Synthesis of a spiro[cyclohex-1,1′-isobenzofuranyl] dopamine receptor antagonist

Article abstract of DOI:10.1021/op990191u

Two syntheses of the novel CNS agent, 2-fluoro-4-(trans)-(4-(3'H-spiro[cyclohex-l,1'-isobenzofuran]-4-yl)-piperazin-1- yl)benzonitrile, 1, are presented. The first relied on a reductive alkylation with low regioselectivity (1:1) but was sufficient for the

Full text of DOI:10.1021/op990191u

Organic Process Research & Development 1999, 3, 460−464
Synthesis of a Spiro[cyclohex-1,1′-isobenzofuranyl] Dopamine Receptor
Antagonist
Frank J. Urban,* Bruce G. Anderson,1 Morgan A. Stewart, and Gregory R. Young
Pfizer Inc, Central Research DiVision, Process Research and DeVelopment Department, Eastern Point Rd.,
Groton, Connecticut, 06340, U.S.A.
Scheme 1
Abstract:
Two syntheses of the novel CNS agent, 2-fluoro-4-(trans)-(4-
(3′H-spiro[cyclohex-1,1′-isobenzofuran]-4-yl)-piperazin-1-yl)-
benzonitrile, 1, are presented. The first relied on a reductive
alkylation with low regioselectivity (1:1) but was sufficient for
the preparation of kilogram quantities. The second used a
selective ketone reduction of 3′H-spiro[cyclohexane-1,1′-isoben-
zofuran]-4-one, 8, with sodium borohydride to provide the cis-
alcohol, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-(cis)-4-ol, 11.
A simple process for the conversion of 11 to 1 is described.
Regioselective reactions with 2,4-difluorobenzonitrile under
mild conditions are described.
Recently, we conducted a kilogram-scale synthesis of
2-fluoro-4-(trans)-(4-(3′H-spiro[cyclohex-1,1′-isobenzofuran]-
4-yl)-piperazin-1-yl)-benzonitrile 1, a novel dopamine recep-
tor antagonist discovered in the lab of Anton Fliri at Pfizer
Central Research.2 The synthesis originally used on lab scale
by Fliri and co-workers had two key areas which were of
concern for large-scale preparation. A protected piperazine
starting material 4a was used which was not available in
large quantities, and the yield for the aromatic nucleophilic
substitution reaction with 4a indicated the possibility of a
problem with the regiochemistry of the reaction with 2,4-
difluorobenzonitrile, 3. More importantly, the diastereose-
lectivity of the reductive alkylation of the spiro-substituted
cyclohexanone 8 with piperazine moiety 5b gave a 3:2 ratio
of isomers, favoring the undesired cis-isomer 2.3
In the original process, the reaction of 2,4-difluoroben-
zonitrile 3 and N-BOC piperazine 4a was carried out in
dimethylsulfoxide solution at 140 °C in the presence of a
slight excess of potassium carbonate for 24 h. The initial
product 5a was deprotected with HCl in ethanol to provide
the hydrochloride salt of 5b in <40% overall yield (Scheme
1). After it was found that the alkylation reaction with 4a in
dimethylformamide at 110 °C worked well, piperazine was
tried due to the lack of a commercial source of 4a. It was
found that combining 2,4-difluorobenzonitrile 3 with pip-
erazine in dimethylformamide or dimethylacetamide in the
presence of potassium carbonate was mildly exothermic and
the desired alkylation was proceeding at room temperature.
Further screening of solvents showed that 5b could be formed
directly by reaction of 3 with piperazine 4b (2.6 equiv) and
potassium carbonate (1 equiv) in acetonitrile at room
temperature. The initial reaction mixture consisted of a 10:1
mixture of 5b and its ortho isomer. Slurrying the crude solids
in isopropyl ether gave pure 5b in 71% yield. A similar
selectivity for the displacement of the para-fluoride in 3 with
alkoxides at low temperatures has been report by Wells and
Shi.4
The preparation of spirocyclic ketone 8 was based on the
work of Parham.5 1,4-Cyclohexanedione mono-2,2-dimeth-
yltrimethylene ketal 6 was treated with the dianion derived
from 2-bromobenzyl alcohol and 2.2 equiv of n-butyllithium
in tetrahydrofuran at - 60 °C to provide diol 7 in 79% yield.6
The next step of cyclization with loss of water and hydrolysis
of the ketal was more complex than any of the earlier
literature examples which involved formation of simpler
spiro-isobenzofurans. A variety of acidic conditions have
been described by Parham to produce either spiro-isoben-
zofurans or indenes related to 9 and 10 in our example
(4) Wells, K. M.; Shi, Y.-J.; Lynch, J. E.; Humphrey, G. R.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 1996, 37, 6439-6442.
(5) Parham, W. E.; Egberg, D. C. J. Org. Chem. 1972, 37, 1545-1549. Parham,
W. E.; Montgomery, W. C. J. Org. Chem. 1974, 39, 2048-2050. Parham,
W. E.; Sayed, Y. A. Synthesis 1976, 116-117.
(6) This monoketal 6 was available from Lancaster Synthesis Inc., Windham,
NH 03087 in multikilogram quantities. Fliri used the mono-ethyleneketal
of 1,4-cyclohexanedione which was available in research quantities only.
This reaction could be run at 0 °C, but the lower temperature was used on
scale-up to allow for shorter addition time. On lab scale, the use of 1 equiv
of methyllithium to deprotonate the alcohol followed by n-butyllithium to
form the dianion gave somewhat higher yields. Only n-butyllithium was
used on scale-up to simplify the operations.
(1) Current address: Ilex Oncology, 14785 Omicron Drive, # 101, San Antonio,
TX 78245-3221.
(2) Butler, T. W.; Fliri, A. F. J.; World Patent Application WO 9808835; Chem.
Abs. 1998, 128, 2117296.
(3) The isomers were named on the basis of the stereochemical relationship
between the oxygen and nitrogen atoms attached to the cyclohexane ring.
The trans-isomer 1 was desired.
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10.1021/op990191u CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry
Published on Web 10/27/1999

Scheme 2
Figure 1. Single-crystal X-ray structure of 12.11
Scheme 4
Scheme 3
(Scheme 2). Two usable procedures were found. Fliri had
surveyed numerous acidic conditions and found that treat-
ment of 7 with 80% trifluoroacetic acid in water at room
temperature effected the desired conversion. We extended
the survey and discovered that 85% phosphoric acid at 50-
60 °C worked well in the laboratory and that 8 could be
precipitated by addition of water. The phosphoric acid
procedure while preferable from a handling perspective was
found to be more prone to give low levels of both 9 and 10
(up to 5 to 10%), and aqueous trifluoroacetic acid was used
on a kilogram scale. Since the excess trifluoroacetic acid
could not be evaporated from the reaction mixture on scale-
up as was done in the lab, it needed to be neutralized. It
was necessary to add a water-miscible organic solvent,
tetrahydrofuran, before the neutralization of the trifluoroacetic
acid with 25% sodium hydroxide solution to prevent the
product from separating as an oil.
The final step in this approach to 1 was the reductive
alkylation of piperazine 5b with ketone 8 (Scheme 3). The
original conditions were those of Abdel-Magid and Mary-
anoff using sodium triacetoxyborohydride as the reducing
agent.7 This provided 1 and its diastereoisomer 2 with the
nitrogen and the oxygen in a cis relationship in a 2:3 ratio.
Surveying a large number of reductive alkylation conditions
produced the following results. Hydrogenation over pal-
ladium on carbon in ethanol gave the same ratio of 2:3, while
initial reaction with titanium tetraisopropoxide in ethanol
followed by sodium borohydride gave 1:14 favoring the
undesired isomer 2.8 The use of the more hindered sodium
tri-(2-ethylhexanoyloxy)-borohydride9 was one practical
method which at least improved the ratio of isomers to 1:1,
and this was used on a large scale to produce 7.5 kg of 1.
The yield for the final step at this scale was 34%, and
compound 1 was isolated in high purity by crystallization
from 2-propanol. Luckily, crystallization of mixtures of 1
and 2 from either ethanol or 2-propanol resulted in the
removal of the undesired 2, even if it was the major
component in the mixture.
While the reductive alkylation chemistry was used on a
large scale, the low diastereoselectivity of the reaction caused
us to examine other options. The reduction of ketone 8 with
sodium borohydride in ethanol gave mainly one alcohol
isomer 11 in 95% yield. The reaction of alcohol 11 with
phthalimide under Mitsunobu conditions provided phthal-
imide 12 in 57% unoptimized yield10 (Scheme 4). The
stereochemistry of 12 was proven by single-crystal X-ray
analysis and was shown to have the desired relationship
between the nitrogen substituent and the spiro-oxygen atom
(Figure 1). The corresponding primary amine derived from
12 by hydrazinolysis of the phthalimide group was also
formed in high yield, but introduction of a piperazine moiety
was expected to require too many steps or hazardous
alkylating reagents.
Displacement of the mesylate 13 which was available in
high yield from alcohol 11 was considered next. Initial
attempts to displace mesylate 13 with a stoichiometric
amount of piperazine 5b were unsuccessful in a variety of
solvents, leading to either elimination of the mesylate or
incorporation of the solvent in the case of alcohols. However,
the reaction of 13 with an excess of piperazine 4b (10:1 by
weight) in a minimum of 2-propanol at reflux gave the
desired piperazine derivative in 70% yield after an acid/base
(7) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett.
1990, 31, 5595-5598.
(8) This was a variation on the work of Mattson who used sodium cyanoboro-
hydride as the reducing agent. Mattson, R. J.; Pham, K. M.; Leuck, D. J.;
Cowen, K. A. J. Org. Chem. 1990, 55, 2552-2554.
(9) McGill, J. M.; LaBell, E. S.; Williams, M. A. Tetrahedron Lett. 1996, 37,
3977-3980.
(11) The figure was plotted in Chem3D Plus (Cambridge Scientific Computing,
Inc.) using the experimentally determined coordinates. Atomic coordinates
have been deposited for the X-ray structure with the Cambridge Crystal-
lographic Data Centre.
(10) Mitsunobu, O. Synthesis 1981, 1-28.
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1
Scheme 5
was 60.9 g, 74.4%: mp 128-132 °C. HMR (CDCl3, 400
MHz) δ 7.35-7.13 (m, 4), 4.81 (s, 2), 3.61 (s, 2), 3.54 (s,
2), 3.50 (s, 2), 2.40-1.70 (m, 8), 1.0 (s, 6).
3′H-Spiro[cyclohexane-1,1′-isobenzofuran]-4-one (8).
Diol 7 (100 g, 0.326 mole) was dissolved in 80% trifluoro-
acetic acid and water (342 mL) at room temperature and
was stirred overnight. The reaction was cooled to -20 °C,
and tetrahydrofuran (210 mL) was added slowly with an
exotherm noted. The reaction was recooled to 0 °C, and 25%
sodium hydroxide solution ( ∼200 mL) was added slowly
to adjust the pH to 11.5. Water (700 mL) was added to the
mixture to precipitate the product. The slurry was stirred
overnight. The solids were filtered and reslurried in water
(350 mL). The solids were collected and dried in vacuo. This
material was suitable for use in the next step. The yield was
work up. The neutral fraction contained up to 15% of the
olefin side product. The final coupling of piperazine 14 and
difluorobenzonitrile 3 was done in refluxing acetonitrile in
the presence of 1 equiv of potassium carbonate and provided
1 in 68% yield (Scheme 5).
In summary, two viable routes for scale-up have been
demonstrated for the synthesis of a novel dopamine (D4)
antagonist. The preferred method utilized a diastereoselective
sodium borohydride reduction and alkylation of piperazine
with the secondary mesylate 13 to make a key bond
connection. This synthesis also allowed for the introduction
of the most expensive starting material 3 for this compound
in the final synthetic step.
1
45.5 g, 69%: mp 102-106 °C. IR (KBr) 2221 cm-1. H
NMR (CDCl3, 400 MHz) δ 2.16-2.11 (m, 4), 2.41-2.36
(m, 2), 2.95-2.83 (m, 2), 5.16 (s, 2), 7.11-7.08 (m, 1),
7.33-7.28 (M, 3). 13C NMR (CDCl3) δ 37.0, 37.9, 71.1,
85.1, 120.5, 121.3, 127.5, 128.0, 138.8, 144.4, 211.6.
Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C,
77.21; H, 7.06.
HPLC: Inertsil, C-8, 5% acetonitrile/16% tetrahydrofuran/
79% water, pH 3.2 with triethylamine phosphoric acid buffer;
retention time: 8, 16 min.
Experimental Section
The following procedures were from laboratory experi-
ments and were followed as described in the large-scale
preparation of 1 by the reductive alkylation process. Melting
points were determined on a Thomas-Hoover capillary
melting point apparatus and were uncorrected. NMR spectra
were obtained on either a Brucker WM 300 (300 MHz) or
a Varian Unity 400 (400 MHz) spectrometer in deuterio-
chloroform. Infrared spectra were taken in KBr by diffuse
reflectance infrared Fourier transform spectroscopy (DRIFTS).
Mass spectra were determined with a Finnigan 4510 mass
spectrometer using fast atom bombardment (FAB). Elemental
analyses were performed by Schwarzkopf Microanalytical
Laboratory, Woodside, NY
9-(2-Hydroxymethyl-phenyl)-3,3-dimethyl-1,5-dioxa-
spiro[5.5]undecan-9-ol (7). 2-Bromobenzyl alcohol (50 g,
0.267 mol) was dissolved in dry tetrahydrofuran (570 mL)
and cooled to -60 °C under nitrogen. n-Butyllithium (246
mL of a 2.5 M solution in hexanes, 0.61 mol) was added
dropwise over 20 min. The reaction was stirred at this
temperature for 0.5 h. 1, 4-Cyclohexanedione mono-2,
2-dimethyl trimethylene ketal (74.1 g, 0.374 mole) in
tetrahydrofuran (250 mL) was added dropwise over twenty
min. The reaction was allowed to warm to -15 °C, and
saturated aqueous ammonium chloride (750 mL) was added,
and there was a mild exotherm which raised the final
temperature to 15 °C. The reaction mixture contained some
precipitated salts which were removed by filtration. The
aqueous layer was separated, and the organics were washed
with saturated ammonium chloride. The organic layer was
concentrated in vacuo with addition of isopropyl ether to
provide a slurry of solids in isopropyl ether with a volume
of 250 mL. This was cooled to room temperature and diluted
with hexanes (500 mL). The solids were collected, washed
with hexanes, and dried in vacuo. The yield of white solids
2-Fluoro-4-piperazin-1-yl-benzonitrile (5b). Piperazine
(116 g, 1.35 mol) and potassium carbonate (74.5 g, 0.54 mol)
were combined in acetonitrile (750 mL) under nitrogen. 2,
4-Difluorobenzonitrile 3 (75 g, 0.54 mol) in acetonitrile (188
mL) was added dropwise over 100 min with the reaction
temperature starting at 15 °C and rising to 29 °C. The
reaction was stirred at room temperature overnight. The
inorganic solids were removed by filtration, and the filtrate
was diluted with water (1125 mL). The mixture was
concentrated under vacuum to remove most of the acetoni-
trile, and the aqueous layer was extracted with ethyl acetate
(2.6 L). The organic layer was separated and washed with
water (3 × 750 mL) and with brine (375 mL). The organics
were dried over magnesium sulfate and concentrated in vacuo
with the addition of isopropyl ether to achieve a final volume
of 375 mL. The solids were collected, washed with fresh
isopropyl ether, and dried in vacuo. The yield of solids was
1
79.5 g, 72%: mp 67-68 °C. H NMR (CDCl3, 400 MHz)
δ 7.33 (dd, 1), 6.58 (dd, 1), 6.49 (dd, 1), 3.27-3.23 (m, 4),
2.97-2.93 (m, 4), 1.70 (s, 1). 13C NMR (CDCl3) δ 166.5,
163.1, 155.7, 155.5, 133.81, 133.78, 115.4, 109.77, 109.75,
100.6, 100.3, 88.2, 87.8, 48.0, 45.6.
Anal. Calcd for C11H12FN3: C, 64.37; H, 5.89, N, 20.47.
Found: C, 64.33; H, 5.82; N, 20.35.
HPLC: Inertsil, C-8, 92.5% acetonitrile/7.5% pH 3.2
buffer (0.1% H3PO4, 0.2% triethylamine): retention times:
5b, 9.685 min; ortho-isomer, 14.2 min.
3′H-Spiro[cyclohexane-1,1′-isobenzofuran]-(cis)-4-ol (11).
Ketone 8 (3.21 g, 15.9 mmol) was dissolved in ethanol (32
mL) and cooled in an ice bath, while sodium borohydride
(0.91 g, 23.8 mmol) was added as a solid. The ice bath was
removed, and the reaction was stirred at room temperature
overnight. The reaction solvent was evaporated in vacuo,
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and methylene chloride (30 mL) was added followed by 1
N HCl (30 mL). The layers were separated, and the organics
were washed with brine, dried over magnesium sulfate, and
evaporated to dryness. Isopropyl ether was added to the crude
material. When crystallization began, the slurry was diluted
with an equal volume of hexanes. The solids were collected
and dried to provide 1.8 g of white solids, 56% yield: mp
117-118 °C. IR (KBr) 3456, 3422, 1477, 1460, 1443 cm-1.
1H NMR (CDCl3, 400 MHz) δ 7.27-7.18 (m, 3), 7.07 (m,
1), 5.05 (s, 2), 3.73 (m, 1), 1.96-1.67 (m, 9). 13C NMR
(CDCl3) δ 31.9, 35.3, 70.13, 70.4, 85.4, 120.5, 121.1, 127.2,
127.5, 138.9, 145.8. Mass spectrum (m/e) 204 (M+).
Anal. Calcd for C13H16O2: C, 76.44; H, 7.89 Found: C,
76.19; H, 7.87.
Methanesulfonic Acid 3′H-Spiro[cyclohex-1,1′-isoben-
zofuran]-(cis)-4-yl Ester (13). cis-Alcohol 11 was dissolved
in methylene chloride (70 mL), and triethylamine (6.24 mL,
44.8 mmol) was added. The reaction was cooled in an ice
bath, and methanesulfonyl chloride (3.55 mL, 44.8 mmol)
was added dropwise. After 1 h, the reaction was washed with
water and then with brine and was dried over magnesium
sulfate. The solvent was evaporated in vacuo to provide the
desired product as a white solid, 11.85 g, 98% yield: mp
123-124 °C. IR (KBr) 3019, 2950, 2933, 1479, 1461, 1458,
1447, 1441 cm-1. 1H NMR (CDCl3, 400 MHz) δ 7.27-7.19
(m, 3), 7.05 (m, 1), 5.05 (s, 2), 4.78 (m, 1), 3.03 (s, 3), 2.11
(m, 4), 1.80 (m, 2), 1.76 (m, 2). 13C NMR (CDCl3) δ 29.0,
35.1, 39.0, 70.9, 80.5, 84.6, 120.4, 121.2, 127.4, 127.8, 138.9,
144.9. Mass spectrum (m/e) 282 (M+).
second half of the 2-ethylhexanoic acid (138 mL, 1.73 mol)
was added. The mixture was stirred overnight at room
temperature. A solution of 2-fluoro-4-piperazin-1-yl-ben-
zonitrile 5b (40.6 g, 0.198 mol) and ketone 8 (50 g, 0.247
mol) in methylene chloride (300 mL) was added over five
min, and the reaction was stirred for 7 h. Water (1000 mL)
was added to the reaction mixture, which caused some gas
evolution. The layers were separated, and the aqueous layer
was extracted a second time with methylene chloride (250
mL). The combined organics were washed with water. The
methylene chloride was removed by distillation at atmos-
pheric pressure as isopropyl alcohol was added. The product
crystallized from the 2-propanol and was collected. The yield
was 26.16 g, 34%. This material contained <1% of the cis-
isomer 2. This was removed during the formation of the
methanesulfonic acid salt.
HPLC: Inertsil, C-8, 5% acetonitrile/16% tetrahydrofuran/
79% water, pH 3.2 with triethylamine phosphoric acid
buffer: retention times: 1, 11.4 min; 2, 14.2 min.
(B) Substituted piperazine 14 (7.82 g, 28.8 mmol), 2,4-
difluorobenzonitrile 3 (4.4 g, 31.6 mmol), and potassium
carbonate (4.36 g, 31.6 mmol were suspended in dry
acetonitrile (80 mL) under nitrogen and heated to reflux for
24 h. The solution was cooled to room temperature and
diluted with water (800 mL) to precipitate the crude product.
The crude solids were refluxed in 95% ethanol (150 mL)
overnight and then were stirred at room temperature for 1
h. The solid product was collected, washed with 2-propanol,
and dried in vacuo to provide 7.47 g, 66% yield: mp 200-
1
Anal. Calcd for C14H18O4S: C, 59.55 H, 6.43 Found: C,
59.82; H, 6.23.
201 °C. IR (KBr) 2221 cm-1. H NMR (CDCl3, 400 MHz)
δ 1.6 (m, 2), 1.9 (m, 4), 2.0 (m, 2), 2.4 (s, 1), 2.69 (m, 4),
3.37 (m, 4), 5.0 (s, 2), 6.63 (m, 2), 7.2 (m, 4), 7.4 (m, 1).
13C NMR (CDCl3) δ 24.7, 33.0, 47.3, 49.4, 58.9, 70.5, 86.7,
100.4, 100.6, 109.7, 115.4, 121.1, 121.2, 127.1, 127.4, 133.9,
139.2, 146.2, 155.2, 155.3, 166.1. Anal. Calcd for C24H26-
FN3O: C, 73.63; H, 6.69; N, 10.73. Found: C, 73.30; H,
6.77; N, 10.69.
1-(3′H-Spiro[cyclohex-1,1′-isobenzofuran]-(trans)-4-yl)-
piperazine (14). Mesylate 13 (11.72 g, 41.6 mmol) and
piperazine (117 g, 10 w/w) were combined in 2-propanol
(120 mL) and heated to 114 °C for 28 h under nitrogen.
The reaction was allowed to start cooling, and water (100
mL) was added while still warm. The mixture was diluted
with more water (200 mL) and extracted with methylene
chloride (3 × 100 mL). The methylene chloride was washed
with water (2 ×), and the solvent was replaced with ethyl
acetate. The desired product was extracted from the ethyl
acetate with 1 N sulfuric acid (2 × 25 mL). The acidic
aqueous layers were combined, and the pH was raised to
pH 12 with 1 N NaOH. The basic aqueous layer was
extracted with methylene chloride. The organics were washed
with brine, dried over magnesium sulfate, and evaporated
to a solid which was suitable for use in the next reaction.
2-3′H-Spiro[cyclohex-1,1′-isobenzofuran]-(trans)-4-yl-
isoindole-1,3-dione (12). cis-Alcohol 11 (18.87 g, 92.5
mmol), triphenylphosphine (26.66 g, 101.8 mmol) and
phthalimide (14.28 g, 97.1 mmol) were dissolved in tetrahy-
drofuran and stirred with ice-bath cooling, while diethyl
azodicarboxylate (16 mL, 101.8 mmol) dissolved in tetrahy-
drofuran (25 mL) was added dropwise over 25 min. The
reaction was warmed to room temperature and stirred
overnight. The reaction was cooled in an ice-water bath.
The solids were collected and washed with tetrahydrofuran.
Concentration of the filtrate to lower volume gave a second
crop. The combined crops were dried in vacuo to provide
17.8 g, 57% yield: mp 203-207 °C. 1H NMR (CDCl3, 400
MHz) δ 8.09 (d, 1), 7.88 (m, 2), 7.75 (m, 2), 7.43-7.28 (m,
2), 7.20 (d, 1), 5.10 (s, 2), 4.40 (m, 1), 2.83 (dq, 2), 2.12-
1.72 (m, 4). 13C NMR (CDCl3) δ 25.6, 36.8, 49.4, 70.8, 86.2,
121.4, 123.3, 123.4, 127.5, 127.8, 132.3, 134.2, 139.9, 145.0,
168.8. The structure was confirmed by single-crystal X-ray
analysis.
1
The yield was 7.85 g (70%): mp 118-119 °C. H NMR
(CDCl3, 400 MHz) δ 7.32-7.17 (m, 4), 5.03 (s, 3), 2.93
(m, 4), 2.53 (m, 4), 2.32 (m, 1), 2.04-1.82 (m, 7), 1.62 (m,
2). 13C NMR (CDCl3) δ 24.6, 33.6, 46.6, 51.2, 60.1, 70.4,
86.9, 121.1, 121.5, 127.0, 127.3, 139.3, 146.3. Mass spectrum
(m/e) 272 (M+).
2-Fluoro-4-(trans)-(4-(3′H-spiro[cyclohex-1,1′-isoben-
zofuran]-4-yl)-piperazin-1-yl)-benzonitrile (1). (A) Sodium
borohydride (18.7 g, 0.494 mole) was suspended in meth-
ylene chloride (750 mL) and treated with 2-ethylhexanoic
acid (138 mL, 1.73 mol). This was stirred for 1 h, and the
Anal. Calcd for C21H19NO3: C, 75.66; H, 5.74; N, 4.20.
Found: C, 75.75; H, 5.79; N, 4.14.
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463

Acknowledgment
We thank Dr. Jon Bordner of Pfizer Central Research for
the determination of the single crystal X-ray structure of 12.
is available free of charge via the Internet at http://
pubs.acs.org.
Received for review April 30, 1999.
OP990191U
Supporting Information Available
Experimental and crystallographic details. This material
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