield (%)b
1
2
3
4
5
13 acid chloride
none
CH2Cl2
Et3N
25
30
20
88
79
75
13 acid chloride
none
CH2Cl2
Et3N
reflux
23–30
0–5
13
13
13
EDCI-HOBT
T3P in EtOAc
T3P in EtOAc
THF
NMM
Et3N
EtOAc–THF
EtOAc–THF
NMM
0–5
a NMM: N-Methylmorpholine.
b Isolated yield.
acid as a solvent for the synthesis of 15 using ammonium was further completed to find the optimum amount of po-
acetate at 140 °C under pressure. This resulted in excel- tassium hydroxide required for the formation of 17 (Table
lent conversion of 15 as determined by HPLC. The reac- 3, entries 9–14). Based upon the data in Table 3, alkyla-
tion workup involved addition of water effecting in tion of 15 using THF as a solvent and powdered KOH pro-
crystallization of 15. Thus, synthesis of 15 was demon- vided a mixture of 17 and 19 in ratio of 91:6 along with
strated at 100 gram scale, which provided product in 89% undesired impurities (20 and 21, Scheme 4). The possible
yield with excellent purity.
pathway for the formation of 20 may involve the reaction
of 17 with 16 to form quaternary salt 20), which upon
elimination under basic conditions leads to formation of
21 (Scheme 5).
A screening study was performed to find a suitable exper-
imental condition for N-alkylation of 15 with 16 (Table
3). Impact of organic and inorganic bases was studied.
HPLC data from this study indicated that use of sodium Keeping the complexity of alkylation reaction in view, a
hydride as a base in THF provided the best result with re- workup involving treatment of reaction mixture with acti-
spect to the formation of 17 (Table 3). Both cesium car- vated carbon followed by crystallization was designed to
bonate and powdered potassium hydroxide provided obtain pure compound 17 in 78% yield. Absorption of 19
similar outcome in the synthesis of 17. As the use of NaH was observed on the carbon and it was determined that
on large scale poses challenges with respect to safety and 30% of carbon was required for removal of 19. N-Alkyla-
handling, we were interested in the development of a pro- tion of 15 was performed at 300 g scale, which provided
cess with the use of alkali metal hydroxide. Thus, a study 17 in 77% isolated yield with excellent purity.
Table 2 A Solvent Screening Study in the Synthesis of 15
Entry
NH4OAc (equiv) Solvent
Volumea
Temp (°C)
Time (h)
Formation of 15 by HPLC (%) Yield (%)b
1
2
20
20
50
50
50
36
36
36
36
20
12
21
EtOH
20
20
20
20
10
10
10
10
10
10
10
21
reflux
reflux
110
140
140
140
140
140
140
140
140
111
24
24
24
10
10
12
10
16
16
16
16
24
20
32
57
94
91
91
93
93
94
68
52
86
NI
NI
NI
NI
NI
NI
NI
89
90
NI
NI
78
i-PrOH
AcOH
AcOH
AcOH
AcOH
EtCO2H
AcOH
AcOH
AcOH
AcOH
toluene
3
4
5
6
7
8
9
10
11
12
a Reaction volume is based upon the quantity of 15 (g) used in the reaction, for example, for entry 9 amount of 15 used was 100 g (1 equiv);
thus 10 solvent volumes correspond to 10 × 100 = 1 L; NI = product not isolated.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2231–2236

2234
R. K. Vaid et al.
PAPER
HO–
17 (90–92%)
Me
+N
H
Me
+
NMe2
Me2N
N
N
17
F
F
21
+
N
N
_
16
F3C
F3C
20
N
N
NMe2
Me2N
Scheme 5 Possible pathway for the formation of impurity 21
19 (5–6%)
Me2N
Cl
+
•HCl
Me
N+
H
workup
16
Our attempts to reduce the pyridine ring of 17 by catalytic
hydrogenation using 5% palladium on carbon in acetic
acid at room temperature and 50 psi gave a mixture of de-
sired product 18 along with corresponding 4-des-fluoro
analogue 22 (Figure 2) after 30 hours.13
NMe2
15
17
N
N
Me
THF (15 vol),
KOH (7 equiv)
reflux, 24 h
F
F3C
N
20 (2%)
+
NMe2
N
N
F
N
N
F3C
F3C
NH
N
22
21 (1%)
Figure 2 Structure of 22
Scheme 4 Impurities observed during 15 alkylation
Table 3 Imidazole 25 N-Alkylation Screening Study and Optimized Conditions Data
In situ analysis of N-alkylation by HPLCb
Solvent (vol)a Temp (°C), time (h) 15 (%) 17 (%) 21 (%) 19 (%) 20 (%) of 17 (%)
Entry Starting material and base (equiv) Reaction conditions
Yield
15
16
Base
1
2
1
1
2
2
NaH (10.0)
THF (20)
DMF (20)
63–65, 18
63–65, 18
ND
94.1
35.4
2.1
0.3
1.05
10.1
0.8
0.3
80
NI
DIPEA (3.5)
K2CO3 (3.5)
52.4
3
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
t-BuOK (7.0)
THF (20)
THF (20)
THF (20)
THF (20)
THF (20)
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
56
–
–
–
–
NI
76
66
77
75
NI
74
74
73
NI
NI
77
74
77
77
78
Cs2CO3 (7.0)
ND
ND
ND
0.03
79.8
ND
0.7
92.3
82.2
90.3
91.5
11.0
89.8
90.5
87.3
30.4
1.2
1.5
1.8
0.7
1.7
0.6
1.4
1.6
1.9
2.6
1.1
1.0
0.6
1.0
0.6
2.1
4.3
0.8
0.5
ND
0.8
0.9
0.1
ND
0.4
1.7
0.7
0.6
0.3
0.6
0.3
0.8
5
NaH (6.0)
13.1
5.4
6
powder KOH (7)
flake KOH (7)
powder NaOH (3)
powder KOH (7)
powder KOH (6)
powder KOH (5)
powder KOH (4)
powder KOH (3)
powder KOH (6)
Cs2CO3 (7.0)
7
5.42
8
DMSO (15) 60–65, 16
7.36
5.4
9
THF (15)
THF (15)
THF (15)
THF (15)
THF (15)
THF (15)
THF (20)
THF (15)
THF (15)
THF (20)
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
63–65, 18
10
11
12
13
14
15
16
17
1
5.5
0.7
7.9
46.4
74.1
0.6
15.7
20.6
6.4
4.8
6.4
6.7
1.1
92.1
91.2
92.1
89.1
94.1
ND
0.6
powder KOH (6)
powder KOH (6)
NaH (10.0)
0.8
ND
a Reaction volume is based upon the quantity of 15 (g) used in the reaction (as explained in footnote a of Table 2).
b ND: not detected.
c Isolated yield. NI: not isolated.
Synthesis 2012, 44, 2231–2236
© Georg Thieme Verlag Stuttgart · New York

PAPER
Practical Synthesis of a Substituted Imidazole Derivative
2235
N
N
F
F
PtO2, H2
N
N
F3C
EtOH–HCl
F3C
N
NH
Me2N
Me2N
19
23
Scheme 6 Synthesis of 23
Table 4 Hydrogenation of 17 Using PtO2 Catalyst
Entry Starting material and conditions
Temp (°C), time (h) In situ analysis by HPLC (18; %) Yield (%)a
17 (g) EtOH (L) Catalyst
Concd HCl (mL) H2 (MPa)
1
2
36
0.50
2.8
PtO2 (5%)
21
1.4–1.6
1.4–1.6
48–52, 28
48–52, 22
96.9
98.9
91
92
200
PtO2 (2.5%) 105
a Isolated yield.
19F NMR (DMSO-d6): δ = –60.3, –108.6.
However, we were successful in catalytic reduction of 17
using PtO2 (2.5%) in ethanol under acidic conditions (Ta-
ble 4).14 Removal of catalyst by filtration followed by
neutralization of reaction solution with sodium hydroxide
provided 18 in good yield with excellent purity. In a sim-
ilar fashion, isomer 23 was also prepared via hydrogena-
tion of 19 (Scheme 6); the latter was obtained by
chromatographic purification.
HRMS: m/z calcd for C15H10F4N2O2: 326.0678; found: 326.0668.
4-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-
yl}pyridine Acetic Acid Salt (15)
Compound 15 (100 g, 0.276 mol) was combined with NH4OAc
(758 g, 9.83 mol) and AcOH (1 L) and the mixture was heated in an
autoclave at 140 °C for 20 h. The mixture was concentrated to re-
move AcOH, and H2O (2 L) was added. The mixture was stirred at
20 °C for 2 h. The material was filtered and washed with H2O (0.5
L). The crude product was purified by reslurrying in EtOAc (0.5 L)
and heptanes (1 L). The material was filtered and dried under vacu-
um; yield: 228 g (89%); brown solid; purity: 99.4%; mp 233–
235 °C.
In conclusion, we have described a practical synthesis of
2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-(piperidin-
4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine.
1H NMR (DMSO-d6): δ = 1.89 (s, 3 H), 7.54 (t, J = 9.7 Hz, 1 H),
7.92 (d, J = 6.2 Hz, 2 H), 8.10 (s, 1 H), 8.22 (d, J = 5.7 Hz, 2 H),
8.65 (d, J = 5.7 Hz, 2 H), 11.95 (s, 1 H), 13.22 (s, 1 H).
13C NMR (DMSO-d6): δ = 172.4, 159.2, 156.7, 150.8, 144.3, 140.0,
137.3, 131.9, 131.1, 123.0, 119.4, 118.1, 118.0, 117.4, 21.5.
1H, 19F, and 13C NMR spectra were recorded in CDCl3 using a Bruk-
er Avance 400 MHz spectrometer. Chemical shifts (δ) are expressed
in ppm downfield relative to TMS (0 ppm) and coupling constants
(J) are given in Hz. Standard abbreviations are used to describe the
signal patterns. High-resolution mass spectra (HRMS) were ob-
tained using a Waters GCT Premier TOF mass spectrometer with EI
source.
19F NMR (DMSO-d6): δ = –60.0, –119.4.
HRMS: m/z calcd for C17H13F4N3O2: 367.0944; found: 367.0941.
N-{2-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}isonico-
tinamide Hydrochloride (15)
2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(pyridin-4-yl)-1H-
imidazol-1-yl}-N,N-dimethylethanamine (17)
The tosylate salt 3 (392 g, 1.00 mole) was combined with isonico-
tinic acid (135 g, 1.09 mol) and THF (5.5 L). The resultant slurry
was cooled to 0–5 °C. T3P (50% in EtOAc; 1001 g, 1.57 mol) dilut-
ed in THF (0.75 L) and Et3N (510 g, 4.94 mol) diluted in THF (0.75
L) were added concurrently over 0.5 h to give a yellow, homoge-
neous solution (addition of T3P solution was slightly faster than
Et3N). The reaction was quenched with brine (3 L) and the aqueous
layer was back-extracted with EtOAc (0.5 L). The combined organ-
ic layers were washed with brine (2 × 3 L), dried (MgSO4), filtered,
and concentrated to give a yellow oil. The crude oil was dissolved
in EtOAc (3 L), cooled to 5–10 °C, and HCl gas was bubbled in for
1 h. The resultant slurry was stirred at 15 °C for 2 h. The mixture
was concentrated to 1.5 L, and MeOH (1.5 L) was added. The slurry
obtained was stirred at r.t. for 6 h. The material was filtered and
dried under vacuum; yield: 280 g (77%); yellow solid; purity:
99.2%; mp 117–119 °C.
The imidazole 15 (192 g, 0.523 mol) was combined with KOH (176
g, 3.14 mol) and THF (3 L). The mixture was heated to 30–40 °C
and stirred for 1 h. 2-Chloro-N,N-dimethylethanamine hydrochlo-
ride (16; 150 g, 1.04 mol) was added and the reaction mixture was
heated at 60–65 °C for 20 h. The mixture was filtered and the cake
washed with EtOAc (0.4 L). Activated carbon (30 wt%) was added
to the filtrate and the mixture was stirred at 60–65 °C for 3 h. The
mixture was filtered through Celite, and the cake rinsed with EtOAc
(0.8 L). The filtrate was concentrated to a brown solid (175 g). The
crude material was slurried in EtOAc (0.1 L) and heptanes (1 L) at
r.t. for 16 h. The material was filtered and dried under vacuum;
yield: 151.8 g (77%); yellow solid; purity: 99.3%; mp 122–126 °C.
1H NMR (DMSO-d6): δ = 2.07 (s, 6 H), 2.59 (t, J = 6.5 Hz, 2 H),
4.21 (t, J = 6.5 Hz, 2 H), 7.53 (t, J = 10.1 Hz, 1 H), 7.71 (dd, J = 4.4
Hz, 2 H), 8.12 (br t, 3 H), 8.70 (dd, J = 4.4 Hz, 2 H).
13C NMR (DMSO-d6): δ = 150.6, 145.3, 138.3, 138.0, 131.7, 131.6,
131.0, 130.9, 123.1, 118.2, 118.0, 59.2, 45.6, 45.5, 40.4.
19F NMR (DMSO-d6): δ = –60.1, –119.3.
1H NMR (DMSO-d6): δ = 4.87 (d, J = 5.3 Hz, 2 H), 7.73 (t, J = 9.7
Hz, 1 H), 7.78 (d, J = 5.7 Hz, 2 H), 8.35 (d, J = 7.0 Hz, 1 H), 8.43
(m, 1 H), 8.75 (d, J = 6.2 Hz, 2 H), 9.3 (t, J = 5.3 Hz, 1 H).
13C NMR (DMSO-d6): δ = 193.5, 165.6, 160.8, 150.8, 141.1, 136.0,
135.9, 132.3, 127.8, 121.7, 118.7, 118.4, 47.1.
HRMS: m/z calcd for C19H18F4N4: 378.1468; found: 3788.1462.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2231–2236

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R. K. Vaid et al.
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2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(pyridin-4-yl)-1H-
imidazol-1-yl}-N,N-dimethylethanamine (18)
19F NMR (DMSO-d6): δ = –60.0, –120.7.
HRMS: m/z calcd for C19H24F4N4: 384.1937; found: 384.1907.
Compound 17 (143 g, 0.378 mol) was charged to an autoclave fol-
lowed by EtOH (1.1 L). PtO2 (2.5%) was added, followed by aq 2
N HCl (0.38 L, 0.755 mol). The mixture was stirred at 70 °C under
140 psi H2 for 24 h. The mixture was filtered through Celite and the
cake was rinsed with EtOH (2 × 0.25 L). The filtrate was concen-
trated to afford a white solid. The crude material was dissolved in
H2O (1.7 L) and EtOH (0.43 L) and cooled to 0–5 °C. By maintain-
ing a temperature of 0–5 °C, the pH of the mixture was adjusted to
10–11 with aq 2 N NaOH. The resultant slurry was held at 0–5 °C
for 2 h. The product was filtered, rinsed with cold EtOH–H2O (1:5,
0.8 L), and dried under vacuum (60–70 °C); yield: 149 g (88%);
white solid; purity: 99.0%; mp 92–95 °C.
1H NMR (DMSO-d6): δ = 1.70 (br q, 4 H), 2.17 (s, 6 H), 2.54 (m, 4
H), 2.81 (m, 1 H), 3.00 (d, J = 11.9 Hz, 2 H), 3.99 (t, J = 6.6 Hz, 2
H), 7.44 (t, J = 10.1 Hz, 1 H), 7.69 (s, 1 H), 8.01 (d, J = 7.0 Hz, 2 H).
13C NMR (DMSO-d6): δ = 32.32, 33.59, 43.08, 45.30, 46.08, 59.45,
116.38, 117.29, 117.40, 121.45, 124.15, 129.88, 132.11, 135.91,
152.21, 155.72, 158.19.
Acknowledgment
We are thankful to Dr. Mike Fogarty for providing analytical data.
Professors M. Miller and W. Roush are acknowledged for thought-
ful discussion and valuable suggestions.
References
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19F NMR (DMSO-d6): δ = –60.0, –120.6.
HRMS: m/z calcd for C19H24F4N4: 384.1937; found: 384.1929.
2-{5-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(pyridine-4-yl)-
1H-imidazol-1-yl}-N,N-dimethylethanamine (19)
The active carbon cake containing crude 19 from the preparation of
17 was added to MeOH (1 L) and refluxed for 1 h. The material was
filtered and the filtrate was concentrated to obtain 33 g of a red sol-
id, which was purified by preparative HPLC; yield: 1.9 g; white sol-
id; purity 98.2%; mp 157–161 °C.
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120801 A1, 2010.
1H NMR (DMSO-d6): δ = 2.18 (s, 6 H), 2.68 (t, J = 5.7 Hz, 2 H),
4.38 (t, J = 5.7 Hz, 2 H), 7.43 (t, J = 9.7 Hz, 1 H), 7.83 (s, 1 H), 8.11
(m, 4 H), 8.42 (d, J = 6.6 Hz, 2 H).
13C NMR (DMSO-d6): δ = 45.01, 55.66, 58.74, 116.42–117.34,
118.47, 121.87, 124.24, 130.08, 132.51, 133.24, 142.75, 147.95,
149.31, 155.49, 157.99.
19F NMR (DMSO-d6): δ = –60.0, –121.2.
HRMS: m/z calcd for C19H18F4N4: 378.1468; found: 378.1472.
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2-{5-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(piperidin-4-yl)-
1H-imidazol-1-yl}-N,N-dimethylethanamine (23)
Reduction of 19 using method outlined for compound 18 provided
23; yield: 4.9 g (64%); white solid; purity: 99.6%; mp 166–169 °C.
1H NMR (DMSO-d6): δ = 1.71 (br q, 2 H), 1.84 (br d, J = 11.4 Hz,
2 H), 2.00 (d, J = 9.7 Hz, 2 H), 2.12 (s, 6 H), 2.33 (m, 4 H), 2.62 (m,
1 H), 2.90 (d, J = 11.0 Hz, 2 H), 7.43 (t, J = 9.7 Hz, 1 H), 7.65 (s, 1
H), 8.01 (d, J = 7.0 Hz, 2 H).
13C NMR (DMSO-d6): δ = 30.78, 35.56, 45.55, 53.47, 56.28, 56.86,
113.25, 117.14, 117.33, 121.45, 121.86, 121.90, 124.15, 130.03,
130.11, 132.37, 136.72, 152.13, 155.68, 158.17.
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Synthesis 2012, 44, 2231–2236
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