Stereoselective synthesis of novel pyrazole derivatives using tert-butansulfonamide as a chiral auxiliary

Article abstract of DOI:10.1039/c2ob06495b

A novel chiral pyrazole derivative was developed by our research program as a potent PDE4 inhibitor for the treatment of anti-inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. The asymmetric synthesis of the inhibitors carrying the pyrazole moiety, including nitrogen directly bonded to a chiral center, through a novel approach is disclosed. The key steps of the synthetic sequence begin with the preparation of chiral toluenesulfinyl imine by the condensation of (R)- and (S)-tert-butanesulfinamide with an aldehyde. Next, a corresponding chiral amine synthesis by a stereoselective addition reaction of 4-picolyl lithium to the chiral toluenesulfinyl imine is performed, followed by desulfination. The preparation of the cis-type enaminone from the addition of the enaminone to the corresponding chiral amine is then accomplished, with further transformation into the pyrazole derivatives through the amination of the enaminones and subsequent dehydro-cyclization. A total of 8 steps are completed to produce a 5.5% yield (100% ee). The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06495b

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PAPER
Stereoselective synthesis of novel pyrazole derivatives using
tert-butansulfonamide as a chiral auxiliary†
Chang Min Park and Dong Ju Jeon*
Received 1st September 2011, Accepted 18th January 2012
DOI: 10.1039/c2ob06495b
A novel chiral pyrazole derivative was developed by our research program as a potent PDE4 inhibitor for
the treatment of anti-inflammatory diseases, such as asthma and chronic obstructive pulmonary disease.
The asymmetric synthesis of the inhibitors carrying the pyrazole moiety, including nitrogen directly
bonded to a chiral center, through a novel approach is disclosed. The key steps of the synthetic sequence
begin with the preparation of chiral toluenesulfinyl imine by the condensation of (R)- and (S)-tert-
butanesulfinamide with an aldehyde. Next, a corresponding chiral amine synthesis by a stereoselective
addition reaction of 4-picolyl lithium to the chiral toluenesulfinyl imine is performed, followed by
desulfination. The preparation of the cis-type enaminone from the addition of the enaminone to the
corresponding chiral amine is then accomplished, with further transformation into the pyrazole derivatives
through the amination of the enaminones and subsequent dehydro-cyclization. A total of 8 steps are
completed to produce a 5.5% yield (100% ee).
type enamine synthesis of the amines. Further transformations
1. Introduction
were performed to give the pyrazole derivatives through the
amination of the enamines and subsequent dehydro-cyclization.
We report the synthetic procedure of racemic 1 and the asym-
metric synthesis of chiral pyrazoles 1R and 1S.8
Phosphodiesterase (PDE), a member of the cyclic nucleotide
phosphodiesterase family, is responsible for the hydrolysis of
cAMP and cGMP. Within the diverse group of PDE isozymes,
PDE4 is a cAMP-specific isoenzyme. cAMP is an important
intracellular secondary messenger in cellular functions that
relays the signals from hormones at specific cell-surface recep-
tors.1 An increase in cAMP due to the stimulation of adenylyl
cyclase or the inhibition of PDEs affects the activity of the
immune system and inflammatory cells.2 Therefore, PDE4 has
received considerable attention as a new drug target for the treat-
ment of inflammatory diseases, such as asthma and chronic
obstructive pulmonary disease.3
During our research program for the development of PDE4
inhibitors,4 compound 1 was identified as a potent PDE4 inhibi-
tor (IC50 = 0.5 nM, Fig. 1).5 The enantiomers of 1 could be sep-
arated by preparative chiral HPLC,6 and the IC50 values toward
PDE4 inhibition were evaluated as 5 nM (1R) and 0.5 nM (1S).
To obtain large amounts of the enantiomers for an in vivo study
in an asthma animal model, we developed an asymmetrical syn-
thetic method for 1R and 1S through a route that included the
preparation of the corresponding chiral amines using (R)- and
(S)-tert-butanesulfinamide as a chiral auxiliary7 followed by cis-
2. Results and discussion
2.1. Synthesis of racemic 1
Synthesis of racemic compound 1 was achieved via Michael
addition of the pyrazole anion to enone 3 using conventional
synthetic procedures, as shown in Scheme 1. Compound 2 was
prepared from 3,4-dihydroxybenzaldehyde, as reported in the lit-
erature.9 Michael adduct 3 was obtained by the condensation of
2 and pyridine-4-yl acetic acid ethyl ester with CH3CO2NH4 by
refluxing in acetic acid for 2 days. Because the Michael addition
Bio-Organic Science Division, Korea Research Institute of Chemical
Technology, P.O. Box 9, Sinseongro, Yuseong, Daejeon 305-600, Korea.
E-mail: djjeon@krict.re.kr
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob06495b
Fig. 1 PDE4 inhibitor structures for 1, 1R and 1S.
Org. Biomol. Chem., 2012, 10, 2613–2620 | 2613
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Scheme 1 Synthesis of racemic 1.
reaction of the pyrazole anion has not been previously reported
in the literature, diverse reaction conditions, including such
bases as LDA, triethylamine, NaH, K2CO3, and Cs2CO3, were
attempted. Only the reaction with LDA afforded the desired
product. Although this reaction proceeded non-stereoselectively,
and the products formed as nearly 1 : 1 cis : trans isomers, the
isomeric mixture was not separated. The products were hydro-
lyzed in situ using LiOH in MeOH–H2O mixed solvent at room
temperature, and the subsequent decarboxylation of the car-
boxylic acid proceeded using dilute hydrogen chloride water sol-
ution to give 4 in two steps with a 37% yield.
The reduction of the nitro group in 4 by a hydrogenation reac-
tion using palladium catalyst was performed to give 5 with a
yield of 72%. This reaction was followed by acylation of the
amino group using acetic anhydride to give 6 with an 81% yield.
Compound 1 was obtained in 77% yield by the oxidation of the
pyridine moiety of 1 with m-CPBA. Compound 1 represents the
potent PDE4 inhibitor (PDE4, IC50 = 0.5 nM).
Fig. 2 X-ray co-crystal structure of 1S and the PDE4 enzyme.
2.2. Synthesis of chiral 1S and 1R
retrosynthetic analysis (Fig. 3), the pyrazole derivative was
obtained from N-amination of the cis-type enaminone derived
from the addition of the enamine to the corresponding chiral
amine, generated from the addition reaction of 4-picolyl lithium
to a chiral sulfinimine, which could be prepared by the conden-
sation of the chiral sulfonamide with 3-nitrobenzaldehyde. First,
the (R)-N-p-toluenesulfinyl group was selected as a chiral auxili-
ary to prepare (R)-N-p-toluenesulfinyl imine (7) by condensation
with aldehyde 2. This reaction led to chiral sulfonamide 8 by the
reaction of 4-picolyl lithium with 7, as shown in Scheme 2.12
(R)-N-p-Toluenesulfinyl imine (7) was synthesized through the
reaction of menthyl p-toluenesulfinate with LiHMDS to give
(R)-N-p-toluenesulfinamide; the subsequent dehydration reaction
of this sulfinamide with aldehyde 2 is a known procedure.
When 4-picolyl lithium reacted with imine 7 at −78 °C in THF,
chiral sulfonamide 8a was yielded preferentially to 8b with
good selectivity (60% yield, 80% de). The diastereoselectivity
of this reaction was not consistent with the closed transition
state. However, an anti-Ellman’s model that suggests rapid E/Z
isomerization of the imine has been proposed in which the
coordination of lithium ion to the catechol part of substrate 8a
1R and 1S, which are enantiomers of 1, were separated by chiral
prep-HPLC, and the inhibitory activities were determined,
showing that 1S (IC50 = 0.5 nM) is more active than 1R (IC50
=
5 nM) against the PDE4 enzyme. The absolute configurations of
these compounds were elucidated by the 1 : 1 X-ray co-crystal
structure of 1S and the PDE4 enzyme (Fig. 2; PDB ID code:
3V9B). In this structure, the pyridine-N-oxide of 1S interacted
with Mg, mediated by water, present in the PDE4 enzyme.
Moreover, the pyridine-N-oxide of 1R was slightly more distant
than that of 1S, as determined from the calculation model.10
Therefore, the inhibitory activity of 1R is probably weaker than
that of 1S.
To obtain large amounts of the enantiomers for an in vivo
study, we developed the asymmetrical synthesis of 1R and 1S. A
novel synthetic procedure for the enantiomers (1R, 1S) needed
to be designed because the preparation of these compounds
using the synthetic method for racemic compound 1 would be
difficult. The structures of 1R and 1S contain the pyrazole
moiety directly bonded to a chiral center.11 The synthesis of this
type of compound has not been previously reported. Using
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Fig. 3 Retrosynthesis of chiral pyrazoles 1S and 1R.
Scheme 2 Synthesis of chiral N-p-toluenesulfinyl imine from chiral methyl p-toluenesulfinate and 4-picolyl lithium by an addition reaction to
imine 7.
Table 1 The stereoselective addition of a metal carbanion to (S)-N-
tert-butanesulfiniminesa
Fig. 4 Two proposed transition states for the reaction between sulfini-
mine and 4-picolyl lithium.
N-Sulfinamide
No.
Imine
RM
10a : 10b
Yieldb (%)
% dec
would play a major role, as proposed by Barrow et al. and
shown in Fig. 4.13
1
2
3
4
9S
9S
9S
9R
MeMgBr
MeLi
PyMeLi
PyMeLi
—
—
1 : 0
0 : 1
80
92
83
82
80
40
100
100
Second, for the purpose of better diastereoselectivity and
yield, we investigated tert-butanesulfinamide as a chiral auxili-
ary. (R)- and (S)-N-tert-butanesulfinamide were condensed with
aldehyde 2 using titanium tetraethoxide as an additive in THF to
generate (R)- and (S)-N-tert-butanesulfinimides 9R and 9S in
good yields, as shown in Table 1. The synthesis of chiral amines
through the addition of organometallic reagents to chiral tert-
butanesulfinamide was studied by Ellman et al.13a This group
demonstrated that chiral amines could be prepared in high yields
with good diastereoselectivity from the reaction of a chiral tert-
butanesulfinamide with diverse organometallic reagents. Taking
into account the reported results, we investigated the addition
reaction of methyllithium and methylmagnesium bromide to (S)-
N-tert-butanesulfinimide 9S in THF. Low diastereoselectivity
(40% de) was observed with methyllithium in good yield, and
a Typical reaction conditions: 9R (7.5 mmol), PyMeLi (11.2 mmol),
−78 °C, 3 h in THF. b Isolated yields. c Chiral HPLC analysis
(CHIRALCEL OD, 0.46 × 25 cm (DAICEL)). A mobile phase of 10%
IPA–n-hexane was passed through the column at 0.8 mL min−1
.
methylmagnesium bromide gave the optimized diastereoselectiv-
ity in 80% de, as listed in Table 1. We did not identify the rela-
tive isomeric structure of the diastereomer.
Surprisingly, the addition reaction of 4-picolyl lithium to 9R
and 9S proceeded with high diastereoselectivity and led to pure
10a or 10b (100% de) in good yield. Two transition states for
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Scheme 3 Synthetic method for 1R from chiral sulfonamide.
the addition reaction of a carbanion to butanesulfinimines have
3. Experimental section
been postulated, as shown in Fig. 4. The anti-Ellman models of
the two transition states are known for a favored transition state
in which the coordination of the lithium ion to the catechol
portion of 9 would be a critical factor, as proposed by Barrow
et al.13 However, the reason for 4-picolyl lithium leading to
extraordinarily high diastereoselectivity relative to that produced
by methyllithium remains unclear. The sulfinyl group of 10R
was eliminated to give chiral amine 11R by treatment with 4 N
HCl solution in dioxane at 0 °C in 93% yield (Scheme 3). This
reaction was followed by coupling with 3-dimethylamino-1-(3-
nitrophenyl)propene to produce the cis-type enamine 12R in
84% yield.14 This type of enamine has been known to be stabil-
ized by hydrogen bonding of the NH to the carbonyl group, and
we confirmed that 12R is the cis-type enamine by characteristic
1H NMR (olefinic proton, δ 5.7, J = 7.5 Hz).
Diverse N-amination methods to yield amines have been pre-
viously reported.15 However, cis-type enamine 12R was inert to
several amination reagents, such as N-Boc-oxaziridines, O-
(mesitylenesulfonyl)hydroxylamine, and tert-butylnitrite. This
enamine was only aminated by O-(p-nitrobenzoyl)hydroxyl
amine and was followed with in situ thermal dehydrocyclization
to produce pyrazole 13R at 100 °C in DMF in 47% yield.
Reduction of the nitro group in 13R by a hydrogenation reaction
using palladium catalyst proceeded and was followed by acyla-
tion of the amino group using acetic anhydride to generate 15R
in 93% yield. Compound 1R was obtained by the oxidation of
the pyridine moiety of 15R using mCPBA in 88% yield. 1S was
prepared by the same synthetic method as that described for
compound 1R.
General methods
1H NMR and 13C NMR were recorded on Varian Gemini 200
(200 MHz 1H) and 500 (500 MHz 1H) spectrometers and a
Bruker AM-300 spectrometer (13C). Tetramethylsilane was used
as an internal standard. IR spectra were recorded on a Travel IR
Portable (ATR-FT IR Spectrometer System, Sens IR) spec-
trometer. Peaks are reported in units of cm−1. Mass spectra
(LMS) were recorded on a JEOL JMS-01 mass spectrometer,
and HRMS were recorded on an Autospec Mass DX-300 mass
spectrometer (Micromass) under electron-impact (EI) conditions.
Optical rotations were recorded on Rudolph Autopol III (Auto-
matic polarimeter) in the solvent indicated. Analytical HPLC
was performed on a Jasco 880-PU Intelligent HPLC pump or a
Jasco BIPP-1 HPLC pump equipped with a Jasco UVDEC-100-
IV UV spectrometer or a Jasco UVDEC-100-UVV spectrometer.
The columns used for this study included a Waters Optipak-XC,
a Daicel OD-H, and a Daicel AD. Reactions were monitored by
thin-layer chromatography performed on 0.25 mm Merck silica-
gel plates (60F-254), which were imaged with UV light, ethano-
lic phosphomolybdic acid, or p-anisaldehyde and heat as the
developing agent. Melting points were determined on a Buchi
510 melting-point apparatus and are uncorrected. Solvents were
distilled before use. In anhydrous reactions, THF, ether, DME,
and toluene were distilled from sodium metal benzophenone
ketyl.
Synthesis of chiral N-(3-{1-[1-(3-cyclopropylmethoxy-4-
difluoromethoxyphenyl)-2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazol-
3-yl}phenyl)acetamide (1)
In summary, we discovered a potent PDE4 inhibitor that
includes a pyrazole moiety directly bonded to a chiral center. We
studied the synthesis of racemic 1 and of chiral 1S and 1R using
chiral tert-butanesulfinamide as a chiral auxiliary using a novel
approach.
(R)-4-Methylbenzenesulfinic acid 3-cyclopropylmethoxy-4-
difluoromethoxybenzylideneamide (7). To a stirred solution of
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(1S,2R,5S)-menthyl-(R)-p-toluenesulfinate (2.0 g, 8.2 mmol) in
THF was added LiHMDS (11 mL, 11.5 mmol) dropwise at
−78 °C and the reaction mixture was stirred for 2 h at 0 °C. 2
(2.0 g, 8.2 mmol) solution in THF was added dropwise to the
reaction mixture at 0 °C and it was stirred for 12 h at room temp-
erature. The reaction mixture was quenched with saturated
aqueous NH4Cl, diluted with ethyl acetate (100 mL) and washed
with water and brine. The organic phase was dried over mag-
nesium sulfate, filtered, and concentrated in vacuo. The crude
mixture was purified by silica gel column chromatography (n-
hexane–EA, 4 : 1) to give 7 (3.0 g, 95.8%).
with saturated aqueous NH4Cl, diluted with ethyl acetate
(100 mL) and washed with water and brine. The organic phase
was dried over magnesium sulfate, filtered, and concentrated in
vacuo. The crude mixture was purified by silica gel column
chromatography (n-hexane–EA, 2 : 1) to give 10R (2.78 g,
82%).
[α]2D3 −30.0° (c 0.025, EtOH); IR (neat) vmax 3206, 2955,
2927, 2871, 1735, 1602, 1562, 1509, 1467, 1413, 1386, 1215,
1116, 1045, 915, 835, 730 cm−1; 1H NMR (500 MHz, CDCl3) δ
8.42–8.41 (2H, m, Ar), 7.08 (1H, d, J = 8.2 Hz, Ar), 6.97–6.96
(2H, m, Ar), 6.85–6.83 (1H, m, Ar), 6.80 (1H, d, J = 1.9 Hz,
Ar), 6.60 (1H, t, J = 75.4 Hz, –CHF2), 4.58 (1H, d, J = 4.6 Hz,
–CH–), 3.76 (2H, d, J = 6.9 Hz, –OCH2–), 3.73 (1H, d, J = 4.6
Hz, –NH–), 3.29–3.25 (1H, m, dd, –CH2–), 3.01–2.97 (1H, m,
dd, –CH2), 1.18–1.15 (1H, m, –CH–), 1.15 (9H, s, –CH3, –CH3,
–CH3), 0.61–0.59 (1H, m, –CH2–), 0.32–0.31 (1H, m, –CH2–);
13C NMR (500 MHz, CDCl3) δ 150.4, 149.6, 146.4, 140.1,
139.7, 124.9, 122.7, 119.3, 118.2, 116.1, 114.1, 113.8, 73.8,
59.8, 56.1, 42.7, 22.5, 10.0, 3.1; MS m/z (%) 438 (M+, 40), 391
(11), 383 (92), 346 (37), 320 (80), 291 (77), 288 (75), 265
(100), 242 (80), 213 (72), 188 (97), 166 (77), 147 (83), 141
(25), 106 (68), 92 (42), 56 (49); HRMS calcd for
C22H28F2N2O3S: 438.1789, found: 438.1782.
1H NMR (500 MHz, CDCl3) δ 8.67 (1H, s, –CH), 7.63–7.59
(2H, m, Ar), 7.45 (1H, s, Ar), 7.34–7.08 (4H, m, Ar), 6.70 (1H,
t, J = 72.5 Hz, –CHF2), 3.87 (2H, d, J = 7.2 Hz, –OCH2–), 2.34
(3H, s, –CH3), 1.25–1.23 (1H, m, –CH–), 0.63–0.59 (2H, m,
–CH2–), 0.34–0.32 (2H, m, –CH2–); MS m/z (%) 379 (M+, 1)
331 (1), 140 (20), 138 (100), 118 (2), 92 (4), 91 (8), 78 (1), 77
(4), 65 (2). 243 (6), 242 (11), 212 (2), 188 (5) 167 (5), 150 (6),
147 (7), 141 (60, 138 (100), 110 (1), 93 (42), 91 (8), 65 (3),
55 (23).
(R)-2-Methylpropane-2-sulfinic acid 3-cyclopropylmethoxy-4-
difluoromethoxylbenzylideneamide (9R). To a stirred solution of
2 (2.0 g, 8.2 mmol) in THF was added Ti(OEt)4 (37.0 g,
33.0 mmol), followed by dropwise (R)-2-methyl-2-propanesulfi-
namide (1.0 g, 8.2 mmol). The reaction mixture was stirred for
12 h at rt. The reaction solution was quenched with saturated
aqueous NH4Cl, diluted with ethyl acetate and washed water and
brine. The organic phase was dried over magnesium sulfate,
filtered, and concentrated in vacuo. The crude mixture was
purified by silica gel column chromatography (n-hexane–EA,
5 : 1) to give 9R (2.85 g, 99.8%).
(S,S)-2-Methylpropane-2-sulfinic acid [1-(3-cyclopropyl-
methoxy-4-difluoromethoxyphenyl)-2-pyridin-4-yl-ethyl]amide
(10S). Prepared as described for compound 10R (8.2 mmol
scale, 83% yield).
[α]2D3 +30.6° (c 0.025, EtOH); IR (neat) vmax 3207, 3078,
2956, 2872, 2358, 2228, 1602, 1563, 1509, 1467, 1413, 1386,
1
1270, 1215, 1116 cm−1; H NMR (200 MHz, CDCl3) δ 8.67
(1H, s, –CH), 7.63–7.59 (2H, m, Ar), 7.45 (1H, s, Ar) 7.34–7.08
(3H, m, Ar), 6.70 (1H, t, J = 72.4 Hz, –CHF2), 3.87 (2H, d, J =
7.2 Hz, –OCH2–), 2.35 (3H, s, –CH3) 1.25–1.23 (1H, m,
–CH–), 0.63–0.59 (1H, m, –CH2–), 0.34–0.32 (1H, m, –CH2–);
13C NMR (500 MHz, CDCl3) δ 150.5, 149.7, 146,4, 140.1,
139.7, 124.9, 122.8, 119.3, 118.2, 116.2, 114.1, 113.9, 73.9,
59.8, 56.2, 42.7, 22.5, 10.1, 3.2; MS m/z (%) 438 (M+, 8), 391
(3), 382 (58), 346 (5), 319 (80), 289 (80), 240 (35), 235 (15),
187 (17), 167 (35), 149 (30), 94 (70), 55 (100); HRMS calcd for
C22H28F2N2O3S: 438.1789, found: 438.1783.
[α]2D3 +204.6° (c 0.025, EtOH); IR (neat) vmax 3085, 3013,
2983, 2901, 2873, 1737, 1598 1580, 1509, 1430, 1270, 1111,
1077, 1047, 1024, 1008, 906.3 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 8.50 (1H, s, –NCH), 7.47 (1H, d, J = 1.8 Hz, Ar),
7.41–7.39 (1H, m, Ar), 7.27–7.25 (1H, m, Ar), 6.72 (1H, t, J =
74.9 Hz, –CHF2), 3.95 (2H, d, J = 6.9 Hz, –OCH2–), 1.32–1.27
(1H, m, –CH–), 1.26 (9H, s, 3 –CH3), 0.69–0.66 (2H, m,
–CH2–), 0.41–0.38 (2H, m, –CH2–); 13C NMR (500 MHz,
CDCl3) δ 161.6, 150.8, 132.3, 123.4, 122.5, 117.8, 115.8, 113.7,
74.0, 57.9, 22.6, 10.0, 3.2; MS m/z (%) 289 (M+, 98), 288 (5),
272 (4), 241 (20), 240 (22), 212 (7), 187 (11), 184 (5), 167 (8),
149 (3), 97 (2), 84 (7), 71 (4), 55 (90); HRMS calcd for
C16H21F2NO3S: 345.1210, found: 345.1213.
(R)-1-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-
pyridin-4-ylethylamine (11R). 4N-HCl (4.1 mL, 16.4 mmol)
was added slowly to a solution of 10R (1.8 g, 4.1 mmol) in
dioxane at 0 °C. After 5 min, the cooling bath was removed. The
reaction was allowed to ambient temperature and stirred for 4 h.
The solid formed during the reaction was filtered up and added
to saturated aqueous NaHCO3, extracted with ethyl acetate. The
organic phase was washed with brine, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The crude mixture
was purified by silica gel column chromatography (CH2Cl2–
MeOH, 20 : 1) to give 11R (1.2 g, 93.6%).
(S)-2-Methylpropane-2-sulfinic acid 3-cyclopropylmethoxy-4-
difluoromethoxylbenzylideneamide (9S). Prepared as described
for compound 9R (8.2 mmol scale, 98.8% yield).
[α]2D3 −206.0° (c 0.025, EtOH); All spectra were identical to
those of compound 9R.
(R,R)-2-Methylpropane-2-sulfinic
methoxy-4-difluoromethoxyphenyl)-2-pyridin-4-yl-ethyl]amide
(10R). To stirred solution of 4-methylpyridine (1.1 g,
acid
[1-(3-cyclopropyl-
a
[α]2D3 −316.8° (c 0.03, EtOH); IR (neat) vmax 3073, 3016,
2926, 2874, 1734, 1666, 1600, 1562, 1506, 1469, 1422, 1411,
11.2 mmol) in THF was added n-BuLi (6.1 mL, 9.8 mmol)
dropwise at −78 °C and the reaction mixture was stirred for
0.5 h at 0 °C. After cooling to −78 °C, 9R (2.6 g, 7.5 mmol) sol-
ution in THF was added dropwise to the reaction mixture and
stirred for 3 h at −78 °C. The reaction solution was quenched
1380, 1269, 1207, 1112, 1016 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 8.48 (2H, d, J = 5.8 Hz, Ar), 7.10 (1H, d, J = 8.2 Hz,
Ar), 7.06–7.05 (2H, m, Ar), 6.91 (1H, d, J = 1.9 Hz, Ar),
6.86–6.84 (1H, m, Ar), 6.61 (1H, t, J = 75.6 Hz, –CHF2),
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4.21–4.18 (1H, m, –CH–), 3.84 (2H, d, J = 3.6 Hz, –OCH2–),
2.93–2.90 (1H, m, dd, –CH2–), 2.84–2.81 (1H, m, dd, –CH2),
1.68 (2H, s, –NH2), 1.24–1.20 (1H, m, –CH–), 0.64–0.61 (1H,
m, –CH2–), 0.35–0.33(1H, m, –CH2–); 13C NMR (500 MHz,
CDCl3) δ 150.5, 149.7, 147,6, 143.4, 139.5, 124.6, 122.6, 118.9,
116.2, 112.4, 73.9, 56.5, 45.7, 10.1, 3.1; MS m/z (%) 334 (M+,
12), 306 (7), 296 (60), 268 (60), 243 (100), 242 (45), 214 (22),
188 (80), 168 (25), 147 (87), 121 (48), 107 (40), 88 (70) 57
(55); HRMS calcd for C18H20F2N2O2: 334.1493, found:
334.1486.
(0.9 g, 4.2 mmol) was added slowly to the reaction mixture and
stirred for 3 h at 0 °C, followed by heating for 10 min. The reac-
tion was allowed to cool to ambient temperature and was
quenched with saturated aqueous NH4Cl, diluted with ethyl
acetate and washed with water and brine. The organic phase was
dried over magnesium sulfate, filtered, and concentrated in
vacuo. The crude mixture was purified by silica gel column
chromatography (n-hexane–EA, 1 : 2) to give 13R (0.5 g,
47.4%).
[α]2D3 −191.0° (c 0.015, EtOH); IR (neat) νmax 3078, 3017,
2927, 1732, 1602, 1531, 1512, 1432, 1411, 1379, 1346, 1215,
1115, 1047, 1019, 907, 862, 808, 763, 732, 673 cm−1; 1H NMR
(500 MHz, CDCl3) δ 8.70–8.69 (1H, m, Ar), 8.45 (2H, d, J =
5.7 Hz, Ar), 8.17–8.15 (1H, m, Ar), 8.13 (1H, d, J = 7.8 Hz,
Ar), 7.59–7.56 (1H, m, Ar), 7.34 (1H, d, J = 2.3 Hz, Ar), 7.13
(1H, d, J = 8.2 Hz, Ar), 7.08 (1H, d, J = 1.9 Hz, Ar), 6.99 (2H,
d, J = 5.6 Hz, Ar), 6.94–6.92 (1H, m, Ar), 6.61 (1H, t, J = 75.3
Hz, –CHF2), 6.58 (1H, d, J = 2.3 Hz, Ar), 5.41–5.38 (1H, m,
–CH–), 3.93–3.90 (1H, m, dd, –CH2–), 3.86 (2H, d, J = 4.6 Hz,
–OCH2–), 3.42–3.39 (1H, m, dd, –CH2), 1.26–1.23 (1H, m,
–CH–), 0.62–0.60 (1H, m, –CH2–), 0.34–0.33 (1H, m, –CH2–);
13C NMR (500 MHz, CDCl3) δ 150.8, 150.0, 149.6, 148.9,
146,6, 140.5, 138.0, 135.4, 131.4, 129.7, 124.4, 122.9, 122.4,
120.5, 119.6, 118.2, 116.2, 113.5, 103.6, 74.1, 67.0, 41.5, 10.2,
3.4; MS m/z (%) 506 (M+, 75) 476 (25), 452 (24), 451 (6), 414
(99), 384 (30), 360 (35), 359 (6), 317 (65), 297 (25), 263 (24),
251 (42), 243 (10), 212 (6), 197 (13), 167 (15), 149(9), 147 (5),
97 (7), 71 (11), 55 (100); HRMS calcd for C27H24F2N4O4:
506.1766, found: 509.1753.
(S)-1-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-
pyridin-4-ylethylamine (11S). Prepared as described for com-
pound 11R (3.1 mmol scale, 82% yield).
[α]2D3 +314.8° (c 0.03, EtOH); All spectra were identical to
those of compound 11R.
(R)-3-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-
pyridin-4-ylethylamino]-1-(3-nitrophenyl)propenone
(12R).
Compound 11R (1.0 g, 2.8 mmol) and (E)-3-(N,N-dimethyla-
mino-1-(4-nitrophenyl)-2-propen-1-one (0.6 g, 2.8 mmol) were
refluxed in ethanol for 12 h. The reaction was allowed to cool to
the ambient temperature and was quenched by adding water then
concentrated in vacuo. The mixture was diluted with ethyl
acetate, washed with water and brine, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified by silica gel column chromatography
(CH2Cl2–MeOH, 80 : 1) to afford 12R (1.2 g, 84.2%).
[α]2D3 −120.8° (c 0.025, EtOH); IR (neat) vmax 3232, 3078,
3018, 2928, 1733, 1626, 1585, 1525, 1500, 1427, 1380, 1347,
1
1267, 1109, 1044, 1021, 1005, 911, 810, 782, 724 cm−1; H
(S)-4-{2-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-
[3-(3-nitrophenyl)-pyrazol-1-yl]-ethyl}-pyridine (13S). Prepared
as described for compound 13R (1.7 mmol scale, 47% yield).
[α]2D3 +195.0° (c 0.015, EtOH); All spectra were identical to
those of compound 13R.
NMR (500 MHz, CDCl3) δ 8.67 (1H, d, J = 1.8 Hz, Ar),
8.53–8.52 (2H, m, Ar), 8.31–8.28 (1H, m, Ar), 8.18–8.16 (1H,
m, Ar), 7.62–7.58 (1H, m, Ar), 7.17 (1H, d, J = 8.2 Hz, olefinic-
H), 7.09–7.08 (1H, m, Ar), 6.86–6.79 (3H, m, Ar) 6.62 (1H, t, J
= 75.3 Hz, –CHF2), 5.70 (1H, d, J = 7.5 Hz, olefinic-H),
4.54–4.49 (1H, m, –CH–), 3.84 (2H, d, J = 6.9 Hz, –OCH2–),
3.16 (1H, d, J = 7.2 Hz, –CH2), 1.65 (1H, s, –NH–), 1.27–1.21
(1H, m, –CH–), 0.66–0.62 (1H, m, –CH2–), 0.36–0.33 (1H, m,
–CH2–); 13C NMR (500 MHz, CDCl3) δ 187.3, 153.7, 151.0,
150.1, 148.3, 145,5, 140.8, 138.9, 132.8, 129.4, 125.5, 124.6,
123.2, 122.1, 119.1, 116.0, 113.9, 112.6, 91.1, 74.1, 63.7, 43.5,
10.0, 3.2; MS m/z (%) 509 (M+, 10), 479 (4), 417 (100), 387
(38), 363 (25), 333 (40), 318 (12), 296 (4), 264 (5), 242 (6), 212
(3), 196 (7), 167 (8), 150 (22), 147 (13), 93 (48), 92 (5), 55
(75); HRMS calcd for C27H25F2N3O5: 509.1762, found:
509.1763.
(R)-3-{1-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-
2-pyridin-4-ylethyl]-1H-pyrazol-3-yl}phenylamine (14R). To a
stirred solution of 13R (0.4 g, 0.79 mmol) in EtOH was added
10% Pd/C followed by being charged with hydrogen gas. The
resulting mixture was stirred at ambient temperature for 5 h and
filtered. The filtrate was diluted with ethyl acetate and washed
water and brine. The organic phase was dried over magnesium
sulfate, filtered, and concentrated in vacuo. The crude mixture
was purified by silica gel column chromatography (CH2Cl2–
MeOH, 20 : 1) to give 14R (0.29 g, 76%).
[α]2D3 −89.0° (c 0.015, EtOH);); IR (neat) vmax 3215, 3026,
2927, 1729, 1604, 1561, 1510, 1477, 1449, 1432, 13829, 1347,
1267, 1206, 1112, 1047, 1025, 907, 807, 786, 757, 727,
(S)-3-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-
pyridin-4-ylethylamino]-1-(3-nitrophenyl)propenone (12S). Pre-
pared as described for compound 12R (2.2 mmol scale, 89%
yield).
1
691 cm−1; H NMR (500 MHz, CDCl3) δ 8.49 (2H, d, J = 5.9
Hz, Ar), 7.32–7.31 (1H, m, Ar), 7.26–7.25 (3H, m, Ar), 7.17
(1H, d, J = 8.2 Hz, Ar), 7.08 (1H, d, J = 2.0 Hz, Ar), 7.03 (1H,
d, J = 5.9 Hz, Ar), 6.98 (2H, d, J = 2.0 Hz, Ar), 6.96 (1H, d, J =
2.0 Hz, Ar), 6.73–6.72 (1H, m, Ar), 6.65 (1H, t, J = 75.4 Hz,
–CHF2), 6.73–6.71 (1H, m, Ar), 5.44–5.41 (1H, m, –CH–),
4.00–3.95 (1H, m, dd, –CH2–), 3.87 (2H, d, J = 6.9 Hz,
–OCH2–), 3.42–3.38 (1H, m, dd, –CH2), 1.32–1.26 (1H, m,
–CH–), 0.67–0.65 (1H, m, –CH2–), 0.39–0.37 (1H, m, –CH2–);
13C NMR (500 MHz, CDCl3) δ 152.0, 150.8, 149.9, 146,8,
[α]2D3 +121.8° (c 0.025, EtOH); All spectra were identical to
those of compound 12R.
(R)-4-{2-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-
[3-(3-nitrophenyl)-pyrazol-1-yl]-ethyl}pyridine
(13R). To
a
stirred solution of 12R (1.1 g, 2.1 mmol) in DMF was added
NaH (0.2 g, 4.2 mmol) slowly at 0 °C and the reaction mixture
was stirred for 1 h at 0 °C. O-(4-Nitrobenzoyl)hydroxylamine
2618 | Org. Biomol. Chem., 2012, 10, 2613–2620
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140.3, 138.6, 134.7, 130.7, 129.7, 124.5, 122.8, 119.5, 118.3,
116.3, 116.2, 114.8, 113.5, 112.3 103.2, 74.0, 66.6, 41.5, 10.2,
3.3; MS m/z (%) 476 (M+, 90), 421 (7), 414 (3), 384 (99), 356
(3), 318 (30), 317 (12), 297 (5), 263 (23), 243 (8), 207 (15), 197
(13), 170 (15), 149 (16), 147 (15), 135 (12), 84 (100), 55 (60);
HRMS calcd for C27H26F2N4O2: 476.2024, found: 476.2021.
column chromatography (CH2Cl2–MeOH, 20 : 1) to give 1R
(0.089 g, 88.7%).
[α]2D3 −122.0° (c 0.018, EtOH); IR (neat) vmax 3010, 2167,
1
2036, 1541, 1276, 1261, 764, 749 cm−1; H NMR (500 MHz,
CDCl3) δ 8.03–8.01 (2H, m, Ar), 7.93 (1H, s, Ar), 7.52–7.48
(2H, m, Ar), 7.34–7.31 (1H, m, Ar), 7.24 (1H, d, J = 2.2 Hz,
Ar), 7.13 (1H, d, J = 8.2 Hz, Ar), 7.05 (1H, d, J = 1.9 Hz, Ar),
6.96–6.91 (3H, m, Ar), 6.61 (1H, t, J = 75.3 Hz, –CHF2), 6.47
(1H, d, J = 2.3 Hz, Ar), 5.33–5.29 (1H, m, –CH–), 3.87–3.86
(1H, m, dd, –CH2–), 3.84 (2H, d, J = 6.9 Hz, –OCH2–),
3.33–3.29 (1H, m, dd, –CH2), 2.18 (3H, s, –CH3) 1.25–1.20
(1H, m, –CH–), 0.62–0.58 (1H, m, –CH2–), 0.33–0.30 (1H, m,
–CH2–); 13C NMR (500 MHz, CDCl3) δ 168.9, 151.6, 150.9,
140.4, 139.0, 138.9, 138.0, 134.2, 131.0, 129.4, 127.0, 122.9,
121.4, 119.5, 119.4, 117.1, 116.1, 114.2, 113.4, 103.6, 74.1,
66.4, 40.6, 24.6, 10.2, 3.3; MS m/z (%) 534 (M+, 52), 518 (72),
464 (5), 426 (100), 372 (12), 317 (32), 297 (10), 263 (30), 251
(18), 243 (7), 197 (12), 184 (8), 159 (25), 130 (8), 104 (3), 93
(10), 92 (7), 55 (78); HRMS calcd for C29H28F2N4O4: 534.2079
found: 534.2065.
(S)-3-{1-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-
2-pyridin-4-ylethyl]-1H-pyrazol-3-yl}phenylamine
(14S). Pre-
pared as described for compound 14R (0.6 mmol scale, 77%
yield).
[α]2D3 +86.3° (c 0.015, EtOH); All spectra were identical to
those of compound 14R.
(R)-N-(3-{1-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphe-
nyl)-2-pyridin-4-yl-ethyl]-1H-pyrazol-3-yl}phenyl)acetamide (15R).
To a stirred solution of 14R (0.15 g, 0.31 mmol) in CH2Cl2 was
added acetic anhydride (0.038 g, 0.38 mmol) and Et3N (0.047 g,
0.47 mmol). Afterwards the reaction was stirred for 12 h at rt,
quenched with saturated aqueous NaHCO3, diluted with ethyl
acetate and washed water and brine. The organic phase was dried
over magnesium sulfate, filtered, and concentrated in vacuo. The
crude mixture was purified by silica gel column chromatography
(CH2Cl2–MeOH, 40 : 1) to give 15R (0.15 g, 93.3%).
(S)-N-(3-{1-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphe-
nyl)-2-(1-oxypyridin-4-yl)-ethyl]-1H-pyrazl-3-yl-phenyl)aceta-
mide (1S). Prepared as described for compound 1R (0.15 mmol
scale, 85% yield).
[α]2D3 −149.7° (c 0.018, EtOH); IR (neat) vmax 3091, 2365,
2329, 2129, 1986, 1794, 1606, 1554, 1507, 1466, 1415, 1375,
[α]2D3 +120.85° (c 0.018, EtOH); All spectra were identical to
those of compound 1R.
1271, 1119, 1111, 1043, 999, 855, 796, 756 cm−1 1H NMR
;
(500 MHz, CDCl3) δ 8.41 (2H, d, J = 5.5 Hz, Ar), 7.99 (1H, s,
Ar), 7.55–7.50 (2H, m, Ar), 7.34–7.31 (1H, m, Ar), 7.26–7.25
(1H, m, Ar), 7.09 (1H, d, J = 8.2 Hz, Ar), 7.01 (1H, d, J = 1.9
Hz, Ar), 6.96 (2H, d, J = 5.7 Hz, Ar), 6.90–6.88 (1H, m, Ar),
6.59 (1H, t, J = 75.4 Hz, –CHF2), 6.46 (1H, d, J = 2.2 Hz, Ar),
5.37–5.34 (1H, m, –CH–), 3.90–3.86 (1H, m, dd, –CH2–), 3.80
(2H, d, J = 6.9 Hz, –OCH2–), 3.50–3.24 (1H, m, dd, –CH2),
2.16 (3H, s, –CH3) 1.25–1.17 (1H, m, –CH–), 0.60–0.56 (1H,
m, –CH2–), 0.31–0.28 (1H, m, –CH2–); 13C NMR (500 MHz,
CDCl3) δ 168.7, 151.4, 150.7, 149.9, 146.9, 140.3, 138.6, 138.5,
134.4, 130.9, 129.4, 124.5, 122.8, 121.6, 119.5, 117.1, 116.2,
114.2, 113.5, 103.2, 74.0, 66.6, 41.5, 24.7, 10.2, 3.3; MS m/z
(%) 518 (M+, 64), 464 (7), 463 (7), 426 (100), 398 (6), 372 (12),
334 (6), 317 (40), 297 (13), 263 (22), 251 (18), 243 (10), 197
(16), 159 (26), 154 (5), 130 (10), 93 (5), 77 (4), 55 (80); HRMS
calcd for C29H28F2N4O3: 518.2129, found: 518.2115.
Acknowledgements
We thank the Center for Biological Modulators, the Converging
Research Center Program through the Ministry of Education,
Science and Technology (2011K000604), and the Korea
Research Institute of Chemical Technology for their generous
financial support.
Notes and references
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5 Of the four PDE4 sub-types (A, B, C, and D), we tested the human
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(S)-N-(3-{1-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphe-
nyl)-2-pyridin-4-yl-ethyl]-1H-pyrazol-3-yl}phenyl)acetamide (15S).
Prepared as described for compound 15R (0.25 mmol scale,
96% yield).
[α]2D3 +148.8° (c 0.018, EtOH); All spectra were identical to
those of compound 15R.
(R)-N-(3-{1-[1-(3-Cyclopropylmethoxy-4-difluoromethoxyphe-
nyl)-2-(1-oxypyridin-4-yl)-ethyl]-1H-pyrazol-3-yl-phenyl)aceta-
mide (1R). To a stirred solution of 15R (0.10 g, 0.19 mmol) in
CH2Cl2 was added MCPBA (0.071 g, 0.028 mmol) and
NaHCO3 (0.024 g, 0.028 mmol). After stirring for 12 h at rt, the
reaction was quenched with saturated aqueous NaHCO3, diluted
with ethyl acetate and washed with water and brine. The organic
phase was dried over magnesium sulfate, filtered, and concen-
trated in vacuo. The crude mixture was purified by silica gel
6 Chiral HPLC analysis was carried out using an Agilent HP 1100 MSD
instrument fitted with a well plate autosampler and a CHIRALCEL OD,
0.46×25 cm (DAICEL). A mobile phase of 10% IPA–hexane was passed
through the column at 0.8 mL min−1
.
7 Chiral tert-butanesulfinamide-mediated asymmetric synthesis of chiral
amines has been used widely, see recent reports and references therein:
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8 Previous reports dealing with the synthesis of pyrazole directly bonded to
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erocycl. Chem., 2005, 42, 563–566.
9 WO 2008/006509A1.
10 Our unpublished results.
11 A. P. Sergey, V. G. Yuri, V. R. Tatjana, A. K. Oxana and V. T. Alexey, Tet-
rahedron: Asymmetry, 1995, 6, 2665–2668.
12 G. Borg, D. A. Cogan and J. A. Ellman, Tetrahedron Lett., 1999, 40,
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7, 713–716; (b) S. Yuehai and K. F. Gregory, J. Org. Chem., 2002, 67,
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C. Zhen-wei, S. W. Barri, M. Steve, J. S. Robert, W. K. Daniel, F. Aberra,
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