3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonists

Article abstract of DOI:10.1021/jm0004998

The development of very high affinity, selective, and bioavailable h5-HT_2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT_2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pKa of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT_2A receptors, with bioavailability of 80% and half-life of 12 h in rats.

Full text of DOI:10.1021/jm0004998

J . Med. Chem. 2001, 44, 1603-1614
1603
3-(4-F lu or op ip er id in -3-yl)-2-p h en ylin d oles a s High Affin ity, Selective, a n d Or a lly
Bioa va ila ble h 5-HT2A Recep tor An ta gon ists†
Michael Rowley,* David J . Hallett, Simon Goodacre, Christopher Moyes, J ames Crawforth, Timothy J . Sparey,
Smita Patel, Rose Marwood, Shil Patel, Steven Thomas, Laure Hitzel, Desmond O’Connor, Nicola Szeto,
J ose L. Castro, Peter H. Hutson, and Angus M. MacLeod
Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received November 22, 2000
The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists
is described. By investigation of the optimal position for the basic nitrogen in a series of
2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the
piperidine it was not necessary to further substitute the piperidine in order to obtain good
binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the
IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improve-
ments could be made to oral bioavailability in this series by reduction of the pKa of the basic
nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-
yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the
6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with
a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist
with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in
rats.
In tr od u ction
Schizophrenia is a severe psychiatric illness which
affects approximately 1% of the population. The disease
is characterized by positive symptoms, including delu-
sions, hallucinations, and irrational fears, negative
symptoms, such as social withdrawal and the inability
to experience pleasure, and cognitive disruption.1 Clas-
sical neuroleptics, which are presumed to act by an-
tagonism of dopamine D2 receptors,2,3 are useful for the
treatment of the positive symptoms but cause mecha-
nism based side effects such as movement disorders and
increases in serum prolactin. The first of the ‘atypical’
neuroleptics, clozapine4 (1, Figure 1), is used to treat
both positive and negative symptoms of the illness, does
not cause extrapyramidal side effects (EPS), and is also
beneficial in a number of patients refractory to the
effects of classical neuroleptics. However, in a small but
significant number of patients, clozapine causes agran-
ulocytosis, and its use must be closely monitored.5 A
decade ago it was suggested6 that an important feature
of atypical antipsychotic drugs was their relative affini-
ties at serotonin 5-HT2 and dopamine D2 receptors, and
that affinity higher at the former than the latter led to
an atypical profile. Recent years have seen the introduc-
tion of a number of new drugs with combined 5-HT2/D2
(among others) affinities, such as risperidone (2),7
olanzapine (3),8 and sertindole (4).9 These drugs have
a decreased, though perhaps not completely absent,
F igu r e 1. Recent and potential neuroleptics.
propensity to cause EPS compared to classical neuro-
leptics,10 and the first two are being used increasingly.
cause of prolongation of corrected QT interval11,12 in
Sertindole has recently been withdrawn from use be-
some patients, presumably due to this compound’s
effects at IKr channels, a voltage gated ion channel
† Dedicated to Professor Ian Fleming on the occasion of his 65th
birthday.
* E-mail: michael_rowley@merck.com. Current address: IRBM, Via
involved13 in control of the heart rhythm. Side effects
that still remain troublesome in the newer neuroleptics
Pontina Km 30600, 00040 Pomezia-Rome, Italy.
include weight gain, sexual dysfunction, and sedation
10.1021/jm0004998 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

1604 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Ta ble 1. Position of the Basic Nitrogen
Rowley et al.
Sch em e 1a
a
Reagents: (i) 1-benzyl-3-piperidone, H3PO4, AcOH; (ii) H2/Pd/
C; (iii) NH4CO2H, Pd/C, MeOH, reflux; (iv) HCHO, NaCNBH3,
AcOH; (v) PhCH2CH2Br, CsCO3, DMF; (vi) 1-(2-chloroethyl)-2-
imidazolidinone, CsCO3, DMF.
binding selectivity to 5 over 5-HT2C receptors and
negligible affinity at dopamine receptors and IKr chan-
nels. We also considered good pharmacokinetics in two
species vital both for safety assessment and to be
predictive of appropriate pharmacokinetics in humans.
Previous reports include the discovery of 2-aryltryp-
tamines as high affinity selective h5-HT2A antagonists,17
albeit with low oral bioavailability, and modifications
to the amine side chain that led to compounds with
modest rat oral bioavailability.18 The phenethylpiperi-
dine (6, Table 1) had subnanomolar 5-HT2A affinity and
12% oral bioavailability in rats, which was improved to
18% by the [3.2.1] bicyclic analogue (7). Along with the
desire to further improve bioavailability, a major issue
with this type of compound was the high affinity at the
IKr potassium channel: compounds 6 and 7 had affini-
ties of 80 and 18 nM, respectively. On the basis of our
knowledge of the pharmacophore for binding to the IKr
channel, we believed that this affinity was in large part
due to the phenethyl group on the basic nitrogen, which
in these series was necessary for high affinity binding
to the 5-HT2A receptor. In this paper we describe the
synthesis of 2-aryl-3-substituted indoles where the
position of the basic nitrogen has been moved and show
that with 3-substituted piperidines the phenethyl group
is not necessary for high affinity. By modifications to
the indole core, and adjustment of the pKa of the basic
nitrogen, compounds with good bioavailability have been
discovered.
a
Affinities at human cloned 5-HT2A, 5-HT2C, and D2 receptors,
rat R1 adrenergic receptors, and the IKr potassium channel
(hERG).
and orthostatic hypotension, the last two probably
arising from antagonism of R1 adrenergic receptors.10
There is clearly still a need for improved therapy in this
area.
Although the importance of the 5-HT2 receptor in
schizophrenia was hypothesized more than 10 years ago,
until recently no selective receptor antagonist had been
tested in clinical trials. 5-HT2 receptors have been
cloned,14 with the current classification being 5-HT2A
5-HT2B, and what was 5-HT1C reclassified as 5-HT2C
,
.
Compound 5 (MDL10090715) is a high affinity human
5-HT2A receptor antagonist with selectivity over h5-
HT2C (40-50-fold in our binding assay) and R1 (>1000-
fold) receptors and very low affinity at all the dopamine
receptor subtypes. In a phase II clinical trial16 for
schizophrenia, 5 was claimed to improve both positive
and negative symptoms, with no increase in body weight
or serum prolactin, and EPS similar to placebo. This
result seemed to indicate the first nondopamine D2
mediated, well-understood mechanism for treating schizo-
phrenia and offered a chance of a real breakthrough in
the treatment of this disease.
Syn th esis
Compounds 6, 7, 8,18 17, and 1820 have been de-
scribed. 3-Substituted piperidines (9, 10, 12-14) were
made by the route shown in Scheme 1. 2-Phenylindole
was condensed under acidic conditions19 with N-benzyl-
3-piperidone to give a mixture of regioisomeric tetrahy-
dropyridines. This unstable mixture was hydrogenated
without purification to give the N-benzylpiperidine (12).
The benzyl group was then hydrogenolyzed from the
basic nitrogen by transfer hydrogenation with am-
monium formate as the reductant. Reductive alkylation
We have described some of our own efforts in this
area, with the objective of discovering a novel high
affinity h5-HT2A antagonist with at least comparable

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1605
Sch em e 2a
Sch em e 4a
a
a
Reagents: (i) sarcosine anhydride, POCl3, 100 °C; (ii) NaBH4,
Reagents: (i) 1-methyl-2-piperidone, POCl3, 80 °C; (ii) NaBH4,
MeOH; (iii) LiAlH4, THF, reflux.
MeOH.
was made as shown in Scheme 4. Activation of N,N-
dimethylpiperazinone with phosphorus oxychloride al-
lowed its condensation with 2-phenylindole, which was
then followed by in situ reduction with sodium borohy-
dride. The resulting piperazinone was further reduced
with lithium aluminum hydride to give the final com-
pound. The synthesis of compounds 17 and 18 were the
subject of a separate paper20 in which we described a
novel rearrangement to give trans 3-indolyl-4-fluoropi-
peridines as single enantiomers. The route is exempli-
fied in Scheme 5 for the 6-fluoroindole analogue (22),
along with one of the methods that was used to make
the required substituted 2-arylindole starting material.
Thus, 2-iodo-5-fluoroaniline (38) was condensed with
phenylacetylene under palladium catalysis, then cy-
clized with copper catalysis to give 6-fluoro-2-phenylin-
dole (39). Condensation with 4-piperidone under acidic
conditions gave the tetrahydropyridine, which was
protected as its benzyloxycarbonyl derivative (40). Hy-
droboration of the double bond with bis-isopinocam-
pheylborane21 (from (1S)-(-)-R-pinene) gave the trans
secondary alcohol (41) in 50% enantiomeric excess. This
ratio was increased by formation of the camphanate
ester using the acid chloride derived from (1R)-(+)-
camphanic acid, separation of diastereosiomers by chro-
matography, and hydrolysis of the ester back to the
alcohol. Having obtained the alcohol with high e.e., this
was treated with diethylaminosulfur trifluoride, giving
as far as we could tell a completely regiospecific and
enantioselective rearrangement to the 3-indolyl-4-fluo-
ropiperidine, which on deprotection gave the target
molecule (22). In this case both diastereoisomers of the
camphanate were hydrolyzed and taken through to the
final products. Having both enantiomers to handle
allowed the determination of enantiomeric excess by
chiral HPLC. In other cases in Table 3, the intermediate
camphanate ester was chromatographed to purity by
TLC and NMR, and the final product was then pre-
sumed to be essentially a single enantiomer. To use this
route, it was necessary to make the required indole
starting materials. Compounds 22, 23, 26, and 33 were
made through the route described above, making the
indoles from the appropriate iodoaniline and substituted
acetylene. The starting materials for compounds 20, 21,
and 25 were made using a Madelung indole synthesis,
illustrated for 5-fluoro-2-phenylindole (43) in Scheme
6. Thus, acylation of 2-amino-5-fluorotoluene (42) with
benzoyl chloride gave the amide, in which the methyl
group was deprotonated with an excess of n-butyl-
lithium leading, after in situ cyclization and dehydra-
tion, to the required compound. 7-Fluoro-2-phenylindole
(46) was not accessible via this route, and was made
using the chemistry22 shown in Scheme 7. 2-Fluoro-
aniline (44) was oxidized with tert-butylhypochlorite,
and on treatment with methylthioacetophenone and
Ta ble 2. Alternatives to Piperidine
a
See footnotes to Table 1.
Sch em e 3a
a
Reagents: (i) MeMgBr, benzene; (ii) chloroacetyl chloride; (iii)
ethanolamine, Et3N, MeOH; (iv) NaBH4, MeOH; (v) HCl, MeOH.
of the basic nitrogen with formaldehyde and sodium
cyanoborohydride gave the N-methyl analogue (10), and
alkylation with the appropriate alkyl halide gave the
phenethyl compound (13) and the imidazolidinone (14).
The 2-substituted piperidine (11) was made (Scheme 2)
by condensation of 2-phenylindole with 1-methyl-2-
piperidone, followed by reduction of the resultant tet-
rahydropyridine without purification with sodium boro-
hydride. Morpholine (15, Table 2) was made by acylation
(Scheme 3) of the anion of 2-phenylindole with chloro-
acetyl chloride. The chloroketone was then displaced
with ethanolamine to give the alcohol (38). Reduction
of the ketone, followed by cyclization under acidic
conditions, gave the desired product. Piperazine (16)

1606 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Rowley et al.
Sch em e 5a
a
Reagents: (i) phenylacetylene, Pd(Ph3P)4, CuI, Et2NH, rt; (ii) CuI, CaCO3, DMF, 120 °C; (iii) 4-piperidone, H3PO4, AcOH; (iv) BnOCOCl;
(v) (-)-Ipc2BH, H2O2, NaOH; (vi) camphanic acid chloride, pyridine; (vii) separate; (viii) K2CO3, MeOH; (ix) DAST, EtOAc, -50 °C to rt;
(x) HCO2H/Pd/C.
Sch em e 8a
Ta ble 3. Indole Substitution
a
Reagents: (i) LiTMP, ZnCl2, 3-bromofuran, Pd(Ph3P)4; (ii)
NaOMe; (iii) HCO2H; (iv) LiTMP, MeOCOCN.
a
See footnotes to Table 1.
described, giving 4720 with 88% enantiomeric excess.
Material was used with this e.e., since it was known
that the minor enantiomer had low affinity for 5-HT2A
receptors. Compounds in Table 4 were presumed to have
this e.e. except 32 and 35, made by the route shown in
Scheme 5 and for which the e.e.’s were measured, and
36 which was racemic. Treatment of 47 with lithium
tetramethylpiperidide gave the 2-lithioindole, which
could then be transmetalated to the organozinc and
cross coupled using Negishi type chemistry,23 leading
to compounds such as the furan (30), or directly
quenched with electrophiles, leading for example to the
amide (35). Compounds 27-32 were made using the
Negishi chemistry, and 34 and 35 using the direct
quench. Protected analogues of compounds 19 and 26
have been described,20 and they were deprotected using
standard methods. The final compound in Table 4,
piperidine (36), was made from 2-(4-fluorophenyl)-6-
fluoroindole, made via the iodoaniline/acetylene route,
using the chemistry shown in Scheme 1.
Sch em e 6a
a
Reagents: (i) PhCOCl, Et3N; (ii) n-BuLi, THF.
Sch em e 7a
a
Reagents: (i) tert-butyl hypochlorite, DCM, -78 °C; (ii) R-
methylthioacetophenone, Et3N; (iii) Raney nickel.
rearrangement with triethylamine gave the 3-meth-
ylthioindole (45). Desulfurization with Raney nickel led
to the desired indole. Finally, to rapidly explore the
effect of substitution at the 2-postion of the indole,
chemistry was developed to introduce this substituent
at the end of the synthesis. The bis BOC protected,
2-unsubstituted indole (47, Scheme 8) was made using
the same DAST rearrangement chemistry that has been
Biology
Compounds were evaluated for their ability to dis-
place [3H]-ketanserin binding to human 5-HT2A recep-
tors24 stably expressed in CHO cells, [3H]-mesurgeline

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1607
Ta ble 5. Pharmacokinetics
Ta ble 4. Indole 2-Substituent
a
Maximum blood concentration after oral dosing at 2 mg/kg
b
po. Area under the concentration-time curve for 0-4 h after 2
mg/kg po. c Bioavailability calculated from dosing at 0.5-2 mg/
kg iv and po. Terminal half-life following iv dosing. e Rat phar-
d
macokinetics measured over 48 h.
Methods for determination of pharmacokinetics and
metabolism are described in the Experimental Section.
Discu ssion
Table 1 shows the results of an investigation of the
optimal position for the basic nitrogen in 2-phenyl-3-
piperidinylindoles. It was known18 that in 4-substituted
piperidines a phenethyl group on the basic nitrogen gave
a 30-fold increase in 5-HT2A receptor affinity (6 com-
pared to 8). However, this also led to high IKr affinity,
which was undesirable. Moving the nitrogen to the
3-position of the piperidine gave the racemic compound
(9) which had a 15-fold improvement in binding affinity
at 5-HT2A receptors over the 4-piperidine (8) and very
little IKr affinity. Unlike the 4-substituted piperidines,
in these 3-substituted analogues alkylation of the basic
nitrogen was detrimental to 5-HT2A receptor affinity,
with decreases along the series methyl, benzyl, phen-
ethyl (10, 12, 13). Interestingly, the imidazolidinone-
ethyl group found in sertindole, while causing a moder-
ate loss of affinity, gave a compound (14) with improved
pharmacokinetics (Table 5), as it had in the 4-piperidi-
nyl series. The reasons for this observation are not clear.
Moving the nitrogen to the 2-position of the piperidine
(11) gave a compound with lower affinity than the
3-piperidine (9), and this type of compound was not
pursued.
a
See footnotes to Table 1.
To determine if these compounds were orally bio-
available, experiments were performed in which the
compound was dosed orally at 2 mg/kg to three rats,
and plasma samples were taken up to 6 h. From
measurements of concentrations in these samples,
maximal plasma concentration (Cmax) and the area
under the curve (AUC) from 0 to 6 h for oral dosing
could be determined. If compounds looked promising in
these experiments, then the intravenous leg of the
pharmacokinetic experiment was also performed, al-
lowing the calculation of bioavailability (F) and half-
life (T1/2). Results of these experiments are shown in
Table 5. It can be seen that, while the 3-piperidine (9)
had greater selectivity over IKr than its 4-substituted
analogues (6 and 7), the AUC was lower for 9 than 7,
probably indicative of poorer oral bioavailability. We had
already learned28 from work on 5-HT1D agonists that
binding to human 5-HT2C receptors stably expressed in
CHO cells, [3H]-spiperone binding to CHO cells stably
expressing hD2 receptors,25 [3H]-prazosin binding to rat
cortical membranes,26 and [3H]-dofetilide binding to
HEK cells stably expressing hERG, which encodes the
IKr potassium channel. For h5-HT2A and hD2 receptors,
the Ki values are quoted as the geometric means of at
least three separate determinations, and the errors of
the mean are within 2-fold of the mean. In other binding
assays, Ki values are the geometric mean of at least two
independent determinations. In a functional assay
compounds were evaluated for their effect alone (agonist
activity) and their ability to block (antagonist activity)
5-HT (1 µM) mediated accumulation of inositol phos-
phates in CHO cells stably expressing h5-HT2A recep-
tors.24,27

1608 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Rowley et al.
in another series of indole-3-alkylamines it was benefi-
cial to pharmacokinetics to lower the pKa of a basic
nitrogen. With this in mind, we investigated a number
of compounds in which the spatial relationship between
the indole and the basic nitrogen was maintained, but
electron withdrawing groups were introduced which
would make the nitrogen less basic.
F igu r e 2. Major metabolite of 17.
Introduction of an oxygen atom into the piperidine,
giving the morpholine (15, Table 2), caused an 18-fold
loss of affinity at 5-HT2A receptors. This reduction was
even more dramatic with the piperazine (16) where the
loss was 2 orders of magnitude. However, attaching a
heteroatom to the ring rather than including it in the
ring proved more successful. The hydroxypiperidine (19)
maintained affinity at 5-HT2A receptors when compared
to the parent compound (9), and its fluorinated analogue
(17), if anything, improved affinity. The binding to
5-HT2A receptors is stereospecific, with the enantiomer
of 17, compound 18, showing at least 400-fold lower
affinity than the active enantiomer (at this level it is
hard to tell whether the inactive enantiomer has some
affinity, or whether there is 0.25% of the active enan-
tiomer present). The measured pKa of 17 was 8.5,
compared to 10.4 for the compound (9) without the
fluorine atom. We were delighted to find that this
change gave a compound with moderate bioavailability
in rats (18%) and good pharmacokinetics in dogs (F 37%,
T1/2 7.4 h). IKr affinity remains low in this compound,
and it has good selectivity over hD2 receptors and
moderate selectivity over 5-HT2C and R1 adrenergic
receptors. In addition to these affinities, 17 was tested
in a Panlabs screen at over 100 different receptors,
enzymes, and uptake proteins and had greater than
1000-fold selectivity for the targeted receptor over off-
target receptors, channels, and enzymes. In CHO cells,
17 was an antagonist at the 5-HT2A receptor, as
determined24,27 by its lack of intrinsic efficacy, and its
ability to block the 5-HT (1 µM) mediated accumulation
of inositol phosphates.
indole (26) having only moderate binding. Large sub-
stituents were allowed, with both 1- (27) and 2- (28)
substituted naphthalenes showing only a small loss in
affinity at 5-HT2A receptors compared to the phenyl
compound (22). Aromatic heterocycles were also allowed,
both six-membered (29) and five-membered, such as
furan (30) and thiophene (31) which had a binding
profile almost identical to 22. The substituent did not
need to be aromatic, with the cyclohexyl compound (32)
having subnanomolar affinity. The ester (33) also
maintained moderate binding, which could be increased
back to very high binding with the anilide (34). How-
ever, the pharmacokinetics of 34 were poor, perhaps due
to metabolism of the amide part of the molecule. The
last two compounds in Table 4 again compare the effect
of having the fluorine on the piperidine ring. Both are
2-(4-fluorophenyl)-6-fluoroindoles, compound 35 having
the fluorine on the piperidine and therefore presumably
a lower pKa, while compound 36 does not. Both had the
same very high affinity at 5-HT2A receptors, but the
compound with the lower pKa had better selectivity,
particularly over dopamine hD2 receptors.
Metabolic studies were performed on compound 17
both in vitro and in vivo. On incubation with rat liver
microsomes at 1 µM the major metabolite had a molec-
ular ion 16 mass units higher than the parent com-
pound, indicative of oxidation. On oral dosing to rats
and collection of urine and faeces, analysis indicated the
presence of the same metabolite. This was isolated,
purified, and analyzed by mass spectrometry and NMR
spectroscopy and assigned as the 6-hydroxyindole me-
tabolite (48, Figure 2). Following this result, the phar-
macokinetic behavior of the 6-fluoroindole (22) was
examined (Table 5). By blocking the major site of
metabolism of 17, the rat pharmacokinetics were dra-
matically improved with bioavailability increased to
80% and the half-life to 12 h. Dog pharmacokinetics
remain essentially the same for 22 as 17, with good
bioavailability and half-life. Thus compound 22 is a very
good example of a case in which knowledge of the route
of metabolism of a series of compounds can lead to the
design of structures with improved in vivo properties.
In this case the fluorine atom introduced to give this
increase in bioavailability also gave a 10-fold increase
in binding affinity at the desired receptor, leading to
an outstanding compound both in vitro and in vivo.
With these results, studies were undertaken of the
effect of substitution of the indole ring, and also of
changes to the phenyl group at the 2-position of the
indole. The results of the indole substitution work are
shown in Table 3. Either a fluorine (20) or a chlorine
(21) atom at the 5-position caused a reduction in affinity
at 5-HT2A receptors, and a small loss was observed with
a chlorine at the 6-position (23). However, a fluorine
atom at this position (22) gave an order of magnitude
increase in binding affinity at 5-HT2A receptor. This very
high affinity led to a compound that is 50-fold selective
over R1 receptors, is 100-fold selective over 5-HT2C
receptors, and had greater than 4 orders of magnitude
selectivity over dopamine hD2 and IKr receptors. In the
functional assay 22 was an antagonist at 5-HT2A recep-
tors. Either a fluorine (24) or a chlorine (25) atom at
the 7-position of the indole had little effect on binding
at any of the receptors of interest, except 5-HT2C, at
which a 10-fold reduction in affinity was seen. It is not
entirely clear what the effect in schizophrenia of binding
to 5HT2C receptors may be, so if it were to be an
undesired effect, then this could be a useful finding.
Con clu sion s
In a series of 2-phenyl-3-(3-piperidyl)indoles it was
not necessary to alkylate on the basic nitrogen for
optimal binding to 5-HT2A receptors, and so earlier
problems of binding to the IKr potassium channel were
avoided. Oral bioavailability could be improved in this
series by introduction of an electron withdrawing fluo-
rine atom onto the piperidine, lowering the pKa of the
basic nitrogen, and in this way 17, with moderate
The effects of altering the indole 2-substituent are
shown in Table 4. A substituent in this position was
necessary for high affinity, with the 2-unsubstituted

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1609
The resulting pellet was resuspended in 50 mM Tris-HCl
buffer, pH 7.5, at 2 mg original wet weight/mL. Incubations
were carried out for 30 min at ambient temperature (22 °C)
in the presence of 1 nM [3H]-prazosin (77.2 Ci/mmol, NEN
USA) and initiated by the addition of 400 µL of membranes
in a final assay volume of 500 µL. Nonspecific binding was
determined by 1 µM prazosin. The reaction was terminated
by rapid filtration over GF/B filters (presoaked in 0.5% Triton)
and washed with ice cold 50 mM Tris-HCl, pH 7.5. The
radioactivity bound was determined as described for [3H]-
ketanserin binding studies.
bioavailability in rats, was found. To still further
improve bioavailability, the metabolism of 17 was
studied in rats both in vitro and in vivo, and it was
found that the compound was metabolized primarily by
hydroxylation at the 6-position of the indole. When this
position was blocked with a fluorine atom to give
compound 22, thereby reducing the metabolism, the
bioavailability in rats was increased to 80%, presumably
by reduction in first-pass metabolism, and the half-life
increased to 12 h due to reduced clearance. This fluorine
atom at the 6-positon of the indole also gave an order
of magnitude improvement in binding to the 5-HT2A
receptor, leading overall to an antagonist with high
affinity at 5-HT2A receptors, very good selectivity over
hD2 receptors and IKr channels, and good oral bioavail-
ability in rats and dogs, with long plasma half-life in
both species.
IKr Bin d in g. Binding to the voltage dependent potassium
channel (delayed rectifier current, IKr) was evaluated by
displacement of 4 nM [3H]-dofetilide binding to HEK cells
stably expressing hERG which encodes the IKr potassium
channel. Incubations were carried out in assay buffer (10 mM
HEPES containing 60 mM KCl, 71.5 mM NaCl, 1 mM CaCl2,
2 mM MgCl2, pH 7.4) for 75 min at ambient temperature (22
°C) and initiated with the addition of cell membranes (4 µg
protein/well) in a total assay volume of 400 µL. Nonspecific
binding was determined with 20 µM dofetilide. The reaction
was terminated by rapid filtration over GF/B filters soaked in
0.1% BSA, and radioactivity bound was determined as de-
scribed for [3H]-ketanserin binding studies.
Exp er im en ta l Section
Melting points were taken on a Reichert Thermovar ap-
paratus and are uncorrected. Proton NMR were measured on
Bruker DPX 400, AM 360, or AC 250 spectrometers, chemical
shifts are reported in parts per million (δ) downfield from
tetramethylsilane as internal standard, and coupling constants
are in hertz. Mass spectra were recorded on a VG 70/250
spectrometer. Merck Kieselgel (230-400) mesh was used for
column chromatography. For reactions, dry solvents were used
as bought from Aldrich. Organic solutions were dried with
anhydrous magnesium sulfate. Elemental analyses were done
by Butterworth Laboratories Ltd, Teddington, Middlesex, U.K.
En a n tiom er ic Excess. Compounds were analyzed on a
Hewlett-Packard 1090M series 2 (HP, Germany) HPLC
equipped with an autosampler and a diode array detector.
Chiralcel OD-H (250 × 4.6 mm) and Chiralpak AD (250 × 4.6
mm) (J . T. Baker, U.K.) columns with mixtures of 2-20% of
EtOH in isohexane with 0.1% diethylamine as eluent were
used. Flow rates were between 1 and 2 mL/min, and the
detection wavelength was 300 nm with a bandwidth of 10 nm.
Typically, compounds were dissolved in ethanol, and 5 µL of
a 1 mg/mL solution was injected on the column. All compounds
were baseline resolved.
5-HT2A Recep tor Bin d in g. Chinese hamster ovary (CHO)
cells stably expressing the human 5-HT2A receptor were lysed
by homogenization in 50 mM Tris-HCl buffer (pH 7.5) and
centrifuged at 50000g for 10 min at 4 °C. The resulting pellet
was resuspended in assay buffer (50 mM Tris-HCl) at 2 mg
wet weight/mL. Incubations were carried out in 96-well plates
for 15 min at 37 °C in the presence of 1 nM [3H]-ketanserin
(66.4 Ci/mmol, NEN USA) for displacement studies and
initiated by addition of 200 µL of membranes in a final assay
volume of 500 µL. The reaction was terminated by rapid
filtration over GF/B filters (presoaked in 0.1% BSA) and
washed with ice-cold 50 mM Tris-HCl buffer. Nonspecific
binding was determined with 1 µM Mianserin, and radioactiv-
ity was determined by counting on a Packard Topcount.
Binding parameters were determined by nonlinear least
squares regression analysis from which the inhibition constant
Ki could be calculated for each test compound.
Or a l Absor p tion a n d P h a r m a cok in etic Deter m in a -
t ion s. Male Sprague-Dawley rats weighing approximately
300 g were surgically prepared at least 36 h prior to dosing.
J ugular veins were cannulated under anaesthesia (Isofluo-
rane), and each rat was given a 100 unit dose of heparin (0.1
mL, 1000 units/mL) via the cannula. Rats were individually
housed after surgery and had free access to food and water.
Test compounds were administered i.v. to three rats via a bolus
injection into a tail vein (1 mL/kg in a suitable vehicle) and
orally via a gavage to the stomach (5 mL/kg in a suitable
vehicle). Serial blood samples (approximately 400 µL) were
collected from the jugular vein at time points up to 8 h
postdose. In each case plasma was separated from the blood
by centrifugation and stored at -20 °C until analysis. Systemic
exposure after oral administration was alternatively deter-
mined by administering each test compound to five male
Sprague-Dawley rats via a gavage to the stomach (5 mL/kg
of a 0.5% methocel A4C suspension). At time points up to 4 h
after dosing, one rat per time point was culled and blood
collected.
Female Beagle dogs weighing approximately 10-12 kg were
used for dog pharmacokinetic studies. Test compounds were
administered i.v. to three dogs via a bolus injection into the
cephalic vein (1 mL/kg of a PEG 300 /water solution) and orally
to three dogs via a gavage to the stomach (5 mL/kg of a 0.5%
methocel A4C suspension). Serial blood samples (approxi-
mately 1 mL) were taken from the jugular, saphenous, and
cephalic (oral phase only) veins at time points up to 24 h post
dose. Plasma was separated from the blood by centrifugation
and stored at -20 °C until analysis.
Typically, to aliquots of plasma or blood (50-200 µL) was
added internal standard (10 µL of a 10 ng/µL solution of a
structural analogue), 100 µL of 0.1 M sodium hydroxide, 1 mL
of water, and 4 mL of ethyl acetate. Samples were vortex mixed
and centrifuged (3000 rpm, 10 min). The supernatant was
removed and evaporated to dryness (70 °C, under nitrogen),
and the residue was dissolved in mobile phase (100 µL) and
transferred to an HPLC vial. Calibration standards covering
appropriate ranges were prepared by spiking solutions of
analyte at appropriate concentrations into the same volume
of control plasma or blood, followed by the same sample
preparation procedure. Typically 30 µL injections were made
onto a KR100-5C18 HPLC column (5 cm × 4.6 mm i.d.) with
an isochratic mobile phase consisting of appropriate ratios of
acetonitrile and 25 mM ammonium formate, adjusted to pH 3
with formic acid at a flow rate of 1.0 mL/min split postcolumn
1:10 into a VG Platform II mass spectrometer operating in the
electropositive mode. Detection was by single ion recording,
monitoring for protonated parent ions. Model independant
5-HT2C Recep tor Bin d in g. Chinese hamster ovary (CHO)
cells stably expressing the human 5-HT2C receptor were lysed
by homogenization in 50 mM Tris-HCl containing 0.1% ascor-
bate and 10 µM pargyline, pH 7.7, centrifuged at 50000g for
10 min at 4 °C, and the pellet was resuspended in assay buffer
at 10 mg wet weight/mL. Incubations were performed for 30
min at 37 °C in the presence of 1 nM [3H]-mesulergine (77
Ci/mmol, Amersham U.K.) and initiated by the addition of 400
µL membranes in a final assay volume of 500 µL. Nonspecific
binding was determined with 1 µM Mianserin, and radioactiv-
ity determined as described above for [3H]-ketanserin binding
studies.
Ra t R1 Recep tor Bin d in g. Rat cortical membranes were
lysed by homogenization in 50 mM Tris-HCl buffer, pH 7.5.

1610 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Rowley et al.
pharmacokinetic parameters were determined using standard
formulas in a Microsoft Excel spreadsheet.
benzylpiperidone. The oil was hydrogenated on Pd/C (10% w/w,
0.6 g) in EtOH (50 mL) and concentrated HCl (3 mL) at 50
psi overnight. The mixture was filtered, poured into saturated
NaHCO3, and extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with H2O and brine,
dried, evaporated in vacuo, and purified by flash chromatog-
raphy, eluting with CH2Cl2:MeOH:880 ammonia (98.5:1.5:0.15
v/v) to give 12 (2.2 g, 58%) as a white solid, oxalate salt mp
267-270 °C (from EtOH): 1H NMR (360 MHz, DMSO-d6) δ
1.6-1.7 (1H, m), 1.8-1.9 (2H, m), 2.0-2.1 (1H, m), 2.6-2.7
(1H, m), 3.0-3.1 (3H, m), 3.2-3.3 (1H, m), 3.95 (2 H, br s),
7.00 (1 H, t, J 7), 7.09 (1 H, t, J 7), 7.2-7.6 (11 H, m), 7.80 (1
H, d, J 7), 11.2 (1H, br s); m/z (ES+) 367 (M+ + H). Anal.
(C26H26N2‚0.7C2H2O4) C, H, N.
Meta bolism of Com p ou n d 17. For feces and urine collec-
tion in rat, 17 was administered orally at 3 mg/kg via a gavage
to the stomach (5 mL/kg of a 0.6 mg/mL 0.5% methocel A4C
suspension). Feces and urine were collected over a 18 h period
into a metabowl. The feces was agitated with 30 mL of MeOH
before centrifugation at 4000 rpm for 10 min. To 0.5 mL of
the supernatant was added 0.5 mL of 25 mM ammonium
formate, pH 3.0. The mixture was vortex mixed and centri-
fuged at 4000 rpm for 15 min before analysis of the superna-
tant by LC-MS and LC-fluorescence on the system described
below. To 0.5 mL of urine collected over 0-18 h was added
0.5 mL acetonitrile. The mixture was vortex mixed and
centrifuged (3000 rpm, 10 min), and the supernatant was
analyzed by LC-MS and LC-fluorescence. The remaining c.a.
29 mL of fecal methanolic supernatant was concentrated under
nitrogen, and the residue was reconstituted in 200 µL of DMSO
3-(P ip er id in -3-yl)-2-p h en yl-1H-in d ole (9). Compound 12
(2.1 g, 5.7 mmol), Pd/C (10% w/w, 0.21 g), and ammonium
formate (2.3 g, 29 mmol) were refluxed in MeOH (30 mL) for
24 h. The mixture was cooled, filtered, and purified by flash
chromatography, eluting with CH2Cl2:MeOH:880 ammonia
(98.5:1.5:0.15 v/v) to give 9 (1.1 g, 50%) as a white solid:
1
and analyzed by H LC NMR.
The metabolite was produced in vitro from liver microsomes.
Compound 17 (final concentration 1 µM) was preincubated
with rat liver microsomes prepared from male Sprague-
Dawley rats (final protein concentration of 0.4 mg/mL) in
Dulbecco’s phosphate buffered saline. After incubation for 5
min at 37 °C, the reaction was initiated by the addition of
NADPH (final concentration 2 mM) and was allowed to
proceed for 45 min at 37 °C before termination with an equal
volume of acetonitrile and centrifugation (3000 rpm, 10 min).
The supernatant was analyzed by LC-MS and LC-fluorescence.
For analysis of the metabolite by LC-MS and LC-fluores-
cence, typically 50 µL injections were made onto a KR100-5C18
HPLC column (15 cm × 4.6 mm i.d.) with a mobile phase
consisting of acetonitrile (A) and 25 mM ammonium formate,
adjusted to pH 3 with formic acid (B) at a flow rate 1.0 mL/
min split postcolumn 1:10 into the mass spectrometer with
the following time program: 0 min, 20% A; 5 min, 20% A; 15
min, 60% A; 20 min, 60% A; 21 min, 20% A; 28 min, 20% A.
Detection was both in scan mode and by single ion recording.
Analysis by fluorescence was achieved in a similar way at a
flow rate of 1 mL/min into the fluorescence detector, with
excitation and emission at 235 and 370 nm, respectively.
1
oxalate salt, white crystals mp 258-262 °C (from EtOH); H
NMR (400 MHz, DMSO-d6) δ 1.6-1.8 (1 H, m), 1.8-1.9 (2 H,
m), 2.2-2.4 (1 H, m), 3.00 (1 H, t, J 12), 3.2-3.5 (4 H, m),
6.98 (1 H, t, J 7), 7.09 (1 H, t, J 7), 7.2-7.5 (6 H, m), 7.84 (1
H, d, J 8), 11.3 (1H, br s); m/z (ES+) 277 (M+ + H). Anal.
(C19H20N2‚0.5C2H2O4) C, H, N.
3-(1-Meth ylpiper idin -3-yl)-2-ph en yl-1H-in dole (10). Com-
pound 9 (200 mg, 0.7 mmol), NaCNBH3 (51 mg, 0.8 mmol),
formaldehyde (60 µL, 40% in H2O, 0.8 mmol), and AcOH (97
µL, 1.7 mmol) were stirred in MeOH (5 mL) at 0 °C for 1 h,
then room temperature for 2 h. The solution was poured into
saturated NaHCO3 solution and extracted with EtOAc. The
organic layer was washed with H2O and brine, dried, evapo-
rated in vacuo, and purified by preparative thin-layer chro-
matography, eluting with CH2Cl2:MeOH:880 ammonia (97:3:
0.3 v/v) to give 10 (172 mg, 82%) as a colorless oil: oxalate
salt, mp 287-290 °C (from EtOH); 1H NMR (360 MHz, DMSO-
d6) δ 1.7-1.8 (1 H, m), 1.8-1.9 (2 H, m), 2.0-2.1 (1 H, m), 2.5
(3 H, s), 2.6-2.7 (1 H, m), 3.0-3.2 (3 H, m), 3.2-3.3 (1 H, m),
6.99 (1 H, t, J 7), 7.09 (1 H, t, J 7), 7.2-7.5 (6 H, m), 7.82 (1
H, d, J 8), 11.2 (1H, br s); m/z (ES+) 291 (M+ + H). Anal.
(C20H22N2‚0.5C2H2O4‚0.7H2O) C, H, N.
3-(1-Met h ylp ip er id in -2-yl)-2-p h en yl-1H -in d ole (11).
POCl3 (2.7 mL, 29 mmol) was added dropwise to 1-methyl-2-
piperidone (3.6 mL, 32 mmol), keeping the internal temper-
ature below 15 °C. The resulting thick paste was stirred at 15
°C with occasional shaking for 30 min before adding a solution
of 37 (5.0 g, 26 mmol) in 1-methyl-2-piperidone (5 mL). This
mixture was stirred and shaken at room temperature for 30
min before heating at 80 °C for 3 h. The reaction was cooled,
and the resulting brown solid triturated with 5% aqueous
ammonia (300 mL) to give a yellow suspension. This was
extracted into EtOAc (300 mL), and the organics were then
washed with H2O (300 mL) and brine (300 mL) and evaporated
in vacuo to give a brown solid [m/z (ES+) 289]. This solid was
dissolved in MeOH (60 mL) and CH2Cl2 (60 mL) and cooled to
0 °C before adding NaBH4 (5.0 g, 130 mmol) portionwise over
15 min. The reaction was stirred at room temperature for 90
min and then diluted with H2O (50 mL). The mixture was
evaporated and the residue partitioned between EtOAc (250
mL) and 5% aqueous ammonia (250 mL). The organics were
then washed with H2O and brine, dried, and evaporated in
vacuo to give a pale green solid. This solid was suspended in
warm ether (400 mL) and filtered while warm through glass
microfiber paper (Whatman GF/A). The filtrate was concen-
trated to give the crude product as a yellow solid contaminated
with 2-phenyl indole. Conversion to the oxalate salt gave 11
as colorless cubes (7.15 g, 73%): mp 186-187 °C (from EtOH);
1H NMR (360 MHz, DMSO-d6) δ 1.48-1.66 (1 H, m), 1.77-
1.98 (3 H, m), 2.00-2.12 (1 H, m), 2.27 (3 H, s), 2.34-2.50 (1
H, m), 2.82-2.98 (1 H, m), 3.32-3.40 (1 H, m), 3.98-4.10 (1
H, m), 7.08 (1 H, t, J 8), 7.18 (1 H, t, J 8), 7.42 (1 H, d, J 8),
7.44-7.60 (5 H, m), 8.00 (1 H, d, J 8), 11.63 (1 H, s); m/z (ES+)
291 (M + H+). Anal. (C20H22N2‚C2H2O4‚C2H6O) C, H, N.
For analysis of the metabolite by LC NMR a 50 µL injection
of the fecal extract was made onto a KR100-5C18 HPLC
column (15 cm × 4.6 mm i.d.) with a mobile phase consisting
of acetonitrile (A) and 0.1% trifluoroacetic acid (B) at a flow
rate of 1.0 mL/min into the NMR probe with the following time
program (with UV detection at 300 nm): 0 min, 20% A; 5 min,
20% A; 15 min, 60% A; 20 min, 60% A; 21 min, 20% A; 28
min, 20% A. The major M + 16 metabolite peak was isolated
in the flow cell of an LC NMR probe and gave a spectrum
consistent with the 6-hydroxyindole structure: 1H NMR (500
MHz, MeCN-d3/D2O) δ 6.84 (1H, dd, J 8.7, 2.3), 7.03 (1H, d, J
2.3), 7.57 (1H, t, J 8.1), 7.64 (2H, t, J 8.1), 7.66 (2H, t, J 8.1),
7.73 (1H, d, J 8.7); m/z (ES+) 311 (M+ + H). The aromatic
1
region of the H spectrum revealed the 2-phenyl moiety to be
intact and the four-spin intact indole to have been replaced
by resonances of a three-spin system. The coupling of the three-
spin system was consistent with either 5- or 6-hydroxylation;
however, chemical shift calculations clearly favored 6-hydroxy-
lation.This result was in agreement with 19F NMR work, where
coincidence of the major metabolite and parent fluorine
resonances (-180 ppm) were inconsistent with piperidine
hydroxylation.
3-(1-Ben zylp ip er id in -3-yl)-2-p h en yl-1H-in d ole (12). 2-
Phenylindole (37) (2 g, 10.4 mmol) was stirred at 80 °C in
AcOH (20 mL), and 1-benzyl-3-piperidone hydrochloride hy-
drate (5 g, 21.4 mmol) and 1 M phosphoric acid (10 mL) were
added. After a further 4 h, the mixture was poured into ice/
NH3 and extracted with EtOAc (2 × 20 mL). The combined
organic layers were washed with H2O and brine, dried,
evaporated in vacuo, and purified by flash chromatography,
eluting with CH2Cl2:MeOH:880 ammonia (97:3:0.3 v/v) to give
a pale yellow oil (6 g). This was a mixture of the two isomeric
tetrahydropyridine products which were unstable and starting

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1611
3-(1-(2-P h e n yle t h yl)p ip e r id in -3-yl)-2-p h e n yl-1H -in -
d ole (13). Compound 9 (210 mg, 0.76 mmol), phenethyl
bromide (140 µL, 1 mmol), and Cs2CO3 (0.35 g, 1 mmol) were
stirred in DMF (3 mL) at 60 °C overnight. The mixture was
poured into water and extracted with EtOAc. The organic layer
was washed with H2O and brine, dried, evaporated in vacuo,
and purified by flash chromatography eluting with CH2Cl2:
MeOH:880 ammonia (97:3:0.3 v/v) to give 13 (251 mg, 87%)
as a colorless oil: oxalate salt, white crystals, mp 142-145 °C
Cl2:MeOH:880 ammonia (98:2:0.5 then 96:4:0.5 v/v) to give 15
(1.45 g, 62%): oxalate salt, mp 190-192 °C (from EtOH-Et2O);
1H NMR (360 MHz, DMSO-d6) δ 3.22-3.48 (3 H, m), 3.62 (1
H, t, J 12.2 and 11.9), 3.86 (1 H, t, J 11.6 and 10.3), 4.07 (1 H,
d, J 12.1), 5.07 (1 H, dd, J 11.2 and 1.8), 7.04 (1 H, t, J 7.7
and 7.1), 7.14 (1 H, t, J 7.7 and 7.3), 7.40-7.46 (2 H, m), 7.51-
7.61 (4 H, m), 7.86 (1 H, d, J 7.9), 9.87 (2 H, br s), 11.59 (1 H,
br s); m/z (ES+) 279 (M + H+). Anal. (C18H18N2O‚C2H2O4) C,
H, N.
1
(from Et2O); H NMR (360 MHz, DMSO-d6) δ 1.8-1.9 (2 H,
3-(1,4-Dim eth ylpiper azin -2-yl)-2-ph en yl-1H-in dole (16).
POCl3 (3.3 mL, 35 mmol) was added dropwise to a suspension
of sarcosine anhydride (5.0 g, 35 mmol) in dichloromethane
(10 mL), keeping the internal temperature below 15 °C. The
resulting thick paste was stirred at 15 °C with occasional
shaking for 30 min before adding a solution of 37 (6.18 g, 32
mmol) in dichloromethane (10 mL). This mixture was stirred
at room temperature for 30 min before heating at 80 °C for 3
h. The reaction was cooled, and the resulting dark solid was
suspended in MeOH (100 mL) and CH2Cl2 (100 mL) and cooled
to 0 °C before adding NaBH4 (5.0 g, 130 mmol) portionwise
over 15 min. The resulting solution was stirred at room
temperature for 16 h and then diluted with H2O (50 mL).
MeOH (100 mL) and CH2Cl2 (100 mL) were then added, and
this mixture was adsorbed directly onto silica. Purification by
flash chromatography, eluting with MeOH:CH2Cl2 (98:2 v/v),
and trituration with ethanol gave 1,4-dimethyl-5-(2-phenyl-
1H-indol-3-yl)piperazin-2-one as a white powder (8.15 g,
80%): mp 143-146 °C; 1H NMR (360 MHz, DMSO-d6) δ 1.92
(3 H, s), 2.80 (1 H, d, J 16), 2.83 (3 H, s), 3.24-3.34 (1 H, m),
3.47 (1 H, d, J 16), 3.74-3.86 (2 H, m), 7.02 (1 H, t, J 8), 7.14
(1 H, t, J 8), 7.36-7.48 (2 H, m), 7.54 (2 H, t, J 7), 7.64 (2 H,
d, J 7), 7.88 (1 H, d, J 8), 11.37 (1 H, s); m/z (ES+) 320 (M +
H+). A suspension of this piperazinone (500 mg, 1.6 mmol) in
THF (20 mL) was treated with LiAlH4 (4 mL, 1 M in THF, 4
mmol). The resulting slurry was heated under reflux for 2 h.
After cooling to 0 °C, powdered sodium sulfate decahydrate
(2.5 g) was added portionwise and stirring continued for 30
min. The reaction was filtered, and the solids were washed
with EtOAc (100 mL). The filtrate was washed with saturated
aqueous NH4Cl, H2O, and brine, dried, evaporated in vacuo,
and purified by flash chromatography eluting with CH2Cl2:
MeOH:880 ammonia (98:1.8:0.2 v/v) to give 16 (330 mg, 69%)
as a foam: maleate salt, mp 191-194 °C (from EtOH); mp
m), 1.9-2.0 (1 H, m), 2.2-2.3 (1 H, m), 2.9-3.0 (2 H, m), 3.02
(1 H, t, J 12), 3.2-3.3 (2 H, m), 3.4-3.5 (4 H, m), 7.00 (1 H, t,
J 7), 7.11 (1 H, t, J 7), 7.2-7.6 (11 H, m), 7.89 (1 H, d, J 8),
11.3 (1H, br s); m/z (ES+) 381 (M+ + H). Anal. (C27H28N2‚
C2H2O4‚0.8H2O) C, H, N.
1-{2-[3-(2-P h en yl-1H-in d ol-3-yl]-)p ip er id in -1-yl]eth yl}-
im id a zolid in -2-on e (14). Compound 9 (172 mg, 0.62 mmol),
1-(2-chloro)ethyl-2-imidazolidinone (119 mg, 0.80 mmol), and
Cs2CO3 (0.29 g, 0.8 mmol) were stirred in DMF (3 mL) at 70
°C for 6 h. The mixture was poured into H2O and extracted
with EtOAc. The organic layer was washed with H2O and
brine, dried, and evaporated in vacuo and purified by flash
chromatography eluting with CH2Cl2:MeOH:880 ammonia (97:
3:0.3 v/v) to give 14 (201 mg, 83%) as a colorless oil: hemi
oxalate salt containing 1 mol of ethanol, white crystals, mp
203-205 °C (from EtOH); 1H NMR (360 MHz, DMSO-d6) δ
1.7-1.8 (1 H, m), 1.8-1.9 (2 H, m), 1.9-2.0 (1 H, m), 2.2-2.3
(1 H, m), 2.7-3.4 (13 H, m), 6.4 (1 H, s), 7.00 (1 H, t, J 7), 7.09
(1 H, t, J 7), 7.2-7.6 (11 H, m), 7.83 (1 H, d, J 8), 11.2 (1H, br
s); m/z (ES+) 389 (M+ + H). Anal. (C24H28N4O‚0.5C2H2O4‚
C2H6O) C, H, N.
3-Mor p h olin -2-yl-2-p h en yl-1H-in d ole (15). A solution of
37 (15 g, 77.7 mmol) in anhydrous benzene (150 mL) was
added via cannula over 10 min to a solution of EtMgBr (26
mL, 3.0 M in Et2O, 77.7 mmol) at room temperature under
N2. After 15 min chloroacetyl chloride (6.2 mL, 77.7 mmol) was
added, and the mixture was stirred for a further 20 min. The
reaction was quenched with saturated NH4Cl (200 mL), and
the products were extracted with EtOAc (2 × 200 mL). The
combined organic extracts were dried, evaporated in vacuo,
and purified by flash chromatography eluting with EtOAc:
hexane (50:50 v/v) to give 2-chloro-1-(2-phenyl-1H-indole)-
ethanone (6.8 g, 35%): 1H NMR (360 MHz, DMSO-d6) δ 4.34
(2 H, s), 7.23-7.32 (2 H, m), 7.46-7.52 (1 H, m), 7.55-7.62 (3
H, m), 7.66-7.72 (2 H, m), 8.17-8.24 (1 H, m), 12.33 (1 H, br
s). A solution of this material (6.8 g, 25 mmol), and ethano-
lamine (20 mL, 331 mmol) in anhydrous 1,2-dichloroethane
(100 mL) under N2 was heated at reflux for 5 h. The mixture
was cooled and washed with saturated NaHCO3 and brine,
dried, evaporated in vacuo, and purified by flash chromatog-
raphy eluting with CH2Cl2:MeOH:880 ammonia (95:5:0.5 then
92:9:0.5 v/v) to give 2-(2-hydroxyethylamino)-1-(2-phenyl-1H-
indol-3-yl)ethanone (38) (4 g, 54%): 1H NMR (360 MHz, CDCl3)
δ 2.62 (2 H, t, J 5.1), 3.44 (2 H, t, J 5.1), 3.51 (2 H, s), 7.26-
7.31 (2 H, m), 7.36-7.38 (1 H, m), 7.46-7.52 (5 H, m), 8.29 (1
H, dd, J 7.7 and 2.1); m/z (ES+) 295 (M + H+). A solution of
38 (4 g, 13.6 mmol) in MeOH (70 mL) was treated with NaBH4
(770 mg, 20.4 mmol) at room temperature. Further quantities
of NaBH4 (514 mg, 13.6 mmol) were added after 1 and 2 h.
After 3 h, the reaction was evaporated in vacuo, and the
residue was partitioned between CH2Cl2 and saturated aque-
ous NaHCO3. The organic phase was dried, evaporated in
vacuo, and purified by flash chromatography eluting with CH2-
Cl2:MeOH:880 ammonia (95:5:0.5 v/v) to give 2-(2-hydroxy-
ethylamino)-1-(2-phenyl-1H-indol-3-yl)ethanol (1.9 g, 47%): 1H
NMR (360 MHz, CDCl3) δ 2.71-2.98 (2 H, m), 2.95 (1 H, dd,
J 12.3 and 4.0), 3.62-3.70 (2 H, m), 5.18 (1 H, dd, J 9.7 and
4.0), 7.08-7.23 (2 H, m), 7.38-7.51 (4 H, m), 7.54-7.58 (2 H,
m), 7.90 (1 H, d, J 7.3). A solution of this material (1.9 g, 6.4
mmol) in MeOH (20 mL) was treated with 2 M HCl (10 mL,
20 mmol). After 5 min, the reaction was basified with 4 M
NaOH, and the products were extracted with CH2Cl2 (3 × 30
mL). The combined organic phases were dried, evaporated in
vacuo, and purified by flash chromatography eluting with CH2-
1
143-146 °C; H NMR (400 MHz, DMSO-d6) δ 1.95 (3 H, s),
2.30-2.45 (1 H, m), 2.82 (3 H, s), 3.07-3.17 (1 H, m), 3.20-
3.55 (4 H, m), 3.67-3.78 (1 H, m), 6.02 (2 H, s), 7.03 (1 H, t,
J 7), 7.13 (1 H, t, J 7), 7.38 (1 H, d, J 8), 7.45-7.48 (1 H, m),
7.50-7.64 (4 H, m), 8.00 (1 H, d, J 8), 9.63 (1 H, br), 11.43 (1
H, s); m/z (ES+) 306 (M + H+). Anal. (C20H23N3 C4H4O4 0.25H2O)
.
.
C, H, N.
(3RS,4RS)-3-(4-H yd r oxyp ip er id in -3-yl)-2-p h en yl-1H -
in d ole (19). A solution of 4-hydroxy-3-(2-phenyl-1H-indol-3-
yl)-piperidine-1-carboxylic acid benzyl ester20 (1.0 g, 2.3 mmol)
in EtOAc (20 mL) and MeOH (5 mL) was treated with 10%
Pd/C (100 mg) and stirred under 1 atm of hydrogen at room
temperature for 4 h. The reaction mixture was filtered and
evaporated in vacuo, the residue was triturated with CHCl3/
Et2O, and the solid was washed with MeOH to afford 19 as a
white powder (583 mg, 85%): 1H NMR (360 MHz, DMSO-d6)
δ 1.49-1.59 (1 H, m), 1.96-2.03 (1 H, m), 3.00-3.45 (4 H, m),
4.19-4.28 (1 H, m), 4.76-4.86 (1 H, m), 7.01-7.10 (1 H, m),
7.37-7.52 (4 H, m), 7.70-7.88 (3 H, m), 11.22 (1H, s); m/z (ES+)
293 (M+ + H). Anal. (C19H20N2O‚0.2CH3OH) C, H, N.
6-F lu or o-2-p h en yl-1H-in d ole (39). A mixture of 5-fluoro-
2-iodoaniline (7.55 g, 31 mmol) and phenylacetylene (5.8 mL,
62 mmol) in N-butylamine (100 mL) was degassed with N2
for 15 min, and then Pd(PPh3)2Cl2 (0.5 g) and CuI (0.1 g) were
added. The mixture was heated to reflux for 16 h under N2
and then evaporated. Flash chromatography eluting with
EtOAc:hexane (5:95 v/v) as eluent gave 5-fluoro-2-phenyleth-
ynylphenylamine (5.23 g, 80%): 1Η ΝΜR (250 MHz, CDCl3) δ
4.30 (2 H, br s), 6.39-6.47 (2 H, m), 7.29-7.53 (6 H, m). A
stirred suspension of this acetylene (5.23 g, 25 mmol), CuI (2.36
g, 12 mmol), and CaCO3 (2.48 g, 25 mmol) in DMF (35 mL)

1612 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10
Rowley et al.
was heated to 120 °C for 20 h. The mixture was cooled, filtered,
evaporated, and partitioned between H2O and EtOAc. The
organic layer was washed with 10% NH4OH, H2O, and brine,
dried, and evaporated to give 6-fluoro-2-phenyl-1H-indole (4.97
g, 95%) as a brown solid: 1Η ΝΜR (250 MHz, CDCl3) δ 6.8 (1
H, d, J 2), 6.9 (1 H, dt, J 10 and 2), 7.1 (1 H, dd, J 10 and 2),
7.25-7.35 (1 H, m), 7.4-7.5 (2 H, m), 7.5-7.6 (1 H, m), 7.6-
7.7 (2 H, m), 8.3 (1 H, br s).
the mixture was stirred at room temperature overnight. Citric
acid (3.05 g, 1.43 mmol) was added, and the mixture was
partitioned between EtOAc and H2O. The organic layer was
washed with H2O and brine, dried over Na2SO4, and evapo-
rated to give 41 (0.94 g, 97%) which was shown by chiral HPLC
to have an e.e. of 99.4%.
(3R,4R)-6-F lu or o-3-(4-flu or op ip er id in -3-yl)-2-p h en yl-
1H-in d ole (22): maleate salt, e.e. ) >99%, white needles, mp
224-225 °C; 1Η ΝΜR (360 MHz, DMSO-d6) δ 1.80-2.00 (1 H,
m), 2.32-2.42 (1 H, m), 3.20-3.65 (5 H, m), 5.20-5.50 (1 H,
dm, J 48), 6.02 (2 H, s), 6.92 (1 H, dt, J 9 and 2), 7.15 (1 H, dd,
J 9 and 2), 7.40-7.48 (1 H, m), 7.50-7.62 (4 H, m), 7.95-8.05
5-F lu or o-2-p h en yl-1H-in d ole (43). Benzoyl chloride (4.6
mL, 40 mmol) was added dropwise over 10 min at 0 °C to a
solution of 4-fluoro-2-methylaniline (42) (5.0 g, 40 mmol) in
CH2Cl2. After complete addition, the reaction mixture was
warmed to room temperature and stirred for a further 3 h.
The mixture was evaporated, and the residue partitioned
between 0.5 N NaOH and EtOAc. The organic layer was
washed with 1 N HCl, H2O, and brine, dried, and evaporated.
Recrystallization from EtOAc gave N-(4-fluoro-2-methylphen-
yl)benzamide as a white solid: 1Η ΝΜR (250 MHz, CDCl3) δ
2.29 (3 H, s), 6.87-6.95 (2 H, m), 7.44-7.68 (4 H, m), 7.85-
7.90 (2 H, m). A solution of nBuLi (50 mL, 1.6 M in hexane, 80
mmol) was added slowly at -25 °C to a stirred solution of the
benzamide in dry THF (75 mL) under N2. After 1 h at -78 °C,
the mixture was warmed to room temperature and stirred for
a further 16 h. The reaction was quenched with 2 N HCl (60
mL), and the product was extracted with EtOAc (2 × 200 mL).
The combined organic solutions were washed with H2O (100
mL) and brine (100 mL), dried, and evaporated. Trituration
(1 H, m), 8.55 (1 H, br s), 11.56 (1 H, s); m/z (ES+) 313 (M+
H). Anal. (C19H18F2N2.C4H4O4) C, H, N.
+
(3R,4R)-5-F lu or o-3-(4-flu or op ip er id in -3-yl)-2-p h en yl-
1H-in d ole (20): maleate salt, white needles, mp 178-179 °C;
1Η ΝΜR (360 MHz, DMSO-d6) δ 1.80-1.95 (1 H, m), 2.34-
2.44 (1 H, m), 3.20-3.60 (5 H, m), 5.20-5.45 (1 H, dm, J 48),
6.02 (2 H, s), 7.00 (1 H, dt, J 9 and 2), 7.35-7.42 (1 H, m),
7.45-7.50 (1 H, m), 7.53-7.62 (4 H, m), 7.85 (1 H, dd, J 11
and 2), 8.80 (1 H, br s), 11.60 (1 H, s); m/z (ES+) 313 (M+
H). Anal. (C19H18F2N2‚C4H4O4‚H2O) C, H, N.
+
(3R,4R)-5-Ch lor o-3-(4-flu or op ip er id in -3-yl)-2-p h en yl-
1H-in d ole (21): maleate salt, white needles, mp 224-225 °C;
1Η ΝΜR (360 MHz, DMSO-d6) δ 1.75-1.95 (1 H, m), 2.34-
2.54 (1 H, m), 3.20-3.70 (5 H, m), 5.20-5.45 (1 H, dm, J 49),
6.02 (2 H, s), 7.15 (1 H, dt, J 9 and 2), 7.42 (1 H, d, J 9), 7.47-
7.53 (1 H, m), 7.55-7.64 (4 H, m), 8.05 (1 H, d, J 2), 8.60 (1 H,
1
with hexane gave 43 (5.26 g, 62%) as a pale brown solid: Η
br s), 11.66 (1 H, s); m/z (ES+) 329 (M+ + H). Anal. (C19H18
ClFN2‚C4H4O4‚0.1H2O) C, H, N.
-
ΝΜR (250 MHz, CDCl3) δ 6.9 (1 H, dt, J 2 and 9), 7.2-7.7 (8
H, m), 8.4 (1 H, br s).
(3R,4R)-6-Ch lor o-3-(4-flu or op ip er id in -3-yl)-2-p h en yl-
1H-in d ole (23): maleate salt, white needles, mp 230-232 °C;
7-F lu or o-2-p h en yl-1H-in d ole (46). Using a procedure
similar to that of Gassman,20 a cooled (-78 °C) solution of
2-fluoroaniline (44) (3.8 mL, 39 mmol) in CH2Cl2 (80 mL) was
treated with a cooled (-78 °C) solution of tert-butyl hypochlo-
rite (4.2 g, 39 mmol) in CH2Cl2 (20 mL). After the mixture was
stirred at -78 °C for 1 h, a cooled (-78 °C) solution of
2-methylsulfanyl-1-phenylethanone (6.6 g, 40 mmol) in CH2-
Cl2 (20 mL) was added, and stirring continued at -78 °C for
1 h. A cooled (-78 °C) solution of Et3N (6.0 mL, 43 mmol) in
CH2Cl2 (20 mL) was then added, and after 20 min at -78 °C
the mixture was allowed to stir to room temperature for 1 h.
H2O (200 mL) was added, and the CH2Cl2 evaporated in vacuo.
The product was extracted into EtOAc (250 mL), and the
organics were washed with brine, dried, evaporated in vacuo,
and purified by flash chromatography eluting with with
isohexane on a gradient of diethyl ether (0-10%) to give
7-fluoro-3-methylsulfanyl-2-phenyl-1H-indole (45) as a red oil
(5.4 g, 53%). This oil was dissolved in EtOH (100 mL), and
the solution was stirred mechanically while Raney nickel
(excess) was added in small portions until complete consump-
tion of starting material had occurred. The reaction was
filtered through a glass microfiber filter paper (Whatman GF/
A) and the filtrate concentrated to furnish 46 as a yellow solid
(4.0 g, 90%): 1H NMR (360 MHz, DMSO-d6) δ 6.84-6.93 (2
H, m), 6.99-7.05 (1 H, m), 7.37 (2 H, t, J 7), 7.46 (2 H, t, J 7),
7.69 (2 H, d, J 7), 8.47 (1 H, br s).
The following compounds were made by the route shown in
Scheme 5, using experimental procedures previously described
in detail for compound 17,20 making the appropriately substi-
tuted indole using the routes described above. To obtain
compounds with high e.e., the following is representative of
the procedure used to increase optical purity:
Resolu tion of 41. Compound 41 (2.0 g, 4.5 mmol) and (1R)-
(-)-camphanic chloride (1.95 g, 9.0 mmol) were dissolved in
pyridine (15 mL) and heated at 45 °C for 18 h. The reaction
mixture was diluted with EtOAc, washed with 1 N citric acid,
H2O, and brine, dried over Na2SO4, and evaporated. Flash
chromatography eluting with EtOAc:iHex (1:4 v/v) gave 4-(6-
fluoro-2-phenyl-1H-indol-3yl)-3-(4,7,7-trimethyl-3-oxo-2-oxa-
bicyclo[2.2.1]heptane-1-carbonyloxy)piperidine-1-carboxylic acid
benzyl ester (Rf EtOAc:iHex (3:7)) 0.35 (1.36 g, 48%) and its
diastereoisomer (Rf EtOAc:iHex (3:7)) 0.25 (1.09 g, 38%). The
major, less polar isomer (1.36 g, 2.18 mmol) was dissolved in
methanol (10 mL), K2CO3 (1.58 g, 10.9 mmol) was added, and
1
Η ΝΜR (360 MHz, DMSO-d6) δ 1.80-2.00 (1 H, m), 2.30-
2.44 (1 H, m), 3.20-3.70 (5 H, m), 5.20-5.45 (1 H, dm, J 53),
6.07 (2 H, s), 7.07 (1 H, dt, J 9 and 2), 7.40-7.70 (6 H, m),
8.00 (1 H, d, J 9), 8.95 (1 H, br s), 11.65 (1 H, s); m/z (ES+) 329
(M+ + H). Anal. (C19
H18ClFN2‚C4H4O4‚0.8H2O) C, H, N.
(3R,4R)-7-F lu or o-3-(4-flu or op ip er id in -3-yl)-2-p h en yl-
1H-in d ole (24): maleate salt, white needles, mp 212-213 °C;
1
Η ΝΜR (360 MHz, DMSO-d6) δ 1.80-2.00 (1 H, m), 2.32-
2.40 (1 H, m), 3.20-3.60 (5 H, m), 5.20-5.45 (1 H, dm, J 49),
6.02 (2 H, s), 6.95-7.10 (2 H, m), 7.45-7.65 (5 H, m), 7.90 (1
H, d, J 8), 8.60 (1 H, br s), 11.86 (1 H, s); m/z (ES+) 313 (M+
+ H). Anal. (C19H18F2N2‚C4H4O4‚0.1H2O) C, H, N.
(3R,4R)-7-Ch lor o-3-(4-flu or op ip er id in -3-yl)-2-p h en yl-
1H-in d ole (25): maleate salt, white needles, mp 218-219 °C;
1
Η ΝΜR (360 MHz, DMSO-d6) δ 1.75-1.95 (1 H, m), 2.32-
2.40 (1 H, m), 3.20-3.60 (5 H, m), 5.20-5.45 (1 H, dm, J 49),
6.02 (2 H, s), 7.08 (1 H, t, J 8), 7.25 (1 H, d, J 8), 7.45-7.65 (5
H, m), 7.97 (1 H, d, J 8), 8.60 (1 H, br s), 11.69 (1 H, s); m/z
(ES+) 329 (M+ + H). Anal. (C19H18ClFN2‚C4H4O4) C, H, N.
2-Cycloh exyl-3-(4-flu or o-p ip er id in -3-yl)-1H-in d ole (32):
white crystals, e.e. ) 76%, mp 223-225 °C; 1H NMR (360 MHz,
DMSO-d6) δ 1.2-1.4 (3 H, m), 1.5-1.9 (9 H, m), 2.2-2.3 (1 H,
m), 2.7-2.8 (1 H, m), 3.1-3.4 (5 H, m), 5.0-5.3 (1 H, m), 6.7-
6.8 (1H, m), 7.0 (dd, 1 H, J 10 and 2 Hz), 7.6-7.7 (1 H, m),
10.9 (1 H, s); m/z (ES+) 319 (M+ + H). Anal. (C19H24F2N2‚
C2H2O4) C, H, N.
(3R,4R)-5-F lu or o-3-(4-flu or op ip er id in -3-yl)-1H-in d ole
(26): oxalate salt, Anal. (C13H14F2N2‚0.5C2H2O4‚0.3H2O) C, H,
N.
(3R,4R)-6-F lu or o-3-(4-flu or op ip er id in -3-yl)-2-fu r a n -3-
yl-1H-in d ole (30). A cooled (-10 °C) solution of 2,2,6,6-
tetramethylpiperidine (506 µL, 3.0 mmol) in THF (20 mL) was
treated with nBuLi (1.9 mL of a 1.6 M solution in hexane, 3.0
mmol). This mixture was stirred at -10 °C for 5 min and then
cooled to -78 °C. To this solution a precooled (-78 °C) solution
of 4718 (475 mg, 1.1 mmol, 88% e.e.) in THF (7 mL) was added
via cannula, and stirring at -78 °C was continued for 2 h.
ZnCl2 (4.4 mL of a 0.5 M solution in diethyl ether, 2.2 mmol)
was then added dropwise over 5 min to the reaction mixture,
and stirring at -78 °C continued for 30 min before allowing
the solution to warm to room temperature. 3-Bromofuran (200
µL, 2.2 mmol) was added, followed by tetrakis(triphenylphos-

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 10 1613
phine)palladium(0) (65 mg), and the reaction was heated at
50 °C for 16 h. After cooling to room temperature, the reaction
mixture was diluted with EtOAc (100 mL) and washed with a
saturated solution of ammonium chloride, H2O, and brine,
dried, evaporated in vacuo, and purified by flash chromatog-
raphy eluting with hexane on a gradient of diethyl ether (10-
35% v/v) to give (3R,4R)-3-(1-tert-butoxycarbonyl-4-fluoro-
piperidin-3-yl)-6-fluoro-2-furan-3-ylindole-1-carboxylic acid tert-
butyl ester as a white foam (372 mg, 68%): 1H NMR (360 MHz,
CDCl3) δ 1.42 (18 H, s), 1.60-1.74 (1 H, m), 2.08-2.22 (1 H,
m), 2.76-3.22 (3 H, m), 3.96-4.14 (1 H, m), 4.18-4.32 (1 H,
m), 4.84-5.12 (1 H, m), 6.46 (1H, d, J 3), 7.00 (1 H, td, J 9
and 2), 7.30-7.44 (3H, m), 7.96-8.04 (1 H, m). A solution of
this ester (370 mg, 0.74 mmol) in MeOH (10 mL) was treated
with NaOMe (160 mg, 3 mmol), and the mixture was heated
at 60 °C for 5 h. The reaction was cooled to room temperature,
and the MeOH was removed on a rotary evaporator. The
residue was suspended in EtOAc, washed with H2O and brine,
dried, and evaporated in vacuo to give an oil. This oil was
dissolved in 95% formic acid (5 mL) and stirred at room
temperature for 16 h. The reaction mixture was neutralized
by the careful addition of a saturated solution of sodium
hydrogen carbonate and then extracted with EtOAc. The
organic extract was then washed with H2O and brine, dried,
evaporated in vacuo, and purified by flash chromatography
eluting with dichloromethane:methanol:880 ammonia (95:4.5:
0.5 v/v) to give the 30 as a cream-colored solid (125 mg, 56%):
maleate salt, white powder, mp 211-213 °C (from EtOH/
EtOAc); 1H NMR (360 MHz, DMSO-d6) δ 1.92-2.00 (1 H, m),
2.12-2.24 (1 H, m), 3.31-3.64 (5 H, m), 5.20-5.42 (1 H, m),
6.02 (2H, s), 6.86-6.96 (2H, m), 7.14 (1 H, dd, J 10 and 2),
7.84-7.92 (2H, m), 8.05 (1 H, s), 8.64 (1 H, br), 11.44 (1H, s).
m/z (ES+) 303 (M+ + H). Anal. (C21H20F2N2O5) C, H, N.
°C, and 47 (1.20 g, 2.75 mmol) in dry THF (20 mL) was added
over 10 min. The mixture was stirred at -78 °C for 3 h, and
then methyl cyanoformate (0.33 mL, 4.13 mmol) was added.
After 10 s, the reaction was quenched by the addition of glacial
acetic acid (0.5 mL) in THF (4.5 mL) and allowed to warm to
room temperature. The mixture was evaporated and parti-
tioned between EtOAc and H2O, and the organic layer was
washed with brine, dried, and evaporated. Flash chromatog-
raphy eluting with EtOAc:hexane (1:5 v/v) gave (3R,4R)-3-(1-
tert-butoxycarbonyl-4-fluoropiperidin-3-yl)-6-fluoroindole-1,2-
dicarboxylic acid 1-tert-butyl ester 2-methyl ester (690 mg,
51%) as a white solid: 1Η ΝΜR (360 MHz, CDCl3) δ 1.47 (9 H,
s), 1.57 (9 H, s), 1.60-1.80 (1 H, m), 2.15-2.25 (1 H, m), 2.80-
2.95 (1 H, m), 3.10-3.35 (2 H, m), 3.95 (3 H, s), 4.20-4.40 (2
H, m), 5.20-5.45 (1 H, dm, J 54), 7.05 (1 H, dt, J 9 and 2),
7.60 (1 H, dd, J 9), 7.80 (1 H, dd, J 9 and 2). The ester (0.10
g, 0.20 mmol) was dissolved in 90% formic acid (10 mL) and
heated at 50 °C for 2.5 h. The solvent was evaporated, and
the residue basified with 10% NH4OH and extracted with
EtOAc. The organic layer was washed with H2O and brine,
dried, and evaporated. Flash chromatography eluting with
CH2Cl2:MeOH:NH3 (98:2:0.2 v/v) gave 32 (47 mg, 79%) as a
1
white solid: maleate salt, white needles, mp 182-183 °C: Η
ΝΜR (360 MHz, DMSO-d6) δ 1.80-2.00 (1 H, m), 2.35-2.42
(1 H, m), 3.20-3.60 (4 H, m), 3.90-3.95 (3 H, s), 4.20-4.40 (1
H, m), 5.20-5.45 (1 H, dm, J 54), 6.02 (2 H, s), 7.00 (1 H, dt,
J 9 and 2), 7.20 (1 H, dd, J 9 and 2), 8.00 (1 H, m), 8.75 (1 H,
br s), 12.00 (1 H, s); m/z (ES+) 295 (M+ + H). Anal.
(C17H16F2N2O2‚1.25C4H4O4‚0.3H2O) C, H, N.
(3R,4R)-6-F lu or o-3-(4-flu or op ip er id in -3-yl)-1H-in d ole-
2-ca r boxylic a cid p h en yla m id e (34): oxalate salt, mp 223-
1
224 °C (from EtOH); H NMR (500 MHz, DMSO-d6) δ 1.85-
2.00 (1 H, m), 2.33-2.41 (1 H, m), 3.23-3.32 (2 H, m), 3.50-
3.60 (2 H, m), 4.12-4.25 (1 H, m), 5.37 (1 H, dtd, J 49, 10 and
5), 7.03 (1 H, t, J 9), 7.14 (1 H, t, J 7), 7.29 (1 H, dd, J 10 and
2), 7.38 (2 H, t, J 8), 7.76 (2 H, d, J 7), 7.93-7.99 (1 H, m),
10.30 (1 H, s); m/z (ES+) 356 (M + H+). Anal. (C20H19F2N3O‚
C2H2O4‚0.5H2O) C, H, N.
The following were made in the same way, with all having
the same enantiomeric excess as the starting material (88%
e.e.).
(3R,4R)-6-F lu or o-3-(4-flu or op ip er id in -3-yl)-2-n a p h th a -
len -2-yl-1H-in d ole (27): hydrochloride salt, white needles,
1
mp 279-280 °C; Η ΝΜR (360 MHz, DMSO-d6) δ 1.80-2.05
(3R,4R)-6-F lu or o-2-(4-flu or op h en yl)-3-(4-flu or op ip er i-
d in -3-yl)-1H-in d ole (35): made in the same way as 23,
maleate salt, white crystals, mp 220-221 °C (from EtOAc),
e.e. ) 93.4%; [R]2D3 -0.7°(c ) 1.0, MeOH); 1H NMR (400 MHz,
DMSO-d6) δ 1.80-1.96 (1 H, m), 2.30-2.43 (1 H, m), 3.30-
3.60 (6 H, m), 5.2-5.4 (1 H, dm, J 53), 6.03 (2 H, s), 6.89-
6.96 (1 H, m), 7.16 (1 H, dd, J 9.8 and 2.3), 7.40 (2 H, t, J 8.8),
7.61 (2 H, dd, J 8.6 and 5.5), 7.97 (1 H, dd, J 8.8 and 5.3),
11.58 (1 H, br s); m/z (ES+) 331 (M + H+). Anal. (C19H17N2F3‚
C4H4O4) C, H, N.
(1 H, m), 2.30-2.40 (1 H, m), 3.40-3.60 (5 H, m), 5.25-5.50
(1 H, dm, J 49), 6.95 (1 H, dt, J 10 and 2), 7.42 (1 H, dd, J 10
and 2), 7.55-7.65 (2 H, m), 7.75 (1 H, d, J 8), 8.00-8.20 (5 H,
m), 9.25 (1 H, br s), 11.73 (1 H, s); m/z (ES+) 363 (M+ + H).
Anal. (C23H20F2N2‚HCl‚0.7H2O) C, H, N.
(3R,4R)-6-F lu or o-3-(4-flu or op ip er id in -3-yl)-2-n a p h th a -
len -1-yl-1H-in d ole (28): hydrochloride salt, white needles,
1
mp 212-213 °C; Η ΝΜR (400 MHz, DMSO-d6) δ 1.65-1.85
(1 H, m), 2.20-2.30 (1 H, m), 3.20-3.50 (5 H, m), 5.10-5.35
(1 H, dm, J 50), 6.95 (1 H, dt, J 9 and 2), 7.15 (1 H, dd, J 9
and 2), 7.40-7.70 (5 H, m), 7.90-8.10 (3 H, m), 9.00 (1 H, br
s), 11.47 (1 H, s); m/z (ES+) 363 (M+ + H). Anal. (C23H20F2N2‚
HCl‚1.6H2O) C, H, N.
6-F lu or o-2-(4-flu or op h en yl)-3-(p ip er id in -3-yl)-1H -in -
d ole (36): made in the same way as 9, white crystals, mp
1
221-223 °C (from EtOAc); H NMR (360 MHz, DMSO-d6) δ
1.40-1.60 (1 H, m), 1.60-1.70 (1 H, m), 1.80-1.90 (1 H, m),
2.0-2.1 (1 H, m), 2.60-2.70 (1 H, m), 2.9-3.0 (3 H, m), 3.0-
31. (1 H, m), 6.83 (1 H, dt J 9 2.3 and 9), 7.16 (1 H, dd, J 9.9
and 2.3), 7.35 (2 H, t, J 8.9), 7.52 (2 H, dd, J 8.7 and 5.5), 7.97
(1 H, dd, J 9 and 5.5), 11.24 (1 H, s); m/z (ES+) 313 (M + H+).
Anal. (C19H18F2N2‚0.3H2O) C, H, N.
(3R,4R)-6-F lu or o-3-(4-flu or o-p ip er id in -3-yl)-2-p yr id in -
3-yl-1H-in d ole (29): hydrochloride salt, mp 212 °C (dec)
(EtOAc); 1H NMR (360 MHz, DMSO-d6) δ 1.90-2.08 (1 H, m),
2.28-2.39 (1 H, m), 3.40-3.48 (2 H, m), 3.50-3.60 (2 H, m),
3.62-3.74 (1 H, m), 5.36 (1 H, dtd, J 48, 9 and 4), 6.98 (1 H,
td, J 10 and 2), 7.25 (1 H, dd, J 10 and 2), 7.91 (1 H, dd, J 8
and 5), 8.08 (1 H, dd, J 9 and 5), 8.43 (1 H, d, J 8), 8.81 (1 H,
d, J 4), 9.00 (1 H, s), 9.46 (2 H, br), 12.02 (1 H, s); m/z (ES+)
314 (M + H+). Anal. (C18H17F2N3‚2HCl‚H2O) C, H, N.
Su p p or tin g In for m a tion Ava ila ble: Microanalyses. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(3R,4R)-6-Flu or o-3-(4-flu or op ip er id in -3-yl)-2-th iop h en -
3-yl-1H-in d ole (31): maleate salt, white needles, mp 212-
Refer en ces
1
213 °C; Η ΝΜR (360 MHz, DMSO-d6) δ 1.80-2.00 (1 H, m),
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