A practical synthesis of the PDE4 inhibitor, SB-207499, from a cyclohexanone precursor

Article abstract of DOI:10.1021/op025584z

The synthesis of SB-207499 is described. Investigation and development of new strategies for the homologation of ketone, 4-cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-cyclohexan-1-one 2 are described which produce SB-207499. Our ultimate route of synthesis to SB-207499 is robust and operationally simple and produces the final drug substance in good yield and purity.

Full text of DOI:10.1021/op025584z

Organic Process Research & Development 2003, 7, 101−108
Technology Reports
A Practical Synthesis of the PDE4 Inhibitor, SB-207499, from a Cyclohexanone
Precursor
Neil F. Badham,*,†,| Jian-Hao Chen,† Paul G. Cummings,‡ Philip C. Dell’Orco,§ Ann M. Diederich,† Ann M. Eldridge,†
Wilford L. Mendelson,† Robert J. Mills,†, Vance J. Novack,† Mark A. Olsen,‡ Abu M. Rustum,‡ Kevin S. Webb,† and
Shawn Yang‡
GlaxoSmithKline Pharmaceuticals, Department of Synthetic Chemistry, 709 Swedeland Road,
King of Prussia, PennsylVania 19406, U.S.A., Department of Analytical Sciences, 709 Swedeland Road,
King of Prussia, PennsylVania 19406, U.S.A., and Department of EnVironmental Research,
801 RiVerside Road, King of Prussia, PennsylVania 19406, U.S.A.
Abstract:
The synthesis of SB-207499 is described. Investigation and
development of new strategies for the homologation of ketone,
4-cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-cyclohexan-
1-one 2 are described which produce SB-207499. Our ultimate
route of synthesis to SB-207499 is robust and operationally
simple and produces the final drug substance in good yield and
purity.
Figure 1. SB-207499.
Scheme 1. Synthesis of SB-207499 using dithiane chemistry
Introduction
SB-207499 is a potent second-generation inhibitor of
PDE4 (phosphodiesterase-4) with decreased side effects
versus those of the well-known first-generation inhibitor, (R)-
rolipram. SB-207499 is in clinical development both for
asthma and chronic obstructive pulmonary disease (COPD),1
Figure 1. At the outset of our work, there were issues
associated with the existing preparation from ketone 2 such
as cost of goods, necessity for column chromatography,
purity of final drug substance, and other operational proce-
dures not amenable to scale-up. These have been addressed
and are discussed here in the preparation of this development
compound (1a).
1,3-dithiane3 at -78 °C in THF to produce ketene dithio-
acetal 3 in 87% yield. Mercury (II) chloride-mediated
methanolysis3 of 3 provided an approximately 11:1 mixture
of cis and trans esters (4a:4b respectively) which were
separated by flash chromatography on silica gel. Saponifica-
tion of ester 4a with potassium hydroxide in a THF/methanol/
water mixture, followed by acidification gave the corre-
sponding acid 1a2 in 44% yield. This sequence had drawbacks
for scale-up. First, 2-(trimethylsilyl)-1,3-dithiane was ex-
pensive (∼$800/kg), was not available in bulk, and required
the use of low temperature. Second, the use of mercury (II)
Results and Discussion
The Medicinal Chemistry synthesis of ketone 2 was six
steps.2 Ketone 2 was then taken four steps to give SB-
207499, shown in Scheme 1.
The homologation of ketone 2 was done using a Peterson-
type reaction with 2.1 equiv of 2-lithio-2-(trimethylsilyl)-
* To whom correspondence should be addressed. E-mail: Neil.Badham@
RhodiaChiRex.com.
† Department of Synthetic Chemistry, 709 Swedeland Road, King of Prussia,
PA 19406, U.S.A.
‡ Department of Analytical Sciences, 709 Swedeland Road, King of Prussia,
PA 19406, U.S.A.
§ Department of Environmental Research, 801 Riverside Road, King of
Prussia, PA 19406, U.S.A.
(2) Christensen, S. B.; Guider, A.; Forster, C. J.; Gleason, J. G.; Bender, P.
E.; Karpinski, J. M.; DeWolf, W. E., Jr.; Barnette, M. S.; Underwood, D.
C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.; Bochnowicz, S.; Osborn,
R. R.; Manning, C. D.; Grous, M.; Hillegas, L. M.; O’Leary Bartus, J.;
Ryan, M. D.; Eggleston, D. S.; Haltiwanger, R. C.; Torphy, T. J. J. Med.
Chem. 1998, 41, 821.
| Current address: Rhodia ChiRex, 383 Phoenixville Pike, Malvern, PA 19355,
U.S.A.
Current address: Genaera Corporation, 5110 Campus Drive, Plymouth
Meeting, PA 19462, U.S.A. E-mail: rmills@genaera.com.
(1) Giembycz, M. A. Expert Opin. InVest. Drugs 2001, 10, 1361.
(3) Jones, P. F.; Lappert, M. F. J. Chem. Soc., Chem. Commun. 1972, 526.
10.1021/op025584z CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/30/2002
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Scheme 2. Hydrolysis of ketene dithiane 3 with copper
sulfate
Scheme 3. Equilibration and hydrolysis of methyl esters 4
using KOtBu
chloride and perchloric acid for hydrolysis of 3 was undesir-
able due to the known dangers associated with perchloric
acid (explosive)4 and the toxicity of the mercury salts. Third,
the esters 4 were separated by chromatography to give the
desired equatorial ester 4a, which on hydrolysis gave the
desired compound 1a. Finally after hydrolysis and isolation,
acid 1a still contained high levels of mercury. Our early focus
was to replace the mercury salts and the perchloric acid to
increase the safety of the synthesis, and to enhance the purity
of the final drug substance. Copper (II) salts and silica gel
have been used to hydrolyze ketene dithioacetals;5 a modi-
fication of this procedure with the use of copper (II) sulfate
in methanol gave the esters 4 (4a:4b, 83:17), Scheme 2.
After a solvent exchange to toluene, removal of the
residual copper salts was easily achieved by washing the
crude reaction mixture with 10% aqueous ammonia. Al-
though this eliminated the use of heavy metals and perchloric
acid, the variability and heterogeneous nature of these
reactions conditions rendered them difficult to scale.
After hydrolysis of 4, acids 1a and 1b could be separated
by crystallization from ethyl acetate/hexanes (eliminating the
need for chromatography of the esters) to give the desired
acid 1a (>99:1, 1a:1b). To increase the yield of the desired
equatorial acid 1a further, equilibration studies6 of the cis/
trans methyl esters 4 were examined. After equilibration of
esters 4, hydrolysis of the esters was performed in situ to
give the acids 1. It was determined that NaH in methanol
epimerized the esters 4 and subsequent hydrolysis gave a
cis:trans ratio of acids 1a:1b, 8:1. By changing the base from
NaH to KOtBu, the ratio of 1a:1b increased from 8:1 to 14:
17 (Scheme 3).
Scheme 4. Use of TFA to hydrolyze ketene dithiane 3
Acids 1a and 1b were then crystallized from ethyl acetate/
hexanes to give the desired acid 1a in 68% yield (>99:1
1a:1b) The use of hypochlorite also allowed for the oxidation
of all the sulfur residues, reducing the odor (Scheme 4).
Although this improved sequence from compound 3 could
produce the target acid 1a without any chromatography, the
throughput was still very inefficient using the TFA hydrolysis
method, and 2-(trimethylsilyl)-1,3-dithiane was still used to
prepare 3. Other alternatives were sought for an efficient
and robust homologation of ketone 2 to give acid 1a. There
are various methodologies in the literature for the homolo-
gation of a ketone to a secondary carboxylic acid in two or
three steps. Representative methodologies have involved
intermediates such as enol ethers,11 epoxides,12 cyanohy-
drins,13 R,â-unsaturated sulfones,14 glycidic esters,15 and
nitriles,16 to add the one-carbon unit. However, most
transformations are not amenable to scale-up. We initially
focused on the classical way of introducing one carbon by
formation of the cyanohydrins 517 (Scheme 5).
We also confirmed that epimerization of the correspond-
ing acids 1a:1b did not occur under the reaction conditions.
These epimerization and hydrolysis results were in agreement
with what Caron and Vazquez reported for a similar
compound.8
It had also been reported that strong acids can hydrolyze
ketene dithianes to the acids directly.9 Various attempts were
tried, and it was found that trifluoroacetic acid in aqueous
acetonitrile followed by calcium hypochlorite (or hydrogen
peroxide) treatment afforded the corresponding acids 1.10
Treatment of ketone 2 with sodium cyanide gave the
cyanohydrin 5 in 93% yield, which was then dehydrated with
thionyl chloride and pyridine in toluene to give the unsatur-
ated nitrile 6 in 92% yield.13a Hydrolysis of nitrile 6 with
(4) Urben, P. G., Ed. Bretherick’s Handbook of ReactiVe Chemical Hazards,
5th ed.; Butterworth-Heinemann Ltd.: Oxford, UK, 1995; Vol. 1, p 1246.
(5) Caballero, G. M.; Gros, E. G. J. Chem. Res., Synop. 1989, 320.
(6) Diederich, A. M.; Eldridge, A. M.; Mills, R. J.; Novack, V. J. PCT Int.
Appl. WO 0110817, 2001.
(7) Ratio of 4a:4b determined by HPLC. (Method: 15 cm Supercocil LC-
ABZ, 40/60/0.1 acetonitrile/water/TFA, 1.5 mL/min, 215 nm UV).
(8) Caron, S.; Vazquez, E. Org. Process Res. DeV. 2001, 5, 587.
(9) Pang, Y.-P.; Kozikowski, A. P. J. Org. Chem. 1991, 56, 4499.
(10) Bordas-Nagy, J.; Gorycki, P.; Webb, K. U.S. Patent 6,013,827, 2000.
(11) Levine, S. G. J. Am. Chem. Soc. 1958, 80, 6150.
(12) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867.
(13) (a) Kuemmerle, E. W., Jr.; Rettig, T. A.; Stille, J. K. J. Org. Chem. 1975,
40, 3665. (b) Ruzicka, L.; Plattner, P. A.; Heusser, H.; Meier, K. HelV.
Chim. Acta 1947, 30, 1342.
(14) Scho¨llkopf, U.; Schroder, R. Angew. Chem., Int. Ed. Engl. 1972, 11, 311.
(15) Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413.
(16) Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1973, 1357.
(17) Webb, K. S. PCT Int. Appl. WO 0151455, 2001.
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Scheme 6. Classical Darzens reaction using
methyldichloroacetate and rearrangement
Figure 2. Tertiary amide hydrolysis impurity 8.
Scheme 5. Use of cyanohydrins to form SB-207499 from
ketone 2
Treatment of ketone 2 with methyldichloroacetate and
potassium tert-butoxide at 0 °C gave the chloroepoxyester
in 93% yield.20 Compound 9 was formed as an approximately
3.5:1 ratio of isomers. Attempted rearrangement of 9 under
Krapcho conditions21 led to several decomposition products
and isolation of 1a in about 30% yield. These steps were
reordered so that hydrolysis of ester 9 gave the epoxy acid
10 in 85% yield. Treatment of acid 10 under the Krapcho
decarboxylation conditions at 150 °C in a pressure vessel
gave acids 1 (1a:1b, 1:1) in a crude yield of 59%.22 This
route was shorter than the cyanohydrin route (Scheme 5)
and avoided the use low temperatures and expensive
reagents; however, this route also suffered from scale-up
issues. The biggest issue was that chloroacid 10 was unstable
and needed to be used directly in the next step. Also, the
rearrangement conditions were harsh (150 °C, pressure
vessel). The formation of product 1 also occurred as a 1:1
mixture of cis and trans acids in 59% (i.e., about 29% yield
1a).
Another strategy along the same lines had been developed
by White.23 This was formation of an epoxynitrile using a
Darzens24 reaction followed by rearrangement to give a
secondary carboxylic acid. To this end we prepared epoxyni-
trile 11 from ketone 2 in 80% yield (Scheme 7) under
modified phase-transfer conditions.25
Isolation of 11 was achieved from methanol, but the
temperature of isolation had to be controlled due to the
formation of the methylimidate 12 at higher temperatures
(Figure 3).
Ba(OH)2‚8H2O gave 7 which had to be purified by reverse
phase HPLC in 21% yield. Pure 7 in turn was hydrogenated
using Pd/C and ammonium formate18 as the hydrogen source
to give the acids 1 (1a:1b, 96:4). Although this approach
required four steps, each step was operationally simple which
lowered the cost of the synthesis. There was still a prob-
lematic step in the synthesis, however. The hydrolysis of
the secondary nitrile in the presence of the tertiary one
(compound 6) was very difficult. Under the basic conditions
tried, there was always some competing hydrolysis of the
tertiary nitrile (Figure 2) to give amide 8 which proved
difficult to remove, resulting in purification by reverse phase
HPLC and a yield of 7 of 21%.
While this work was proceeding, other approaches were
also being considered. It is known that ketones can be treated
under classical Darzens conditions to give epoxyesters, which
in turn can be rearranged to give homologated secondary
aldehydes.19 For our system we theorized that treatment of
the ketone 2 with methyldichloroacetate in place of the more
traditional methylchloroacetate would give a chloroepoxy-
ester, which could be rearranged to an acid chloride. This
acid chloride could then be used for subsequent traditional
transformations, Scheme 6.
(20) Castro, B.; Amos, J. Bull. Soc. Chim. Fr. 1974, 2559.
(21) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 957.
(22) Diederich, A. M.; Novack, V. J. PCT Int. Appl. WO 0110822, 2001.
(23) (a) White, D. R.; Wu, D. K. J. Chem. Soc., Chem. Commun. 1974, 988.
(b) White, D. R. U.S. Patents 3,994,964, 39,7431, 4,021,478.
(24) Rosen, T. Compr. Org. Synth. 1991, 2, 409.
(18) Godar, E. M. J. Org. Chem. 1960, 25, 557.
(19) Rodriguez, J. G.; Benito, Y.; Temprano, F. J. Heterocycl. Chem. 1985, 22,
1207.
(25) Jonczyk, A.; Fedorynski, M.; Makosza, M. Tetrahedron Lett. 1972, 2395.
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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Scheme 8. Rearrangement of epoxynitrile 11
Figure 3. Methyl imidate impurity 12.
Scheme 9. Proposed mechanism of rearrangement of 11
Scheme 7. Attempted rearrangement of epoxynitrile 11
This methylimidate impurity was shown to carry through
and therefore had to be minimized. Alternative non-nucleo-
philic combinations of solvents or binary solvents were tried
which had the same cohesive energy density values as
methanol.26 Ultimately methylcyclohexane/THF, 5:1, was
found to be a good alternative solvent mixture for the
isolation of 11, eliminating the formation of the imidate
impurity 12.
The second stage of the homologation strategy, however,
was not successful; treatment of 11 using White’s conditions
to give the acid 1a (exposure of 11 to anhydrous HCl)
resulted in decomposition of compound 11 without formation
of White’s disclosed intermediates. Therefore, we tried other
conditions for rearrangement of 11 which avoided the use
of strong acid. In the same publication, White had reported
conditions specific for rearrangement of aryl-substituted
epoxynitriles to acids.23 This synthetic approach looked
attractive since it involved a one-pot rearrangement of the
aryl precursors. However, application of this methodology
to 11, for example, using White’s Lewis acids, LiClO4, Li(O2-
CCF3), and KHSO4 in toluene or xylene at reflux, resulted
in recovery of starting material. We therefore extended our
studies to other Lewis acids and solvents with the hope that
they could be applied to substrate 11. Ultimately, we found
a set of conditions that worked well for this pivotal
transformation. The combination of lithium bromide (or
magnesium bromide) in DMF, acetonitrile, and a small
amount of water at 90-95 °C efficiently transformed 11 into
acids 127 in 75% yield, (1a:1b, 9:1, Scheme 8). This ratio
reflects a thermodynamic ratio of products. The acid 1a was
also shown to be more stable than 1b by molecular
modelling.
conditions. This methodology has been further investigated
for its generality.28 The proposed mechanism of the rear-
rangement is shown in Scheme 9. The investigation and
supporting data for this mechanism are described elsewhere.27
During the rearrangement of 11, hydrogen cyanide was
liberated. To eliminate the cyanide, the reaction was treated
with base and then with sodium hypochlorite which oxidized
the hydrogen cyanide to cyanate29 and subsequently to
ammonia and carbon dioxide (Scheme 10).30
Although this method eliminates the need for expensive
reagents and low temperature, there were still some scale-
up issues to address. The cyanide liberation required ap-
(28) Badham, N. F.; Mendelson, W. L.; Allen, A.; Diederich, A. M.; Eggleston,
D. S.; Filan, J. J.; Freyer, A. J.; Killmer, L. B., Jr.; Kowalski, C. J.; Liu,
L.; Novack, V. J.; Vogt, F. G.; Webb, K. S.; Yang, J. J. Org. Chem. 2002,
67, 5440.
By contrast with other procedures, this method required
only inexpensive reagents and very moderate reaction
(26) Barton, A. M. Handbook of Solubility Parameters and Other Cohesion
Parameters, 2nd ed.; CRC Press LLC: Boca Raton, FL, 1991.
(27) Allen, A.; Diederich, A. M.; Mendelson, W.; Liu, L. PCT Int. Appl. WO
9834584, 1998.
(29) Gerritsen, C. M.; Margerum, D. W. Inorg. Chem. 1990, 29, 2757.
(30) Khan, Z.; Rafiquee, M. Z. A.; Kabir-ud-din; Niaz, M. Arif; Khan, A. Aziz,
Indian J. Chem., Sect. A: Inorg., Bio-inorg., Phys., Theor. Anal. Chem.
1996, 35A, 1116.
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Scheme 12. Protonation of the lithium salt 15
Figure 4. Primary amide 13 and isopropyl ester 14 impurities.
Scheme 13. Final route of synthesis of SB-207499 from
ketone 2
Scheme 10. Oxidation of hydrogen cyanide with basic
sodium hypochlorite
Scheme 11. Isolation of the lithium salt 15 after
rearrangement of 11
propriate safety precautions. The oxidative workup to remove
cyanide was very volume-inefficient, and it generated a lot
of waste. Also, since the oxidative workup is done in the
presence of the product 1a, small amounts of impurities
were produced in the final drug substance (e.g., the primary
amide 13, Figure 4). This facilitated introducing a crystal-
lization from 2-propanol/water to bring the purity of 1a
up to an acceptable level. However, we found on scaling
the 2-propanol/water crystallization that care had to be
taken to avoid the formation of the isopropyl ester 14 (Figure
4).
We were pleased to find that the lithium salt 15 in ethyl
acetate and protonation with 3 N HCl gave 1a, which could
be subsequently crystallized from ethyl acetate/heptane to
give pure 1a in 85% yield (Scheme 12).
Alternatives were needed to isolate the product from the
rearrangement without introducing new impurities in the
workup. Isolation of the carboxylate salt of 1a was inves-
tigated.31 Bases such as sodium hydroxide, lithium hydroxide,
and potassium hydroxide were tried to isolate the sodium,
lithium, or potassium salt of 1a. Lithium hydroxide gave the
best results, allowing the lithium salt 15 to be isolated as a
stable white solid directly from the reaction liquors in 79%
yield (Scheme 11).
The pH of this reaction was found to be critical. A pH
<1.5 was needed for subsequent isolation of 1a with an
acceptable ROI. The final route of synthesis of SB-207499
from ketone 2 is shown in Scheme 13.
The overall yield of SB-207499 (1a) from ketone 2 by
the final route of synthesis was 54%. The original Medicinal
Chemistry approach (Scheme 1) produced 1a from ketone 2
in 23% overall yield.
The lithium salt of the undesired isomer, 1b, was mainly
soluble in the mother liquors, allowing an easier separation
from 1a. By isolating the lithium salt, 15, the vast majority
of the cyanide waste was eliminated in the waste stream and
thus did not need to be destroyed via an oxidative workup
in the presence of 1a. This greatly reduced the impurities
(such as the primary amide 13) that were produced as a result
of the oxidative workup. Another major benefit was that
throughput was dramatically increased. Protonation of 15
with mineral acid in organic solvent was then investigated.
Conclusions
Various methodologies for homologation of ketone 2 to
the preparation of SB-207499, 1a, have been investigated.
The final route of synthesis no longer requires low or high
temperatures or chromatography, is operationally simple, and
is amenable to multikilogram scale. In summary, methodol-
ogy was developed for a two-step homologation of ketone
2 to acid 1a via an epoxynitrile intermediate and rearrange-
ment. Isolation of the lithium salt 15 after the rearrangement
allowed for the separation of product 15 from the reaction
byproducts and cyanide waste.
(31) Chen, J.-H.; Mendelson, W.; Webb. K. PCT Int. Appl. WO 9918793, 1999.
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Experimental Section
ment. Appropriate safety precautions need to be taken. A
solution of DMF (580 g), acetonitrile (480 g), lithium
bromide (72 g, 830 mmol), and water (20 g, 1.1 mol) was
stirred at 25-30 °C to give a homogeneous mixture. To this
was added compound 3 (180 g, 510 mmol). The reaction
was stirred at 90-95 °C for 16 h. The reaction was cooled
to 20 °C, followed by addition of sodium hydroxide solution
(92 g NaOH, 2.3 mol, dissolved in 200 mL water). The
suspension was stirred at 20 °C for 30 min and treated with
sodium hypochlorite (600 mL, 460 mmol). The contents were
stirred for an additional 90 min, followed by addition of
TBME and 6 N HCl (644 mL, 3.86 mol). The bottom
aqueous layer was separated and back-extracted with TBME;
the combined organic layers were washed four times with
water. The organic layer was concentrated to a residue, and
then ethyl acetate was added and heated to reflux. The
solution was cooled to 50 °C; hexanes were added, and the
solution was then cooled to 0 °C. After 1 h, the solid was
collected, washed with hexanes:ethyl acetate (9:1), and dried
in vacuo to give 1a as an off-white powder (125 g, 69%). A
small portion was recrystallized for characterization purposes.
The other product, 1b, remained in the crystallization mother
liquors. A small portion of the crude solid from the mother
liquors was recrystallized for characterization purposes. The
analytical data were consistent with the literature.2
4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-1-
cyclohexanecarboxylic acid, 1. Method 1: Hydrolysis of
Ketene Dithiane 3 Using TFA. To a suspension of ketene
dithiane 3 (140 g, 0.34 mol) in acetonitrile (500 mL) and
water (140 mL) was added trifluoroacetic acid (136 g, 1.19
mol). The suspension was heated to 65 °C for 1.25 h,
followed by the addition of 20% NaOH (420 g, 2.1 mol).
The solution was heated to 70-75 °C for an additional 1.25
h and then cooled to 45 °C where water (420 mL) and 3 N
HCl (392 mL, 1.18 mol) were added. The suspension was
cooled to 5 °C and held for 1 h. The suspension was then
filtered, washed with cold water, and dried in vacuo. The
crude solid in acetonitrile (425 mL) was heated to 65 °C,
and 1 N NaOH (425 mL, 0.425 mol) was added. The solution
was cooled to 60 °C where calcium hypochlorite (4.25 g,
0.03 mol) was added and the reaction stirred for 2 h. The
reaction was partially concentrated and ethyl acetate added.
This was repeated, and at 55 °C, ethyl acetate and 6 N HCl
(10:1) were added. The organic layer was isolated and
washed three times with water. Ethyl acetate was added and
the reaction partially concentrated. The solution was cooled
to 65 °C, and hexane was added. The suspension was cooled
to 5 °C, held at this temperature for 1 h and then filtered,
and the solid washed with cold ethyl acetate/hexane (1:9).
The solid was dried in vacuo to give 1a as a white solid
(78.7 g, 68%). The analytical data were consistent with the
literature.2
Method 2: Equilibration and Hydrolysis of Esters 4.
Methyl esters 4 (2.94 g, 8.2 mmol) (4a:4b 1:1) were
dissolved in tBuOH (30 mL). Potassium tert-butoxide (1.8
g, 16.5 mmol) was added and the mixture stirred for 5 d at
ambient temperature. Ratio (4a:4b, 14:1) was determined by
HPLC.7 Water (2 drops) was added, the solution stirred for
1 h, and then 5% HCl and TBME were added. The organic
layer was separated and concentrated in vacuo. The oil was
dissolved in warm ethyl acetate, and the product was
precipitated by adding hexanes. The reaction was cooled to
0 °C, and the product 1a was isolated and dried in vacuo
(1.75 g, 62%). The analytical data were consistent with the
literature.2
Method 6: Protonation of Compound 15. Compound
15 (58.5 g, 0.167 mol) was stirred in ethyl acetate (500 mL).
To this was added 3 N HCl (70 mL, 0.21 mol) and the
reaction stirred for 10 min. The organic layer was isolated
and washed with water. The solution was partially distilled
to remove about 40% of the ethyl acetate and cooled to 60
°C where heptane was added (ethyl acetate:heptane, about
1:1). The suspension was cooled to 5 °C and held at this
temperature for 2 h. The solid was filtered, washed with cold
heptane (5 °C), and dried in vacuo to give 1a (50.0 g, 85%).
The analytical data were consistent with the literature.2
cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-
r-1-cyclohexanecarboxylic acid (1a): mp 148-150 °C; IR
1
(KBr pellet) cm-1 3300-2400, 2231, 1707, 1694; H (400
MHz, CDCl3) δ 11.75 (1Η, br s), 7.02 (1H, d, J ) 2.3 Hz),
6.98 (1H, dd, J ) 2.3, 8.4 Hz), 6.87 (1H, d, J ) 8.4 Hz),
4.82 (1H, m), 3.86 (3H, s), 2.43 (1H, tt, J ) 3.7, 12.2 Hz),
2.29 (2H, br d, J ) 15.6 Hz), 2.25 (2H, br d, J ) 16.4 Hz),
2.05 (2H, m), 1.94 (4H, m), 1.86 (2H, m), 1.82 (2H, m),
1.64 (2H, m); 13C (100 MHz, CDCl3) δ 180.5, 149.8, 147.8,
132.8, 122.2, 117.3, 112.9, 111.9, 80.7, 56.1, 43.0, 41.7, 36.4,
32.8, 25.9, 24.0.
Method 3: Hydrogenation of Compound 7. To com-
pound 7 (15 mg, 0.04 mmol) in DMF (0.5 mL) was added
ammonium formate (36 mg, 0.6 mmol) and 10% Pd/C (6
mg, 40%w/w). The reaction was stirred at 20 °C for 48 h
and then filtered. The product was extracted into ethyl
acetate, and the combined organic layers were washed with
water and brine. The organics were concentrated in vacuo
to give crude 1 (10.3 mg, 68%) (1a:1b, 96:4). The analytical
data were consistent with the literature.2
trans-4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-
1-cyclohexanecarboxylic acid (1b): mp 157-158 °C; IR
1
(KBr pellet) cm-1 3427, 2229, 1701, 1262; H (400 MHz,
CDCl3) δ 11.24 (1Η, br s), 7.00 (1H, d, J ) 2.3 Hz), 6.95
(1H, dd, J ) 2.3, 8.4 Hz), 6.85 (1H, d, J ) 8.4 Hz), 4.80
(1H, m), 3.85 (3H, s), 2.87 (1H, m), 2.28 (2H, m); 2.08 (6H,
m), 1.90 (4H, m), 1.85 (2H, m), 1.61 (2H, m); 13C (100 MHz,
CDCl3) δ 180.7, 149.8, 147.8, 132.8, 122.6, 117.5, 113.2,
111.9, 80.8, 56.1, 42.7, 37.7, 33.6, 32.8, 24.3, 24.1.
Method 4: Rearrangement of Compound 10. To
compound 10 (1.26 g, 2.79 mmol) in DMSO (7.5 mL) and
water (0.5 mL) was added sodium chloride (50 mg, 0.85
mmol). The reaction was heated to 150 °C in a pressure
vessel for 3.5 h. The solution was then cooled and assayed
for 1. (0.57 g, 59%), (1a:1b, 1:1).
Method 5: Rearrangement of Compound 11. WARN-
ING: Hydrogen Cyanide is liberated during the rearrange-
Methyl 4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphe-
nyl)]cyclohexane-r-1-carboxylate (4). Ketene dithiane 3 (0.5
106
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g, 1.2 mmol), copper sulfate heptahydrate (0.62 g, 2.5 mmol),
and MeOH (12 mL) were heated at 65 °C for 2 h. The
reaction was then concentrated in vacuo and partitioned
between toluene/10% aqueous ammonia. The organic layer
was separated and washed twice with 10% aqueous am-
monia. Concentration in vacuo gave crude 4 (0.29 g, 67%)-
(4a:4b, 83:17). Chromatography on silica gel (85:15 hexane:
ethyl acetate) provided pure samples of 4a and 4b. The
analytical data were consistent with the literature.2
then at reflux and held for an additional 2 h. The solution
was cooled and poured into a mixture of aqueous HCl and
ice. The reaction was extracted with ethyl acetate. The
organic phase was washed three times with 0.6 N HCl, 5%
sodium carbonate, and brine, respectively. The organic layer
was dried, filtered, and evaporated to give a white solid 6
(0.44 g, 92%).
mp 133.5-134.5°C; 1H (400 MHz, CDCl3) δ 6.83-6.95
(3H, m), 6.67 (1H, m), 4.80 (1H, m), 3.84 (3H, s), 2.6-2.9
(2H, m), 2.2-2.5 (2H, m), 2.05-2.18 (2H, m), 1.80-2.0
(3H, m), 1.55-1.67 (3H, m). Calcd C20H22N2O2, C 74.51,
H 6.88, N 8.69. Found C 74.23, H 6.98, N 8.64.
cis-Methyl 4-Cyano-4-[3-(cyclopentyloxy)-4-(methox-
yphenyl)]cyclohexane-r-1-carboxylate (4a): mp 118-119
1
°C; IR (KBr pellet) 2230, 1734, 1254 cm-1; H (400 MHz,
CDCl3) δ 7.00 (1H, d, J ) 2.3 Hz), 6.97 (1H, dd, J ) 2.3,
8.4 Hz), 6.87 (1H, d, J ) 8.4 Hz), 4.82 (1H, m), 3.85 (3H,
s), 3.72 (3H, s), 2.37 (1H, tt, J ) 3.7, 12.2 Hz), 2.27-1.78
(14H, m), 1.62 (2H, m); 13C (100 MHz, CDCl3) δ 174.8,
149.8, 147.8, 132.9, 122.3, 117.4, 113.0, 112.0, 80.8, 56.1,
51.8, 43.0, 42.0, 36.6, 32.8, 26.1, 24.0. Calcd C21H27NO4, C
70.56, H 7.61, N 3.92. Found C 70.63, H 7.54, N 3.88.
trans-Methyl 4-cyano-4-[3-(cyclopentyloxy)-4-(meth-
oxyphenyl)]cyclohexane-r-1-carboxylate (4b): mp 50-51
4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-1-
cyclohexene-1-carboxylic acid (7). Compound 6 (2.00 g,
6.16 mmol) was heated at reflux in absolute ethanol (25 mL)
to give a clear solution. To this was added a suspension of
Ba(OH)2‚8H2O in water (6.00 g, 19 mmol, in 25 mL water).
The solution was then heated at reflux for 3.5 h and then
cooled to ambient temperature. The reaction was acidified
with 3 N HCl and extracted with ethyl acetate, then TBME.
The organic layers were combined and washed with water
and brine. After drying, the unsaturated acid 7 was isolated
as an oil by concentration in vacuo. The crude reaction was
purified by preparative reverse phase liquid chromatography
to give 7 (450 mg, 21%).
1
°C; IR (KBr pellet) 2235, 1729, 1257 cm-1; H (400 MHz,
CDCl3) δ 7.00 (1H, d, J ) 2.3 Hz), 6.99 (1H, dd, J ) 2.3,
8.4 Hz), 6.86 (1H, d, J ) 8.4 Hz), 4.80 (1H, m), 3.85 (3H,
s), 3.72 (3H, s), 2.81 (1H, m), 2.28-1.79 (14H, m), 1.63
(2H, m); 13C (100 MHz, CDCl3) δ 174.9, 149.7, 147.8, 133.0,
122.8, 117.6, 113.2, 112.0, 80.8, 56.1, 51.8, 42.9, 37.7, 33.7,
32.8, 24.6, 24.1. Calcd C21H27NO4, C 70.56, H 7.61, N 3.92.
Found C 70.47, H 7.67, N 3.85.
4-[3-(Cyclopentyloxy)-4-(methoxyphenyl)]-1,4-dicarbo-
nitrile-cyclohexan-1-ol (5). To ketone 2 (1.00 g, 3.2 mmol)
in water (5 mL) was added sodium cyanide (0.325 g, 6.6
mmol). The reaction was cooled to 0-5 °C, and an aqueous
solution of sodium bisulfite (0.625 g, in 2.5 mL water) was
then added. After the addition the temperature reached 8 °C.
The reaction was cooled and after 30 min set solid. The
reaction was warmed to 8-10 °C and acetone (2 mL) added.
The reaction was continued at 20 °C for an additional 90
min. The reaction was then partitioned between water and
ethyl acetate (1:2), and the organic layer was washed with
water and brine and then dried. Filtration and evaporation
of the organic layer gave a white solid 5, which was dried
in vacuo (1.01 g, 93%). A small sample was recrystallized
for characterization.
1H (400 MHz, CDCl3) δ 7.0 (2H, m), 6.85 (1H, d, J ) 8
Hz), 4.80 (1H, m), 3.85 (3H, s), 2.90 (1H, s), 2.1-2.48 (7H,
m), 2.20 (1H, s), 1.75-2.0 (6H, m), 1.59-1.62 (2H, m);
m/z (neg ion/DCI methane) 375 [M + Cl]- (88%), 348 [M
+ Cl - HCN]- (100%), 339 [M - H]- (100%). Calcd
C20H24N2O3, C 70.58, H 7.11, N 8.23. Found C 70.66, H
7.03, N 8.47.
4-[3-(Cyclopentyloxy)-4-(methoxyphenyl)]-1-cyclohex-
ene-1,4-dicarbonitrile (6). Cyanohydrins 5 (0.50 g, 1.46
mmol) were added to toluene (1.5 mL) and pyridine (0.60
mL, 7.4 mmol), and the reaction was cooled to 0 °C. To
this was added a solution of thionyl chloride (0.35 g, 2.95
mmol) in toluene (0.5 mL). A precipitate formed after 1-2
min, and then the reaction was heated to 80 °C for 1 h and
1
IR (KBr pellet) 3305, 2235, 1689, 1650 cm-1; H (360
MHz, C6D6) δ 7.1 (1H, d, J ) 2.0 Hz), 7.0 (1H, s), 6.82
(1H, dd, J ) 2.0, 8.4 Hz), 6.63 (1H, d, J ) 8.4 Hz), 4.72
(1H, m), 3.50 (3H, s), 2.80 (1H, m), 2.15-2.52 (3H, m),
1.41-2.09 (10H, m); 13C (90 MHz, CDCl3) δ 170.7, 149.9,
147.9, 137.4, 131.5, 129.7, 122.3, 117.5, 112.7, 111.9, 80.7,
56.1, 39.7, 33.0, 32.8, 32.6, 24.1, 22.3.
Methyl 2-Chloro-6-cyano-6-[3-(cyclopentyloxy)-4-(meth-
oxyphenyl)]-1-oxospiro[2.5]octane-2-carboxylate (9). Ke-
tone 2 (4.0 g, 12.8 mmol) and methyldichloroacetate (2.74
g, 19.1 mmol) were added to THF (40 mL). The solution
was cooled to 0 °C, and potassium tert-butoxide (19.1 mL,
19.1 mmol, 1 M in THF) was added while maintaining the
temperature below 5 °C. The reaction was then stirred at
this temperature for 30 min and then poured in ethyl acetate
and 5% HCl. The layers were separated, and the aqueous
layer was extracted with ethyl acetate. The combined organic
layers were washed with 5% sodium bicarbonate and then
brine. The organic layer was concentrated in vacuo to give
an oil. Purification through a plug of silica gel (hexanes:
ethyl acetate, 3:1) gave 9 as a colorless oil (5.00 g, 93%)
(ratio of isomers 3.5:1). The major isomer is shown below.
IR (neat) 2233, 1755, 1259 cm-1; 1H (400 MHz, CDCl3)
δ 10.35 (1H, br s), δ 7.01 (1H, d, J ) 2.3 Hz), 6.96 (1H,
dd, J ) 2.3, 8.4 Hz), 6.88 (1H, d, J ) 8.4 Hz), 4.81 (1H,
m), 3.89 (3H, s), 3.85 (3H, s), 1.75-2.54 (14H, m), 1.46-
1.68 (2H, m); 13C (100 MHz, CDCl3) δ 164.6, 150.1, 148.0,
131.1, 121.7, 117.5, 113.2, 112.0, 80.9, 79.1, 67.3, 56.6, 53.6,
42.5, 36.1, 35.8, 32.8, 28.1, 27.2, 24.0; m/z (CH4/Cl) [M +
H]+ 420 (44%), [M - H]+ 418 (75%), [MH - HCN]+ 393
(100%), 325 (44%).
2-Chloro-6-cyano-6-[3-(cyclopentyloxy)-4-(methoxyphe-
nyl)]-1-oxospiro[2.5]octane-2-carboxylic acid (10). To
Vol. 7, No. 1, 2003 / Organic Process Research & Development
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107

chloroepoxyester 9 (221 mg, 0.53 mmol) in methanol (2.2
mL) was added sodium methoxide (0.6 mL, 2.62 mmol, 25%
w/w solution in methanol) and water (90 mL, 5.0 mmol).
The solution was stirred for 15 min, and then 1% HCl and
TBME (1:1) were added. The organic layer was washed with
water and then with brine and was concentrated in vacuo to
give a white foam 10 (185 mg, 85%). (Ratio of isomers 3.5:
1).The major isomer is shown below.
8.3 Hz), 6.87 (1H, d, J ) 8.3 Hz), 4.82 (1H, m), 3.85 (3H,
s), 3.32 (1H, s), 2.54 (2H, m), 2.39 (2H, m), 2.07 (4H, m),
1.90 (4H, m), 1.62 (2H, m), 1.50 (2H, m); 13C (100 MHz,
CDCl3) δ 150.21, 140.01, 130.96, 121.50, 117.49, 115.75,
113.05, 112.12, 80.88, 63.90, 56.10, 47.19, 42.33, 36.27,
35.88, 32.79, 30.25, 28.17, 24.03.
Lithium c-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxy-
phenyl)]-r-1-cyclohexanecarboxylate (15). WARNING:
Hydrogen cyanide is liberated during the rearrangement.
Appropriate safety precautions need to be taken! A suspen-
sion of DMF (200 mL), acetonitrile (200 mL), lithium
bromide (32.4 g, 0.37 mol), and water (5.6 g, 0.31 mol) was
stirred until homogeneous. To this was added epoxynitrile
11 (90.0 g, 0.25 mol). The reaction was heated to 90-95
°C for 8-12 h. The reaction was cooled to 60 °C, where
DMF (270 mL) was added. To this was then added an
aqueous solution of lithium hydroxide (21.65 g, 0.51 mol in
112.5 mL of water). The suspension was stirred at 60 °C
for 1 h, then cooled to 5 °C, and held at this temperature for
1 h. The suspension was filtered and washed with ethyl
acetate and dried to give 15 (70.5 g, 79%). To obtain a pure
sample of the salt, 15 was slurried in wet acetonitrile, filtered,
then dried.
1
IR (neat) 3481, 2237, 1727, 1259 cm-1; H (400 MHz,
CDCl3) δ 10.35 (1H, br s), δ 7.01 (1H, d, J ) 2.3 Hz), 6.96
(1H, dd, J ) 2.3, 8.4 Hz), 6.88 (1H, d, J ) 8.4 Hz), 4.81
(1H, m), 3.85 (3H, s), 1.75-2.56 (14H, m), 1.58-1.72 (2H,
m); 13C (100 MHz, CDCl3) δ 166.0, 149.9, 147.8, 131.2,
121.6, 117.5, 113.0, 112.1, 81.0, 79.0, 67.4, 56.1, 42.6, 36.0,
35.8, 32.7, 28.0, 27.3, 24.0; m/z (CH4/Cl) [M + H]+ 406
(8%), [MH - HCN]+ 379 (100%), 345 (61%), 311 (37%).
cis-6-[3-(Cyclopentyloxy)-4-(methoxyphenyl)]-1-oxospiro-
[2.5]octane-2,6-dicarbonitrile (11). To 50% potassium
hydroxide in water (22 g) and THF (55 mL) was added
benzyltriethylammonium chloride (0.81 g, 3.5 mmol) and
the solution cooled to 0 °C. A separate solution was made
by dissolving the ketone 2 (23.0 g, 73 mmol) and chloro-
acetonitrile (5.9 g, 78 mmol) in THF (55 mL) at room
temperature. While the base solution was stirred at 0 °C,
the ketone solution was added in small portions over 15 min.
The temperature during the addition was maintained between
0 and 5 °C and the reaction stirred for 1 h. The reaction was
warmed to 25 °C and diluted with water:ethyl acetate (1:1).
The layers were separated, and the organic layer was
concentrated in vacuo. Methycyclohexane/THF (5:1) was
added, and the residue was heated to 60 °C then cooled to
20 °C over 90 min; the product began to crystallize at 40
°C. Cooling was continued to 0 °C and held at 0 °C-5 °C
for 2 h. The product was collected and washed with a
methanol mixture (0 °C). The product was dried to afford
11 (20.69 g, 80%). The analytical data were consistent with
the literature.28
1
IR (KBr pellet) 3319, 3208, 2230, 1647 cm-1; H (400
MHz, CDCl3) δ 7.00 (1H, d, J ) 2.3 Hz), 6.99 (1H, dd, J )
2.3, 9.2 Hz), 6.93 (1H, J ) 9.2 Hz), 4.81 (1H, m), 3.72 (3H,
s), 2.06 (2H, m), 2.01 (2H, m), 1.96 (1H, m), 1.87 (2H, m),
1.76 (2H, m), 1.69 (4H, m), 1.63 (2H, m), 1.56 (2H, m);
13C (100 MHz, CDCl3) δ 178.9, 149.2, 147.0, 133.7, 123.1,
117.5, 112.7, 112.2, 79.6, 55.6, 44.5, 43.0, 36.5, 32.2, 27.5,
23.6. Calcd C21H24N4Li‚H2O, C 65.38, H 7.15, N 3.81. Found
C 65.10, H 7.08, N 3.68.
Acknowledgment
We thank Analytical Sciences, GlaxoSmithKline for their
valuable support during the course of this work.
Received for review August 21, 2002.
OP025584Z
1
IR (KBr pellet) 2242, 2233, 1257 cm-1; H (400 MHz,
CDCl3) δ 7.00 (1H, d, J ) 2.4 Hz), 6.98 (1H, dd, J ) 2.4,
108
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