Synthesis of (2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1 H-imidazol-1-yl}ethyl)dimethylamine

Article abstract of DOI:10.1055/s-0033-1338467

An efficient eight-step synthesis of the title compound, starting from oxoacetic acid monohydrate, was developed. Condensation of oxoacetic acid monohydrate with N,N-dimethylethanamine followed by reductive amination and protection gave N-(tert-butoxycarb

Full text of DOI:10.1055/s-0033-1338467

1534▌
PAPER
paper
Synthesis of (2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-
imidazol-1-yl}ethyl)dimethylamine
(2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine
Radhe K. Vaid,*a Sathish Boini,a Jeremy T. Spitler,a Yangwei John Pu,a Scott A. May,a Hannah Yu,a Wu Sizhong,b
Jie Fu,b Guoliang Zhangb
a
Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Fax +1(317)2764507; E-mail: vaid_radhe_k@lilly.com
b
Shanghai PharmExplorer, Shanghai, 20120, P. R. of China
Received: 01.02.2013; Accepted after revision: 25.03.2013
O
O
O
Br-
Abstract: An efficient eight-step synthesis of the title compound,
starting from oxoacetic acid monohydrate, was developed. Conden-
sation of oxoacetic acid monohydrate with N,N-dimethylethana-
mine followed by reductive amination and protection gave N-(tert-
butoxycarbonyl)-N-[2-(dimethylamino)ethyl]glycine. Activation of
this intermediate with 1,1′-carbonylbis-1H-imidazole followed by
treatment with (methoxyamino)methane gave tert-butyl [2-(dimeth-
ylamino)ethyl]{2-[methoxy(methyl)amino]-2-oxoethyl}carbamate,
which upon reaction with [4-fluoro-3-(trifluoromethyl)phe-
nyl]magnesium bromide, generated in situ, and subsequent deprot-
ection gave 2-{[2-(dimethylamino)ethyl]amino}-1-[4-fluoro-3-
(trifluoromethyl)phenyl]ethanone dihydrochloride. Coupling of
this diamine with an activated carboxylic acid gave tert-butyl 4-{1-
[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]-
1H-imidazol-2-yl}piperidine-1-carboxylate, which on treatment
with sodium acetate in ethanol followed by deprotection in situ and
neutralization gave the title compound in good yield.
Br
TsOH·H2O
EtOH, 4 h
NH2
N+
TsOH
F
F
F
N
HMTA
1
N
CF3
CF3
N
3
CF3
O
2
·HCl
T3P, Et3N
THF
N
0–5 °C
OH
4
CF3
NH
F
NH4OAc, AcOH
140 °C
F
O
N
F3C
N
N
H
·CH3CO2H
O
N
6
HCl
5
·HCl
Cl
KOH
THF
Me2N
7
H2
PtO2
HCl–EtOH
NMe2
NH
Key words: alkylation, heterocycles, imidazoles
NMe2
N
N
F
F
N
N
CF3
CF3
8
9
N
Syntheses of substituted imidazoles have received consid-
erable attention, not only because these heteroaromatic
compounds exhibit a broad range of biological proper-
ties,1–11 such as antifungal activity,1 analgesic activity,2,3
and antiinflammatory activity in inhibiting the release of
p38 MAP kinase and cytokines,4,5 but also because they
are important building blocks found in naturally occurring
compounds. Because of our interest in kinase inhibitors,11
we were interested in developing an efficient synthesis
of (2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-
4-yl-1H-imidazol-1-yl}ethyl)dimethylamine (9), and we
recently reported a synthesis of the title compound
through hydrogenation of its pyridinyl analogue 8
(Scheme 1).12
Scheme 1 Original synthesis of (2-{4-[4-fluoro-3-(trifluorometh-
yl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine
(9)
N
F
N
F3C
N
Me2N
10 (5–6%)
Figure 1 Structure of impurity 10
We were therefore interested in developing a route that
would avoid the use of lachrymator 1 and eliminate the
need for selective alkylation of the imidazole intermediate
6. Here we report an efficient synthesis of the title com-
pound starting from oxoacetic acid monohydrate (11)
(Scheme 2).
Although, this is a practical synthesis, it involves the use
of the lachrymator 1, which requires special handling in
large-scale production. Also, the synthesis of amine 3
from intermediate 2 produces formaldehyde, the handling
of which required special controls with respect to person-
nel exposure and disposal. In addition, alkylation of inter-
mediate 6 results in the formation of isomer 10 (Figure 1),
so that additional purification is required.
A retrosynthetic analysis of the protected intermediate 21
(Scheme 3) revealed that it might be synthesized either by
N-alkylation of amide 23 (path a)11 or by acylation of di-
amine 19 with carboxylic acid 20 (path b). Diamine (19)
could be obtained through reductive amination of keto al-
dehyde 24.13
SYNTHESIS 2013, 45, 1534–1540
Advanced online publication: 16.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338467; Art ID: SS-2013-M0095-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
(2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine
1535
O
HO
Boc
HO
NH
step 2
step 1
HO
N
NMe2
H
O
H2N
+
O
O
*H2O
(Boc)2O
Et3N, MeOH
10% Pd/C
NMe2
12
13
11
NMe2
14
step 3
CDI, MeCN
MeNHOMe·HCl
or morpholine
F3C
F
Br
i-PrMgCl
THF
16
O
O
Boc
N
F3C
MgBr
step 4
THF
F3C
F
NMe2
X
+
N
F
Boc
Me2N
17
18
15a X = N(Me)OMe
15b X = morpholin-4-yl
EtOAc
HCl
Boc
N
NMe2
O
step 5
HO
F
N
O
O
H
N
CF3
O
20
F3C
F
NMe2
CDMT·NMM
step 6
·2HCl
21
N
19
Boc
NH4OAc
EtOH
step 7
step 8
NBoc
F3C
F
1. HCl–EtOH
2. NaOH, H2O
N
N
9
NMe2
22
Scheme 2 Synthesis of (2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine (9) from oxoace-
tic acid monohydrate (11)
O
diate 21 by alkylation of amide 23 with chloro amine 7 in
HN
O
the presence of a powdered mixture of sodium hydroxide,
potassium carbonate and tetrabutylammonium hydrogen
sulfate in toluene or in the presence of sodium hydroxide
or potassium hydroxide in various solvents (Scheme 4).
N-Alkylation of 23 under these conditions led to the for-
mation of complex mixtures of products, possibly as a re-
sult of competing reactions at the methylene group in the
position α to the ketone group.
Me2N
O
a
path a
O
N
N
Boc
23
CF3
F
b
N
Boc
O
21
CF3
F
F3C
F
c
path b
NH
19
powdered NaOH, K2CO3
(n-Bu)4NHSO4, toluene
NMe2
+
NMe2
23
21
+
X
Cl
or
Cl–
powdered KOH or NaOH
DMSO or THF or toluene
7
O
H
F3C
reductive amination
O
F
+
+
3
24
12
X
19
X
7
24
Scheme 4 Attempted syntheses of the protected intermediate 21 and
diamine 19
Scheme 3 Retrosynthetic analysis for the protected intermediate 21
A survey of the literature revealed that N-alkylation of un-
substituted or N-substituted carboxamides with alkyl ha-
lides under basic conditions can be accomplished in good
yields.14–16 We therefore attempted to synthesize interme-
On the basis of a report in the literature,17 we attempted an
alternative synthesis of diamine 19 by reductive amina-
tion on a palladium/carbon catalyst of the imine generated
in situ by condensing keto aldehyde 24 with N,N-dimeth-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1534–1540

1536
R. K. Vaid et al.
PAPER
ylethane-1,2-diamine (12) in methanol, but this was un- are listed in Table 2. On the basis of these results, we syn-
successful. Similarly, attempts to synthesize diamine 19 thesized the protected diamine 18 by using 2.3 equivalents
by direct alkylation of amino ketone 3 with chloro amine of 17 generated in situ.
7 failed.18 Finally, we focused our efforts on synthesizing
diamine 19 from oxoacetic acid hydrate (11; Scheme 2).
We also conducted a second screening study to identify a
suitable acid-activating agent for coupling of acid 20 with
Because the isolated yield of diamino acid 13 was low, we
diamine 19. The results of this study are listed in Table 3.
planned to synthesize this intermediate from oxoacetic
On the basis of these results, we chose 2-chloro-4,6-di-
acid hydrate (11) and diamine 12 by reductive amination
methoxy-1,3,5-triazine (CDMT) for the synthesis of am-
ide 21 by coupling of acid 20 with amine 19 in
tetrahydrofuran.
in the presence of a palladium-on-carbon catalyst and then
to protect the intermediate 13 in situ to obtain the protect-
ed derivative 14 for subsequent use in formation of the ac-
We studied the cyclization of amide 21 by ammonium
tive amide 15. We performed a screening study to identify
acetate to give the imidazole 22 in methanol, ethanol, or
a suitable coupling agent for activation of acid 14, the re-
isopropyl alcohol. The reaction was slow and did not go
sults of which are reported in Table 1.
to completion in refluxing methanol. Solvents ethanol and
isopropyl alcohol gave similar in situ yields of 21. On the
basis of the high solubility of 21 and 9 in ethanol, we de-
The results in Table 1 show that both 1-propanephosphon-
ic acid cyclic anhydride (T3P) and 1,1′-carbonylbis-1H-
imidazole (CDI) gave similar yields of 15a. We therefore
veloped the synthesis of 9 from 21 by using ethanol as a
prepared the active amide 15a by activation of the acid
solvent. Thus, reaction of amide 21 with ammonium ace-
with CDI followed by addition of (methoxyamino)meth-
tate in refluxing ethanol gave an excellent conversion
ane hydrochloride and extractive workup. Similarly, the
(>99%). Solvent exchange with ethanol was performed
active amide 15b was successfully synthesized by activa-
and deprotection of the tert-butoxycarbonyl group was
tion of diamino acid 14 with CDI followed by the addition
completed in ethanol by using concentrated hydrochloric
acid. Concentration of the reaction mixture followed by
of morpholine. Active amides 15a and 15b were not puri-
fied and were used as prepared in the synthesis of aroyl
neutralization with aqueous sodium hydroxide gave the
derivative 18.
desired product 9 in excellent yield and purity. The results
The synthesis of the diamine 19 began with preparation of obtained for the syntheses of 22 and 9 are listed in Table 4.
the arylmagnesium bromide 17 by the reaction of aryl bro-
In conclusion, we have developed an efficient and stream-
lined synthesis of (2-{4-[4-fluoro-3-(trifluoromethyl)phe-
mide 16 with isopropylmagnesium chloride in tetrahydro-
furan.19 Addition of 17 in situ to the activated amide 15 in
nyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethyl-
tetrahydrofuran, subsequent deprotection of the resulting
amine starting from oxoacetic acid monohydrate; this
route avoids the use of a lachrymatory compound and of
diamine 18, and formation of the dihydrochloride salt by
treatment with hydrogen chloride gas in ethyl acetate gave
hexamethyltetramine, and it eliminates the need for N-al-
the required diamine dihydrochloride 19. The effect of the
kylation of an imidazole.
stoichiometry of the aryl bromide 16 was studied to deter-
mine the optimal conditions, and the results of this study
Table 1 Screening of Acid Activating Agents for Synthesis of Intermediate 15a
Entry
1
2
3
4
5
Compound 14 (g) (equiv)
MeNHOMe·HCl (equiv)
Coupling agent (equiv)
2 (1.0)
1.1
2 (1.0)
1.1
2 (1.0)
1.1
259 (1.0)
1.1
274 (1.0)
1.1
T3Pa 1.1
EDCIb (1.5)
HOBtc (1.0)
CDId (1.5)
CDI (1.5)
CDI (1.5)
Solvent
EtOAc
50
THF
30
MeCN
15
MeCN
15
MeCN
18
Temp (°C)
Time (h)
19
15
16
19
18
Yield of 15a (g)
Three-step yield of 15a (%)
2.3
0.78
23.0
2.4
259
68.0
274
69.0
68.0
69.0
a 1-Propanephosphonic acid cyclic anhydride.
b N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride.
c 1H-Benzotriazol-1-ol.
d 1,1′-Carbonylbis-1H-imidazole.
Synthesis 2013, 45, 1534–1540
© Georg Thieme Verlag Stuttgart · New York

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(2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine
1537
Table 2 Synthesis of Compounds 18 and 19: Screening Study of Aryl Bromide Stoichiometry
Quantity of 15 (g) (equiv)
16 (equiv)
4 (1)
1.7
1.7
0.02
30
20 (1)
2.2
100 (1)
2.3
200 (1)
2.3
i-PrMgCl (equiv)
THF (L)
2.2
2.5
2.5
(Step 4)
0.14
30
1.00
30
2.00
30
Temp (°C)
Time (h)
2
6
17
17
EtOAc (L)
0.04
2.3
36
0.20
2.3
1.00
2.3
2.00
2.3
HCl (equiv)
(Step 5)
Two-step yield of 19 (%)
HPLC purity of 19 (%)
45
48
49
98.0
94.0
95.4
96.2
Table 3 Results of a Screening Study of Acid-Activating Agents for the Synthesis of Amide 21
Entry
Coupling agent
(equiv)
Base
(equiv)
Solvent
Conditionsa
Yield (%)
of 21
HPLC purity (%)
of 21
1
2
3
4
5
CDI (1.2)
–
MeCN
THF
A
B
C
C
D
30 °C, 16 h
0
0
T3P (1.5)
NMM (5)
NMM (4)
NMM (4)
NMM (6)
10 °C, 3 h
0 °C, 4 h
0 °C, 4 h
50.0
65.0
56.0
42.0
57.9
72.7
68.0
47.6
i-BuO2CCl (1.0)
i-BuO2CCl (1.0)
CDMTb (1.2)
THF
THF
CH2Cl2
22 °C, 1 h then
–30 °C to 3 °C, 6 h
6
7
CDMT (1.2)
CDMT (1.2)
NMM (6)
NMM (6)
MeCN
THF
D
D
22 °C, 1 h then
–30 °C to 3 °C, 6 h
58.0
78.0
67.1
99.2
22 °C, 1 h then
–30 °C to 3 °C, 6 h
a A = 20 mixed with CDI then added to 19; B = 20 mixed with T3P and NMM; C = 20 mixed with i-BuO2CCl then 19 added, followed by NMM;
D = 20 mixed with CDMT and NMM for 1 h then 19 added.
b CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine.
Table 4 Results for Syntheses of 22 and 9
Synthesisa of 22
Synthesisb of 9
Scale (g) NH4OAc EtOH (L) HPLC areas for 21
HPLC
purity (%)
Concd HCl (mL) HPLC areas for 22
and 9 (%)
HPLC
purity (%)
Yield (%)
(equiv)
20
and 22 (%)
NDc, 99.5
ND, 99.2
ND/ 99.4
5
0.05
1.14
2.15
99.2
99.0
99.4
4.5
ND, 98.7
ND, 98.8
ND, 99.4
99.5
99.0
99.0
90.4
92.9
87.7
114
245
20
103
224
20
a 76–80 °C, 4 h.
b 50–60 °C, 4 h
c ND = not detected.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1534–1540

1538
R. K. Vaid et al.
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1H NMR (400 MHz, DMSO-d6): δ = 1.21 and 1.28 (s, 9 H), 2.02 and
2.03 (s, 6 H), 2.24 (m, 2 H), 2.97 and 2.99 (s, 3 H), 3.13 (m, 2 H),
3.55 and 3.57(s, 3 H), 3.99 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8, 155.24, 79.09, 61.34,
57.75, 57.48, 48.51, 47.98, 45.99, 45.62, 45.59, 32.43, 28.33, 28.30.
HRMS: m/z [M + H]+ calcd for C13H28N3O4: 290.2074; found:
290.2074.
Melting points were measured on a Buchi R-535 apparatus and are
uncorrected. All reagents were purchased from Aldrich and were
used as received without further purification. IR spectra were re-
corded on Shimadzu 100 FTIR and Nicolet Magna 550-FTIR spec-
1
trophotometers. H NMR, 19F NMR, and 13C NMR spectra were
recorded on a Bruker Avance 400-MHz spectrometer. Chemical
shifts (δ) are expressed in ppm downfield relative to TMS (0 ppm).
High-resolution mass spectra were obtained by using a Waters GCT
Premier TOF mass spectrometer with an EI source. Elemental anal-
yses were performed using a Carlo Erba-106 elemental analyzer.
tert-Butyl [2-(Dimethylamino)ethyl](2-morpholin-4-yl-2-oxo-
ethyl)carbamate (15b)
A 2-L round-bottomed flask was charged with product 14 (147.4 g,
0.598 mol), CDI (106.7 g, 0.658 mol) and MeCN (1.2 L) at 10–
15 °C, and the mixture was stirred at 10–15 °C for 2 h. Morpholine
(52.0 g, 0.596 mol) was added, and the mixture was stirred for 3 h.
Analysis of the resulting mixture by LC/MS indicated the presence
of 92.0% of the desired product. The mixture was then concentrated
under vacuum, and H2O (400 mL) was added with stirring. The
aqueous phase was separated and extracted with CH2Cl2 (2 × 300
mL). The organic layers were combined, washed with 27% aq
NH4Cl (2 × 200 mL), dried (Na2SO4), and concentrated to give a
brown oil that was used in next step without further purification;
yield: 108 g (86%); purity: 96.8% (HPLC).
N-[2-(Dimethylamino)ethyl]glycine (13)
A 1-L, three-necked, round-bottomed flask was charged with oxo-
acetic acid hydrate (11; 60.0 g, 0.652 mol) and MeOH (500 mL).
The mixture was stirred at 22 °C for 0.2 h then cooled to 0 °C. N,N-
Dimethylethane-1,2-diamine (12, 57.0 g; 0.646 mol) was added to
the mixture over 0.2 h, and then 10% Pd/C (8.2 g) was added, fol-
lowed by MeOH (10 mL). The mixture was degassed three times
with H2 and then stirred at 24–28 °C for 18 h under an H2-filled bal-
loon. Analysis of the reaction mixture by LC/MS indicated the pres-
ence of the desired product 13. The reaction was stopped and the
soln of 13 was filtered through diatomite and washed with MeOH
(150 mL). The filtered soln of 13 was used without further purifica-
tion in the synthesis of 14; in situ yield (HPLC): 93 g (98%).
IR (neat): 1697, 1647 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.32 and 1.39 (s, 9 H), 2.12 (s,
3 H), 2.13 (s, 3 H), 2.31 (m, 2 H), 3.20 (m, 2 H), 3.41 (m, 4 H), 3.55
(m, 4 H), 4.03 (d, J = 11.9 Hz, 2 H).
N-[2-(Dimethylamino)ethyl]glycine Dihydrochloride (13·2HCl)
A sample of the soln of 13 (15 mL) was concentrated and purified
as the dihydrochloride salt by treatment with concd HCl; mp 202–
213 °C
13C NMR (100 MHz, DMSO-d6): δ = 167.1, 154.9, 78.5, 66.1, 57.1,
IR (KBr): 1720 (sharp) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.80 (s, 6 H), 3.42 (m, 2 H),
48.2, 45.2, 44.5, 41.7, 27.9.
HRMS: m/z [M + H]+ calcd for C15H30N3O4: 316.2231; found:
316.2231.
3.46 (m, 2 H), 3.92 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.60, 51.96, 45.96, 42.33,
41.02.
tert-Butyl [2-(Dimethylamino)ethyl]{2-[4-fluoro-3-(trifluoro-
methyl)phenyl]-2-oxoethyl}carbamate (18)
A 20-L, three-necked, round-bottomed flask was charged with 4-
bromo-1-fluoro-2-(trifluoromethyl)benzene (1.0 L, 4.1 mol) and
THF (6.0 L) under an inert atmosphere, and the mixture was stirred
for 0.5 h at 10–23 °C. A 1.3 M soln of i-PrMgCl in THF (3.18 L; 4.1
mol) was added at 10–23 °C and the mixture was then stirred for 2
h at 10–23 °C. The formation of the Grignard reagent was moni-
tored by GC/MS analysis of a sample of the soln of the Grignard re-
agent quenched with a soln of PhCHO in MeCN. A soln of the
active amide 15a (474.6 g, 1.6 mol) or 15b (620 g, 1.6 mol) in THF
(1 L) was added dropwise over 0.5 h to the soln of the Grignard re-
agent at 23–30 °C, and then the resulting mixture was stirred for 3
h until no starting material was detected by LC/MS. H2O (2.0 L)
was added and the mixture was stirred at 23 °C for 0.5 h. The sol-
vent was evaporated, the residue was dissolved in 18% aq NH4Cl
(4.0 L), and the mixture was extracted with EtOAc (2 × 2.25 L). The
organic layers were combined, washed with H2O (2 × 1.25 L), dried
(Na2SO4), and concentrated under vacuum to give a brown oil that
was used as such in next step without further purification; yield: 625
g (97%).
1H NMR (400 MHz, DMSO-d6): δ = 1.25 and 1.42 (s, 9 H), 2.73 (s,
3 H), 2.74 (s, 3 H), 3.18 (m, 2 H), 3.61 (m, 2 H), 4.88 (s, 2 H), 7.75
(t, J = 10.1 Hz, 1 H), 8.35 (m, 1 H), 8.40 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): 193.96, 162.13 (d, J = 263.4 Hz),
155.34, 135.93, 132.19, 127.65, 122.61 (q, J = 272.8 Hz), 118.56,
80.56, 80.09, 54.87, 54.57, 54.18, 43.32, 43.08, 42.61, 28.34, 28.14.
19F NMR (376 MHz, DMSO-d6): δ = –60.39, –108.46.
HRMS: m/z [M]+ calcd for C18H24F4N2O3: 392.1723; found:
N-(tert-Butoxycarbonyl)-N-[2-(dimethylamino)ethyl]glycine
(14)
A three-necked round-bottomed flask was charged with the soln of
13 (95.3 g, 0.650 mol) and MeOH (600 mL), and the mixture was
stirred for 0.2 h at 10 °C. Et3N (132.0 g, 1.3 mol) followed by di-
tert-butyl dicarbonate (142.2 g, 0.652 mol) were added over 0.5 h
and the mixture was stirred for 2 h. Analysis of the mixture by
LC/MS indicated consumption of the starting material and forma-
tion of the desired product. The mixture was then concentrated to
dryness under vacuum at 45 °C, and toluene (200 mL) was added.
The mixture was again concentrated under vacuum at 50–55 °C to
give a brown oil that was used in the synthesis of 15a or 15b without
further purification; yield: 147 g (92% based upon HPLC purity);
purity: 96.0% (HPLC).
tert-Butyl [2-(Dimethylamino)ethyl]{2-[methoxy(methyl)ami-
no]-2-oxoethyl}carbamate (15a)
Product 14 (550 g, 2.2 mol) and MeCN (2.75 L) were placed in a
dry, three-necked, round-bottomed flask at 15–25 °C. The mixture
was cooled to 10–15 °C, CDI (542.5 g, 3.4 mol) was added over 0.2
h under N2, and the mixture was stirred at r.t. for 1 h.
MeNHOMe·HCl (326.5 g, 3.4 mol) was added under N2 and the
mixture was stirred at 10–15 °C for 21 h. The mixture was then con-
centrated under reduced pressure at 50–55 °C. H2O (3.4 L) was add-
ed to dissolve the residue, followed by EtOAc (2.8 L). The resulting
mixture was stirred at 15–35 °C for 1 h, then the aqueous layer was
separated and the EtOAc layer was discarded. The aqueous layer
was washed with EtOAc (2.8 L) then extracted with CH2Cl2 (3 × 3.4
L). The organic layers were combined, dried (Na2SO4), filtered, and
concentrated under vacuum to give a yellow oil that was used in
next step without further purification; yield: 791 g (87%); purity:
96.0% (HPLC).
392.1728.
2-{[2-(Dimethylamino)ethyl]amino}-1-[4-fluoro-3-(trifluoro-
methyl)phenyl]ethanone Dihydrochloride (19)
A 5-L round-bottomed flask was charged with carbamate 18 (625 g,
1.593 mol) and EtOAc (1.25 L), and the mixture was stirred and
IR (neat): 1697, 1684 cm–1.
Synthesis 2013, 45, 1534–1540
© Georg Thieme Verlag Stuttgart · New York

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(2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine
1539
cooled to 4–6 °C. A 4.44 M soln of HCl gas in EtOAc (3.5 L, 15.5
mol) was added at 5 °C, and the mixture was warmed to r.t. and
stirred for 3 h. The resulting slurry was cooled to 10 °C and stirred
at 10 °C for 2 h to give an off-white slurry. The product was recov-
ered by filtration, washed with EtOAc (1.5 L), and dried in a vacu-
um oven at 50 °C; yield: 304 g (52%); purity: 95.4% (HPLC); mp
125–127 °C.
L) was then added and the mixture was stirred for a further 0.5 h
then transferred to a 5-L separatory funnel. The EtOAc layer was
separated and the aqueous layer was extracted with EtOAc (1.4 L).
The organic layers were combined and concentrated under vacuum
at 45 °C. EtOH (780 mL) was added and the mixture was stirred for
5 min. Concd aq HCl (220 mL; 2.7 mol) was added dropwise over
0.5 h at r.t. and the resulting mixture was heated to 50–55 °C for 4
h until analysis by HPLC indicated consumption of the starting ma-
terial and the presence of 99.37% of the desired product. H2O (480
mL) was added and the soln was transferred to a dropping funnel
and added over 3 h to a 5-L, three-necked, round-bottomed flask
charged with 5 M aq NaOH (750 mL) and H2O (2.08 L) while the
temperature was maintained at 0–5 °C. During the initial addition,
a pale-yellow slurry formed and after complete addition, a slurry
was obtained; the pH of the final reaction mixture was 11. The prod-
uct was recovered by filtration, washed with H2O (1.2 L), and dried
under vacuum at 50 °C for 72 h to give a white solid; yield: 149 g
(88%); purity: 99.0% (HPLC); mp 92–93 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.70 (m, 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), 3.15 (br s,
1 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 (100 MHz, DMSO-d6): δ = 32.32, 33.59, 43.08, 45.30,
46.08, 59.45, 116.38, 117.41, 121.75, 124.15, 129.88, 129.96,
132.11, 132.15, 135.91, 152.21, 155.72, 158.19.
IR (KBr): 3393 (br), 1701 (sharp) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.83 (s, 6 H), 3.47 (m, 2 H),
3.57 (m, 2 H), 4.97 (s, 2 H), 7.81 (t, J = 9.7 Hz, 1 H), 8.18 (m, 1 H),
8.23 (d, J = 6.6 Hz, 1 H), 10.07 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 190.33, 163.83, 162.52 (d,
J = 263.4 Hz), 136.11, 136.06, 130.99, 130.96, 128.18, 121.72 (q,
J = 272.6 Hz), 118.80, 118.57, 52.70, 52.39, 42.73, 41.60.
19F NMR (376 MHz, DMSO-d6): δ = –60.41, –107.03.
Anal. Calcd for C13H18Cl2F4N2O: C, 42.76; H, 4.97; Cl, 19.42; F,
20.81; N, 7.67. Found: C, 42.74; H, 4.93; Cl, 19.40; F, 20.81; N,
7.64.
tert-Butyl 4-[([2-(dimethylamino)ethyl]{2-[4-fluoro-3-(trifluo-
romethyl)phenyl]-2-oxoethyl}amino)carbonyl]piperidine-1-
carboxylate (21)
A three-necked, 2-L, round-bottomed flask was charged with acid
20 (62.8 g, 0.27 mole) and THF (1 L). The mixture was cooled to
0–5 °C and CDMT (48.1 g, 0.27 mole) was added, followed by
NMM (41.5 g, 0.41 mole) added dropwise over 0.4 h. The mixture
was then warmed to r.t., stirred at 20–30 °C for 3 h, and cooled to
–30 °C. Diamine 19 (100 g, 0.27 mol) was added followed by drop-
wise addition of NMM (83.1 g, 0.822 mole) over 0.2 h. The mixture
was then slowly warmed to 10–15 °C and stirred for 18 h, when a
sample drawn for HPLC analysis showed the presence of 0.3% of
18 and 92.2% of the desired product 21. The mixture was then con-
centrated to 1–2 volumes under reduced pressure at 40–50 °C and
the residue was dissolved in CH2Cl2 (600 mL). H2O (500 mL) and
7% aq NaHCO3 (500 mL) were added, and the mixture was stirred
for 0.5 h. The organic layer was separated, washed with 7% aq
NaHCO3 (1.0 L), transferred to a flask, and concentrated to 1–2 vol-
umes. EtOAc (200 mL) was added and the mixture was concentrat-
ed to 1–2 volumes under reduced pressure at 30–50 °C to give the
crude product that was dissolved in EtOAc (500 mL) at 70–80 °C.
Slow dropwise addition of heptane (500 mL) gave a slurry that was
cooled to 0–5 °C over 2 h. The product was then collected by filtra-
tion and dried under vacuum at 55 °C; yield: 114 g (78%); purity:
99.2% (HPLC); mp 146–151 °C.
19 F NMR (376 MHz, DMSO-d6): δ = –60.0, –120.6.
HRMS: m/z [M + H]+ calcd for C19H25F4N4: 385.2009; found:
385.2010.
Acknowledgment
We are grateful to Dr. Mike Fogarty for providing analytical data
and to Professors M. Miller and W. Roush for thoughtful discussion
and valuable suggestions.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2013, 45, 1534–1540
© Georg Thieme Verlag Stuttgart · New York