The synthesis of a selective PDE4/TNFα inhibitor

Article abstract of DOI:10.1021/op010223p

Two syntheses of cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid (1), a selective PDE₄/TNFα inhibitor are described. The first synthesis relied on a solvolysis of a tertiary benzylic alcohol to the nitrile using T

Full text of DOI:10.1021/op010223p

Organic Process Research & Development 2001, 5, 587−592
The Synthesis of a Selective PDE /TNFr Inhibitor
4
Ste´phane Caron* and Enrique Vazquez†
Process Research, Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment,
Groton, Connecticut 06340-8156, U.S.A.
Abstract:
This approach relied on the establishment of the desired
Two syntheses of cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-inda-
zol-6-yl)cyclohexanecarboxylic acid (1), a selective PDE4/TNFr
inhibitor are described. The first synthesis relied on a solvolysis
of a tertiary benzylic alcohol to the nitrile using TMSCN and
on the epimerization of an ester to its thermodynamically
favored position prior to its hydrolysis. It was demonstrated
that the selectivity was controlled by the rate of hydrolysis of
the two diastereomeric esters. The second synthesis proved to
be more efficient and used a novel nucleophilic aromatic
substitution of a fluoroindazole with the anion of a tertiary
nitrile. Another key element of the route was a selective Pinner
reaction of a secondary nitrile in the presence of a tertiary
nitrile.
tertiary nitrile by solvolysis of a tertiary benzylic alcohol
which would arise from the addition of an arylmetal species
to a cyclohexanone.
We first developed an efficient synthesis of the desired
bromoindazole 2 starting from 3-bromophenol (3),3 and
studied the halogen-metal exchange and addition to 4-oxo-
cyclohexanecarboxylic acid ethyl ester (4).4 In our initial
attempt, the aryllithium was generated using n-BuLi in THF
at -78 °C and the resulting anion was added to a THF
solution of 4 cooled to -78 °C, affording esters 5 as a
mixture of diastereoisomers in 64% yield along with 35%
of the protonated indazole 6. Trapping experiments using
benzaldehyde afforded a quantitative yield of the desired
adduct showing that indazole 6 originated from the enoliza-
tion of 4 in our previous experiment. Furthermore, we found
that the generation of the lithium species had to be performed
below -50 °C to avoid decomposition of the anion. Forma-
tion of the organomagnesium and organocerium5 reagents
or the presence of additives such as MgBr2 or n-Bu4NI6,7
did not improve the reaction. Generation of the anion in
DME, MTBE, diisopropyl ether, toluene, or xylenes also
proved to be difficult. Fortunately, we found that preparation
of the lithium anion in toluene in the presence of 2 equiv of
THF allowed for the formation of the diastereomeric mixture
of esters 5 in 84% yield containing only 16% indazole 6.8
However, it was necessary to rely on a chromatographic
separation for the removal of 6. Interestingly, the reaction
had to be quenched below 0 °C to avoid the conversion of
the esters 5 to lactone 7. (Scheme 1)
Introduction
Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cy-
clohexanecarboxylic acid (1) is a PDE4/TNFR inhibitor for
the treatment of inflammatory diseases which was recently
discovered and nominated for development at Pfizer Global
Research and Development.1 Structurally, the compound
presents the interesting challenge of generating a tertiary
benzylic nitrile on a 1,4-disubstituted cyclohexane with the
appropriate control of the relative stereochemistry of a
carboxylic acid, and also offered the opportunity for the
development of new methodology for the construction of
6-substituted indazoles. Our goal was to find a safe and cost-
effective synthesis for the preparation of 1.
The next step was the conversion of the tertiary benzylic
alcohol to a nitrile. It is precedented that the reaction of
1-phenylcyclohexanol with TMSCN (2-3 equiv) in the
presence of SnCl4 (1.5 equiv) leads to formation of the nitrile9
and that the conversion of substituted cyclobutanols to the
corresponding nitriles also proceeds using either BF3‚Et2O
or ZnI2.10 We found that SnCl4 was the optimal Lewis acid
In this article, we report two different approaches for the
synthesis of this drug candidate.
(2) Nakazaki, M.; Isoe, S. Bull. Chem. Soc. Jpn. 1963, 36, 1198-1204.
(3) Caron, S.; Vazquez, E. Synthesis 1999, 588-592.
(4) Although the desired ketone is commercially available, we found that
material of higher quality was obtained by oxidation of the corresponding
alcohol with TEMPO and bleach prior to the condensation. See: de Nooy,
A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153-1174.
(5) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233-
4236.
(6) Richey, H. G.; DeStephano, J. P. J. Org. Chem. 1990, 55, 3281-3286.
(7) Chastrette, M.; Amouroux, R. J. Chem. Soc., Chem. Commun. 1970, 470-
471.
(8) Bernasconi, C. F. Pure Appl. Chem. 1982, 54, 2335-2348.
(9) Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6331-6342.
(10) Kobayashi, K.; Kanno, Y.; Seko, S.; Suginome, H. J. Chem. Soc., Perkin
Trans. 1 1992.
Results and Discussion
We originally hoped that the requisite carboxylic acid
stereochemistry could be obtained by epimerization of an
ester to its thermodynamically favored equatorial position.2
* Author for correspondence. E-mail: stephane_caron@groton.pfizer.com.
Telephone: (860) 441-3103. Fax (860) 441-3630.
† Current address: Merck & Co. Inc., RY-800-C367, P.O. Box 2000, Rahway,
NJ 07065-0900.
(1) Marfat, A. and Damon, D. B. Manuscript in preparation.
10.1021/op010223p CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 10/03/2001
Vol. 5, No. 6, 2001 / Organic Process Research & Development
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587

Scheme 1
Scheme 3
Scheme 2
Scheme 4
in our case and that it could be used catalytically. The
conversion of ester 5a and 5b to a diastereomeric mixture
of nitriles 8a and 8b was accomplished by using TMSCN
(5 equiv) and SnCl4 (0.25 equiv) in CH2Cl2 in near quan-
titative yield. The excess of TMSCN proved to be necessary
in order to minimize the generation of alkene 9 (about 1%
of 9 was obtained using our protocol). Other Lewis acids
were studied (BF3‚Et2O, BCl3, ZnCl2, AlCl3, AlCl(OiPr)2,
Al(OiPr)3, TiCl4) but none were as effective as SnCl4.
Subjection of lactone 7 to these conditions generated the
tertiary carbocation as an intermediate since it provided a
1:1 mixture of diastereomeric carboxylic acids (1a and 1b)
which could not be epimerized to the desired diastereomer.
(Scheme 2)
We next explored the isomerization of the mixture of ethyl
esters and discovered that treatment of 8a and 8b with
t-BuOK in methanol in the presence of MeOAc (in order to
scavenge any KOH present) allowed for the selective
crystallization of a single diastereomer of methyl ester 10a.
Hydrolysis of 10a could be accomplished without noticeable
epimerization upon treatment with aqueous NaOH in EtOH.
More importantly, we found that rather than isolating methyl
ester 10a, slow addition of water to the reaction mixture
during the epimerization provided carboxylic acid 1 directly
in greater than 20:1 diastereoselectivity and 94% yield.
(Scheme 3) We demonstrated that epimerization of the esters
11a and 11b (as a mixture of methyl and ethyl esters) was
achieved (about 4:1 ratio at equilibrium in EtOH)11 and that
hydrolysis of the desired equatorial ester proceeded at a
greater rate than the axial one. Since 11a and 11b are in a
rapid equilibrium, the rate of hydrolysis dictates the final
ratio of 1a and 1b as we confirmed that epimerization of
the corresponding carboxylate did not occur under the reac-
tion conditions.12 (Scheme 4)
While our original synthesis of 1 proved to be efficient
(six steps, 38% overall yield from 3-bromophenol), it suffered
from several drawbacks regarding its feasibility on large
scale. First, the halogen metal exchange and addition to
ketone 4 appeared to be too capricious to become a robust
process and required a chromatographic purification. Second,
the use of TMSCN would not be preferable on larger scale,
although it suited our needs to provide kilogram quantities
of nitrile 8. Finally, all intermediates proved to be oils, which
made isolations difficult and left no room for purification
by crystallization. Although the HBr salt of bromoindazole
2 could be prepared, it proved to be a weak salt and difficult
to handle. These issues forced us to seek a better alternative
for the long-term preparation 1.
An appealing approach for the synthesis of 1 was the
nucleophilic aromatic substitution of a fluoroindazole 11 with
the anion of a 1,4-dicyanocyclohexane 12 followed by a
(11) Eliel, E. L.; Haubenstock, H.; Acharya, R. V. J. Am. Chem. Soc. 1961, 83,
2351-2354.
(12) Seeman, J. I. J. Chem. Educ. 1986, 63, 42-48.
588
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Scheme 5
Scheme 6
selective hydrolysis of the secondary nitrile of compound
13 through a Pinner reaction.13 Although it appeared that
there was no precedent for the addition of a nitrile anion to
an arene not containing strong electron-withdrawing groups
prior to our work, we chose to investigate this potential route
as it presented several advantages, especially the elimination
of TMSCN as a reagent. We hoped that formation of
fluoroindazole 11 would be achieved from difluoropro-
piophenone 14 and cyclohexylhydrazine 15,14 using lower
temperatures than required with the mesylate in our first
synthesis of 2 (Scheme 1). The high level of convergency
in the proposed synthesis was also attractive since it required
three simple starting materials: 2,4-difluoropropiophenone
(14), 1,4-dicyanocyclohexane (12),15 and cyclohexylhydra-
zine (15). (Scheme 5)
We were pleased to find that reaction between difluoro-
propiophenone 14 and the mesylate salt of cyclohexylhy-
drazine (15)16 in the presence of sodium acetate in refluxing
toluene and removing water with a Dean-Stark apparatus
occurred rapidly and resulted in a 98% yield of indazole 11.
Although indazole 11 was an oil, the purity was sufficiently
high to carry on in the next step which we found proceeded
best in toluene. Since toluene distillation provides an efficient
azeotrope with water, concentration of the toluene solution
containing fluoroindazole 11 assured us of anhydrous condi-
tions for our key nucleophilic aromatic substitution. As
previously communicated in the description of our methodol-
ogy,17 the use of 1.5 equiv of KHMDS in toluene at 100 °C
proved to be optimal for the coupling of fluoroindazole 11
with 1,4-dicyanocyclohexane 12 (4 equiv), providing a
mixture of diastereomeric nitriles 13a and 13b (77%). The
major impurity resulting from this process proved to be dimer
16 which was generated in approximately 5% as a single
diastereomer and could be removed by crystallization from
methanol to a level below 1%. Although dinitrile 13a and
13b could be separated by chromatography, the crude
mixture of diastereomers was usually taken on directly to
the hydrolysis of the nitrile. (Scheme 6)
Scheme 7
To the best of our knowledge, the selective hydrolysis of
a secondary nitrile in the presence of a tertiary nitrile is
unprecedented. Our initial attempt, using methanol saturated
with HCl, proved to be encouraging since only the desired
product as well as the dimethyl ester, were generated in about
equal amounts. This result led us to believe that a more
hindered alcohol could increase selectivity. Indeed, when we
used ethanol, none of the undesired diethyl ester was
observed. We found that formation of the imidate hydro-
chloride using ethanol with HCl gas and its hydrolysis
(toluene/H2O) provided the desired ethyl ester 8a and 8b in
81% yield. Final hydrolysis of the ester to 1 could be
accomplished as discussed previously (Scheme 7).
Conclusions
The second route to our synthetic target 1 proved to be
very efficient since the molecule was assembled in four steps
and 57% overall yield from 2,4-difluoropropiophenone (14).
Furthermore, the synthesis no longer required cryogenic or
high temperature (>130 °C) reactions and could be amenable
to multikilogram scale. The process research work on 1
allowed for the development of new methodologies, namely
a two-step synthesis of indazoles from phenols, the nucleo-
philic aromatic substitution of secondary nitriles with aryl
fluorides using KHMDS as a base, as well as the demonstra-
tion of the selective hydrolysis of a secondary nitrile in the
presence of a tertiary nitrile.
Experimental Section
(13) Roger, R.; Neilson, D. G. Chem. ReV. 1961, 61, 179-211.
(14) Villalobos, A.; Blake, J. F.; Biggers, C. K.; Butler, T. W.; Chapin, D. S.;
Chen, Y. L.; Ives, J. L.; Jones, S. B.; Liston, D. R.; Nagel, A. A.; Nason,
D. M.; Nielsen, J. A.; Shalaby, I. A.; White, W. F. J. Med. Chem. 1994,
37, 2721-2734.
(15) Malachowski, R.; Jankiewicz, J. W.; Jozkiewicz, S. Chem. Ber. 1938, 71,
759-767.
General. Unless otherwise noted, starting materials were
obtained from commercial suppliers and used without further
purification. Silica gel chromatography was carried out with
J.T. Baker 40 mm silica gel according to Still’s procedure.18
Thin-layer chromatography was performed with EM Separa-
tions Technology silica gel F254, HPLC was performed with
(16) Ghali, N. I.; Venton, D. L.; Hung, S. C.; Le Breton, G. C. J. Org. Chem.
1981, 46, 5413-5414.
(17) Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000, 122, 712-
713.
(18) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
Vol. 5, No. 6, 2001 / Organic Process Research & Development
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589

a Hewlett-Packard Series 1100 using a Puresil C18 column
(4.6 mm × 150 mm) and 50/50 or 80/20 CH3CN/H2O mobile
phase. Melting points were measured in open capillary tubes
and are uncorrected. 1H (400 MHz) and 13C NMR (100 MHz)
were measured in CDCl3 unless otherwise indicated. IR
spectra were recorded as thin films on NaCl plates unless
otherwise indicated.
4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclo-
hexanecarboxylic Acid Ethyl Ester (8a + 8b). To solution
of 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cy-
clohexanecarboxylic acid ethyl ester (5a + 5b) (13.5 g, 33.9
mmol) in CH2Cl2 (135 mL) cooled to 0 °C was added
trimethylsilyl cyanide (22.6 mL, 169 mmol) followed by a
slow addition of SnCl4 (13.6 mL of a 1.0 M solution in
CH2Cl2, 13.6 mmol). The reaction mixture was allowed to
warm to room temperature overnight. K2CO3 (18.7 g, 136
mmol) and KF‚2H2O (12.8 g, 136 mmol) were added,
followed by dropwise addition of H2O (4.30 mL, 239 mmol).
The reaction mixture was stirred vigorously for 90 min, after
which silica gel (25 g) was added. The mixture was filtered
and washed thoroughly with CH2Cl2. The filtrate was washed
with saturated aqueous NaHCO3 (250 mL), dried over
MgSO4, filtered, and concentrated to an oil to yield 13.2 g
(96% recovery) of 4-cyano-4-(1-cyclohexyl-3-ethyl-1H-in-
dazol-6-yl)cyclohexanecarboxylic acid ethyl ester (8) as a
mixture of diastereoisomers. For characterization purposes,
a sample of each diastereoisomer was obtained by chro-
matographic purification on silica gel eluting with 4:1
hexanes/EtOAc. Higher Rf diastereoisomer (cis diastereo-
isomer): 1H NMR δ 1.28 (t, 3, J ) 7.1), 1.36 (t, 3, J )
7.7), 1.43-1.56 (m, 2), 1.74-1.77 (m, 2), 1.93-2.10 (m,
10), 2.20-2.24 (m, 2), 2.31 (d, 2, J ) 12.9), 2.30 (tt, 1, J )
12.2, 3.5), 2.95 (q, 2, J ) 7.7), 4.15 (q, 2, J ) 7.1), 4.29-
4.37 (m, 1), 7.13 (d, 1, J ) 8.5), 7.52 (s, 1), 7.68 (d, 1, J )
8.5). 13C NMR δ 14.06, 14.23, 20.62, 25.35, 25.81, 26.20,
32.57, 36.77, 42.15, 44.27, 57.67, 60.63, 106.08, 116.96,
121.22, 121.95, 122.19, 138.23, 139.61, 146.31, 174.30.
IR: 2933, 2856, 2231, 1732, 1189, 1041, 810 cm-1. Analysis
calculated for C25H33BrN3O2: C, 73.68; H, 8.15; N, 10.31.
Found: C, 73.58; H, 8.28; N, 10.38. Lower Rf diastereo-
isomer (trans diastereoisomer): mp ) 89-91 °C. 1H NMR
δ 1.26 (t, 3, J ) 7.1), 1.33 (t, 3, J ) 7.7), 1.40-1.54 (m, 2),
1.71-1.78 (m, 2), 1.89-2.19 (m, 13), 2.23-2.31 (m, 2),
2.94 (q, 2, J ) 7.7), 4.17 (q, 2, J ) 7.1), 4.26-4.33 (m, 1),
7.10 (d, 1, J ) 8.5), 7.47 (s, 1), 7.64 (d, 1, J ) 8.5). 13C
NMR δ 14.07, 14.29, 24.71, 25.35, 25.80, 32.58, 33.74,
37.57, 44.26, 57.59, 60.59, 106.05, 117.26, 121.16, 121.85,
122.61, 138.42, 139.60, 146.27, 174.47. IR: 2973, 2939,
2861, 2233, 1721, 1452, 1206, 1185, 1169, 813 cm-1.
Analysis calculated for C25H33BrN3O2: C, 73.68; H, 8.15;
N, 10.31. Found: C, 73.62; H, 8.53; N, 10.30.
6-Bromo-1-cyclohexyl-3-ethyl-1H-indazole (2). Meth-
anesulfonic acid 5-bromo-2-propionyl-phenyl ester3 (36.6 g,
119 mmol) was combined with cyclohexylhydrazine (16)
(27.2 g, 238 mmol) and NH4OAc (23.0 g, 299 mmol) in
xylenes (220 mL). The reaction mixture was heated to 135
°C in a Dean-Stark apparatus for 48 h. The reaction was
cooled to room temperature and concentrated to a low
volume under reduced pressure. The crude product was
filtered through a pad of silica gel (ratio product/silica gel
1/5) eluting first with hexanes and then with a 10/90 mixture
of EtOAc and hexanes to yield 28.0 g of 6-bromo-1-cyclo-
hexyl-3-ethyl-1H-indazole (2) (76% yield) after concentra-
tion.1H NMR δ 1.35 (t, 3, J ) 7.7), 1.39-2.06 (m, 10), 2.95
(q, 2, J ) 7.7), 4.21-4.28(m, 1), 7.15 (d, 1, J ) 8.5), 7.51
(d, 1, J ) 8.5), 7.56 (s, 1). 13C NMR δ 13.95, 20.50, 25.35,
25.84, 32.44, 58.15, 112.01, 120.10, 121.37, 121.65, 122.82,
140.37, 146.60. IR 2934, 2855, 1606, 1502, 1451, 1048, 951,
834 cm-1. Analysis calculated for C15H19BrN2: C, 58.64;
H, 6.23; N, 9.12. Found: C, 58.82; H, 6.20; N, 9.01.
4-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cy-
clohexanecarboxylic Acid Ethyl Ester (5a + 5b). To a
solution of 6-bromo-1-cyclohexyl-3-ethyl-1H-indazole (2)
(12.7 g, 41.3 mmol) in toluene (64 mL) was added THF
(6.70 mL, 82.6 mmol). The solution was cooled to -78 °C,
and n-butyllithium (17.3 mL of a 2.5 M solution in hexanes,
43.4 mmol) was added dropwise. The solution was stirred
10 min and added to a solution of 4-oxo-cyclohexanecar-
boxylic acid ethyl ester (4) (8.80 g, 51.7 mmol) in toluene
(127 mL) at -78 °C. The reaction mixture was stirred 15
min and poured into 1 N aqueous HCl (200 mL). The layers
were separated, and the aqueous layer was extracted with
toluene (60 mL). The organic extracts were combined, dried
over MgSO4, filtered, and concentrated to an oil which was
purified by filtration through a pad of silica gel eluting with
4:1 hexanes/EtOAc. The product-rich fractions were con-
centrated to yield 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-
4-hydroxy-cyclohexanecarboxylic acid ethyl ester (5) (13.5
g, 82%) as a mixture of diastereoisomers. Upon standing,
one of the diastereoisomers crystallized and was triturated
with hexanes (cis diastereoisomer 5a): mp ) 118-120 °C.
1H NMR δ 1.25-1.40 (m, 4), 1.27 (t, 3, J ) 7.1), 1.35 (t, 3,
J ) 7.7), 1.65-2.07 (m, 15), 2.37-2.44 (m, 1), 2.96 (q, 2,
J ) 7.7), 4.15 (q, 2, J ) 7.1), 4.30-4.38 (m, 1), 7.13 (d, 1,
J ) 8.5), 7.58 (s, 1), 7.63 (d, 1, J ) 8.5). 13C NMR δ 14.16,
14.26, 20.69, 24.60, 25.39, 25.91, 32.54, 38.22, 42.57, 57.59,
60.34, 72.80, 104.49, 116.80, 120.28, 121.26, 139.84, 146.09,
146.93, 175.63. IR 3504, 2937, 1715, 1372, 1258, 1221,
1042, 976 cm-1. Analysis calculated for C24H34N2O3: C,
72.33; H, 8.60; N, 7.03. Found: C, 72.11; H, 8.55; N, 6.92.
An X-ray single-crystal structure was obtained on ester 5a
and appears in the Supporting Information.19
4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclo-
hexanecarboxylic Acid Methyl Ester (10a + 10b). To
solution of 4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-
yl)cyclohexanecarboxylic acid ethyl ester (8) (1.80 g, 4.42
mmol) in MeOH (5.4 mL) containing MeOAc (0.35 mL,
4.40 mmol) was added t-BuOK (1.50 g, 13.4 mmol) in
portions at 0 °C. The reaction mixture was allowed to warm
to room temperature and was stirred overnight. The mixture
was cooled to 0 °C and filtered, and the solids were washed
with MeOH and dried under vacuum to afford 4-cyano-4-
(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxy-
(19) The author has deposited atomic coordinates for structures 5a, 13a, and
13b with the Cambridge Crystallographic Data Centre. The coordinates can
be obtained on request from the Director Cambridge Crystallographic Data
Centre 12 Union Road Cambridge CB2 1EZ UK.
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lic acid methyl ester (10a) as a single diastereomer (1.20 g,
68%): mp 158-159 °C. 1H NMR (400 MHz, CDCl3) δ 1.36
(t, 3, J ) 7.7), 1.42-1.54 (m, 2), 1.74-1.78 (m, 1), 1.92-
2.20 (m, 11), 2.22 (dd, 2, J ) 13.9, 2.7), 2.31 (d, 2, J )
12.5), 2.42 (tt, 1, J ) 12.1, 3.5), 2.98 (q, 2, J ) 7.7), 3.72
(s, 3), 4.30-4.37 (m, 1), 7.13 (d, 1, J ) 8.5), 7.52 (s, 1),
7.68 (d, 1, J ) 8.5). 13C NMR (100 MHz, CDCl3) δ 14.06,
20.62, 25.35, 25.82, 26.20, 32.58, 36.73, 42.02, 44.25, 51.89,
57.67, 106.08, 116.97, 121.23, 121.96, 122.18, 138.19,
139.61, 146.31, 174.73. IR: 2939, 2859, 2237, 1730, 1621,
1461, 1452, 1320, 1264, 1170, 1039 cm-1. Analysis calcu-
lated for C24H31N3O2: C, 73.25; H, 7.94; N, 10.68. Found:
C, 72.95; H, 8.15; N, 10.61.
over MgSO4, filtered, and concentrated to yield 30.07 g of
1-cyclohexyl-3-ethyl-6-fluoro-1H-indazole (11) (98% yield).
1H NMR δ 1.33 (t, 3, J ) 7.7), 1.35-1.44 (m, 2), 1.47-
1.96 (m, 8), 2.93 (q, 2, J ) 7.7), 4.14-4.22 (m, 1), 6.81 (dt,
1, J ) 8.9, 2.1), 6.99 (dd, 1, J ) 9.8, 2.1), 7.40 (ddd, 1, J )
8.7, 5.2, 0.4). 13C NMR δ 13.97, 20.53, 25.37, 25.84, 32.32,
58.18, 94.77 (d, J ) 27.4), 109.11 (d, J ) 26.0), 119.38,
121.75 (d, J ) 11.5), 139.89 (d, J ) 13.0), 146.61, 161.95
(d, J ) 242). IR: 2968, 2934, 2856, 1624, 1507, 1174, 1125,
825 cm-1. Analysis calculated for C15H19FN2: C, 73.14; H,
7.77; N, 11.37. Found: C, 73.33; H, 7.90; N, 11.46.
1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexane-
1,4-dicarbonitrile (13a + 13b). To a solution of 1-cyclo-
hexyl-3-ethyl-6-fluoro-1H-indazole (11) (1.50 g, 6.09 mmol)
and cylohexane-1,4-dicarbonitrile (12) 15 (3.27 g, 24.4 mmol)
in toluene (15 mL) was added KHMDS (1.82 g, 9.12 mmol).
The reaction mixture was heated to 100 °C, stirred for 5 h,
cooled to room temperature and poured into 1 N HCl (15
mL). The layers were separated, and the organic extracts were
concentrated. The crude product was stirred in 20% EtOAc/
hexanes (15 mL) for 20 min, and the solids were filtered
(1.1 g of cylohexane-1,4-dicarbonitrile (12) recovered). The
filtrate was concentrated to a crude oil. For characterization
purposes, the diastereoisomers were obtained by purification
by chromatography on silica gel (125 g) eluting with 2:1
hexanes/EtOAc (1.69 g of product isolated, 77% yield).
Higher Rf diastereoisomer (trans-dinitrile diastereoisomer
cis-4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-
cyclohexanecarboxylic Acid (1). To a solution of 4-cyano-
4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarbox-
ylic acid methyl ester (10) (5.00 g, 12.7 mmol) in EtOH (25
mL) was added 10% aqueous NaOH (25 mL). The mixture
was stirred overnight and cooled to 0 °C before addition of
6 N HCl (14 mL). A white solid precipitated, the mixture
was stirred for 15 min, and the solids were filtered, washed
with H2O, and dried under vacuum to afford cis-4-cyano-
4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarbox-
ylic acid (1) (4.82 g, 100%). The acid had identical
spectroscopic and physical properties of the compound
prepared from the direct hydrolysis described below.
cis-4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-
cyclohexanecarboxylic Acid (1). To a solution of crude
4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohex-
anecarboxylic acid ethyl ester (8) (3.51 g, 8.61 mmol) in
MeOH (130 mL) was added t-BuOK (2.90 g, 25.8 mmol).
The solution was stirred at room temperature 10 h, and H2O
(3.50 mL, 194 mmol) was added. The reaction mixture was
stirred until complete disappearance of the starting material
(14 h). Most of the methanol was distilled off, H2O was
added (10 mL) followed by addition of 6 N HCl until pH )
2. The solid was triturated for 90 min, filtered, and dried
under vacuum to afford cis-4-cyano-4-(1-cyclohexyl-3-ethyl-
1H-indazol-6-yl)cyclohexanecarboxylic acid (1) (3.00 g,
1
13a): mp ) 140-142 °C. H NMR δ 1.37 (t, 3, J ) 7.7),
1.24-1.78 (m, 4), 1.92-2.10 (m, 6), 2.19-2.35 (m, 8), 2.98
(q, 2, J ) 7.7), 3.15-3.17 (m, 1), 4.30-4.39 (m, 1), 7.19
(dd, 1, J ) 8.5, 1.7), 7.51 (d, 1, J ) 0.8), 7.71 (d, 1, J )
8.5). 13C NMR δ 14.07, 20.60, 25.34, 25.79, 25.92, 32.61,
33.36, 44.30, 57.66, 105.92, 117.04, 121.00, 121.52, 121.79,
122.09.137.33, 139.54, 146.41. IR: 2934, 2239, 1620, 1448,
1435, 1238, 1049, 803 cm-1. Analysis calculated for
C25H28N4: C, 76.63; H, 7.83; N, 15.54. Found: C, 76.69;
H, 7.87; N, 15.65. Lower Rf diastereoisomer (cis-dinitrile
diastereoisomer 13b): mp ) 136-138 °C. 1H NMR δ 1.36
(t, 3, J ) 7.7), 1.42-1.53 (m, 2), 1.74-1.82 (m, 2), 1.89-
2.08 (m, 8), 2.17-2.34 (m, 6), 2.58 (tt, 1, J ) 12.2, 3.5),
2.97 (q, 2, J ) 7.7), 4.28-4.36 (m, 1), 7.09 (dd, 1, J ) 8.5,
1.7), 7.49 (d, 1, J ) 1.0), 7.69 (d, 1, J ) 8.5). 13C NMR δ
14.02, 20.57, 25.32, 25.81, 27.07, 27.27, 32.57, 36.04, 43.63,
57.75, 106.05, 116.65, 121.17, 121.50, 122.13, 137.17,
139.54, 146.38. IR: 2935, 2231, 1620, 1447, 1211, 1061,
807 cm-1. Analysis calculated for C25H28N4: C, 76.63; H,
7.83; N, 15.54. Found: C, 76.52; H, 7.95; N, 15.37. An X-ray
single-crystal structure was obtained on both compounds 13a
and 13b, and both appear in the Supporting Information.19
4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclo-
hexanecarboxylic Acid Ethyl Ester (8a + 8b). Into a
solution of 1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclo-
hexane-1,4-dicarbonitrile (13a + 13b) (2.58 g, 7.16 mmol)
in EtOH (35 mL) was bubbled dry HCl gas for 20 min. The
reaction mixture was stirred 20 min, after which it was
concentrated. To the crude product was added toluene (20
mL) and H2O (20 mL) and the mixture was stirred for 8 h.
The layers were separated, and the toluene layer was
1
94%). H NMR δ 1.34 (t, 3, J ) 7.9), 1.42-1.51 (m, 2),
1.74 (d, 1, J ) 12.9), 1.90-2.13 (m, 11), 2.23-2.33 (m, 4),
2.46 (tt, 1, J ) 12.0, 3.5), 2.96 (q, 2, J ) 7.9), 4.28-4.36
(m, 1), 7.13 (dd, 1, J ) 8.5, 1.3), 7.67 (d, 1, J ) 8.3). 13C
NMR δ 13.97, 20.47, 25.27, 25.76, 25.91, 32.47, 36.57,
41.64, 44.14, 57.70, 106.05, 116.96, 121.25, 121.88, 122.01,
138.15, 139.53, 146.34, 179.80. IR: 3504, 3788-2866 (br),
2236, 1726, 1621, 1453, 1254, 1171, 964, 814 cm-1. Analysis
calculated for C23H29N3O2: C, 72.79; H, 7.70; N, 11.07.
Found: C, 72.60; H, 7.63; N, 10.95.
1-Cyclohexyl-3-ethyl-6-fluoro-1H-indazole (11). To a
solution of 1-(2,4-difluoro-phenyl)-propan-1-one (14) (21.29
g, 125.1 mmol) in toluene (120 mL) was added NaOAc
(26.75 g, 326.1 mmol) and cyclohexylhydrazine mesylate
(15) (34.0 g, 163 mmol). The reaction mixture was heated
to reflux in a Dean-Stark apparatus for 12 h. The reaction
was cooled to room temperature and poured into 1 N HCl
(100 mL). The toluene layer was separated and washed with
H2O (75 mL) and brine (75 mL). The organic layer was dried
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591

concentrated to a crude foam. The diastereoisomeric mixture
was isolated by purification by chromatography on silica gel
eluting with 4:1 hexanes/ethyl acetate (2.37 g product
isolated, 81% yield) and had identical spectroscopic proper-
ties of the diastereomeric mixture of the compound prepared
from the previous route.
Eisenbeis, Alex Grodski, Rich Buzon and Cliff Meltz for
several helpful discussions with regards to the scale-up of
this chemistry.
Supporting Information Available
X-ray crystallographic data for compounds 5a, 13a and
13b. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment
We thank Jon Bordner and Debra DeCosta of Pfizer
Global Research and Development for the determination of
the single-crystal X-ray structure of compounds 5a, 13a and
13b and Raymond Bemish for his help in the identification
of impurities using mass spectrometry. We also thank Shane
Received for review July 30, 2001.
OP010223P
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