U.S. patent application number 11/734809 was filed with the patent office on 2007-10-25 for nk-1 and serotonin transporter inhibitors.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Andrew P. Degnan, Derek J. Denhart, Jonathan L. Ditta, Kevin W. Gillman, Ying Han, Ramkumar Rajamani, George O. Tora.
Application Number | 20070249607 11/734809 |
Document ID | / |
Family ID | 38510473 |
Filed Date | 2007-10-25 |
United States Patent
Application |
20070249607 |
Kind Code |
A1 |
Degnan; Andrew P. ; et
al. |
October 25, 2007 |
NK-1 AND SEROTONIN TRANSPORTER INHIBITORS
Abstract
The invention encompasses compounds of Formula I, including
pharmaceutically acceptable salts, their pharmaceutical
compositions, and their use in treating disorders associated with
an excess or imbalance of tachykinins or serotonin or both.
##STR1##
Inventors: |
Degnan; Andrew P.; (Rocky
Hill, CT) ; Gillman; Kevin W.; (Madison, CT) ;
Denhart; Derek J.; (Durham, CT) ; Ditta; Jonathan
L.; (Middletown, CT) ; Rajamani; Ramkumar;
(Middletown, CT) ; Han; Ying; (Cheshire, CT)
; Tora; George O.; (Meriden, CT) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
38510473 |
Appl. No.: |
11/734809 |
Filed: |
April 13, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60792604 |
Apr 17, 2006 |
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Current U.S.
Class: |
514/235.5 ;
514/241; 514/252.03; 514/253.01; 514/255.05; 514/269; 514/307;
514/314; 514/317; 514/318; 514/326; 544/129; 544/209; 544/238;
544/310; 544/333; 544/360; 544/405; 546/148; 546/176; 546/184;
546/208; 546/209; 546/210 |
Current CPC
Class: |
C07D 401/12 20130101;
C07D 417/12 20130101; C07D 211/22 20130101; C07D 409/12 20130101;
A61P 25/00 20180101; C07D 405/12 20130101; A61P 7/00 20180101 |
Class at
Publication: |
514/235.5 ;
544/129; 544/360; 544/333; 544/405; 544/238; 544/209; 546/148;
546/176; 546/208; 546/209; 546/210; 546/184; 544/310; 514/241;
514/252.03; 514/253.01; 514/269; 514/255.05; 514/318; 514/326;
514/317; 514/314; 514/307 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/53 20060101 A61K031/53; A61K 31/497 20060101
A61K031/497; A61K 31/496 20060101 A61K031/496; A61K 31/513 20060101
A61K031/513; A61K 31/501 20060101 A61K031/501; A61K 31/4545
20060101 A61K031/4545; A61K 31/454 20060101 A61K031/454; C07D
413/02 20060101 C07D413/02; C07D 403/02 20060101 C07D403/02; C07D
401/02 20060101 C07D401/02 |
Claims
1. A compound of Formula I ##STR661## where: R.sup.1 is hydrogen,
alkyl, cycloalkyl, or benzyl; R.sup.2 is hydrogen or alkyl; R.sup.3
is hydrogen or alkyl; R.sup.4 is hydrogen, alkyl, haloalkyl,
hydroxy, alkoxy, haloalkoxy, cyano, or COR.sup.6; R.sup.5 is
hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or
COR.sup.6; R.sup.6 is hydroxy, alkoxy, benzyloxy, amino,
alkylamino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl,
N-alkylpiperazinyl, or morpholinyl; Ar.sup.1 is phenyl or
pyridinyl, and is substituted with 0-2 substituents selected from
the group consisting of halo, alkyl, haloalkyl, cyano, phenyl and
furanyl; Ar.sup.2 is phenyl substituted with 1-5 substituents or is
naphthyl substituted with 0-3 substituents where the substituents
are selected from the group consisting of halo, alkyl, cycloalkyl,
haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy,
benzyloxy, alkylthio, cyano, nitro, amino, alkylamino,
dialkylamino, (alkylcarbonyl)amino, (alkoxycarbonyl)amino
(benzyloxycarbonyl)amino, carboxy, alkoxycarbonyl,
benzyloxycarbonyl, alkylSO.sub.2, phenyl, phenoxy, acetyl, and
formyl; or Ar.sup.2 is furanyl, thienyl, pyrrolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl,
pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl, quinolinyl, or
isoquinolinyl, and is substituted with 0-3 substituents selected
from the group consisting of amino, alkylamino, dialkylamino, oxo,
halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano,
nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl,
and morpholinyl; or Ar.sup.2 is benzodioxolyl, dibenzofuranyl,
thianthrenyl, or trimethylenedioxybenzen-yl; or a pharmaceutically
acceptable salt thereof.
2. A compound of claim 1 where: R.sup.1 is hydrogen or alkyl;
R.sup.4 is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or
cyano; R.sup.5 is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy,
or cyano; Ar.sup.1 is phenyl substituted with 0-2 substituents
selected from the group consisting of halo, alkyl, haloalkyl, and
cyano; Ar.sup.2 is phenyl substituted with 1-3 substituents or is
naphthyl substituted with 0-3 substituents where the substituents
are selected from the group consisting of halo, alkyl, haloalkyl,
hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, alkylthio,
cyano, nitro, amino, alkylamino, dialkylamino, phenyl, phenoxy,
acetyl, and formyl; or Ar.sup.2 is furanyl, thienyl, pyrrolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
pyridinyl, pyridazinyl, pyrmidinyl, triazinyl, quinolinyl, or
isoquinolinyl, and is substituted with 0-3 substituents selected
from the group consisting of amino, alkylamino, dialkylamino, oxo,
halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano,
nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl,
or morpholinyl; or Ar.sup.2 is benzodioxolyl, dibenzofuranyl or
thianthrenyl.
3. A compound of claim 1 where R.sup.1 is hydrogen.
4. A compound of claim 1 where R.sup.2 and R.sup.3 are
hydrogen.
5. A compound of claim 1 where R.sup.2 is methyl and R.sup.3 is
hydrogen.
6. A compound of claim 1 where Ar.sup.1 is phenyl.
7. A compound of claim 1 where Ar.sup.2 is phenyl substituted with
1-5 substituents or is naphthyl substituted with 0-3 substituents
where the substituents are selected from the group consisting of
halo, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
hydroxy, alkoxy, haloalkoxy, benzyloxy, alkylthio, cyano, nitro,
amino, alkylamino, dialkylamino, (alkylcarbonyl)amino,
(alkoxycarbonyl)amino (benzyloxycarbonyl)amino, carboxy,
alkoxycarbonyl, benzyloxycarbonyl, alkylSO.sub.2, phenyl, phenoxy,
acetyl, and formyl.
8. A compound of claim 1 where Ar.sup.2 is furanyl, thienyl,
pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl,
quinolinyl, or isoquinolinyl, and is substituted with 0-3
substituents selected from the group consisting of amino,
alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy,
alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl,
piperazinyl, N-alkylpiperazinyl, and morpholinyl.
9. A compound of claim 1 selected from the group consisting of
##STR662## ##STR663## ##STR664## ##STR665## ##STR666## ##STR667##
##STR668## ##STR669## ##STR670## ##STR671## ##STR672## ##STR673##
##STR674## ##STR675## ##STR676## ##STR677## ##STR678## ##STR679##
##STR680## ##STR681## ##STR682## ##STR683## ##STR684## ##STR685##
##STR686## ##STR687## ##STR688## ##STR689## ##STR690## ##STR691##
##STR692## ##STR693## ##STR694## ##STR695## ##STR696## ##STR697##
##STR698## ##STR699## or a pharmaceutically acceptable salt
thereof.
10. A composition comprising a pharmaceutically acceptable amount
of a compound of claim 1 and at least one pharmaceutically
acceptable carrier.
11. A method for treating a disorder associated with aberrant
levels of tachykinins or serotonin comprising administering an
effective amount of a compound of claim 1 to a patient afflicted
with the disorder.
12. The method of claim 11 where the disorder is anxiety.
13. The method of claim 11 where the disorder is depression,
obsessive compulsive disorder, bulimia, or panic disorder.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application No. 60/792,604, filed Apr. 17, 2006.
BACKGROUND OF THE INVENTION
[0002] Tachykinins are a group of naturally occurring peptides
found widely distributed throughout mammals, both within the
central nervous system and in the peripheral nervous and
circulatory systems. The three known mammalian tachykinins are
Neurokinin-1 (NK-1, substance P), Neurokinin A, and Neurokinin B.
These compounds act as neurotransmitters and immunomodulators and
may contribute to the pathophysiology of a wide variety of human
diseases.
[0003] Receptors for tachykinins have been identified and include
neurokinin-1 (NK-1 or Substance P-preferring), NK-2 (Neurokinin
A-preferring) and NK-3 (Neurokinin B-preferring). NK-1 receptor
antagonists are being developed for the treatment of physiological
conditions associated with an excess or imbalance of tachykinins,
particularly substance P. Such conditions include affective
disorders such as anxiety, depression, obsessive compulsive
disorder, bulimia, and panic disorder. See Gentsch et al. Behav.
Brain Res. 2002, 133, 363; Varty et al. Neuropsychopharmacology
2002, 27, 371; Papp et al. Behav. Brain Res. 2000, 115, 19; Kramer
et al. Science 1998, 281, 1640; and Rosen et al. Bioorg. Med. Chem.
Lett. 1998, 8, 281.
[0004] NK-1 antagonists are believed to modulate 5-HT function via
noradrenergic pathways and have been shown to attenuate presynaptic
5-HT.sub.1A receptor function. Thus, the combination of serotonin
reuptake inhibition with NK-1 antagonism may lead to new classes of
drugs with improved characteristics.
DESCRIPTION OF THE INVENTION
[0005] The invention encompasses compounds of Formula I, including
pharmaceutically acceptable salts, pharmaceutical compositions, and
their use in treating disorders related to levels of tachykinins or
serotonin or both.
[0006] One aspect of the invention are compounds of Formula I
##STR2## where: [0007] R.sup.1 is hydrogen, alkyl, cycloalkyl, or
benzyl; [0008] R.sup.2 is hydrogen or alkyl; [0009] R.sup.3 is
hydrogen or alkyl; [0010] R.sup.4 is hydrogen, alkyl, haloalkyl,
hydroxy, alkoxy, haloalkoxy, cyano, or COR.sup.6; [0011] R.sup.5 is
hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or
COR.sup.6; [0012] R.sup.6 is hydroxy, alkoxy, benzyloxy, amino,
alkylamino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl,
N-alkylpiperazinyl, or morpholinyl; [0013] Ar.sup.1 is phenyl or
pyridinyl, and is substituted with 0-2 substituents selected from
the group consisting of halo, alkyl, haloalkyl, cyano, phenyl and
furanyl; [0014] Ar.sup.2 is phenyl substituted with 1-5
substituents or is naphthyl substituted with 0-3 substituents where
the substituents are selected from the group consisting of halo,
alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy,
alkoxy, haloalkoxy, benzyloxy, alkylthio, cyano, nitro, amino,
alkylamino, dialkylamino, (alkylcarbonyl)amino,
(alkoxycarbonyl)amino (benzyloxycarbonyl)amino, carboxy,
alkoxycarbonyl, benzyloxycarbonyl, alkylSO.sub.2, phenyl, phenoxy,
acetyl, and formyl; [0015] or Ar.sup.2 is furanyl, thienyl,
pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl,
quinolinyl, or isoquinolinyl, and is substituted with 0-3
substituents selected from the group consisting of amino,
alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy,
alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl,
piperazinyl, N-alkylpiperazinyl, and morpholinyl; [0016] or
Ar.sup.2 is benzodioxolyl, dibenzofuranyl, thianthrenyl, or
trimethylenedioxybenzen-yl; [0017] or a pharmaceutically acceptable
salt thereof.
[0018] Another aspect of the invention are compounds of Formula I
where [0019] R.sup.1 is hydrogen or alkyl; [0020] R.sup.4 is
hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; [0021]
R.sup.5 is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or
cyano; [0022] Ar.sup.1 is phenyl substituted with 0-2 substituents
selected from the group consisting of halo, alkyl, haloalkyl, and
cyano; [0023] Ar.sup.2 is phenyl substituted with 1-3 substituents
or is naphthyl substituted with 0-3 substituents where the
substituents are selected from the group consisting of halo, alkyl,
haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy,
alkylthio, cyano, nitro, amino, alkylamino, dialkylamino, phenyl,
phenoxy, acetyl, and formyl; [0024] or Ar.sup.2 is furanyl,
thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl,
thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl, triazinyl,
quinolinyl, or isoquinolinyl, and is substituted with 0-3
substituents selected from the group consisting of amino,
alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy,
alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl,
piperazinyl, N-alkylpiperazinyl, or morpholinyl; [0025] or Ar.sup.2
is benzodioxolyl, dibenzofuranyl or thianthrenyl.
[0026] Another aspect of the invention are compounds of Formula I
where R.sup.1 is hydrogen.
[0027] Another aspect of the invention are compounds of Formula I
where R.sup.2 and R.sup.3 are hydrogen.
[0028] Another aspect of the invention are compounds of Formula I
where R.sup.2 is methyl and R.sup.3 is hydrogen.
[0029] Another aspect of the invention are compounds of Formula I
where Ar.sup.1 is phenyl.
[0030] Another aspect of the invention are compounds of Formula I
where Ar.sup.2 is phenyl substituted with 1-5 substituents or is
naphthyl substituted with 0-3 substituents where the substituents
are selected from the group consisting of halo, alkyl, cycloalkyl,
haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy,
benzyloxy, alkylthio, cyano, nitro, amino, alkylamino,
dialkylamino, (alkylcarbonyl)amino, (alkoxycarbonyl)amino
(benzyloxycarbonyl)amino, carboxy, alkoxycarbonyl,
benzyloxycarbonyl, alkylSO.sub.2, phenyl, phenoxy, acetyl, and
formyl.
[0031] Another aspect of the invention are compounds of Formula I
where Ar.sup.2 is phenyl substituted with 1-3 substituents or is
naphthyl substituted with 0-3 substituents where the substituents
are selected from the group consisting of halo, alkyl, haloalkyl,
hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, alkylthio,
cyano, nitro, amino, alkylamino, dialkylamino, phenyl, phenoxy,
acetyl, and formyl.
[0032] Another aspect of the invention are compounds of Formula I
where Ar.sup.2 is furanyl, thienyl, pyrrolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl,
pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl, quinolinyl, or
isoquinolinyl, and is substituted with 0-3 substituents selected
from the group consisting of amino, alkylamino, dialkylamino, oxo,
halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano,
nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl,
and morpholinyl.
[0033] Another aspect of the invention are compounds of Formula I
where Ar.sup.2 is furanyl, thienyl, pyrrolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl,
pyridazinyl, pyrmidinyl, triazinyl, quinolinyl, or isoquinolinyl,
and is substituted with 0-3 substituents selected from the group
consisting of amino, alkylamino, dialkylamino, oxo, halo, alkyl,
haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro,
pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, or
morpholinyl.
[0034] Another aspect of the invention are compounds of Formula I
where Ar.sup.2 is furanyl, thienyl, pyrazolyl, thiazolyl,
imidazolyl, tetrazolyl, pyridinyl, pyrmidinyl, quinolinyl, or
isoquinolinyl and is substituted with 0-3 substituents selected
from the group consisting of halo, alkyl, haloalkyl, alkoxy,
haloalkoxy, or cyano.
[0035] Any scope of any substituent, including R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, Ar.sup.1, or Ar.sup.2, can be
used independently with the scope of any other instance of a
substituent.
[0036] Unless specified otherwise, these terms have the following
meanings. "Alkyl" means a straight or branched alkyl group composed
of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl
group composed of 2 to 6 carbons with at least one double bond.
"Cycloalkyl" means a monocyclic ring system composed of 3 to 7
carbons. "Hydroxyalkyl," "alkoxy" and other terms with a
substituted alkyl moiety include straight and branched isomers
composed of 1 to 6 carbon atoms for the alkyl moiety. "Haloalkyl"
and "haloalkoxy" include all halogenated isomers from monohalo
substituted alkyl to perhalo substituted alkyl. "Aryl" includes
carbocyclic and heterocyclic aromatic substituents. Parenthetic and
multiparenthetic terms are intended to clarify bonding
relationships to those skilled in the art. For example, a term such
as ((R)alkyl) means an alkyl substituent further substituted with
the substituent R.
[0037] Trimethylenedioxybenzen-yl means ##STR3##
[0038] The invention includes all pharmaceutically acceptable salt
forms of the compounds. Pharmaceutically acceptable salts are those
in which the counter ions do not contribute significantly to the
physiological activity or toxicity of the compounds and as such
function as pharmacological equivalents. These salts can be made
according to common organic techniques employing commercially
available reagents. Some anionic salt forms include acetate,
acistrate, besylate, bromide, chloride, citrate, fumarate,
glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide,
lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate,
sulfate, tartrate, tosylate, and xinofoate. Some cationic salt
forms include ammonium, aluminum, benzathine, bismuth, calcium,
choline, diethylamine, diethanolamine, lithium, magnesium,
meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,
tromethamine, and zinc.
[0039] Some Formula I compounds contain at least one asymmetric
carbon atom, an example of which is shown below. The invention
includes all stereoisomeric forms of the compounds, both mixtures
and separated isomers. Mixtures of stereoisomers can be separated
into individual isomers by methods known in the art. ##STR4##
Synthetic Methods
[0040] Compounds of Formula I can be made according to methods
known in the art and those illustrated in the schemes below and in
the specific embodiments section. The schemes encompass reasonable
variations known in the art. The variables describing general
structural formulas and features in the synthetic schemes are
distinct from and should not be confused with the variables in the
claims or the rest of the specification. These variables are meant
only to illustrate how to make some of the compounds of this
invention. ##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10##
##STR11## ##STR12## ##STR13## ##STR14## ##STR15## ##STR16##
##STR17## ##STR18## ##STR19## ##STR20##
Biological Methods
[0041] NK-1 Binding assay. U373 cells, a human
glioblastoma-astrocytoma cell line that endogenously expresses the
neurokinin-1 (NK-1) receptor, were grown in a monolayer culture at
37.degree. C. in 5% CO.sub.2 and fed with Minimum Essential Medium
(MEM) supplemented with 10% fetal bovine serum. Membranes were
prepared as follows: Cells were washed twice with ice-cold
phosphate-buffered saline (pH 7.4) and then incubated for 5-10
minutes with ice-cold 10 mM Tris buffer (pH 7.4) containing 5 mM
EDTA. Cells were removed from plates, homogenized, and centrifuged
at 32,000.times.g for 20 minutes. The resulting supernatant was
discarded, and the pellet resuspended by homogenization in 50 mM
Tris buffer (pH 7.4) containing 1 mM EDTA and centrifuged at
32,000.times.g for 20 minutes. The resulting supernatant was
discarded, and the pellet resuspended by homogenization in NK-1
binding assay buffer (50 mM Tris-HCL (pH 7.4), 3 mM MnCl2, 200
.mu.g/ml BSA, 5 .mu.g/ml chymostatin, 40 .mu.g/ml bacitracin and 4
.mu.g/ml leupeptin).
[0042] On the day of an experiment the membrane preparation was
thawed, homogenized and diluted with NK-1 binding assay buffer to
the appropriate concentration. Competition binding assays were
performed in 96 well plate format by incubating membranes (5-10
.mu.g/well) with Bolton Hunter labeled [.sup.125I] Substance P, at
a concentration of 200 nM, and concentrations of drugs ranging from
10000 to 0.01 nM. Samples were incubated for 30 min at 20.degree.
C. then filtered through GF/B glass fiber filters (pretreated with
1% polyethyleneimine and 0.3% Triton X-100) using a Brandel cell
harvester. The filters were then washed with 10 ml ice cold 50 mM
Tris-HCL (pH 7.4) containing 3 mM MgCl.sub.2. Non-specific was
defined in the presence of 2 .mu.M L-733,060 (a non-peptide NK-1
antagonist). The amount of radioligand bound in the presence and
absence of competitor was analyzed by plotting (-)log drug
concentration versus the amount of radioligand specifically bound.
The midpoint of the displacement curve (IC.sub.50, nM), signifies
the potency. Ki values can be calculated using the method of Cheng
and Prusoff (Cheng and Prusoff, BiochemicalPharmacology, Vol 22,
pp. 3099-3108, Pergamon Press (1973)).
[0043] Serotonin transporter binding assay. HEK-293 cells that
stably express human serotonin transporters (HEK-hSERT cells) were
grown at 37.degree. C. in 5% CO.sub.2 as a monolayer in medium
consisting of EMEM supplemented with 10% fetal bovine serum and
G418 sulfate (500 .mu.g/ml). To prepare membranes for radioligand
binding experiments, cells were rinsed twice with
phosphate-buffered saline (138 mM NaCl, 4.1 mM KCl, 5.1 mM
Na.sub.2PO.sub.4, 1.5 mM KH.sub.2PO.sub.4, 11.1 mM glucose, pH
7.4). Cells were transferred from plates to polypropylene tubes
(16.times.100 mm), centrifuged at 1,200.times.g for 5 min and were
frozen at -80.degree. C. until assay. Following centrifugation,
pellets were resuspended by homogenization in buffer consisting of
50 mM Tris (pH 7.7 at 25.degree. C.), 120 mM NaCl and 5 mM KCl and
then centrifuged at 32,000.times.g for 10 min. Following
centrifugation, supernatants were discarded and pellets were
resuspended in buffer consisting of 50 mM Tris (pH 7.4 at
25.degree. C.), 150 mM NaCl and 5 mM KCl. Membrane homogenates (200
.mu.l/plate) were incubated with 1 nM [.sup.3H]-citalopram
(specific activity=85 Ci/mmol) and increasing concentrations of
test compounds for 1 hr at 25.degree. C. in a total volume of 250
.mu.l. The assay buffer consisted of 50 mM Tris (pH 7.4 at
25.degree. C.), 120 mM NaCl and 5 mM KCl (pH 7.4 with conc. HCl).
Plates were incubated for 1 hr at 25.degree. C., then filtered
through 0.5% PEI treated Whatman GF/B filters using a Brandel cell
harvester. Filters were washed three times with 3 ml of ice-cold
tris wash buffer. Non-specific binding was defined with 10 .mu.M
fluoxetine. Amount of radioligand bound in the presence and absence
of competitor was analyzed by plotting (-)log drug concentration
versus the amount of radioligand specifically bound. The midpoint
of the displacement curve (IC.sub.50, nM), signifies the potency.
Ki values can be calculated using the method of Cheng and Prusoff
(Cheng and Prusoff, BiochemicalPharmacology, Vol 22, pp. 3099-3108,
Pergamon Press (1973)). NK-1 and serotonin transporter binding
results are shown in Tables 1 and 2. TABLE-US-00001 TABLE 1
Structure NK-1 IC.sub.50 (nM) SERT IC.sub.50 (nM) ##STR21## A A
##STR22## C A ##STR23## A A ##STR24## A A ##STR25## A A ##STR26## A
A ##STR27## A A ##STR28## A A ##STR29## C B ##STR30## A A ##STR31##
B A ##STR32## C A ##STR33## C B ##STR34## A A ##STR35## B A
##STR36## B A ##STR37## A A ##STR38## B A ##STR39## A A ##STR40## A
A ##STR41## A A ##STR42## A A ##STR43## C A ##STR44## A A ##STR45##
A A ##STR46## A A ##STR47## C B ##STR48## A A ##STR49## A A
##STR50## A A ##STR51## A A ##STR52## A A ##STR53## A A ##STR54## B
B ##STR55## B A ##STR56## C C ##STR57## B A ##STR58## A A ##STR59##
B A ##STR60## C B ##STR61## -- -- ##STR62## A A ##STR63## C A
##STR64## A A ##STR65## A A ##STR66## B B ##STR67## B A ##STR68## A
A ##STR69## A A ##STR70## A A ##STR71## A A ##STR72## C A ##STR73##
A A ##STR74## A A ##STR75## A A ##STR76## A A ##STR77## -- --
##STR78## A B ##STR79## C B ##STR80## B B ##STR81## A A ##STR82## C
C ##STR83## A A ##STR84## A A ##STR85## A A ##STR86## A A ##STR87##
A A ##STR88## B A ##STR89## B A ##STR90## C A ##STR91## -- --
##STR92## B B ##STR93## B A ##STR94## B A ##STR95## B B ##STR96## A
A ##STR97## B A ##STR98## C C ##STR99## C A ##STR100## C A
##STR101## A A ##STR102## A A ##STR103## A A ##STR104## A A
##STR105## A A ##STR106## A A ##STR107## B A ##STR108## C A
##STR109## B A ##STR110## A A ##STR111## A A ##STR112## C A
##STR113## C B ##STR114## B A ##STR115## A A ##STR116## A A
##STR117## B A ##STR118## A A ##STR119## C A ##STR120## B A
##STR121## A A ##STR122## A A ##STR123## A A ##STR124## A A
##STR125## A A ##STR126## A A ##STR127## A A
##STR128## A A ##STR129## A A Values: A = 0.01-100 nM; B = 100-300
nM; C > 300 nM.
[0044] TABLE-US-00002 TABLE 2 Structure NK-1 IC.sub.50 (nM) SERT
IC.sub.50 (nM) ##STR130## A A ##STR131## A A ##STR132## C A
##STR133## A A ##STR134## B A ##STR135## A A ##STR136## C A
##STR137## C B ##STR138## A A ##STR139## A A ##STR140## C A
##STR141## C A ##STR142## B A ##STR143## B A ##STR144## C B
##STR145## A A ##STR146## A A ##STR147## A A ##STR148## B A
##STR149## A A ##STR150## A A ##STR151## C A ##STR152## A A
##STR153## B A ##STR154## C A ##STR155## A A ##STR156## A A
##STR157## C B ##STR158## ##STR159## C A ##STR160## C A ##STR161##
A A ##STR162## B B ##STR163## C A ##STR164## B A ##STR165## B B
##STR166## C B ##STR167## A A ##STR168## C B ##STR169## B A
##STR170## A A ##STR171## C B ##STR172## C A ##STR173## C A
##STR174## A A ##STR175## A A ##STR176## ##STR177## C B ##STR178##
##STR179## A A ##STR180## A A ##STR181## A A ##STR182## A A
##STR183## A A ##STR184## A A ##STR185## A A ##STR186## A A
##STR187## A A ##STR188## A A ##STR189## A A ##STR190## A A
##STR191## A B ##STR192## A A ##STR193## C A ##STR194## A A
##STR195## B A ##STR196## A A ##STR197## A A ##STR198## A A
##STR199## A C ##STR200## A C ##STR201## A C ##STR202## A A
##STR203## A A ##STR204## C A ##STR205## C A ##STR206## C A
##STR207## C A ##STR208## A A ##STR209## C A ##STR210## A A
##STR211## A C ##STR212## A A ##STR213## A A ##STR214## A A
##STR215## A A ##STR216## A A ##STR217## A A ##STR218## A A
##STR219## A A ##STR220## A A ##STR221## A A ##STR222## A A
##STR223## A A ##STR224## A A ##STR225## A A ##STR226## A A
##STR227## A A ##STR228## A A ##STR229## A A ##STR230## A A
##STR231## A A ##STR232## A A ##STR233## A A ##STR234## A A
##STR235## A A ##STR236## A A ##STR237## A A ##STR238## A A
##STR239## A A ##STR240## A A ##STR241## A A ##STR242## A A
##STR243## A A ##STR244## A B ##STR245## A A ##STR246## A A
##STR247## A A ##STR248## A A ##STR249## A A ##STR250## A A
##STR251## A A
##STR252## A A ##STR253## A A ##STR254## A A ##STR255## A A
##STR256## A A ##STR257## A A ##STR258## A A ##STR259## A B
##STR260## A A Values: A = 0.01-100 nM; B = 100-300 nM; C > 300
nM.
Pharmaceutical Composition and Methods of Use
[0045] The compounds of Formula I demonstrate inhibition of
neurokinin-1 or serotonin reuptake or both. Inhibition of these
receptors correlates with efficacy for affective disorders such as
anxiety, depression, obsessive compulsive disorder, bulimia, and
panic disorder. As such, the compounds of Formula I can be useful
for the treatment of these disorders and other aspects of the
invention are compositions and methods of using the compounds to
treat these conditions and other conditions associated with
aberrant levels of tachykinins or serotonin or both.
[0046] The compounds of this invention are generally given as
pharmaceutical compositions comprised of a therapeutically
effective amount of a compound of Formula I, or a pharmaceutically
acceptable salt, and a pharmaceutically acceptable carrier and may
contain conventional exipients. A therapeutically effective amount
is the amount needed to provide a meaningful patient benefit as
determined by practitioners in that art. Pharmaceutically
acceptable carriers are those conventionally known carriers having
acceptable safety profiles. Compositions encompass all common solid
and liquid forms including capsules, tablets, losenges, and powders
as well as liquid suspensions, syrups, elixers, and solutions.
Compositions are made using common formulation techniques and
conventional excipients (such as binding and wetting agents) and
vehicles (such as water and alcohols).
[0047] Solid compositions are normally formulated in dosage units
providing from about 1 to about 1000 mg of the active ingredient
per dose. Some examples of solid dosage units are 1 mg, 10 mg, 100
mg, 250 mg, 500 mg, and 1000 mg. Liquid compositions are generally
in a unit dosage range of 1-100 mg/mL. Some examples of liquid
dosage units are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100
mg/mL. Generally, the dosage unit will be in a unit range similar
to agents of that class used clinically, for example
fluoxetine.
[0048] The invention encompasses all conventional modes of
administration; oral and parenteral methods are preferred.
Generally, the dosing regimen will be similar to agents of that
class used clinically, for example fluoxetine. Typically, the daily
dose will be 0.01-100 mg/kg body weight daily. Generally, more
compound is required orally and less parenterally. The specific
dosing regime, however, should be determined by a physician using
sound medical judgment.
[0049] Tachykinin and serotonin modulators are associated with
depression. Accordingly, another aspect of the invention are
methods for treating depressive disorders including Major
Depressive Disorders (MDD), bipolar depression, unipolar
depression, single or recurrent major depressive episodes,
recurrent brief depression, catatonic features, melancholic
features including feeding disorders, such as anorexia, weight
loss, atypical features, anxious depression, or postpartum onset.
Other central nervous system disorders encompassed within the term
MDD include neurotic depression, post-traumatic stress disorders
(PTSD) and social phobia, with early or late onset dementia of the
Alzheimer's type, with depressed mood, vascular dementia with
depressed mood, mood disorders and tolerance induced by drugs such
as alcohol, amphetamines, cocaine, inhalants, opioids, sedatives,
anxiolytics and other substances, schizoaffective disorder of the
depressed type, and adjustment disorder with depressed mood.
[0050] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of schizophrenic disorders.
Accordingly, another aspect of the invention are methods for
treating schizophrenic disorders including paranoid schizophrenia,
disorganized schizophrenia, catatonic schizophrenia,
undifferentiated schizophrenia, residual schizophrenia.
[0051] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of anxiety. Accordingly, another aspect
of the invention are methods for treating anxiety disorders
including panic disorders, agoraphobia, phobias,
obsessive-compulsive disorder, stress disorders including
post-traumatic stress disorders, generalized anxiety disorders,
acute stress disorders and mixed anxiety-depression disorders.
[0052] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of cognitive disorders. Accordingly,
another aspect of the invention are methods for treating cognitive
disorders including dementia, and amnesia disorders. Tachykinin and
serotonin modulators are also associated with the treatment or
prevention of memory and cognition in healthy humans.
[0053] Tachykinin and serotonin modulators are also associated with
use as analgesics. Accordingly, another aspect of the invention are
methods for treating pain, including the treatment of traumatic
pain such as postoperative pain, chronic pain such as arthritic
pain such as occurring in osteo-, rheumatoid or psoriatic
arthritis, neuropathic pain such as post-herpetic neuralgia,
trigeminal neuralgia, segmental or intercostal neuralgia,
fibromyalgia, peripheral neuropathy, diabetic neuropathy,
chemotherapy-induced neuropathy, AIDS-related neuropathy, various
forms of headache such as migraine, acute or chronic tension
headache, cluster headaches, maxillary sinus pain, cancer pain,
pain of bodily origin, gastrointestinal pain, sport's injury pain,
dysmennorrhoea, menstrual pain, meningitis, musculoskeletal pain,
low back pain e.g. spinal stenosis, prolapsed disc, sciatica,
angina, ankylosing spondyolitis, gout, burns, scar pain, itch and
thalamic pain such as post stroke thalamic pain.
[0054] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of sleep disorders. Accordingly,
another aspect of the invention are methods for treating sleep
disorders including insomnia, sleep apnea, narcolepsy, and
circadian rhymic disorders.
[0055] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of inflammation. Accordingly, another
aspect of the invention are methods for treating inflammation,
including the treatment of inflammation in asthma, influenza and
chronic bronchitis, in the treatment of inflammatory diseases of
the gastrointestinal tract such as Crohn's disease, ulcerative
colitis, inflammatory bowel disease and non-steroidal
anti-inflammatory drug induced damage, inflammatory diseases of the
skin such as herpes and eczema, inflammatory diseases of the
bladder such as cystitis and urge incontinence, and eye and dental
inflammation.
[0056] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of allergic disorders. Accordingly,
another aspect of the invention are methods for treating allergic
disorders, in particular allergic disorders of the skin such as
urticaria, and allergic disorders of the airways such as
rhinitis.
[0057] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of emesis, nausea, retching and
vomiting. Accordingly, another aspect of the invention are methods
for treating these disorders.
[0058] Tachykinin and serotonin modulators are also associated with
the treatment or prevention of premenstrual dysphoric disorder
(PMDD), in chronic fatigue syndrome and multiple sclerosis.
Accordingly, another aspect of the invention are methods for
treating these disorders.
DESCRIPTION OF SPECIFIC EMBODIMENTS
[0059] The following experimental procedures describe the synthesis
of some Formula I compounds. Standard chemistry conventions are
used in the text unless otherwise noted. The experimental encompass
reasonable variations known in the art. Method A involves the use
of a Suzuki coupling. Method B involves the use of a Stille
coupling. Method D involves reductive amination. The following HPLC
conditions were used in the preparing the compounds below. HPLC
method 1: Xterra C18 2.0.times.50 mm, A=95% H.sub.2O/5% ACN, B=95%
ACN/5% H.sub.2O, Modifier 10 mM NH.sub.4OAC, 1 mL/min, 0.00 min=10%
B, 2.00 min=100% B; HPLC method 2: Xterra C18 2.0.times.50 mm,
A=95% H.sub.2O/5% ACN, B=95% ACN/5% H.sub.2O, Modifier 10 mM
NH4OAC, Flow rate=1 mL/min, 0.00 min=10% B, 0.80 min=60% B, 1.99
min=95% B, 2.00 min=100% B (1.5 mL/min); HPLC method 3: Phenomenex
C18 4.6.times.50 mm, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA, Gradient time=4 min., Flow rate=4
mL/min; HPLC method 4: Phenomenex C18 4.6.times.50 mm, A=95%
H.sub.2O/5% ACN, B=95% ACN/5% H.sub.2O, Modifier 10 mM NH.sub.4OAc,
0.00 min=10% B, 3.5 min=95% B, Flow rate=1.5 mL/min; HPLC method 5:
Phenomenex Luna 3.0.times.50 mm, A=90% H.sub.2O/10% MeOH, B=90%
MeOH/10% H.sub.2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100%
B, Flow rate=4 mL/min; HPLC method 6: Xterra C18 2.1.times.50 mm,
A=95% H.sub.2O/5% ACN, B=95% ACN/5% H.sub.2O, Modifier 10 mM
NH.sub.4OAc, 0.00 min=0% B, 0.80 min=80% B, 2.00 min=100% B, Flow
rate=1.0 mL/min. ##STR261##
[0060] tert-Butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate.
4-Phenyl-4-piperidinecarboxylic acid p-methylbenzenesulfonate (19.0
g, 50.3 mmol) was suspended in dry tetrahydrofuran (100 mL) and
cooled to 0.degree. C. To this was added borane tetrahydrofuran
complex (1 M in THF, 100 mL, 100 mmol) cautiously over 15 min and
the reaction mixture allowed to warm to room temperature overnight.
The reaction mixture was cooled to 0.degree. C., treated with
di-tert-butyl carbonate (15.0 g, 218 mmol) and 10 N sodium
hydroxide (12 mL), stirred at 0.degree. C., and at room temperature
overnight. The reaction mixture was diluted with ethyl acetate,
washed with water (2.times.), brine (2.times.), dried over sodium
sulfate and concentrated. The crude product was triturated with 10%
ethyl acetate/hexanes solution to afford 9.2 g (63%) of the title
compound. .sup.1H-NMR (CD.sub.3OD, 300 MHz) .delta. 7.35-7.43 (m,
4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m, 2H), 3.49 (s, 2H), 2.97 (m,
2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H), 1.46 (s, 9H). Mass
spec.: 292.17 (MH).sup.+. ##STR262##
[0061] 1-(tert-Butoxycarbonyl)-4-phenylpiperidine-4-carboxylic
acid. To a suspension of 4-phenyl-4-piperidinecarboxylic acid
p-methylbenzenesulfonate (100 g, 265 mmol) and triethylamine (111
mL, 795 mmol) in tetrahydrofuran (1200 mL) was added di-tert-butyl
dicarbonate (63.6 g, 291 mmol). The reaction was slowly heated to a
gentle reflux and held there for 1 h. After one hour, gas evolution
had ended and the reaction had become a clear solution. The
reaction was cooled to room temperature and concentrated to remove
most of the tetrahydrofuran. The residue was dissolved in
water/ether and the aqueous made very basic by the addition of 10 M
sodium hydroxide (50 mL). The aqueous was washed with ether
(2.times.) which was discarded. The aqueous was transferred to an
erlenmeyer flask and made acidic (ca. pH 5) by addition of acetic
acid to give a white precipitate. The precipitate was collected by
filtration and air dried overnight to give a white powder. The last
traces of water were removed under high vacuum to give the product
(78.9 g, 258 mmol, 98% yield). .sup.1H-NMR (CD.sub.3OD, 500 MHz)
.delta. 10.5 (bs, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H),
3.90 (bs, 2H), 3.08, (bs, 2H), 2.48 (d, J=13.4 Hz, 2H), 1.85 (m,
2H), 1.44 (s, 9H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm
179.6, 155.0, 141.6, 128.8, 127.6, 126.1, 79.9, 49.3, 41.7, 33.4,
28.5. Mass spec.: 328.12 (MNa).sup.+. ##STR263##
[0062] tert-Butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate. To a suspension
of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (40
g, 131 mmol) in tetrahydrofuran (131 mL) at room temperature was
added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 131
mL, 131 mmol). There was effervescence and the substrate quickly
went into solution. The reaction was stirred at room temperature
for 3 days. The reaction was cooled to 0.degree. C. and quenched by
the cautious addition of 1 M sodium hydroxide. The reaction was
diluted with ether, washed with water (2.times.), then brine, dried
over magnesium sulfate, and concentrated. Trituration with 10%
EtOAc/Hex (300 mL) gave a white powder which was collected by
filtration to give 36.9 g (97%). .sup.1H-NMR (CD.sub.3OD, 300 MHz)
.delta. 7.35-7.43 (m, 4H), 7.24-7.26 (m, 1H), 3.78-3.85 (m, 2H),
3.49 (s, 2H), 2.97 (m, 2H), 2.17-2.21 (m, 2H), 1.77-1.87 (m, 2H),
1.46 (s, 9H). Mass spec.: 292.17 (MH).sup.+. ##STR264##
[0063] tert-Butyl
4-(3-bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.47 (s, 1H), 7.39
(m, 1H), 7.27 (m, 2H), 3.72 (m, 2H), 3.55 (s, 2H), 3.06 (m, 2H),
2.05 (m, 2H), 1.76 (m, 2H), 1.42 (s, 9H). Mass spec.: 370.12
(MH).sup.+. ##STR265##
[0064] tert-Butyl
4-(3-chlorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.30 (m, 2H), 7.23
(m, 2H), 3.72 (m, 2H), 3.53 (s, 2H), 2.08 (m, 2H), 1.76 (m, 2H),
1.41 (s, 9H). Mass spec.: 326.16 (MH).sup.+. ##STR266##
[0065] tert-Butyl
4-(3,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.10-7.18 (m, 2H),
7.05 (m, 1H), 3.68-3.73 (m, 2H), 3.54 (m, 2H), 3.01-3.08 (m, 2H),
2.08 (m, 2H), 1.74-1.79 (m, 2H), 1.42 (s, 9H). ##STR267##
[0066] tert-Butyl
4-(4-bromophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.50 (m, 2H), 7.21
(m, 2H), 3.70 (m, 2H), 3.53 (s, 2H), 3.02 (m, 2H), 2.10 (m, 2H),
1.75 (m, 2H), 1.42 (s, 9H). Mass spec.: 370.15 (MH).sup.+.
##STR268##
[0067] tert-Butyl
4-(hydroxymethyl)-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.49-7.57 (m, 4H),
3.71-3.75 (m, 2H), 3.59 (s, 2H), 3.01-3.10 (m, 2H), 2.15 (m, 2H),
1.85 (m, 2H), 1.42 (s, 9H). Mass spec.: 360.26 (MH).sup.+.
##STR269##
[0068] tert-Butyl
4-(hydroxymethyl)-4-(3-methoxyphenyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.31 (m, 1H),
6.87-6.93 (m, 1H), 6.88 (s, 1H), 6.80 (m, 1H), 3.80 (s, 3 H),
3.72-3.78 (m, 2 H), 3.53 (d, J=6.41 Hz, 2 H), 3.05 (t, J=11.14 Hz,
2 H), 2.14 (d, J=14.04 Hz, 2 H), 1.73 (ddd, J=14.11, 10.30, 3.97
Hz, 2 H), 1.42 (s, 9 H). Mass spec.: 322.22 (MH).sup.+.
##STR270##
[0069] tert-Butyl
4-(2-bromo-4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. ppm 7.33-7.40 (m, 2H),
7.00-7.06 (m, 1H), 4.04 (d, J=6.3 Hz, 2H), 3.59 (m, 2H), 3.19-3.26
(m, 2H), 2.45-2.49 (m, 2H), 1.95-2.02 (m, 2H), 1.43 (s, 9H). Mass
spec.: 390.15 (MH).sup.+. ##STR271##
[0070] tert-Butyl
4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. ppm7.22 (m, 1H), 6.85 (m,
1H), 6.77 (m, 1H), 3.70 (s, 2H), 3.67 (m, 2H), 3.08 (m, 2H), 2.21
(m, 2H), 1.78 (m, 2H), 1.64 (m, 1H), 1.41 (s, 9H). Mass spec.:
328.27 (MH).sup.+. ##STR272##
[0071]
3'-(hydroxymethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. A
solution of (3-bromo-5-(trifluoromethyl)phenyl)methanol (3.0 g,
11.8 mmol), 4-cyanophenyl boronic acid (5.2 g, 35 mmol),
tetrakis(triphenylphosphine) palladium(0) (2.7 g, 2.4 mmol), and
aqueous potassium hydroxide (41 mL, 1N, 41 mmol) in THF (80 mL) was
degassed with nitrogen for 10 minutes and then heated at
120.degree. C. for 18 hours. The reaction was cooled to ambient
temperature and poured into water (100 mL), then was diluted with
ethyl acetate (100 mL) and the layers were separated. The aqueous
layer was extracted with ethyl acetate (2.times.20 mL) and the
combined organic layers were dried with MgSO.sub.4 and evaporated.
The residue was purified by chromatography on SiO.sub.2 with a
gradient of ethyl acetate/hexanes of 5%-40%. The product
3'-(hydroxymethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile
(1.66 g, 51%) was obtained as a white solid. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 7.65-7.80 (m, 7H), 4.85 (s, 2H), 1.90
(bs, 1H). Mass spec.:278.2 (M+H). ##STR273##
[0072]
3'-(bromomethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile.
N-bromosuccinimide (2.24 g, 12.6 mmol) was added to a 0.degree. C.
solution of
3'-(hydroxymethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile
(1.66 g, 6.0 mmol) and triphenylphosphine (3.14 g, 12.0 mmol) in
THF (100 mL). The reaction was warmed to ambient temperature and
stirred for 18 hours. The solvent was evaporated and the residue
was purified by chromatography on SiO.sub.2 with a gradient of
ethyl acetate/hexanes of 5% to 40%. The product
3'-(bromomethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile (1.30
g, 64%) was obtained as a white solid. .sup.1H-NMR (CDCl.sub.3, 400
MHz) .delta. 7.65-7.80 (m, 7H), 4.56 (s, 2H). ##STR274##
[0073] tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)pi-
peridine-1-carboxylate. tert-Butyl
4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate
(220 mg, 0.67 mmol) and
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (450 mg, 1.41
mmol) were combined in tetrahydrofuran (2 mL) and cooled to
0.degree. C. The reaction was treated with sodium tert-butoxide (75
mg, 0.355 mmol) and stirred at 0.degree. C. for 20 min. The
reaction was treated with another aliquot of sodium tert-butoxide
(75 mg, 0.355 mmol), allowed to warm to room temperature, and
stirred for 30 min. The reaction was diluted with 10% sodium
bicarbonate and extracted with ethyl acetate (2.times.). The
organic layers were pooled together, washed with brine (1.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (0%.fwdarw.25% ethyl acetate/hexanes) gave 200 mg
(50%). Mass spec.: 586.04 (MH).sup.+ LC t.sub.r=2.552 min.
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow
rate=4 mL/min). ##STR275##
[0074] tert-butyl
4-(2-bromo-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate. Potassium tert-butoxide
(266 mg, 2.37 mmol) was added to a 0.degree. C. solution of
tert-butyl
4-(2-bromo-4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate
(460 mg, 1.18 mmol) and
3'-(bromomethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile (524
mg, 1.54 mmol) in THF (10 mL) and was allowed to warm to ambient
temperature and stir for 24 hours. The solvent was evaporated and
the residue was purified by chromatography on SiO.sub.2 with a
gradient of ethyl acetate/hexanes from 5% to 40%. The product
tert-butyl
4-(2-bromo-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate (520 mg, 68%) was isolated
as a clear syrup. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.75
(d, J=8.3 Hz, 2H), 7.67 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.36 (m,
3H), 7.22 (m, 1H), 6.99 (m, 1H), 4.49 (s, 2H), 3.94 (s, 2H), 3.57
(m, 1H), 3.24 (m 1H), 2.48 (m, 2H), 2.05 (m, 2H), 1.42 (s, 9H).
Mass spec.: 647.2 (M+H). ##STR276##
[0075] tert-Butyl
4-(3-bromophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)-
methyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.75 (m, 2H), 7.67 (br s, 1H), 7.60 (m, 2H), 7.48 (m,
1H), 7.41 (m, 2H), 7.31 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 4.45
(m, 2H), 3.72 (m, 2H), 3.45 (m, 2H), 3.04 (m, 2H), 2.13 (m, 2H),
1.85 (m, 2H), 1.42 (s, 9H). Mass spec.: 629.22 (MH).sup.+.
##STR277##
[0076] tert-Butyl
4-(3-chlorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy-
)methyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.74 (m, 2H), 7.66 (s, 1H), 7.61 (s, 1H), 7.44 (s, 1H),
7.37 (s, 1H), 7.18-7.29 (m, 4H), 7.17 (m, 1H), 4.47 (s, 2H), 3.73
(m, 2H), 3.43 (s, 2H), 3.03 (m, 2H), 2.16 (m, 2H), 1.85 (m, 2H),
1.42 (s, 9H). Mass spec.: 585.27 (MH).sup.+. ##STR278##
[0077] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3,4-dif-
luorophenyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. ppm 7.75 (m, 2H), 7.68 (s, 1H), 7.59 (m, 2H), 7.42 (s,
1H), 7.38 (s, 1H), 7.01-7.19 (m, 3H), 4.47 (s, 2H), 3.69 (m, 2H),
3.42 (s, 2H), 3.05 (m, 2H), 2.07 (m, 2H), 1.83 (m, 2H), 1.42 (s,
9H). ##STR279##
[0078] tert-Butyl
4-(4-bromophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)-
methyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.78 (m, 2H), 7.68 (s, 1H), 7.59 (m, 2H), 7.43 (m, 4H),
7.23 (m, 2H), 4.46 (s, 2H), 3.72 (m, 2H), 3.43 (s, 2H), 3.02 (s,
2H), 2.14 (m, 2H), 1.83 (m, 2H), 1.42 (s, 9H). Mass spec.: 653.06
(MNa).sup.+. ##STR280##
[0079] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3-(trif-
luoromethyl)phenyl)piperidine-1-carboxylate. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. ppm 7.74 (m, 2H), 7.68 (s, 1H),
7.51-7.59 (m, 4H), 7.36-7.45 (m, 4H), 4.46 (s, 2H), 3.70 (m, 2H),
3.47 (s, 2H), 3.03-3.09 (m, 2H), 2.18 (m, 2H), 1.87-1.92 (m, 2H),
1.42 (s, 9H). Mass spec.: 619.27 (MH).sup.+. ##STR281##
[0080] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3-metho-
xyphenyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. ppm 7.74-7.76 (m, 2H), 7.67 (s, 1H), 7.59-7.62 (m,
2H), 7.47 (s, 1H), 7.41 (s, 1H), 7.22-7.26 (m, 1H), 6.92-6.95 (m,
1H), 6.90 (m, 1H), 6.73-6.76 (m, 1H), 4.45 (s, 2H), 3.70-3.78 (m,
2H), 3.75 (s, 3H), 3.44 (s, 2H), 3.02 (m, 2H), 2.14-2.19 (m, 2H),
1.80-1.88 (m, 2H), 1.41 (s, 9H). Mass spec.: 581.14 (MH).sup.-.
##STR282##
[0081] tert-butyl
4-(2-cyano-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate. A mixture of tert-butyl
4-(2-bromo-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate (50 mg, 0.077 mmol), Zinc
cyanide (13.60 mg, 0.1 16 mmol), and
tetrakis(triphenylphosphine)palladium(0) (8.92 mg, 7.72 .mu.mol)
were placed in a sealable vessel and degassed with nitrogen for 5
min. The vessel was then sealed and heated at 120.degree. C. for 3
h. The reaction was poured into brine (20 mL) and extracted with
ethyl acetate (4.times.5 mL). The combined organic layers were
dried (MgSO.sub.4) and evaporated to dryness. The resulting residue
was purified by chromatography on SiO.sub.2 with a ethyl
acetate/hexanes gradient from 12% to 100%. The product tert-butyl
4-(2-cyano-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate (39 mg, 85%) was obtained
as a clear oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.75 (d,
J=8.7 Hz, 2H), 7.68 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.45 (m, 1H),
7.40 (s, 1H), 7.22-7.32 (m, 3H), 4.51 (s, 2H), 3.86 (s, 2H), 3.59
(m, 1H), 3.28 (m, 2H), 2.47 (m, 2H), 2.10 (m, 2H), 1.42 (s, 9H).
Mass spec.: 594.3 (M+H). ##STR283##
[0082] tert-butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(5-fluor-
obiphenyl-2-yl)piperidine-1-carboxylate. A mixture of tert-butyl
4-(2-bromo-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate (100 mg, 0.15 mmol),
phenyl boronic acid (19 mg, 0.15 mmol), potassium carbonate (43 mg,
0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.
15 mmol) were placed in a sealable vessel and degassed with
nitrogen for 5 min. The vessel was then sealed and heated at
120.degree. C. for 3 h. The reaction was poured into brine (20 mL)
and extracted with ethyl acetate (4.times.5 mL). The combined
organic layers were dried (MgSO.sub.4) and evaporated to dryness.
The resulting residue was purified by chromatography on SiO.sub.2
with a ethyl acetate/hexanes gradient from 12% to 100%. The product
tert-butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(5-fluor-
obiphenyl-2-yl)piperidine-1-carboxylate (39 mg, 39%) was isolated
as a clear oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.68-7.76
(m, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.44 (m, 3H), 7.18-7.28 (m, 3H),
7.03 (m, 1H), 6.94 m, 2H), 6.67 (m, 1H), 4.52 (s, 2H), 3.52 (m,
2H), 3.47 (s, 2H), 2.90 (m, 2H), 1.91 (m, 2H), 1.45 (m, 2H), 1.38
(s, 9H). Mass spec.: 645.2 (M+H). ##STR284##
[0083] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(3-cyano-
phenyl)piperidine-1-carboxylate. A mixture of tert-Butyl
4-(3-bromophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)-
methyl)piperidine-1-carboxylate (150 mg, 0.238 mmol), zinc cyanide
(33.6 mg, 0.286 mmol), palladium tetrakis triphenylphosphine (27.5
mg, 0.024 mmol), and dimethylformamide (1 mL) was charged to a
conical vial and purged with nitrogen for 5 minutes. The vial was
sealed and heated at 120.degree. C. for 2 hours and then held at
room temperature overnight. The resulting mixture was filtered
through a syringe tip filter and applied directly to a silica gel
column. Gradient elution with 5-40% ethyl acetate/hexanes afforded
the product as a clear oil (83 mg, 61%). .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. ppm 7.76 (m, 2H), 7.68 (s, 1H), 7.56-7.64 (m, 4H),
7.45-7.49 (m, 1H), 7.38-7.43 (m, 2H), 7.34 (s, 1H), 3.69 (m, 2H),
3.45 (s, 2H), 3.05 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.42 (s,
9H). Mass spec.: 576.17 (MH).sup.+. ##STR285##
[0084] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-cyano-
phenyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.77 (m, 2H), 7.68 (s, 1H), 7.58-7.63 (m, 4H), 7.46 (m,
2H), 7.43 (s, 1H), 7.35 (s, 1H), 4.46 (s, 2H), 3.68 (m, 2H), 3.47
(s, 2H), 3.05 (m, 2H), 2.17 (m, 2H), 1.85-1.92 (m, 2H), 1.42 (s,
9H). Mass spec.: 576.16 (MH).sup.+. ##STR286##
[0085] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-(fura-
n-2-yl)phenyl)piperidine-1-carboxylate. A solution of tert-butyl
4-(4-bromophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)-
methyl)piperidine-1-carboxylate (175 mg, 0.278 mmol),
2-(tributylstannyl)furan (109 mg, 0.306 mmol), and toluene (1.5 ml)
in a conical reaction vial was purged with nitrogen for 10 minutes.
Palladium tetrakistriphenylphosphine (321 mg, 0.278 mmol) was
added. The vial was sealed and heated 120.degree. C. overnight. The
resulting mixture was cooled to room temperature and partitioned
between ethyl acetate and brine. The organics were dried over
sodium sulfate, filtered, and concentrated to a light amber oil.
Silica gel column chromatography (5-40% ethyl acetate/hexanes)
afforded the product as a colorless oil (130 mg, 72%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. ppm 7.64 (s, 1H), 7.57-7.60 (m, 4H),
7.49 (m, 3H), 7.41 (s, 1H), 7.32-7.37 (m, 3H), 6.61 (m, 1H), 6.51
(m, 1H), 4.47 (s, 2H), 3.74 (br m, 2H), 3.46 (s, 2H), 3.04 (m, 2H),
2.22 (m, 2H), 1.83 (m, 2H), 1.42 (s, 9H). Mass spec.: 617.25
(MH).sup.+. ##STR287##
[0086] (3-Nitro-5-(trifluoromethyl)phenyl)methanol.
3-Nitro-5-(trifluoromethyl)benzoic acid (5.0 g, 21.2 mmol) was
combined with tetrahydrofuran (43 mL) and cooled to 0.degree. C. To
this solution was added a 1 M borane tetrahydrofuran complex (42
mL, 42 mmol) cautiously over 15 min and the reaction mixture
allowed to warm to room temperature overnight. The mixture was
cooled to 0.degree. C., treated with excess methanol and
concentrated in vacuo to afford 4.0 g (85%) which was used without
further purification. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.
8.39 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 4.87 (s, 2H).
##STR288##
[0087] (3-Amino-5-(trifluoromethyl)phenyl)methanol.
(3-Nitro-5-(trifluoromethyl)phenyl)methanol (2.6 g, 11.6 mmol) in
methanol (30 mL) was flushed with nitrogen, and treated with
palladium (10% on charcoal, 260 mg). The flask was flushed with
hydrogen and allowed to stir under an atmosphere of hydrogen
overnight. The reaction was flushed with nitrogen, filtered through
celite, and concentrated. Column chromatography on silica gel (50%
ethyl acetate/hexanes) afforded 1.9 g (85%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 6.95 (s, 1H), 6.80 (s, 1H), 6.79 (s,
1H), 4.61 (s, 2H). Mass spec.: 192.15 (MH).sup.+. ##STR289##
[0088] (3-Bromo-5-(trifluoromethyl)phenyl)methanol.
(3-Amino-5-(trifluoromethyl)phenyl)methanol (1.6 g, 8.4 mmol) in
dry acetonitrile (10 mL) was added dropwise to a solution of copper
(II) bromide (2.24 g, 10.0 mmol) and tert-butyl nitrite (1.48 mL,
12.0 mmol) in acetonitrile (20 mL) at 65.degree. C. After stirring
for 30 min at 65.degree. C., the reaction mixture was cooled to
room temperature, poured into a 1 N hydrochloric acid solution, and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (20%
ethyl acetate/hexanes) afforded 1.48 g (69%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s,
1H), 4.75 (s, 2H). ##STR290##
[0089] 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene.
(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.3 mmol) and
triphenylphosphine (3.3 g, 12.6 mmol) were combined in
tetrahydrofuran (30 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (2.4 g, 13.2 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.73 (s, 1H), 7.70 (s,
1H), 7.58 (s, 1H), 4.44 (s, 2H). ##STR291##
[0090] tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate. 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0
g, 3.14 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70 g, 2.4
mmol) were combined in dimethylformamide (8 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (115 mg,
4.8 mmol), stirred at 0.degree. C. for 1 h, and at room temperature
for 30 min. The reaction mixture was diluted with water and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (20%
ethyl acetate/hexanes) gave 1.6 g (96%). .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H),
7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H),
3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s,
9H). Mass spec.: 530.21 (MH).sup.+. ##STR292##
[0091] tert-Butyl
4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)pipe-
ridine-1-carboxylate. To a solution of tert-butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate (5.5 g, 10.4 mmol) in tetrahydrofuran (60 mL) at
-78.degree. C. was added n-butyllithium (1.6 M in hexane, 7.48 mL,
12.0 mmol) dropwise. The reaction was stirred at -78.degree. C. for
20 min and treated with tributyltin chloride (3.25 mL, 12.0 mmol).
The reaction was allowed to gradually warm to room temperature in
the dewar over several hours. The reaction was poured into pentane,
washed with water (2.times.), then brine, dried over magnesium
sulfate, and concentrated. Column chromatography (5%.fwdarw.8%
ethyl acetate/hexanes) gave 6.1 g (79%) as a colorless oil.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.56 (s, 1H), 7.44 (s,
1H), 7.37 (m, 5H), 7.24 (m, 1H), 4.38 (s, 2H), 3.74 (m, 2H), 3.43
(s, 2H), 3.06 (m, 2H), 2.20 (m, 2H), 1.90 (m, 2H), 1.54 (m, 6H),
1.44 (s, 9H), 1.34 (m, 6H), 1.09 (m, 6H), 0.90 (m, 9H); .sup.13C
NMR (126 MHz, CDCl.sub.3) .delta. ppm 155.1143.6, 142.9, 138.4,
138.3, 131.7 (q, J=3.8 Hz), 130.0 (q, J=32 Hz), 128.5, 127.3,
126.5, 124.6 (q, J=273 Hz), 123.7 (q, J=3.8 Hz), 79.6, 79.3, 72.9,
41.7, 40.2 (br), 32.1, 29.1, 28.6, 27.3, 13.7, 9.8. ##STR293##
[0092] (3-Chloro-5-(trifluoromethyl)phenyl)methanol.
(3-Amino-5-(trifluoromethyl)phenyl)methanol (1.0 g, 5.23 mmol) in
dry acetonitrile (6 mL) was added dropwise to a solution of copper
(II) chloride (0.83 g, 6.2 mmol) and tert-butyl nitrite (0.9 mL,
7.5 mmol) in acetonitrile (6 mL) at 65.degree. C. After 30 min at
65.degree. C., the reaction mixture was cooled to room temperature,
poured into a 1 N hydrochloric acid solution, and extracted with
ethyl acetate (2.times.). The organic layers were pooled together,
washed with brine (2.times.), dried over sodium sulfate, and
concentrated. Column chromatography on silica gel (30% ethyl
acetate/hexanes) afforded 0.8 g (73%). .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.54 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 4.74 (s,
2H). ##STR294##
[0093] 1-(Bromomethyl)-3-chloro-5-(trifluoromethyl)benzene.
(3-Chloro-5-(trifluoromethyl)phenyl)methanol (0.78 g, 3.7 mmol) and
triphenylphosphine (1.94 g, 7.4 mmol) were combined in
tetrahydrofuran (18 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (1.4 g, 7.8 mmol) was introduced in portions and
the reaction allowed to warm to room temperature. After 16 h, the
reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (10% ethyl acetate/hexanes) gave 0.94 g (92%).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.55 (s, 1H), 7.52 (s,
1H), 7.51 (s, 1H), 4.42 (s, 2H). ##STR295##
[0094] tert-Butyl
4-((3-chloro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-ca-
rboxylate. 1-(Bromomethyl)-3-chloro-5-(trifluoromethyl)benzene
(0.94 g, 3.4 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.0 g, 3.4
mmol) were combined in dimethylformamide (8 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (95 mg,
3.7 mmol), stirred at 0.degree. C. for 1 h, and at room temperature
overnight. The reaction mixture was diluted with water and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (20%
ethyl acetate/hexanes) gave 0.78 g (52%). LC/MS (HPLC method 3):
t.sub.R=3.65 min, 484.20(MH).sup.+. ##STR296##
[0095] 1-(Bromomethyl)-3-nitro-5-(trifluoromethyl)benzene.
(3-Nitro-5-(trifluoromethyl)phenyl)methanol (0.5 g, 2.26 mmol) and
triphenylphosphine (1.19 g, 4.5 mmol) were combined in
tetrahydrofuran (15 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (0.8 g, 4.8 mmol) was introduced in portions and
the reaction allowed to warm to room temperature. After 16 h, the
reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (10% ethyl acetate/hexanes) gave 0.58 g (91%).
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.42 (s, 1H), 8.39 (s,
1H), 7.97 (s, 1H), 4.90 (s, 2H). ##STR297##
[0096] tert-Butyl
4-((3-nitro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate. 1-(Bromomethyl)-3-nitro-5-(trifluoromethyl)benzene (150
mg, 0.53 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (142 mg, 0.49
mmol) were combined in dimethylformamide (3 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (14 mg,
0.53 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature overnight. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (10% ethyl acetate/hexanes) gave 138 mg (53%). LC/MS (HPLC
method 3): t.sub.R=3.42 min, 495.18(MH).sup.+. ##STR298##
[0097] tert-Butyl
4-((3-amino-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate. tert-Butyl
4-((3-nitro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate (118 mg, 0.24 mmol) in methanol (2.5 mL) was flushed with
nitrogen, and treated with palladium (10% on charcoal, 12 mg). The
flask was flushed with hydrogen and allowed to stir under an
atmosphere of hydrogen overnight. The reaction was flushed with
nitrogen, filtered through celite, and concentrated to afford 90 mg
(80%). LC/MS (HPLC method 3): t.sub.R=3.10 min, 465.22(MH).sup.+.
##STR299##
[0098] tert-Butyl
4-phenyl-4-((3-(2,2,2-trifluoroacetamido)-5-(trifluoromethyl)benzyloxy)me-
thyl)piperidine-1-carboxylate. tert-Butyl
4-((3-amino-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate (90 mg, 0.19 mmol) and triethylamine (52.0 .mu.L, 0.37
mmol) were combined in methylene chloride (2 mL) and cooled to
0.degree. C. The reaction was treated with trifluoroacetic
anhydride (33.0 .mu.L, 0.23 mmol), stirred at 0.degree. C. for 2 h,
and at room temperature overnight. The reaction was cooled to
0.degree. C., quenched by addition of a few drops of methanol and
concentrated. Flash chromatography on silica gel (40% ethyl
acetate/hexanes) gave 106 mg (98%). LC/MS (HPLC method 3):
t.sub.R=3.38 min, 561.18(MH).sup.+. ##STR300##
[0099] tert-Butyl
4-phenyl-4-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)-
benzyloxy)methyl)piperidine-1-carboxylate. tert-Butyl
4-phenyl-4-((3-(2,2,2-trifluoroacetamido)-5-(trifluoromethyl)benzyloxy)me-
thyl)piperidine-1-carboxylate (100 mg, 0. 18 mmol) in carbon
tetrachloride (3 mL) was treated with triphenylphosphine (117 mg,
0.45 mmol) and heated at reflux overnight. After cooling to room
temperature, the reaction was concentrated and the residue
dissolved in dimethylformamide (2 mL). The mixture was treated with
sodium azide (25 mg, 0.37 mmol) and stirred at room temperature for
5 h. The solvents were evaporated and the crude product purified by
flash chromatography on silica gel (30% ethyl acetate/hexanes) to
afford 46 mg (45%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.61
(s, 1H), 7.59 (s, 1H), 7.30-7.32 (m, 2H), 7.23-7.26 (m, 2H), 7.12
(s, 1H), 7.05-7.08 (m, 1H), 4.51 (s, 2H), 3.74 (m, 2H), 3.46 (s,
2H), 2.99-3.03 (m, 2H), 2.21-2.24 (m, 2H), 1.79-1.84 (m, 2H), 1.42
(s, 9H). Mass spec.: 608.16 (MNa).sup.+. ##STR301##
[0100] Methyl 5-formyl-2-methoxybenzoate. 5-Formyl salicylic acid
(2.0 g, 12.0 mmol), methyl iodide (1.5 mL, 25 mmol) and potassium
carbonate (3.06 g, 22.2 mmol) were combined in dimethylformamide
(15 mL). After stirring at room temperature for 16 h, the solvent
was removed in vacuo and the crude product dissolved in ethyl
acetate, washed with water (2.times.), brine (2.times.), dried over
sodium sulfate, concentrated, and purified by column chromatography
to afford 1.85 g (79%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
9.91 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H),
7.11 (d, J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.:
195.05 (MH).sup.+. ##STR302##
[0101] Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate. Methyl
5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylamine
hydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75
mmol) were combined in a ethanol/water mixture (1:1, 40 mL) and
stirred at 50.degree. C. for 1 h. After cooling to room
temperature, the reaction mixture was poured in to ice water and
extracted with methylene chloride (2.times.). The combined organic
layers were washed with brine (2.times.), dried over sodium sulfate
and concentrated to afford 1.04 g (97%) which was used without
purification. LC/MS (HPLC method 3): t.sub.R=1.63 min,
210.06(MH).sup.+. ##STR303##
[0102] Methyl 5-cyano-2-methoxybenzoate. Methyl
5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) was
dissolved in methylene chloride (25 mL) and cooled to 0.degree. C.
The reaction was treated with thionyl chloride (0.59 mL, 8.1 mmol)
and stirred at 0.degree. C. for 2 h. After warming to room
temperature, the reaction was diluted with methylene chloride,
washed with saturated sodium bicarbonate (2.times.), brine
(2.times.), dried over sodium sulfate, and concentrated to afford
0.87 g (92%) which was used without further purification.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.09 (d, J=2.1 Hz, 1H),
7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.96 (s, 3H),
3.90 (s, 3H). Mass spec.: 192.02 (MH).sup.+. ##STR304##
[0103] Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate. A stirred
solution of methyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in
toluene (4 mL) was treated with azidotrimethyltin (1.85 g, 9.0
mmol) and heated at reflux overnight. After cooling to room
temperature, the solvents were evaporated. The crude product was
dissolved in ethyl acetate, washed with brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (5% methanol/methylene chloride) afforded 0.78 g (75%).
LC/MS (HPLC method 3): t.sub.R=1.66 min, 235.05(MH).sup.-.
##STR305##
[0104] Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate.
Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol)
methyl iodide (0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g,
3.33 mmol) were combined in acetone (8 mL) and heated at reflux
overnight. After cooling to room temperature, the mixture was
filtered and concentrated. Flash chromatography on silica gel
afforded 170 mg (21%). LC/MS(HPLC method 3): t.sub.R=2.01 min,
249.09(MH).sup.+ ##STR306##
[0105] (2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol.
Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg,
0.52 mmol) was dissolved in methylene chloride (2 mL), cooled to
-78.degree. C. and treated with diisobutylaluminum hydride (1 M in
methylene chloride, 1.5 mL, 1.5 mmol). After stirring at
-78.degree. C. for 1 h the reaction was quenched by a few drops of
methanol (until no bubbling was observed) followed by addition of
excess saturated sodium potassium tartarate (2 mL). The reaction
was stirred at room temperature overnight, the layers were
separated and the organic layer washed with brine (2.times.), dried
over sodium sulfate and concentrated to afford 100 mg (86%). LC/MS
(HPLC method 3): t.sub.R=1.68 min, 221.11 (MH).sup.+ ##STR307##
[0106] 5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole.
(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg,
0.45 mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined
in methylene chloride (3 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (170 mg, 0.95 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with methylene chloride and washed
with concentrated sodium bicarbonate (2.times.), brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (30% ethyl acetate/hexanes) gave 80 mg (63%) of the
desired material. LC/MS (HPLC method 3): t.sub.R=2.69 min,
285.02(MH).sup.+. ##STR308##
[0107] tert-Butyl
4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpipe-
ridine-1-carboxylate.
5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg,
0. 12 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0. 14
mmol) were combined in dimethylformamide (1 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (3.2 mg,
0.14 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature overnight. The solvents were removed in vacuo and the
crude product purified by column chromatography on silica gel (30%
ethyl acetate/hexanes) to afford 30 mg (50%). LC/MS (HPLC method
3): t.sub.R=3.29 min, 494.25(MH).sup.+. ##STR309##
[0108] Methyl 5-formyl-2-methoxybenzoate. 5-Formyl salicylic acid
(2.0 g, 12.0 mmol), methyl iodide (1.5 mL, 25 mmol) and potassium
carbonate (3.06 g, 22.2 mmol) were combined in dimethylformamide
(15 mL). After stirring at room temperature for 16 h, the solvent
was removed in vacuo and the crude product dissolved in ethyl
acetate, washed with water (2.times.), brine (2.times.), dried over
sodium sulfate, concentrated, and purified by column chromatography
to afford 1.85 g (79%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
9.91 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H),
7.11 (d, J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.:
195.05 (MH).sup.+. ##STR310##
[0109] Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate. Methyl
5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylamine
hydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75
mmol) were combined in a ethanol/water mixture (1:1, 40 mL) and
stirred at 50.degree. C. for 1 h. After cooling to room
temperature, the reaction mixture was poured in to ice water and
extracted with methylene chloride (2.times.). The combined organic
layers were washed with brine (2.times.), dried over sodium sulfate
and concentrated to afford 1.04 g (97%) which was used without
purification. LC/MS (HPLC method 3): t.sub.R=1.63 min,
210.06(MH).sup.+. ##STR311##
[0110] Methyl 5-cyano-2-methoxybenzoate. Methyl
5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) was
dissolved in methylene chloride (25 mL) and cooled to 0.degree. C.
The reaction was treated with thionyl chloride (0.59 mL, 8.1 mmol)
and stirred at 0.degree. C. for 2 h. After warming to room
temperature, the reaction was diluted with methylene chloride,
washed with saturated sodium bicarbonate (2.times.), brine
(2.times.), dried over sodium sulfate, and concentrated to afford
0.87 g (92%) which was used without further purification.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.09 (d, J=2.1 Hz, 1H),
7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.96 (s, 3H),
3.90 (s, 3H). Mass spec.: 192.02 (MH).sup.+. ##STR312##
[0111] Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate. A stirred
solution of methyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in
toluene (4 mL) was treated with azidotrimethyltin (1.85 g, 9.0
mmol) and heated at reflux overnight. After cooling to room
temperature, the solvents were evaporated. The crude product was
dissolved in ethyl acetate, washed with brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (5% methanol/methylene chloride) afforded 0.78 g (75%).
LC/MS (HPLC method 3): t.sub.R=1.66 min, 235.05(MH).sup.-.
##STR313##
[0112] Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate.
Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol)
methyl iodide (0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g,
3.33 mmol) were combined in acetone (8 mL) and heated at reflux
overnight. After cooling to room temperature, the mixture was
filtered and concentrated. Flash chromatography on silica gel
afforded 170 mg (21%). LC/MS(HPLC method 3): t.sub.R=2.01 min,
249.09(MH).sup.+ ##STR314##
[0113] (2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol.
Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg,
0.52 mmol) was dissolved in methylene chloride (2 mL), cooled to
-78.degree. C. and treated with diisobutylaluminum hydride (1 M in
methylene chloride, 1.5 mL, 1.5 mmol). After stirring at
-78.degree. C. for 1 h the reaction was quenched by a few drops of
methanol (until no bubbling was observed) followed by addition of
excess saturated sodium potassium tartarate (2 mL). The reaction
was stirred at room temperature overnight, the layers were
separated and the organic layer washed with brine (2.times.), dried
over sodium sulfate and concentrated to afford 100 mg (86%). LC/MS
(HPLC method 3): t.sub.R=1.68 min, 221.11 (MH).sup.+ ##STR315##
[0114] 5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole.
(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg,
0.45 mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined
in methylene chloride (3 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (170 mg, 0.95 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with methylene chloride and washed
with concentrated sodium bicarbonate (2.times.), brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (30% ethyl acetate/hexanes) gave 80 mg (63%) of the
desired material. LC/MS (HPLC method 3): t.sub.R=2.69 min,
285.02(MH).sup.+. ##STR316##
[0115] tert-Butyl
4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpipe-
ridine-1-carboxylate.
5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg,
0.12 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0.14
mmol) were combined in dimethylformamide (1 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (3.2 mg,
0.14 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature overnight. The solvents were removed in vacuo and the
crude product purified by column chromatography on silica gel (30%
ethyl acetate/hexanes) to afford 30 mg (50%). LC/MS (HPLC method
3): t.sub.R=3.29 min, 494.25(MH).sup.+. ##STR317##
[0116] Methyl 5-formyl-2-methoxybenzoate. 5-Formyl salicylic acid
(2.0 g, 12.0 mmol), methyl iodide (1.5 mL, 25 mmol) and potassium
carbonate (3.06 g, 22.2 mmol) were combined in dimethylformamide
(15 mL). After stirring at room temperature for 16 h, the solvent
was removed in vacuo and the crude product dissolved in ethyl
acetate, washed with water (2.times.), brine (2.times.), dried over
sodium sulfate, concentrated, and purified by column chromatography
to afford 1.85 g (79%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
9.91 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H),
7.11 (d, J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.:
195.05 (MH).sup.+. ##STR318##
[0117] Methyl 5-((hydroxyimino)methyl)-2-methoxybenzoate. Methyl
5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylamine
hydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75
mmol) were combined in a ethanol/water mixture (1:1, 40 mL) and
stirred at 50.degree. C. for 1 h. After cooling to room
temperature, the reaction mixture was poured in to ice water and
extracted with methylene chloride (2.times.). The combined organic
layers were washed with brine (2.times.), dried over sodium sulfate
and concentrated to afford 1.04 g (97%) which was used without
purification. LC/MS (HPLC method 3): t.sub.R=1.63 min,
210.06(MH).sup.+. ##STR319##
[0118] Methyl 5-cyano-2-methoxybenzoate. Methyl
5-((hydroxyimino)methyl)-2-methoxybenzoate (1.04 g, 4.94 mmol) was
dissolved in methylene chloride (25 mL) and cooled to 0.degree. C.
The reaction was treated with thionyl chloride (0.59 mL, 8.1 mmol)
and stirred at 0.degree. C. for 2 h. After warming to room
temperature, the reaction was diluted with methylene chloride,
washed with saturated sodium bicarbonate (2.times.), brine
(2.times.), dried over sodium sulfate, and concentrated to afford
0.87 g (92%) which was used without further purification.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.09 (d, J=2.1 Hz, 1H),
7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.96 (s, 3H),
3.90 (s, 3H). Mass spec.: 192.02 (MH).sup.+. ##STR320##
[0119] Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate. A stirred
solution of methyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in
toluene (4 mL) was treated with azidotrimethyltin (1.85 g, 9.0
mmol) and heated at reflux overnight. After cooling to room
temperature, the solvents were evaporated. The crude product was
dissolved in ethyl acetate, washed with brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (5% methanol/methylene chloride) afforded 0.78 g (75%).
LC/MS (HPLC method 3): t.sub.R=1.66 min, 235.05(MH).sup.-.
##STR321##
[0120] Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate.
Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol)
methyl iodide (0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g,
3.33 mmol) were combined in acetone (8 mL) and heated at reflux
overnight. After cooling to room temperature, the mixture was
filtered and concentrated. Flash chromatography on silica gel
afforded 170 mg (21%). LC/MS(HPLC method 3): t.sub.R=2.01 min,
249.09(MH).sup.+ ##STR322##
[0121] (2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol.
Methyl 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzoate (130 mg,
0.52 mmol) was dissolved in methylene chloride (2 mL), cooled to
-78.degree. C. and treated with diisobutylaluminum hydride (1 M in
methylene chloride, 1.5 mL, 1.5 mmol). After stirring at
-78.degree. C. for 1 h the reaction was quenched by a few drops of
methanol (until no bubbling was observed) followed by addition of
excess saturated sodium potassium tartarate (2 mL). The reaction
was stirred at room temperature overnight, the layers were
separated and the organic layer washed with brine (2.times.), dried
over sodium sulfate and concentrated to afford 100 mg (86%). LC/MS
(HPLC method 3): t.sub.R=1.68 min, 221.11 (MH).sup.+ ##STR323##
[0122] 5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole.
(2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)phenyl)methanol (100 mg,
0.45 mmol) and triphenylphosphine (238 mg, 0.9 mmol) were combined
in methylene chloride (3 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (170 mg, 0.95 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with methylene chloride and washed
with concentrated sodium bicarbonate (2.times.), brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (30% ethyl acetate/hexanes) gave 80 mg (63%) of the
desired material. LC/MS (HPLC method 3): t.sub.R=2.69 min,
285.02(MH).sup.+. ##STR324##
[0123] tert-Butyl
4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpipe-
ridine-1-carboxylate.
5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg,
0.12 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0.14
mmol) were combined in dimethylformamide (1 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (3.2 mg,
0.14 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature overnight. The solvents were removed in vacuo and the
crude product purified by column chromatography on silica gel (30%
ethyl acetate/hexanes) to afford 30 mg (50%). LC/MS (HPLC method
3): t.sub.R=3.29 min, 494.25(MH).sup.+. ##STR325##
[0124] 3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile.
(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.4 g, 5.5 mmol),
tetrakis(triphenylphosphine) palladium(0) (0.64, 0.55 mmol) and
zinc cyanide (388 mg, 3.31 mmol) were combined in dimethylformamide
(6 mL). The reaction mixture degassed repeatedly using the
freeze-thaw method. After warming to room temperature, the reaction
was heated at 90.degree. C. for 1 h, cooled to room temperature and
concentrated. The crude product was dissolved in ethyl acetate,
washed with water (2.times.), 1 N hydrochloric acid (2.times.),
brine (2.times.), dried over sodium sulfate, and concentrated.
Flash chromatography on silica gel gave 0.37 g (33%). LC/MS (HPLC
method 3): t.sub.R=2.06 min, 202.02(MH).sup.+. ##STR326##
[0125] 3-(Bromomethyl)-5-(trifluoromethyl)benzonitrile.
3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile (0.33 mg, 1.64
mmol) and triphenylphosphine (0.86 g, 3.28 mmol) were combined in
methylene chloride (6 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (0.61 mg, 3.43 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with methylene chloride, washed
with concentrated sodium bicarbonate (2.times.), brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (20% ethyl acetate/hexanes) gave 0.36 g (83%).
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.97 (s, 2H), 7.84 (s,
1H), 4.50 (s, 2H). ##STR327##
[0126] tert-Butyl
4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpip-
eridine-1-carboxylate.
3-(Bromomethyl)-5-(trifluoromethyl)benzonitrile (0.35 g, 1.32 mmol)
and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate
(0.35 g, 1.2 mmol) were combined in tetrahydrofuran (4 mL) and
cooled to 0.degree. C. The reaction was treated with sodium hydride
(33.2 mg, 1.32 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature overnight. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated to afford a crude product which
was dissolved in toluene (2.0), treated with azidotrimethytin (104
mg, 0.5 mmol) and heated at reflux overnight. After cooling to room
temperature, the solvents were evaporated. The crude mixture was
dissolved in methylene chloride, washed with water (2.times.),
brine (2.times.), dried over sodium sulfate and concentrated. Flash
chromatography on silica gel afforded 102 mg (12%, 2 steps). LC/MS
(HPLC method 3): t.sub.R=3.25 min, 518.29(MH).sup.+. ##STR328##
[0127] tert-Butyl
4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate and tert-Butyl
4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate. tert-Butyl
4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpip-
eridine-1-carboxylate (80 mg, 0.15 mmol) methyl iodide (10.0 .mu.L,
0.15 mmol) and potassium carbonate (21.0 mg, 0.15 mmol) were
combined in acetone (1.5 mL) and heated at reflux overnight. After
cooling to room temperature, the mixture was filtered and
concentrated. Flash chromatography on silica gel (20% ethyl
acetate/hexanes) afforded tert-Butyl
4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate (7.0 mg, 9%) and tert-Butyl
4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate (48 mg, 60%). Retention time: 4.75
min and 5.20 min. (Phenomenex C18 4.6.times.50 mm, 10% MeOH/90%
H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient
time=6 min., Flow rate=4 mL/min.): Mass spec.: 532.31(MH).sup.+ and
532.31(MH).sup.+ respectively. ##STR329##
[0128] Methyl 3-nitro-5-(trifluoromethyl)benzoate.
3-Nitro-5-(trifluoromethyl) benzoic acid (25.0 g, 106.3 mmol) was
dissolved in methanol (60 mL) which was bubbled with hydrochloric
acid gas for 1 h. The reaction was allowed to stir at room
temperature overnight and concentrated. The crude product was
dissolved in ethyl acetate, washed with water (2.times.), brine
(2.times.) dried over sodium sulfate and concentrated. Flash
chromatography on silica gel afforded 23.4 g (88%) of the desired
compound. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 9.02 (s, H),
8.66 (s, 1H), 8.61 (s, 1H), 4.03 (s, 3H). ##STR330##
[0129] Methyl 3-amino-5-(trifluoromethyl)benzoate. Methyl
3-nitro-5-(trifluoromethyl)benzoate (9.0 g, 36.1 mmol) in methanol
(30 mL) was flushed with nitrogen, and treated with palladium (10%
on charcoal, 0.90 g). The flask was flushed with hydrogen and
allowed to stir under an atmosphere of hydrogen overnight. The
reaction was flushed with nitrogen, filtered through celite, and
concentrated. Flash chromatography on silica gel (30% ethyl
acetate/hexanes) afforded 6.8 g (86%). .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.64 (s, H), 7.49 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H).
Mass spec.: 220.05 (MH).sup.+. ##STR331##
[0130] Methyl
3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzoate.
Trimethylorthoacetate (0.41 mL, 3.4 mmol) in acetic acid (3 mL) was
added dropwise to a solution of methyl
3-amino-5-(trifluoromethyl)benzoate (0.5 g, 2.28 mmol) in acetic
acid (5 mL) at 75.degree. C. After stirring for 45 min at
75.degree. C., the reaction was treated with sodium azide (0.21 g,
3.4 mmol) carefully in portions over 15 min and stirring continued
for 3 h. After cooling to room temperature, the reaction was
concentrated and the residue dissolved in ethyl acetate. This was
washed with water (2.times.), 1 N hydrochloric acid (2.times.),
brine (2.times.), dried over sodium sulfate, and concentrated.
Flash chromatography on silica gel (20% ethyl acetate/hexanes) gave
0.38 g (58%). LC/MS (HPLC method 3): t.sub.R=2.17 min,
287.12(MH).sup.-. ##STR332##
[0131]
3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenyl)methanol.
Methyl 3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzoate
(0.38 g, 1.33 mmol) was dissolved in a diethyl ether (5 mL) and
tetrahydrofuran (2.5 mL) mixture and cooled to 0.degree. C. The
reaction was treated with water (24.0 .mu.L, 1.33 mmol) and lithium
borohydride (32.0 mg, 1.46 mmol), stirred at 0.degree. C. for 30
min, and at room temperature for 1 h. The reaction mixture was
diluted with ethyl acetate, carefully quenched with methanol (1.8
mL) and washed with water (2.times.), brine (2.times.), dried over
sodium sulfate, and concentrated. Flash chromatography on silica
gel gave 0.14 g (41%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
7.83 (s, H), 7.75 (s, 1H), 7.63 (s, 1H), 4.91 (s, 2H), 2.63 (s,
3H). Mass spec.: 259.10 (MH).sup.+. ##STR333##
[0132]
1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazol-
e.
(3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenyl)methanol
(110 mg, 0.46 mmol) and triphenylphosphine (240 mg, 0.93 mmol) were
combined in methylene chloride (4 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (171 mg, 0.96 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (20% ethyl acetate/hexanes) gave 120 mg (82%). LC/MS
(HPLC method 3): t.sub.R=2.30 min, 323.01(MH).sup.+. ##STR334##
[0133] tert-Butyl
4-((3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate.
1-(3-(Bromomethyl)-5-(trifluoromethyl)phenyl)-5-methyl-1H-tetrazole
(30.0 mg, 0.09 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (29.0 mg, 0.1
mmol) were combined in dimethylformamide (2 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (2.4 mg,
0.1 mmol), stirred at 0.degree. C. for 1 hr and at room temperature
for 30 min. The reaction mixture was diluted with water and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (40%
ethyl acetate/hexanes) gave 40 mg (81%). LC/MS (HPLC method 3):
t.sub.R=3.14 min, 532.24(MH).sup.+. ##STR335##
[0134] tert-Butyl
4-((2-methoxy-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.
2-(Bromomethyl)-1-methoxy-4-nitrobenzene (100.0 mg, 0.34 mmol) and
tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (93.0
mg, 0.38 mmol) were combined in dimethylformamide (4 mL) and cooled
to 0.degree. C. The reaction was treated with sodium hydride (9.0
mg, 0.38 mmol), stirred at 0.degree. C. for 1 hr and at room
temperature for 30 min. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (15% ethyl acetate/hexanes) gave 110 mg (71%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 8.11 (dd, J=6.1, 3.1 Hz, 1H), 8.08
(d, J=2.8 Hz, 1H), 7.34 (m, 4H), 7.21-7.24 (m, 1H), 6.80 (d, J=8.9
Hz, 1H), 4.37 (s, 2H), 3.85 (s, 3H), 3.74-3.75 (m, 2H), 3.48 (s,
2H), 3.02-3.07 (m, 2H), 2.21-2.24 (m, 2H), 1.87-1.93 (m, 2H), 1.43
(s, 9H). Mass spec.: 479.16 (MNa).sup.+. ##STR336##
[0135] tert-Butyl
4-((5-amino-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.
tert-Butyl
4-((2-methoxy-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(110 mg, 0.24 mmol) in methanol (3 mL) was flushed with nitrogen,
and treated with palladium (10% on charcoal, 11.0 mg). The flask
was flushed with hydrogen and allowed to stir under an atmosphere
of hydrogen overnight. The reaction was flushed with nitrogen,
filtered through celite, and concentrated to afford 96.0 mg (94%).
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.33-7.38 (m, 4H),
7.22-7.25 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 6.51 (dd, J=5.8, 2.7 Hz,
1H), 6.29 (d, J=2.8 Hz, 1H), 4.37 (s, 2H), 3.70-3.74 (m, 2H), 3.43
(s, 3H), 3.42 (s, 2H), 3.03-3.07 (m, 2H), 2.15-2.18 (m, 2H),
1.88-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 427.25 (MH).sup.+.
##STR337##
[0136] tert-Butyl
4-((2-methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzyloxy)methyl)-4-phenylpipe-
ridine-1-carboxylate. Trimethylorthoacetate (40.0 .mu.L, 0.32 mmol)
in acetic acid (0.5 mL) was added dropwise to a solution of methyl
3-amino-5-(trifluoromethyl)benzoate (0.5 g, 2.28 mmol) in acetic
acid (1.5 mL) at 75.degree. C. After stirring for 45 min at
75.degree. C., the reaction was treated with sodium azide (21.0 mg,
0.32 mmol) carefully and stirring continued for 3 h. After cooling
to room temperature, the reaction was concentrated and the residue
dissolved in ethyl acetate, washed with water (2.times.), 1 N
hydrochloric acid (2.times.), brine (2.times.), dried over sodium
sulfate, and concentrated. Flash chromatography on silica gel (30%
ethyl acetate/hexanes) gave 50.0 mg (56%). LC/MS (HPLC method 3):
t.sub.R=3.06 min, 494.23(MH).sup.+. ##STR338##
[0137] 4-Bromo-2-(bromomethyl)-1-methoxybenzene. To a solution of
(5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in
dichloromethane (10 mL) at 0.degree. C. was added tribromophosphine
(1 M in dichloromethane, 9.2 mL, 9.2 mmol). The ice bath was
removed and the reaction stirred for 15 min. The reaction was
concentrated, poured onto cold saturated sodium bicarbonate,
extracted with pentane, dried over magnesium sulfate, and
concentrated to give 1.15 g (89%) as a white crystalline solid.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.44 (d, J=2.5 Hz,
1H), 7.38 (dd, J=8.9, 6.1 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 156.7, 133.6, 132.8,
128.4, 112.8, 112.7, 56.0, 27.5. ##STR339##
[0138] tert-Butyl
4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.
To a solution of tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.40 g, 1.37
mmol) and 4-bromo-2-(bromomethyl)-1-methoxybenzene (0.46 g, 1.65
mmol) in dimethylformamide (4 mL) at 0.degree. C. was added sodium
hydride (66 mg, 2.75 mmol). After 20 min at 0.degree. C., the ice
bath was removed and the reaction stirred for 15 min. The reaction
was poured into a separatory funnel containing ether and water. The
ethereal was washed with water (2.times.), then brine, dried over
magnesium sulfate, and concentrated. Column chromatography (10%
ethyl acetate/hexanes.fwdarw.25% ethyl acetate/hexanes) gave 640 mg
(95%) as a colorless viscous oil. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. ppm 7.20-7.45 (m, 7H), 6.65 (d, J=8.9 Hz, 1H), 4.36 (s,
2H), 3.76 (m, 2H), 3.72 (s, 3H), 3.44 (s, 2H), 3.08 (m, 2H), 2.19
(m, 2H), 1.91 (m, 2H), 1.44 (s, 9H); .sup.13C NMR (126 MHz,
CDCl.sub.3) .delta. ppm 155.8, 155.1, 143.0, 130.8, 129.5, 128.6,
127.3, 126.5, 113.0, 111.8, 104.3, 79.8, 79.4, 67.6, 55.6, 41.8,
40.3, 32.0, 28.6. ##STR340##
[0139] tert-Butyl
4-((2-methoxy-5-(pyridin-4-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carb-
oxylate. A microwave tube was charged with tert-butyl
4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(50 mg, 0.102 mmol), pyridin-4-ylboronic acid (50.1 mg, 0.408
mmol), and tetrakis(triphenylphosphine)-palladium(0) (12 mg, 10
.mu.mol). The tube was flushed with nitrogen, treated with
tetrahydrofuran (2 mL) and potassium hydroxide (1 M in water, 0.401
mL, 0.41 mmol). The tube was sealed and heated at 120.degree. C.
for 1 h via microwave. The reaction was cooled, poured into ether,
washed with water (2.times.), then brine, dried over magnesium
sulfate, and concentrated. Column chromatography (ethyl
acetate/hexanes) gave 26 mg (52%) as a colorless oil. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm 8.61 (d, J=5.8 Hz, 2H), 7.50 (dd,
J=8.6, 2.5, 1H), 7.30-7.45 (m, 7H), 7.21 (m, 1H), 6.89 (d, J=8.5,
1H), 4.47 (s, 2H), 3.82 (s, 3H), 3.73 (bs, 2H), 3.50 (s, 2H), 3.07
(m, 2H), 2.20 (m, 2H), 1.91 (m, 2H), 1.42 (s, 9H); .sup.13C NMR
(126 MHz, CDCl.sub.3) .delta. ppm 157.7, 155.1, 150.1, 148.1,
143.3, 130.1, 128.5, 128.1, 127.3, 126.7, 126.6, 126.4, 121.2,
110.6, 79.8, 79.3, 67.9, 55.6, 41.8, 40.3, 32.2, 28.6. Mass spec.:
489.37 (MH).sup.-. ##STR341##
[0140] tert-Butyl
4-((5-(6-cyanopyridin-3-yl)-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-
-1-carboxylate. A microwave tube was charged with tert-butyl
4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(50 mg, 0.102 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (94
mg, 0.408 mmol), and tetrakis(triphenylphosphine)-palladium(0)
(11.78 mg, 10.20 .mu.mol). The tube was flushed with nitrogen,
treated with tetrahydrofuran (2 mL) and potassium hydroxide (1 M in
water, 0.41 mL, 0.41 mmol). The tube was sealed and heated at
120.degree. C. for 1 h via microwave. The reaction was cooled,
poured into ether, washed with water (2.times.), then brine, dried
over magnesium sulfate, and concentrated. Column chromatography
(ethyl acetate/hexanes) gave 46 mg (88%) as a colorless oil.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 8.80 (d, J=2.1 Hz,
1H), 7.80 (dd, J=7.9, 2.1 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.44
(dd, J=8.5, 2.4 Hz, 1H), 7.37 (m, 2H), 7.31 (m, 3H), 7.20 (m, 1H),
6.92 (d, J=8.5 Hz, 1H), 4.47 (s, 2H), 3.83 (s, 3H), 3.73 (m, 2H),
3.50 (s, 2H), 3.06 (m, 2H), 2.20 (m, 2H), 1.89 (m, 2H), 1.42 (s,
9H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 157.8, 155.1,
149.3, 143.2, 139.6, 134.1, 131.5, 128.7, 128.5, 128.4, 127.9,
127.3, 127.1, 126.6, 126.4, 117.6, 110.9, 102.9, 79.9, 79.4, 67.7,
55.6, 41.8, 40.3, 32.2, 28.6. Mass spec.: 514.45 (MH).sup.+.
##STR342##
[0141] tert-Butyl
4-(((4'-cyano-4-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-
-carboxylate. A microwave tube was charged with tert-butyl
4-((5-bromo-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(50 mg, 0.102 mmol), 4-cyanophenylboronic acid (60 mg, 0.41 mmol),
and tetrakis(triphenylphosphine)-palladium(0) (12 mg, 10 .mu.mol).
The tube was flushed with nitrogen, treated with tetrahydrofuran (2
mL) and potassium hydroxide (1 M in water, 0.41 mL, 0.41 mmol). The
tube was sealed and heated at 120.degree. C. for 1 h via microwave.
The reaction was cooled, poured into ether, washed with water
(2.times.), then brine, dried over magnesium sulfate, and
concentrated. Column chromatography (12%.fwdarw.18% ethyl
acetate/hexanes) gave 47 mg (90%) as a white solid. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm 7.69 (d, J=8.5 Hz, 2H), 7.53 (d,
J=8.5 Hz, 2H), 7.44 (dd, J=8.6, 2.4 Hz, 1H), 7.37 (m, 3H), 7.32 (m,
2H), 7.20 (m, 1H), 6.89 (m, 1H), 4.48 (s, 2H), 3.82 (s, 3H), 3.74
(m, 2H), 3.50 (s, 2H), 3.07 (m, 2H), 2.20 (m, 2H), 1.91 (m, 2H),
1.43 (s, 9H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 157.4,
155.2, 145.4, 143.2, 134.2, 132.6, 131.3, 128.5, 128.1, 127.3,
127.2, 126.9, 126.8, 126.3, 116.5, 110.6, 79.8, 79.5, 67.9, 55.6,
41.8, 40.3, 32.2, 28.6. Mass spec.: 513.45 (MH).sup.+.
##STR343##
[0142] tert-Butyl
4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate.
1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic
acid (9.5 g, 29.3 mmol) was suspended in tetrahydrofuran (60 mL)
and cooled to 0.degree. C. To this solution was added borane
tetrahydrofuran complex (1 M in tetrahydrofuran, 59 mL, 59 mmol)
cautiously over 15 min. The reaction mixture was allowed to warm to
room temperature overnight and then heated at reflux for 24 h. The
mixture was cooled to 0.degree. C., treated with excess methanol,
diluted with ethyl acetate, washed with 1 N sodium hydroxide
(2.times.), then brine (2.times.), dried over sodium sulfate, and
concentrated. Column chromatography on silica gel (40% ethyl
acetate/hexanes) gave 6.6 g (72%) as a white powder. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) 7.24-7.29 (m, 2H), 7.00-7.05 (m, 2H),
3.66-3.71 (m, 2H), 3.49 (s, 2H), 2.96-3.05 (m, 2H), 2.06-2.10 (m,
2H), 1.69-1.77 (m, 2H), 1.40 (s, 9H). Mass spec.: 310.21
(MH).sup.+. ##STR344##
[0143] tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(4-fluorophenyl)piperi-
dine-1-carboxylate.
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78
mmol) and tert-butyl
4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96
g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled
to 0.degree. C. The reaction was treated with sodium hydride (151
mg, 6.3 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature for 30 min. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.61 (s, 1H), 7.35 (s,
1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s,
2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16
(m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl.sub.3, 126
MHz) .delta. 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3,
132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8,
122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5,
25.7. Mass spec.: 548.16 (MH)+. ##STR345##
[0144] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluor-
ophenyl)piperidine-1-carboxylate. tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(4-fluorophenyl)piperi-
dine-1-carboxylate (130.0 mg, 0.24 mmol), 4-cyanophenylboronic acid
(140.0 mg, 0.95 mmol), and tetrakis(triphenylphosphine)
palladium(0) (37.1 mg, 0.024 mmol) were combined in dry
tetrahydrofuran (3 mL) in a microwave tube and sealed. The mixture
was flushed with nitrogen. To this was added potassium hydroxide (1
N in water, 0.75 mL, 0.75 mmol). The mixture was heated at
120.degree. C. for 1 h via microwave. After cooling to room
temperature, the reaction mixture was concentrated and purified by
flash chromatography on silica gel (25% ethyl acetate/hexanes) to
afford 61.0 mg (48%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
7.74-7.76 (m, 2H), 7.67 (s, 1H), 7.57-7.60 (m, 2H), 7.41 (s, 1H),
7.40 (s, 1H), 7.29-7.32 (m, 2H),6.98-7.02 (m, 2H), 4.47 (s, 2H),
3.71-3.74 (m, 2H), 3.43 (s, 2H), 3.01-3.06 (m, 2H), 2.14-2.17 (m,
2H), 1.82-1.88 (m, 2H), 1.42 (s, 9H). Mass spec.: 569.25
(MH).sup.+. ##STR346##
[0145] 1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanone. A flask was
charged with water (42 ml), cooled to 0.degree. C., and treated
with concentrated hydrochloric acid (21.7 ml) and sulfuric acid
(5.66 ml). To this was added 3-amino-5-bromobenzotrifluoride (8.77
ml, 62.5 mmol). The reaction was treated with a solution of sodium
nitrite (5.39 g, 78 mmol) in water (10 mL). The resulting reaction
mixture was stirred for 30 min at 0.degree. C. The reaction was
transferred to a solution of acetaldoxime (5.71 ml, 94 mmol) and
copper(II) sulfate (0.499 g, 3.12 mmol) in water (30 mL) at room
temperature. After stirring for 1 h at room temperature, the
reaction was heated to reflux and held there for 3 h. The reaction
was cooled and diluted with pentane. It gave an intractable
suspension. The reaction mixture was filtered through a sintered
glass funnel. The layers were separated. The organics were washed
with water, then brine, dried over magnesium sulfate, and
concentrated. The crude residue was distilled (high vacuum,
75.degree. C.) to give 3 fractions of varying levels of purity.
Total yield was 8.5 g (51%) with purity that ranged from 10:1 to
1:1. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 8.25 (s, 1H),
8.11 (s, 1H), 7.95 (s, 1H), 2.63 (s, 3H). ##STR347##
[0146] (.+-.)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. To a
solution of 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (ca. 60%
pure, 500 mg, 1.1 mmol) in ethanol (10 mL) at 0.degree. C. was
added sodium borohydride (32 mg, 0.85 mmol). The ice bath was
removed and the reaction stirred at room temperature for 20 min.
The reaction was cooled to 0.degree. C., quenched by the cautious
addition of saturated ammonium chloride, and concentrated to remove
most of the ethanol. The residue was dissolved in water and
extracted with ether. The ethereal was washed with water, then
brine, dried over magnesium sulfate, and concentrated. Column
chromatography (8%.fwdarw.16% ethyl acetate/hexanes) gave 216 mg
(72%) as a colorless oil which solidified upon standing. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.71 (s, 1H), 7.66 (s, 1H),
7.56 (s, 1H), 4.93 (q, J=6.4 Hz, 1H), 2.03 (bs, 1H), 1.50 (d, J=6.7
Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 149.1,
132.6 (q, J=33.6 Hz), 132.1, 127.5 (q, J=3.8 Hz), 123.2 (q, J=273
Hz), 122.9, 121.1 (q, J=3.8 Hz), 69.4, 25.5. ##STR348##
[0147] (.+-.)-1-Bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene.
To a solution of
(.+-.)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (390 mg, 1.45
mmol) and carbon tetrabromide (577 mg, 1.74 mmol) in
tetrahydrofuran (2 mL) at 0.degree. C. was added triphenylphosphine
(456 mg, 1.74 mmol). The resulting solution was stirred at room
temperature for 2 h. The reaction was treated with an additional
portion of carbon tetrabromide (289 mg, 0.87 mmol)) and
triphenylphosphine (228 mg, 0.87 mmol). The reaction was stirred at
room temperature for 1 h, diluted with several volumes of pentane,
and filtered to remove undissolved solids. The organics were
concentrated and purified by column chromatography (1.fwdarw.3%
ethyl acetate/hexanes) to give 439 mg (91%) as a colorless oil.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.76 (s, 1H), 7.68
(s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz,
3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 146.4, 133.5,
132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0 (q, J=273
Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6. ##STR349##
[0148] (.+-.)-tert-Butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate. To a solution of tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (435 mg, 1.49
mmol) and
(.+-.)-1-bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene (496 mg,
1.49 mmol) in dimethylformamide (1.5 mL) at 0.degree. C. was added
sodium hydride (72 mg, 3.0 mmol). The ice bath was removed and the
resulting mixture stirred at room temperature for 1 h. The reaction
was cooled to 0.degree. C., diluted with ether, and quenched by the
cautious addition of saturated ammonium chloride. The mixture was
poured into water and extracted into ether. The ethereal was washed
with water, then brine, dried over magnesium sulfate, and
concentrated. Column chromatography (8.fwdarw.12% ethyl
acetate/hexanes) gave 188 mg (23%) as a colorless oil. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm 7.59 (s, 1H), 7.28-7.42 (m, 5H),
7.24 (m, 2H), 4.17 (q, J=6.4 Hz, 1H), 3.76 (m, 2H), 3.27 (d, J=8.9
Hz, 1H), 3.21 (d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.17 (m, 2H), 1.87
(m, 2H), 1.44 (s, 9H), 1.28 (d, J=6.4 Hz, 3H); .sup.13C NMR (126
MHz, CDCl.sub.3) .delta. ppm 155.1, 147.7, 142.6, 132.5 (q, J=32.6
Hz), 132.4, 128.5, 127.4 (q, J=3.8 Hz), 127.2, 126.6, 123.2 (q,
J=273 Hz), 122.8, 121.6 (q, J=3.8 Hz), 79.4, 78.3, 41.7, 40.2,
32.1, 31.7, 28.6, 23.8. Mass spec.: 542.13 (MH).sup.+.
##STR350##
[0149] (.+-.)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate. A microwave tube was charged with
(.+-.)-tert-butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate (40 mg, 0.074 mmol), 4-cyanophenylboronic acid (43
mg, 0.30 mmol), and tetrakis(triphenylphosphine) palladium(0) (8.5
mg, 7.4 .mu.mol). The tube was flushed with nitrogen, treated with
tetrahydrofuran (2 mL) and potassium hydroxide (1 M in water, 0.30
mL, 0.30 mmol). The tube was sealed and heated at 120.degree. C.
for 1 h via microwave. The reaction was cooled, poured into ether,
washed with water (2.times.), then brine, dried over magnesium
sulfate, and concentrated. Column chromatography (12%.fwdarw.25%
ethyl acetate/hexanes) gave 36 mg (86%) as a colorless film.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.74 (m, 2H), 7.65
(s, 1H), 7.55 (m, 2H), 7.37 (s, 2H), 7.26-7.34 (m, 4H), 7.17 (m,
1H), 4.30 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.32 (m, 1H), 3.25 (m,
1H), 3.02 (m, 2H), 2.23 (m, 1H), 2.12 (m, 1H), 1.75-1.97 (m, 2H),
1.43 (m, 9H), 1.35 (m, 3H). Mass spec.: 587.22 (MNa).sup.+.
##STR351##
[0150] (S)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. A flask
was charged with isopropanol (10 mL), dichloro(p-cymene)ruthenium
(II) dimer (8.60 mg, 0.014 mmol), and
(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (4.19 mg, 0.028 mmol).
After aging for 30 min,
1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (375 mg, 1.4 mmol)
was added and the reaction degassed by cooling it to -78.degree.
C., putting it under high vacuum, venting to nitrogen, and
repeating the process ca. 6 times. The reaction was warmed to room
temperature, treated with sodium hydroxide (5 M in water, 0.013 mL,
0.063 mmol), and stirred at room temperature for 5 hours. The
reaction was quenched by addition of 1 M hydrochloric acid and
extracted into pentane. The organics were washed with water, then
brine, dried over magnesium sulfate, and concentrated. Column
chromatography (10.fwdarw.20% ethyl acetate/hexanes) gave 292 mg
(77%) as a light brown oil. Chiral SFC (ChiralCel OD-H, 1:99
ethanol/carbon dioxide) showed the optical purity to be 81% ee.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.71 (s, 1H), 7.66
(s, 1H), 7.56 (s, 1H), 4.93 (q, J=6.4 Hz, 1H), 2.03 (bs, 1H), 1.50
(d, J=6.7 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm
149.1, 132.6 (q, J=33.6 Hz), 132.1, 127.5 (q, J=3.8 Hz), 123.2 (q,
J=273 Hz), 122.9, 121.1 (q, J=3.8 Hz), 69.4, 25.5. ##STR352##
[0151] (S)-1-Bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene. To
a solution of (S)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (150
mg, 0.56 mmol) in dichloromethane (3 mL) at 0.degree. C. was added
thionyl bromide (0.086 mL, 1.12 mmol). The ice bath was removed and
stirring continued for 1 h. The reaction was warmed to reflux and
held there for 1 h. The reaction was treated with a second portion
of thionyl bromide (0.086 mL, 1.12 mmol) and the reaction held at
reflux for 2 h. The reaction was cooled to 0.degree. C., quenched
by addition of water, and diluted with pentane. The organics were
washed with water (2.times.), then brine, dried over magnesium
sulfate, and concentrated. Column chromatography (100% hexanes)
gave 78 mg (42%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm
7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H),
2.03 (d, J=7.0 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta.
ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0,
123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.
##STR353##
[0152] (R)-tert-butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate. To a solution of tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (65.8 mg, 0.23
mmol) and (S)-1-bromo-3-(1-bromoethyl)-5-(trifluoromethyl)benzene
(75 mg, 0.23 mmol) in dimethylformamide (0.4 mL) at 0.degree. C.
was added sodium hydride (10.8 mg, 0.45 mmol). The reaction was
stirred at 0.degree. C. for 1 h. The reaction was quenched by
addition of saturated ammonium chloride. The mixture was extracted
with ether which was washed with water (2.times.), then brine,
dried over magnesium sulfate, and concentrated to give 37 mg (30%)
as a colorless oil. Chiral SFC (ChiralCel OJ-H, 1:99
methanol/carbon dioxide) showed the optical purity to be 44% ee.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.59 (s, 1H),
7.28-7.42 (m, 5H), 7.24 (m, 2H), 4.17 (q, J=6.4 Hz, 1H), 3.76 (m,
2H), 3.27 (d, J=8.9 Hz, 1H), 3.21 (d, J=8.9 Hz, 1H), 3.03 (m, 2H),
2.17 (m, 2H), 1.87 (m, 2H), 1.44 (s, 9H), 1.28 (d, J=6.4 Hz, 3H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 155.1, 147.7, 142.6,
132.5 (q, J=32.6 Hz), 132.4, 128.5, 127.4 (q, J=3.8 Hz), 127.2,
126.6, 123.2 (q, J=273 Hz), 122.8, 121.6 (q, J=3.8 Hz), 79.4, 78.3,
41.7, 40.2, 32.1, 31.7, 28.6, 23.8. Mass spec.: 542.13 (MH).sup.+.
##STR354##
[0153] (R)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate. A microwave tube was charged with
(R)-tert-butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate (20 mg, 0.037 mmol), 4-cyanophenylboronic acid
(21.7 mg, 0.15 mmol), and tetrakis(triphenylphosphine) palladium(0)
(4.3 mg, 3.7 .mu.mol). The tube was flushed with nitrogen, treated
with tetrahydrofuran (1 mL) and potassium hydroxide (1 M in water,
0.15 mL, 0.15 mmol). The tube was sealed and heated at 120.degree.
C. for 1 h via microwave. The reaction was cooled, poured into
ether, washed with water (2.times.), then brine, dried over
magnesium sulfate, and concentrated. Column chromatography
(12%.fwdarw.25% ethyl acetate/hexanes) gave 15.4 mg (74%) as a
colorless film. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.74
(m, 2H), 7.65 (s, 1H), 7.55 (m, 2H), 7.37 (s, 2H), 7.26-7.34 (m,
4H), 7.17 (m, 1H), 4.30 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.32 (m,
1H), 3.25 (m, 1H), 3.02 (m, 2H), 2.23 (m, 1H), 2.12 (m, 1H),
1.75-1.97 (m, 2H), 1.43 (m, 9H), 1.35 (m, 3H). Mass spec.: 587.22
(MNa).sup.+. ##STR355##
[0154] (S)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. A flask
was flushed with nitrogen, charged with isopropanol (15 mL), and
degassed by bubbling nitrogen for 20 min. To this was added
bis-[rutheniumdichloride(p-cymene)] (0.017 g, 0.028 mmol), and
(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (8.4 mg, 0.056 mmol). The
mixture was stirred while bubbling nitrogen for 30 min. The
resulting mixture was cooled to 0.degree. C. and treated with
1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (1.5 g, 5.62 mmol)
and sodium hydroxide (5 M, 0.025 mL, 0.126 mmol). The reaction was
stirred for 7 h at 0.degree. C. The reaction was quenched by
addition of 1 M hydrochloric acid and extracted into pentane
(2.times.). The organics were washed with brine, dried over
magnesium sulfate, and concentrated. Column chromatography
(10.fwdarw.20% ethyl acetate/hexanes) gave 1.45 g (96%) as a light
yellow oil. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.71 (s,
1H), 7.66 (s, 1H), 7.56 (s, 1H), 4.93 (q, J=6.4 Hz, 1H), 2.03 (bs,
1H), 1.50 (d, J=6.7 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3)
.delta. ppm 149.1, 132.6 (q, J=33.6 Hz), 132.1, 127.5 (q, J=3.8
Hz), 123.2 (q, J=273 Hz), 122.9, 121.1 (q, J=3.8 Hz), 69.4, 25.5.
##STR356##
[0155] (S)-4-(1-(3-Bromo-5-(trifluoromethyl)phenyl)ethyl)
1-tert-butyl 4-phenylpiperidine-1,4-dicarboxylate. To a suspension
of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid
(1.98 g, 6.47 mmol) in toluene (18 mL) and dichloromethane (3 mL)
at 0.degree. C. was added dicyclohexylcarbodiimide (1.56 g, 7.54
mmol) in small portions. The ice bath was removed and the resulting
slurry stirred at room temperature for 30 min. The reaction was
recooled to 0.degree. C., treated with
(S)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (1.45 g, 5.39
mmol) and dimethylaminopyridine (0.658 g, 5.39 mmol). The reaction
was allowed to warm to room temperature overnight and stirred for 3
d. The reaction was poured into pentane (.about.100 mL). The
resulting solid was filtered and discarded. The eluent was washed
with 1 M hydrochloric acid, then 1 M sodium hydroxide, then brine,
dried over magnesium sulfate, and concentrated. Column
chromatograpy (8%.fwdarw.12% ethyl acetate/hexanes) gave 2.48 g
(83%) as a colorless gum. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
ppm 7.58 (s, 1H), 7.23-7.33 (m, 6H), 7.19 (s, 1H), 5.80 (q,
J=3.82-3.97 (m, 2H), 2.97-3.09 (m, 2H), 2.44-2.53 (m, 2H),
1.76-2.01 (m, 2H), 1.42 (s, 9H), 1.40 (m, 3H). Mass spec.: 558.06
(MH).sup.+. ##STR357##
[0156] (S)-tert-Butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate. To a solution of
(S)-4-(1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl) 1-tert-butyl
4-phenylpiperidine-1,4-dicarboxylate (1.5 g, 2.70 mmol) in
dichloromethane (15 ml) at -78.degree. C. was added
diisobutylaluminum hydride (1 M in dichloromethane, 5.39 mL, 5.39
mmol) dropwise. The reaction was stirred at -78.degree. C. for 1 h,
and treated with pyridine (0.654 ml, 8.09 mmol),
dimethylaminopyridine (0.659 g, 5.39 mmol), and acetic anhydride
(1.53 ml, 16.2 mmol). The reaction was allowed to slowly warm to
-10.degree. C. in the dewar over 2 h. The reaction was diluted with
diethyl ether, quenched by a few drops of methanol, and treated
with saturated sodium potassium tartrate. The suspension was
stirred vigorously at room temperature for a couple of hours. The
mixture was poured into a separatory funnel and the layers
separated. The aqueous was extracted with diethyl ether twice more.
The pooled organics were washed with 1 M sodium bisulfate, then
saturated sodium bicarbonate, then brine, dried over magnesium
sulfate, and concentrated. Column chromatography (ethyl
acetate/hexanes on silica gel that was pre-treated with 2% Et3N in
ethyl acetate/hexanes) gave the intermediate acetate (0.80 g, 49%)
as an oil which was used immediately without purification. To a
solution of the intermediate acetate (0.80 g, 1.3 mmol) and
triethylsilane (1.06 ml, 6.66 mmol) in dichloromethane (15 mL) at
-78.degree. C. was added boron trifluoride-etherate (0.253 mL, 2.0
mmol). The reaction was allowed to slowly warm to 0.degree. C. in
the dewar. The reaction was stirred at 0.degree. C. for 7 h,
quenched by addition of saturated sodium bicarbonate, poured into
diethyl ether, and the layers separated. The ethereal was washed
with water, then brine, dried over magnesium sulfate, and
concentrated. Column chromatography (8.fwdarw.12% ethyl
acetate/hexanes) gave 36 mg (5%) as a colorless oil. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm 7.59 (s, 1H), 7.28-7.42 (m, 5H),
7.24 (m, 2H), 4.17 (q, J=6.4 Hz, 1H), 3.76 (m, 2H), 3.27 (d, J=8.9
Hz, 1H), 3.21 (d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.17 (m, 2H), 1.87
(m, 2H), 1.44 (s, 9H), 1.28 (d, J=6.4 Hz, 3H); .sup.13C NMR (126
MHz, CDCl.sub.3) .delta. ppm 155.1, 147.7, 142.6, 132.5 (q, J=32.6
Hz), 132.4, 128.5, 127.4 (q, J=3.8 Hz), 127.2, 126.6, 123.2 (q,
J=273 Hz), 122.8, 121.6 (q, J=3.8 Hz), 79.4, 78.3, 41.7, 40.2,
32.1, 31.7, 28.6, 23.8. Mass spec.: 542.13 (MH).sup.+.
##STR358##
[0157] (R)-1-(3-Bromo-5-(trifluoromethyl)phenyl)ethanol. A flask
was charged with isopropanol (10 mL), dichloro(p-cymene)ruthenium
(II) dimer (32 mg, 0.05 mmol), and
(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (16 mg, 0.1 mmol). After
aging for 30 min, 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone
(2.8 g, 10.5 mmol) was added and the reaction degassed by cooling
it to -78.degree. C., putting it under high vacuum, venting to
nitrogen, and repeating the process ca. 6 times. The reaction was
warmed to 0.degree. C., treated with sodium hydroxide (5 M in
water, 48 .mu.L, 0.23 mmol), stirred at 0.degree. C. for 5 hours
and at room temperature overnight. The reaction was quenched by
addition of 1 M hydrochloric acid and extracted into pentane. The
organics were washed with water (2.times.), then brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
(15% ethyl acetate/hexanes) gave 2.79 g (99%) as a yellowish oil.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.69 (s, 1H), 7.63
(s, 1H), 7.53 (s, 1H), 4.91 (q, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz,
3H). ##STR359##
[0158] (R)-4-(1-(3-Bromo-5-(trifluoromethyl)phenyl)ethyl)
1-tert-butyl 4-phenylpiperidine-1,4-dicarboxylate. A suspension of
1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (3.8
g, 10.3 mmol) in a dichloromethane (5 mL) and toluene (30 mL)
mixture was treated with 1,3-dicyclohexylcarbodiimide (2.96 g, 14.4
mmol) and stirred for 30 min. The suspension was cooled to
0.degree. C. and treated with
(R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (2.79 g, 10.3
mmol) and dimethylaminopyridine (1.26 g, 10.3 mmol). The ice bath
was removed and the suspension stirred at room temperature for 60
h. The reaction mixture was poured into pentane, filtered, and the
solids washed several times with pentane. The filtrate was washed
with 1 N hydrochloric acid (1.times.), water (2.times.), then 1 N
sodium hydroxide, then brine (2.times.), dried over sodium sulfate,
and concentrated. Flash chromatography on silica gel (12% ethyl
acetate/hexanes) gave 4.8 g (84%) as a light yellow oil. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.58 (s, 1H), 7.23-7.33 (m,
6H), 7.19 (s, 1H), 5.80 (q, J=6.6 Hz, 1H), 3.82-3.97 (m, 2H),
2.97-3.09 (m, 2H), 2.44-2.53 (m, 2H), 1.76-2.01 (m, 2H), 1.42 (s,
9H), 1.40 (m, 3H). Mass spec.: 558.06 (MH).sup.+. ##STR360##
[0159] (R)-tert-Butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate. (R)-4-(1-(3-Bromo-5-(trifluoromethyl)phenyl)ethyl)
1-tert-butyl 4-phenylpiperidine-1,4-dicarboxylate (3.8 g, 6.9 mmol)
was dissolved in methylene chloride (40 mL), cooled to -78.degree.
C. and treated with diisobutylaluminum hydride (1 M in methylene
chloride (13.8 mL, 13.8 mmol). After stirring at -78.degree. C. for
1 h, the reaction was treated with pyridine (1.64 mL, 20.6 mmol),
dimethylaminopyridine (1.68 g, 13.8 mmol), and acetic anhydride
(2.9 mL, 41.2 mmol). The reaction was warmed to -10.degree. C. over
several hours in a dewar, quenched by addition of a few drops of
methanol (until no bubbling was observed) followed by addition of
excess saturated sodium potassium tartarate. The reaction was
stirred at room temperature overnight. The layers were separated
and the organic layer washed with brine (2.times.), dried over
sodium sulfate, and concentrated to afford a precipitate which was
immediately dissolved in methylene chloride (50 mL) and treated
with triethylsilane (6.7 mL, 45.3 mmol). The solution was cooled to
-78.degree. C. and treated with boron trifluoride diethyl etherate
(1.8 mL, 3.8 mmol). After 1 h, the reaction mixture was allowed to
warm slowly to 0.degree. C. and stirred for 7 h. The reaction was
quenched by addition concentrated sodium bicarbonate and the layers
were separated. The organic layer was washed with water (2.times.),
then brine (2.times.), dried over sodium sulfate, and concentrated.
Flash chromatography on silica gel (10% ethyl acetate/hexanes) gave
1.7 g in a 1:1 ratio of the desired material and the ester starting
material which could not be separated. The mixture in 1:1
tetrahydrofuran/methanol (12 mL) at room temperature was treated
with a solution of lithium hydroxide monohydrate (271 mg, 1.62
mmol) in water (6 mL). The solution was stirred at room temperature
for 1 h, diluted with ethyl acetate, washed with water (2.times.),
then brine (2.times.), dried over sodium sulfate, and concentrated
to afford 900 mg (24%) as a clear oil. Chiral SFC (ChiralCel OJ-H,
1:99 methanol/carbon dioxide) showed the optical purity to be 92%
ee. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.59 (s, 1H),
7.29-7.36 (m, 5H), 7.22-7.25 (m, 2H), 4.16 (q, J=6.4 Hz, 1H), 3.74
(m, 2H), 3.25 (d, J=9.2 Hz, 1H), 3.21 (d, J=8.9 Hz, 1H), 2.99-3.06
(m, 2H), 2.11-2.21 (m, 2H), 1.83-1.90 (m, 2H), 1.43 (s, 9H), 1.28
(m, 3H). Mass spec.: 544.01 (MH).sup.+. ##STR361##
[0160] (R)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate. (R)-tert-Butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate (0.35 g, 0.65 mmol), 4-cyanophenylboronic acid (284
mg, 1.93 mmol), and tetrakis(triphenylphosphine) palladium(0) (75
mg, 0.07 mmol) were combined in dry tetrahydrofuran (5 mL) in a
microwave tube and sealed. After flushing with nitrogen, 2.3 mL of
a 1 N potassium hydroxide aqueous solution was introduced. The
mixture was heated at 120.degree. C. for 1 h via microwave. After
cooling to room temperature, the reaction mixture was concentrated
and purified by flash chromatography on silica gel (15% ethyl
acetate/hexanes) to afford 300 mg (82%) as an oil. LC/MS:
t.sub.R=3.51 min, 565.23 (MH).sup.+. (Phenomenex C18 4.6.times.50
mm, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10%
H.sub.2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
##STR362##
[0161] tert-Butyl
4-(((4'-fluoro-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluo-
rophenyl)piperidine-1-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.64 (s, 1H), 7.46 (m, 2H), 7.40 (s, 1H), 7.28-7.35
(m, 3H), 7.15 (m, 2H), 7.01 (m, 2H), 4.46 (s, 2H), 3.73 (m, 2H),
3.43 (s, 2H), 3.05 (m, 2H), 2.16 (m, 4H), 1.86 (m, 2H), 1.43 (s,
9H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 164.0, 162.5,
162.1, 160.5, 155.0, 141.2, 140.3, 138.6 (m), 135.8 (m), 131.5 (q,
J=32 Hz), 128.9, 129.83, 128.80, 124.1 (q, J=273 Hz), 122.9 (q,
J=3.8 Hz), 122.6 (q, J=3.8 Hz), 116.1, 115.9, 115.4, 115.2, 79.5,
72.5, 41.3, 40.1, 32.3, 28.5. ##STR363##
[0162] (.+-.)-tert-Butyl
4-((1-(4'-cyano-5-fluorobiphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-
-carboxylate. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.71 (d,
J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.32 (m, 4H), 7.20 (m, 1H),
7.10 (m, 1H), 7.00 (s, 1H), 6.77 (d, J=9.2 Hz, 1H), 4.22 (q, J=6.4
Hz, 1H), 3.74 (m, 2H), 3.27 (q.sub.AB, J.sub.AB=9.2 Hz, 2H), 3.02
(m, 2H), 2.21 (m, 1H), 2.13 (m, 1H), 1.88 (m, 2H), 1.43 (s, 9H),
1.32 (d, J=6.4 Hz, 3H). Mass spec.: 515.32 (MH).sup.+.
##STR364##
[0163] (S)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate. A microwave tube was charged with
(S)-tert-butyl
4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate (36 mg, 0.066 mmol), 4-cyanophenylboronic acid (39
mg, 0.27 mmol), and tetrakis(triphenylphosphine) palladium(0) (7.7
mg, 6.6 .mu.mol). The tube was flushed with nitrogen, treated with
tetrahydrofuran (2 mL) and potassium hydroxide (1 M in water, 0.265
mL, 0.265 mmol). The tube was sealed and heated at 110.degree. C.
for 1 h via microwave. The reaction was cooled, poured into diethyl
ether, washed with water (2.times.), then brine, dried over
magnesium sulfate, and concentrated. Column chromatography
(12%.fwdarw.15% ethyl acetate/hexanes) gave 21 mg (56%) as a white
foam solid. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.74 (m,
2H), 7.65 (s, 1H), 7.55 (m, 2H), 7.37 (s, 2H), 7.26-7.34 (m, 4H),
7.17 (m, 1H), 4.30 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.32 (m, 1H),
3.25 (m, 1H), 3.02 (m, 2H), 2.23 (m, 1H), 2.12 (m, 1H), 1.75-1.97
(m, 2H), 1.43 (m, 9H), 1.35 (m, 3H). Mass spec.: 587.22
(MNa).sup.+. ##STR365##
[0164] (3-Bromo-5-fluorophenyl)methanol. 3-Bromo-5-fluorobenzoic
acid (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (8 mL) and
cooled to 0.degree. C. To this solution was added borane
tetrahydrofuran complex (1 M in tetrahydrofuran, 9 mL, 9.0 mmol)
cautiously over 15 min. The reaction mixture was allowed to warm to
room temperature overnight. The mixture was cooled to 0.degree. C.,
treated with excess methanol, diluted with ethyl acetate, washed
with 1 N sodium hydroxide (2.times.), then brine (2.times.), dried
over sodium sulfate, and concentrated to afford 0.88 g (95%) as a
white powder. .sup.1H-NMR (CDCl.sub.3, 500 MHz) 7.29 (s, 1H), 7.16
(d, J=7.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).
##STR366##
[0165] 1-Bromo-3-(bromomethyl)-5-fluorobenzene.
(3-Bromo-5-fluorophenyl)methanol (0.78 g, 3.8 mmol) and
triphenylphosphine (2.0 g, 7.6 mmol) were combined in
tetrahydrofuran (20 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (1.4 g, 7.98 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), then brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (5% ethyl acetate/hexanes) gave 0.8 g (79%) as a
white powder. .sup.1H-NMR (CDCl.sub.3, 300 MHz) 7.30 (s, 1H),
7.14-7.18 (m, 1H), 7.01-7.05 (m, 1H), 4.36 (s, 2H). ##STR367##
[0166] tert-Butyl
4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.
1-Bromo-3-(bromomethyl)-5-fluorobenzene (0.8 g, 3.0 mmol) and
tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.72
g, 2.5 mmol) were combined in dimethylformamide (8 mL) and cooled
to 0.degree. C. The reaction was treated with sodium hydride (120
mg, 4.98 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature for 30 min. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (20% ethyl acetate/hexanes) gave 1.2 g (84%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.34-7.38 (m, 4H), 7.24-7.25 (m, 1H),
7.08-7.10 (m, 1H), 7.01 (s, 1H), 6.70-6.72 (m, 1H), 4.29 (s, 2H),
3.74-3.77 (m, 2H), 3.38 (s, 2H), 3.00-3.06 (m, 2H), 2.17-2.20 (m,
2H), 1.84-1.90 (m, 2H), 1.44 (s, 9H). Mass spec.: 501.32
(MNa).sup.+. ##STR368##
[0167] 3-Bromo-5-fluorobenzaldehyde. To a solution of
(3-bromo-5-fluorophenyl)methanol (2 g, 9.75 mmol) and triethylamine
(2.72 mL, 19.5 mmol) in dimethylsulfoxide (25 mL) at 10.degree. C.
was added sulfur trioxide-pyridine (3.11 g, 19.5 mmol) in several
portions. The mixture was stirred at room temperature for 30 min.
The reaction was poured into ice water/pentane and the layers
separated. The organics were washed with 1 M potassium bisulfate,
then water, then brine, dried over magnesium sulfate, and
concentrated. Column chromatography (3% ethyl acetate/hexanes) gave
1.45 g (73%) as a white solid. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 9.92 (d, J=1.8 Hz, 1H), 7.80 (m, 1H), 7.50 (m, 2H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 189.2, 164.0, 162.0,
139.3, 129.0 (m), 125.0, 124.8, 123.8, 123.7, 114.8, 114.6.
##STR369##
[0168] (.+-.)-1-(3-Bromo-5-fluorophenyl)ethanol. To a solution of
3-bromo-5-fluorobenzaldehyde (1.45 g, 7.14 mmol) in tetrahydrofuran
(15 mL) at -78.degree. C. was added methylmagnesium bromide (3M in
diethyl ether, 2.98 mL, 8.93 mmol). The reaction was stirred at
-78.degree. C. for 30 min and then at 0.degree. C. for 30 min. The
reaction was quenched by addition of saturated ammonium chloride
and poured into pentane/water. The organics were washed with water
(2.times.), then brine, dried over magnesium sulfate, and
concentrated. Column chromatography (12%.fwdarw.25% ethyl
acetate/hexanes) gave 1.38 g (88%) as a colorless oil. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.29 (s, 1H), 7.13 (m, 1H), 7.02 (m,
1H), 4.84 (q, J=6.4 Hz, 1H), 2.06 (bs, 1H), 1.46 (d, J=6.4 Hz, 3H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 163.9, 161.9, 150.1
(m), 124.5 (m), 122.7, 122.6, 118.1, 117.9, 111.6, 111.4, 69.4,
25.3. ##STR370##
[0169] (.+-.)-1-Bromo-3-(1-bromoethyl)-5-fluorobenzene. To a
solution of (.+-.)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6
mmol) and carbon tetrabromide (1.82 g, 5.48 mmol) in
tetrahydrofuran (5 mL) at 0.degree. C. was added triphenylphosphine
(1.44 g, 5.48 mmol). The resulting solution was stirred at room
temperature for 45 min. The reaction was diluted with several
volumes of pentane, and filtered to remove the undissolved solids
which were discarded. The organics were concentrated and purified
by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g
(98%) as a colorless oil. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
7.35 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H),
2.00 (d, J=7.0 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta.
ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8, 122.7, 119.2, 119.0,
113.3, 113.1, 46.5, 26.7. ##STR371##
[0170] (.+-.)-tert-Butyl
4-((1-(3-bromo-5-fluorophenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxy-
late. To a solution of tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (827 mg, 2.84
mmol) and (.+-.)-1-bromo-3-(1-bromoethyl)-5-fluorobenzene (800 mg,
2.84 mmol) in dimethylformamide (3 mL) at 0.degree. C. was added
sodium hydride (75 mg, 3.1 mmol). The ice bath was removed and the
resulting mixture stirred at room temperature for 1 h. The reaction
was cooled to 0.degree. C., diluted with diethyl ether, and
quenched by the cautious addition of saturated ammonium chloride.
The mixture was poured into water and extracted into diethyl ether.
The ethereal was washed with water, then brine, dried over
magnesium sulfate, and concentrated. Column chromatography
(12.fwdarw.18% ethyl acetate/hexanes) gave 260 mg (19%) as a
colorless oil. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.33 (m,
4H), 7.24 (m, 1H), 7.06 (m, 1H), 6.95 (s, 1H), 6.63 (d, J=9.2 Hz,
1H), 4.09 (t, J=6.4 Hz, 1H), 3.75 (m, 2H), 3.22 (q.sub.AB,
J.sub.AB=8.9 Hz, 2H), 3.02 (m, 2H), 2.16 (m, 2H), 1.87 (m, 2H),
1.44 (s, 9H), 1.25 (d, J=6.4 Hz, 3H); .sup.13C NMR (126 MHz,
CDCl.sub.3) .delta. ppm 163.8, 161.8, 155.1, 148.63, 148.57, 142.7,
128.5, 127.3, 126.5, 125.0 (m), 122.5, 122.4, 118.0, 117.8, 111.9,
111.8, 79.4, 78.1, 77.5, 41.7, 40.3 (br), 32.0, 31.7, 28.6, 23.8.
Mass spec.: 492.15 (MH).sup.+. ##STR372##
[0171] (3-Amino-5-bromophenyl)methanol
(3-Bromo-5-nitrophenyl)methanol (3.9 g, 16.8 mmol) in methanol (35
mL) was flushed with nitrogen, and treated with platinum (IV) oxide
(390 mg). The flask was flushed with hydrogen and allowed to stir
under an atmosphere of hydrogen for 1 h. The reaction was flushed
with nitrogen, filtered through celite, and concentrated to afford
3.1 g (94%). .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 6.95 (s,
1H), 6.80 (s, 1H), 6.79 (s, 1H), 4.61 (s, 2H). Mass spec.: 203.96
(MH).sup.+. ##STR373##
[0172] 3'-Amino-5'-(hydroxymethyl)biphenyl-4-carbonitrile. A
microwave tube was charged with (3-amino-5-bromophenyl)methanol
(1.0 g, 4.98 mmol), 4-cyanophenylboronic acid (2.2 g, 15 mmol), and
tetrakis(triphenylphosphine) palladium(0) (77.6 mg, 0.05 mmol). The
tube was flushed with nitrogen, treated with tetrahydrofuran (6 mL)
and potassium hydroxide (2 M in water, 3.0 mL, 6.0 mmol). The tube
was sealed and heated at 120.degree. C. for 1 h via microwave. The
reaction was cooled, poured into ethyl acetate, washed with water
(2.times.), brine, dried over sodium sulfate, and concentrated.
Column chromatography (10% ethyl acetate/hexanes) gave 0.51 g (46%)
as a colorless oil. LC/MS: t.sub.R=1.25 min, 225.11 (MH).sup.+.
(Phenomenex C18 4.6.times.50 mm, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient time=4 min.,
Flow rate=4 mL/min.). ##STR374##
[0173] 3'-Chloro-5'-(hydroxymethyl)biphenyl-4-carbonitrile. A
solution of 3'-amino-5'-(hydroxymethyl)biphenyl-4-carbonitrile (120
mg, 0.54 mmol) in dry acetonitrile (1 mL) was added dropwise to a
solution of copper (II) chloride (86 mg, 0.64 mmol) and tert-butyl
nitrite (91 .mu.L, 0.78 mmol) in acetonitrile (2 mL) at 65.degree.
C. After stirring for 30 min at 65.degree. C., the reaction mixture
was cooled to room temperature, poured into a 1 N hydrochloric acid
solution, and extracted with ethyl acetate (2.times.). The organic
layers were pooled together, washed with brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (20% ethyl acetate/hexanes) afforded 46 mg (35%). LC/MS:
t.sub.R=2.54 min, 244.03 (MH).sup.+. (Phenomenex C18 4.6.times.50
mm, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10%
H.sub.2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
##STR375##
[0174] 3'-(Bromomethyl)-5'-chlorobiphenyl-4-carbonitrile.
(3-Bromo-5-(trifluoromethyl)phenyl)methanol (34 mg, 0.14 mmol) and
triphenylphosphine (73.4 mg, 0.28 mmol) were combined in
tetrahydrofuran (2 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (51.1 mg, 0.29 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), then brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (5% ethyl acetate/hexanes) gave 40 mg (93%).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.71-7.74 (m, 2H),
7.62-7.64 (m, 2H), 7.45-7.47 (m, 2H), 7.40-7.42 (m, 1H), 4.46 (s,
2H). ##STR376##
[0175] tert-Butyl
4-(((5-chloro-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1--
carboxylate. 3'-(Bromomethyl)-5'-chlorobiphenyl-4-carbonitrile
(38.3 mg, 0.12 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (30.3 mg, 0.1
mmol) were combined in dimethylformamide (2 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (5 mg,
0.2 mmol), stirred at 0.degree. C. for 1 h, and at room temperature
for 30 min. The reaction mixture was diluted with water and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (25%
ethyl acetate/hexanes) gave 35 mg (56%). .sup.1H-NMR (CDCl.sub.3,
300 MHz) .delta. 7.71 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.52 (s,
1H), 7.39 (s, 1H), 7.28-7.35 (m, 4H), 7.19-7.21 (m, 1H), 7.10-7.13
(m, 2H), 4.36 (s, 2H), 3.69-3.76 (m, 2H), 3.41 (s, 2H), 2.97-3.06
(m, 2H), 2.15-2.19 (m, 2H), 1.80-1.90 (m, 2H), 1.40 (s, 9H). Mass
spec.: 517.21 (MH).sup.+. ##STR377##
[0176] 3'-Chloro-5'-formylbiphenyl-4-carbonitrile. To a solution of
3'-chloro-5'-(hydroxymethyl)biphenyl-4-carbonitrile (330 mg, 1.35
mmol) and triethylamine (0.377 mL, 2.71 mmol) in dimethylsulfoxide
(5 mL) at 10.degree. C. was added sulfur trioxide-pyridine (259 mg,
1.63 mmol) in one portion. The bath was removed and stirring
continued for 30 min. The reaction was poured into ice water and
extracted with ethyl acetate (3.times.) and the layers separated.
The organics were washed with 1 M potassium bisulfate, then water,
then brine, dried over magnesium sulfate, and concentrated. Column
chromatography (12%.fwdarw.50% ethyl acetate/hexanes) gave 280 mg
(86%) as a white solid. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
10.04 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.80 (m,
2H), 7.75 (m, 2H). ##STR378##
[0177] (.+-.)-3'-Chloro-5'-(1-hydroxyethyl)biphenyl-4-carbonitrile.
To a solution of 3'-chloro-5'-formylbiphenyl-4-carbonitrile (280
mg, 1.16 mmol) in tetrahydrofuran (5 mL) at -78.degree. C. was
added methylmagnesium bromide (3M in diethyl ether, 0.772 mL, 2.32
mmol). The reaction was stirred at -78.degree. C. for 15 min and
then allowed to gradually warm to -20.degree. C. over 1 h. The
reaction was recooled to -78.degree. C. and quenched by the
dropwise addition of saturated ammonium chloride. The mixture was
poured into water and extracted into diethyl ether. The ethereal
was washed with brine, dried over magnesium sulfate, and
concentrated. Column chromatography (25%.fwdarw.50% ethyl
acetate/hexanes) gave 171 mg (57%) as a colorless oil. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.69 (d, J=8.2 Hz, 2H), 7.64 (d,
J=8.2 Hz, 2H), 7.46 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 4.93 (q,
J=6.4 Hz, 1H), 2.37 (bs, 1H), 1.51 (d, J=6.7 Hz, 3H); .sup.13C NMR
(126 MHz, CDCl.sub.3) .delta. ppm 149.0, 144.3, 141.1, 135.2,
132.8, 127.9, 126.3, 125.9, 122.6, 118.7, 111.7, 69.7, 25.6.
##STR379##
[0178] (.+-.)-3'-(1-Bromoethyl)-5'-chlorobiphenyl-4-carbonitrile.
To a solution of
(.+-.)-3'-chloro-5'-(1-hydroxyethyl)biphenyl-4-carbonitrile (171
mg, 0.664 mmol) and carbon tetrabromide (264 mg, 0.796 mmol) in
tetrahydrofuran (2 mL) at 0.degree. C. was added triphenylphosphine
(209 mg, 0.796 mmol). The resulting solution was stirred at room
temperature for 45 min. The reaction was diluted with ca. 2 volumes
of pentane and filtered to remove the undissolved solids which were
discarded. The organics were concentrated and purified by column
chromatography (3%.fwdarw.8% ethyl acetate/hexanes) to give 201 mg
(94%) as a colorless oil. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
7.74 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.47
(s, 2H), 5.18 (q, J=6.7 Hz, 1H), 2.06 (d, J=7.0 Hz, 3H); .sup.13C
NMR (126 MHz, CDCl.sub.3) .delta. ppm 146.1, 143.8, 141.5, 135.4,
132.8, 127.9, 127.3, 127.1, 124.2, 118.6, 112.1, 47.4, 26.8.
##STR380##
[0179] (.+-.)-tert-Butyl
4-((1-(5-chloro-4'-cyanobiphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-
-carboxylate. To a solution of tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (182 mg, 0.624
mmol) and (.+-.)-3'-(1-bromoethyl)-5'-chlorobiphenyl-4-carbonitrile
(200 mg, 0.624 mmol) in dimethylformamide (1.5 mL) at 0.degree. C.
was added sodium hydride (16.5 mg, 0.686 mmol). The reaction was
stirred at room temperature for 1 h. The reaction was cooled to
0.degree. C., diluted with diethyl ether, and quenched by the
cautious addition of saturated ammonium chloride. The mixture was
poured into water and extracted into diethyl ether. The ethereal
was washed with water, then brine, dried over magnesium sulfate,
and concentrated. Column chromatography (12.fwdarw.18% ethyl
acetate/hexanes) gave 82 mg (25%) as a colorless foam. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.71 (d, J=8.5 Hz, 2H), 7.52 (d,
J=8.5 Hz, 2H), 7.38 (s, 1H), 7.31 (m, 4H), 7.18 (m, 1H), 7.07 (s,
1H), 7.05 (s, 1H), 4.20 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.26
(q.sub.AB, J.sub.AB=8.9 Hz, 2H), 3.01 (m, 2H), 2.22 (m, 1H), 2.11
(m, 1H), 1.87 (m, 2H), 1.43 (s, 9H), 1.32 (d, J=6.7 Hz, 3H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 155.1, 147.3, 144.2,
142.8, 141.0, 135.1, 132.7, 128.5, 127.9, 127.4, 126.4, 126.3,
126.2, 122.9, 118.8, 111.7, 79.4, 78.1, 77.8, 41.6, 40.2 (br),
32.1, 31.7, 28.6, 24.1. Mass spec.: 531.31 (MH).sup.+.
##STR381##
[0180] Methyl 3-(hydroxymethyl)-5-nitrobenzoate.
3-(Methoxycarbonyl)-5-nitrobenzoic acid (20.0 g, 88.9 mmol) was
combined with tetrahydrofuran (150 mL) and cooled to 0.degree. C.
To this solution was added a 1 M borane tetrahydrofuran complex
(178 mL, 178 mmol) cautiously over 15 min and the reaction mixture
allowed to warm to room temperature overnight. The mixture was
cooled to 0.degree. C., treated with excess methanol and
concentrated in vacuo to afford to afford a precipitate which was
dissolved in ethyl acetate, washed with concentrated sodium
bicarbonate (2.times.), then brine (2.times.), dried over sodium
sulfate, and concentrated to afford 18.2 g (97%) which was used
without further purification. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.70 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 4.84 (s, 2H),
3.95 (s, 3H). Mass spec.: 212.06 (MH).sup.+. ##STR382##
[0181] Methyl 3-amino-5-(hydroxymethyl)benzoate. Methyl
3-(hydroxymethyl)-5-nitrobenzoate (11.2 g, 53 mmol) in methanol (50
mL) was flushed with nitrogen, and treated with palladium (10% on
charcoal, 1.1 g). The flask was flushed with hydrogen and allowed
to stir under an atmosphere of hydrogen overnight. The reaction was
flushed with nitrogen, filtered through celite, and concentrated.
Column chromatography on silica gel (50% ethyl acetate/hexanes)
afforded 2.8 g (29%). .sup.1H-NMR (CD.sub.3OD, 300 MHz) .delta.
7.34 (s, 1H), 7.27 (s, 1H), 6.94 (s, 1H), 4.55 (s, 2H), 3.88 (s,
3H). Mass spec.: 182.09 (MH).sup.+. ##STR383##
[0182] Methyl 3-bromo-5-(hydroxymethyl)benzoate. Methyl
3-amino-5-(hydroxymethyl)benzoate (2.4 g, 13.2 mmol) in dry
acetonitrile (10 mL) was added dropwise to a solution of copper
(II) bromide (3.54 g, 15.8 mmol) and tert-butyl nitrite (2.24 mL,
18.9 mmol) in acetonitrile (20 mL) at 65.degree. C. After stirring
for 30 min at 65.degree. C., the reaction mixture was cooled to
room temperature, poured into a 1 N hydrochloric acid solution, and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (30%
ethyl acetate/hexanes) afforded 2.0 g (62%). .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.04 (s, 1H), 7.90 (s, 1H), 7.69 (s,
1H), 4.70 (s, 2H), 3.89 (s, 3H). Mass spec.: 246.98 (MH).sup.+.
##STR384##
[0183] Methyl 3-bromo-5-(bromomethyl)benzoate. Methyl
3-bromo-5-(hydroxymethyl)benzoate (2.0 g, 8.2 mmol) and
triphenylphosphine (4.28 g, 16.3 mmol) were combined in
tetrahydrofuran (20 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (3.05 g, 17.1 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), then brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (10% ethylacete/hexanes) gave 2.1 g (83%) as a light
brown oil. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.07 (s, 1H),
7.96 (s, 1H), 7.70 (s, 1H), 4.42 (s, 2H), 3.90 (s, 3H). Mass spec.:
308.93 (MH).sup.+. ##STR385##
[0184]
3-Bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methox-
y)methyl)benzoic acid. Methyl 3-bromo-5-(bromomethyl)benzoate (2.1
g, 6.81 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.8 g, 6.2
mmol) were combined in dimethylformamide (21 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (298 mg,
12.4 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature for 30 min. The reaction was cooled to 0.degree. C. and
treated lithium hydroxide monohydrate (0.54 g, 13.6 mmol). The
solution was stirred at room temperature for 16 h and the solvents
evaporated. The resultant residue was diluted with water (10 mL)
and the pH adjusted to ca. 1 with 1 N hydrochloric acid. The
resultant white suspension was stored at 4.degree. C. overnight and
the product was collected by filtration, washed with a small amount
of water, and dried in vacuo for several hours to afford 2.4 g
(70%) as a white powder. LC/MS: t.sub.R=3.33 min, 506.20
(MH).sup.+. (Phenomenex C18 4.6.times.50 mm, 10% MeOH/90%
H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient
time=4 min., Flow rate=4 mL/min.). ##STR386##
[0185] tert-Butyl
4-((3-bromo-5-(dimethylcarbamoyl)benzyloxy)methyl)-4-phenylpiperidine-1-c-
arboxylate. A stirred solution of
3-bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methy-
l)benzoic acid (160 mg, 0.32 mmol) in dimethylformamide (5 mL) was
cooled to 0.degree. C. and sequentially treated with methylene
chloride (2 mL), dimethylamine (1 N in tetrahydrofuran, 0.32 mL,
0.32 mmol), N,N-diisopropylethylamine (90 .mu.L, 0.64 mmol), and
PyBop.RTM. (0.21 g, 0.38 mmol). The solution was stirred for 1.5 h
and concentrated. The product was purified by column chromatography
(30% ethyl acetate/hexanes) to give 120 mg (70%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.38-7.40 (m, 1H), 7.33-7.35 (m, 4H),
7.22-7.24 (m, 2H), 7.03 (s, 1H), 4.32 (s, 2H), 3.74-3.77 (m, 2H),
3.38 (s, 2H), 3.08 (s, 3H), 2.99-3.05 (m, 2H), 2.90 (s, 3H),
2.16-2.19 (m, 2H), 1.83-1.89 (m, 2H), 1.43 (s, 9H). Mass spec.:
533.24 (MH).sup.+. ##STR387##
[0186] tert-Butyl
4-((3-bromo-5-(piperidine-1-carbonyl)benzyloxy)methyl)-4-phenylpiperidine-
-1-carboxylate. LC/MS: t.sub.R=3.31 min, 573.38 (MH).sup.+.
(Phenomenex C18 4.6.times.50 mm, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient time=4 min.,
Flow rate=4 mL/min.). ##STR388##
[0187] tert-Butyl
4-((3-bromo-5-(morpholine-4-carbonyl)benzyloxy)methyl)-4-phenylpiperidine-
-1-carboxylate. LC/MS: t.sub.R=3.15 min, 575.36 (MH).sup.+.
(Phenomenex C18 4.6.times.50 mm, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient time=4 min.,
Flow rate=4 mL/min.). ##STR389##
[0188] tert-Butyl
4-(((5-carbamoyl-4'-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate.
3-Bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methy-
l)benzoic acid (0.66 g, 1.31 mmol), 4-fluorophenylboronic acid
(0.55 g, 3.93 mmol), and tetrakis(triphenylphosphine) palladium(0)
(82 mg, 0.05 mmol) were combined in dry tetrahydrofuran (10 mL) in
a microwave tube and sealed. After flushing with nitrogen, 5.5 mL
of a 1 N potassium hydroxide aqueous solution was introduced. The
mixture was heated at 120.degree. C. for 1 h via microwave. After
cooling to room temperature, the reaction mixture was concentrated,
dissolved in dimethylformamide (6 mL) and cooled to 0.degree. C.
The reaction mixture was sequentially treated with methylene
chloride (2 mL), 7 N ammonia in methanol (0.33 mL, 2.3 mmol),
N,N-diisopropylethylamine (0.51 mL, 2.9 mmol), and PyBop.RTM. (0.72
g, 1.4 mmol). The ice bath was removed and the solution stirred for
1.5 h and concentrated. The product was purified by column
chromatography (50% ethyl acetate/hexanes) to give 0.4 g (66%).
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.85 (s, 1H), 7.43-7.46
(m, 2H), 7.41 (s, 1H), 7.37 (s, 1H), 7.28-7.31 (m, 4H), 7.15-7.18 9
(m, 1H), 7.07-7.10 (m, 2H), 4.40 (s, 2H), 3.67-3.69 (m, 2H), 3.40
(s, 2H), 2.96-3.00 (m, 2H), 2.14-2.16 (m, 2H), 1.80-1.86 (m, 2H),
1.37 (s, 9H). Mass spec.: 519.39 (MH).sup.+. ##STR390##
[0189] tert-Butyl
4-(((5-cyano-4'-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1--
carboxylate. A stirred solution of tert-butyl
4-(((5-carbamoyl-4'-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidin-
e-1-carboxylate (0.38 g, 0.72 mmol) in pyridine (6 mL) at 0.degree.
C. was treated with trifluoroacetic anhydride (1.0 mL, 7.2 mmol).
The ice bath was removed and the reaction stirred at room
temperature for 4 h. The reaction was cooled to 0.degree. C. and
quenched by the addition of excess methanol. The solvents were
evaporated and the crude mixture dissolved in ethyl acetate and
washed with 5% citric acid (2.times.), then water (2.times.), then
brine (2.times.), dried over sodium sulfate, and concentrated. The
residue was purified by column chromatography (30% ethyl
acetate/hexanes) to afford 0.3 g (83%) as a white powder.
.sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.65 (s, 1H), 7.41-7.44
(m, 3H), 7.34-7.36 (m, 4H), 7.22-7.24 (m, 2H), 7.13-7.17 (m, 2H),
4.41 (s, 2H), 3.75 (m, 2H), 3.44 (s, 2H), 2.01-3.06 (m, 2H),
2.19-2.22 (m, 2H), 1.83-1.88 (m, 2H), 1.43 (s, 9H). Mass spec.:
501.37 (MH).sup.+. ##STR391##
[0190] (5-Amino-4'-fluorobiphenyl-3-yl)methanol. A dry round
bottomed flask was charged with (3-amino-5-bromophenyl)methanol
(2.5 g, 12.4 mmol), 4-fluorophenylboronic acid (5.2 g, 37.2 mmol),
and tetrakis(triphenylphosphine) palladium(0) (0.39 g, 0.25 mmol).
The flask was flushed with nitrogen and treated with
tetrahydrofuran (30 mL) and potassium hydroxide (2 M in water, 19
mL, 38 mmol). The mixture was heated at reflux for 4 h. The
reaction was cooled, poured into ethyl acetate, washed with water
(2.times.), then brine, dried over magnesium sulfate, and
concentrated. Column chromatography (40% ethyl acetate/hexanes)
gave 1.52 g (56%) as a colorless oil. LC/MS: t.sub.R=1.48 min,
218.18 (MH).sup.+. (Phenomenex C18 4.6.times.50 mm, 10% MeOH/90%
H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient
time=4 min., Flow rate=4 mL/min.). ##STR392##
[0191] (5-Bromo-4'-fluorobiphenyl-3-yl)methanol. A solution of
(5-bromo-4'-fluorobiphenyl-3-yl)methanol (1.52 g, 7.0 mmol) in dry
acetonitrile (6 mL) was added dropwise to a solution of copper (II)
bromide (1.88 g, 8.4 mmol) and tert-butyl nitrite (1.2 mL, 10.0
mmol) in acetonitrile (3 mL) at 65.degree. C. After stirring for 30
min at 65.degree. C., the reaction mixture was cooled to room
temperature, poured into a 1 N hydrochloric acid solution, and
extracted with ethyl acetate (2.times.). The organic layers were
pooled together, washed with brine (2.times.), dried over sodium
sulfate, and concentrated. Column chromatography on silica gel (30%
ethyl acetate/hexanes) afforded 420 mg (17%). .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 7.55-7.57 (m, 1H), 7.46-7.50 (m, 3H),
7.42 (m, 1H), 7.02-7.12 (m, 2H), 4.70 (s, 2H). ##STR393##
[0192] 3-Bromo-5-(bromomethyl)-4'-fluorobiphenyl.
(5-Bromo-4'-fluorobiphenyl-3-yl)methanol (0.42 g, 1.5 mmol) and
triphenylphosphine (0.78 g, 2.98 mmol) were combined in
tetrahydrofuran (8 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (0.59 g, 3.1 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), then brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (5% ethyl acetate/hexanes) gave 0.4 g (78%) as a
white powder. .sup.1H-NMR (CDCl.sub.3, 500 MHz) 7.60 (m, 1H),
7.50-7.54 (m, 3H), 7.47 (m, 1H), 7.12-7.15 (m, 2H), 4.47 (s, 2H).
##STR394##
[0193] tert-Butyl
4-(((5-bromo-4'-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1--
carboxylate. 3-Bromo-5-(bromomethyl)-4'-fluorobiphenyl (398 mg,
1.16 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (280 mg, 0.96
mmol) were combined in dimethylformamide (5 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (46 mg,
1.92 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature for 30 min. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (20% ethyl acetate/hexanes) gave 470 mg (73%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.51 (s, 1H), 7.28-7.42 (m, 6H),
7.19-7.23 (m, 2H), 7.06-7.14 (m, 3H), 4.34 (s, 2H), 3.69-3.74 (m,
2H), 3.40 (s, 2H), 2.98-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.81-1.90
(m, 2H), 1.41 (s, 9H). Mass spec.: 556.37 (MH).sup.+.
##STR395##
[0194] tert-Butyl
4-(((4'-fluoro-5-hydroxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine--
1-carboxylate. tert-Butyl
4-(((5-bromo-4'-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1--
carboxylate (0.47 g, 0.85 mmol) was dissolved in dry
tetrahydrofuran (5 mL) and stirred at room temperature for 15 min.
The stirred mixture was cooled to -78.degree. C. and treated with a
solution of n-butyllithium (1.6 M in hexanes, 0.61 mL, 0.98 mmol)
over several minutes. After 30 min, the mixture was treated with
trimethylborate (0.28 mL, 2.55 mmol). The reaction mixture was
stirred at 78.degree. C. for 1 h, then allowed to warm to room
temperature over several hours. The mixture was cooled to 0.degree.
C. and treated with a 10 N sodium hydroxide solution (60 .mu.L) and
hydrogen peroxide (30% in water, 0.44 mL, 3.9 mmol). The reaction
was warmed to room temperature over several hours and then treated
with saturated ammonium chloride. The reaction was diluted with
ethyl acetate. The layers were separated and the organic layer
washed with brine (2.times.), dried over sodium sulfate, filtered,
and concentrated. Flash chromatography on silica gel (30% ethyl
acetate/hexanes) afforded 280 mg (67%). .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. 7.38-7.43 (m, 2H), 7.19-7.35 (m, 5H), 7.02-7.09
(m, 2H), 6.86-6.88 (m, 1H), 6.79 (s, 1H), 6.46 (s, 1H), 4.33 (s,
2H), 3.70-3.74 (m, 2H), 3.38 (s, 2H), 2.98-3.07 (m, 2H), 2.13-2.17
(m, 2H), 1.83-1.92 (m, 2H), 1.41 (s, 9H). Mass spec.: 492.41
(MH).sup.+. ##STR396##
[0195] 5-Bromo-2-hydroxy-3-methylbenzoic acid. To a mixture of
2-hydroxy-3-methylbenzoic acid (2.1 g, 13.5 mmol) in acetic acid
(30 mL) was added bromine (0.7 mL, 13.7 mmol) slowly over 5
minutes. After 24 h, water was added slowly to the reaction mixture
and the reaction stirred for 30 min. The resulting precipitate was
collected by filtration and washed several times with water. The
product was dried overnight under high vacuum to afford 2.8 g
(90%). LC/MS: t.sub.R=2.86 min, 229.14 (MH).sup.+. (Phenomenex C18
4.6.times.50 mm, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10%
H.sub.2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
##STR397##
[0196] Methyl 5-bromo-2-methoxy-3-methylbenzoate.
5-Bromo-2-hydroxy-3-methylbenzoic acid (2.8 g, 12.1 mmol),
iodomethane (1.97 mL, 31.6 mmol) and potassium carbonate (16.9 g,
123 mmol) were combined in dimethylformamide (30 mL). After
stirring at room temperature for 16 h, the solvent was removed in
vacuo and the crude product dissolved in ethyl acetate, which was
washed with water (2.times.), then brine (2.times.), dried over
sodium sulfate, and concentrated. Flash chromatography on silica
gel (10% ethyl acetate/hexanes) gave 2.26 g (72%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.74-7.75 (m, 1H), 7.45-7.46 (m, 1H),
3.90 (s, 3H), 3.80 (s, 3H), 2.28 (s, 3H). Mass spec.: 261.08
(MH).sup.+. ##STR398##
[0197] (5-Bromo-2-methoxy-3-methylphenyl)methanol. Methyl
5-bromo-2-methoxy-3-methylbenzoate (2.26 g, 8.7 mmol) was dissolved
in methylene chloride (30 mL), cooled to -78.degree. C., and
treated with diisobutylaluminum hydride (1 M in methylene chloride,
26.1 mL, 26.1 mmol). After stirring at -78.degree. C. for 1 h the
reaction was quenched by a few drops of methanol (until no bubbling
was observed) followed by addition of excess saturated sodium
potassium tartarate (2 mL). The reaction was stirred at room
temperature overnight. The layers were separated and the organic
layer washed with brine (2.times.), dried over sodium sulfate, and
concentrated to afford 2.0 g (quant). .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.30-7.31 (m, 1H), 7.21-7.22 (m, 1H), 4.62 (s, 2H),
3.71 (s, 3H), 2.23 (s, 3H). ##STR399##
[0198] 5-Bromo-1-(bromomethyl)-2-methoxy-3-methylbenzene.
(5-Bromo-2-methoxy-3-methylphenyl)methanol (2.0 g, 8.7 mmol) and
triphenylphosphine (4.5 g, 17.4 mmol) were combined in
tetrahydrofuran (30 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (3.2 g, 17.4 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), then brine (2.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (hexanes) gave 1.87 g (73%) as a white powder.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.32-7.33 (m, 1H),
7.23-7.24 (m, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 2.25 (s, 3H).
##STR400##
[0199] tert-Butyl
4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carb-
oxylate. 5-Bromo-1-(bromomethyl)-2-methoxy-3-methylbenzene (0.88 g,
3.0 mmol) and tert-butyl
4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.79 g, 2.7
mmol) were combined in dimethylformamide (9 mL) and cooled to
0.degree. C. The reaction was treated with sodium hydride (144 mg,
5.99 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature for 30 min. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (10% ethyl acetate/hexanes) gave 1.24 g (82%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.34-7.35 (m, 4H), 7.21-7.24 (m, 1H),
7.19-7.20 (m, 1H), 7.10 (m, 1H), 4.34 (s, 2H), 3.72-3.76 (m, 2H),
3.53 (s, 3H), 3.43 (s, 2H), 3.01-3.07 (m, 2H), 2.21 (s, 3H),
2.17-2.19 (m, 2H), 1.85-1.91 (m, 2H), 1.43 (s, 9H). Mass spec.:
506.45 (MH).sup.+. ##STR401##
[0200] tert-Butyl
4-(((4,5-dicyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carbox-
ylate. tert-Butyl
4-(((5-bromo-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-c-
arboxylate (52 mg, 0.09 mmol), tetrakis(triphenylphosphine)
palladium(0) (14 mg, 0.01 mmol), and zinc cyanide (12 mg, 0.1 mmol)
were combined in dimethylformamide (1.5 mL). The reaction mixture
was degassed repeatedly using the freeze-pump-thaw method. After
warming to room temperature, the reaction was heated at 90.degree.
C. for 1 h, cooled to room temperature, and concentrated. Flash
chromatography on silica gel (30% ethyl acetate/hexanes) gave 15 mg
(33%). .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.78-7.75 (m, 3H),
7.52-7.55 (m, 2H), 7.31-7.33 (m, 4H), 7.20-7.23 (m, 2H), 4.41 (s,
2H), 3.70-3.77 (m, 2H), 3.43 (s, 2H), 2.97-3.06 (m, 2H), 2.17-2.21
(m, 2H), 1.78-1.88 (m, 2H), 1.40 (s, 9H). Mass spec.: 508.28
(MH).sup.+. ##STR402##
[0201] tert-Butyl
4-(((4'-cyano-5-methylbiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1--
carboxylate. A microwave tube was charged with tert-butyl
4-(((5-bromo-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-c-
arboxylate (48 mg, 0.09 mmol), trimethyl boroxine (13 .mu.L, 0.09
mmol), and tetrakis(triphenylphosphine) palladium(0) (10 mg, 9
.mu.mol). The tube was flushed with nitrogen, treated with a
mixture of 1,4-dioxane/water (9:1, 2 mL) and potassium carbonate
(35.1 mg, 0.25 mmol). The tube was sealed and heated at 120.degree.
C. for 1 h via microwave. After cooling to room temperature, the
reaction was concentrated and purified by preparative HPLC to give
11 mg (27%). LC/MS: t.sub.R=3.50 min, 497.33 (MH).sup.+.
(Phenomenex C18 4.6.times.50 mm, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient time=4 min.,
Flow rate=4 mL/min.). ##STR403##
[0202] (3-Bromo-5-nitrophenyl)methanol. 3-Bromo-5-nitrobenzoic acid
(3.2 g, 13.0 mmol) was suspended in tetrahydrofuran (25 mL) and
cooled to 0.degree. C. To this solution was added borane
tetrahydrofuran complex (1 M in tetrahydrofuran, 26 mL, 26 mmol)
cautiously over 15 min. The reaction mixture was allowed to warm to
room temperature overnight. The mixture was cooled to 0.degree. C.,
treated with excess methanol, diluted with ethyl acetate, washed
with 1 N sodium hydroxide (2.times.), then brine (2.times.), dried
over sodium sulfate, and concentrated to afford 3.0 g (99%) as a
white powder. .sup.1H-NMR (CDCl.sub.3, 300 MHz) 8.24 (s, 1H), 8.13
(s, 1H), 7.82 (s, 1H), 4.78 (s, 2H). Mass spec.: 233.88 (MH).sup.+.
##STR404##
[0203] 1-Bromo-3-(bromomethyl)-5-nitrobenzene.
(3-Bromo-5-nitrophenyl)methanol (2.0 g, 8.65 mmol) and
triphenylphosphine (4.5 g, 17.3 mmol) were combined in
tetrahydrofuran (40 mL) and cooled to 0.degree. C.
N-Bromosuccinimide (3.2 g, 18.2 mmol) was introduced in portions
and the reaction allowed to warm to room temperature. After 16 h,
the reaction mixture was diluted with ethyl acetate, washed with
concentrated sodium bicarbonate (2.times.), brine (2.times.), dried
over sodium sulfate, and concentrated. Column chromatography on
silica gel (5% ethyl acetate/hexanes) gave 2.2 g (84%) as a white
powder. .sup.1H-NMR (CDCl.sub.3, 300 MHz) 8.27 (s, 1H), 8.16 (s,
1H), 7.84 (s, 1H), 4.45 (s, 2H). ##STR405##
[0204] tert-Butyl
4-((3-bromo-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.
1-Bromo-3-(bromomethyl)-5-nitrobenzene (2.12 g, 7.21 mmol) and
tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.75
g, 6.0 mmol) were combined in dimethylformamide (18 mL) and cooled
to 0.degree. C. The reaction was treated with sodium hydride (288
mg, 12.0 mmol), stirred at 0.degree. C. for 1 h, and at room
temperature for 30 min. The reaction mixture was diluted with water
and extracted with ethyl acetate (2.times.). The organic layers
were pooled together, washed with brine (2.times.), dried over
sodium sulfate, and concentrated. Column chromatography on silica
gel (20% ethyl acetate/hexanes) gave 1.4 g (38%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 8.20 (s, 1H), 7.88 (s, 1H), 7.50 (s,
1H), 7.33-7.38 (m, 4H), 4.37 (s, 2H), 3.75-3.78 (m, 2H), 3.43 (s,
2H), 3.00-3.04 (m, 2H), 2.20-2.22 (m, 2H), 1.82-1.87 (m, 2H), 1.42
(s, 9H). Mass spec.: 507.10 (MH).sup.+. ##STR406##
[0205] tert-Butyl
4-((3-amino-5-bromobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate.
tert-Butyl
4-((3-bromo-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(1.36 g, 2.69 mmol) and tin (II) chloride dihydrate (6.48 g, 28.7
mmol) were combined in ethyl acetate (20 mL) and heated at reflux
for 4 h. After cooling to room temperature, the reaction mixture
was diluted with ethyl acetate and washed with saturated sodium
bicarbonate (2.times.), brine (2.times.), dried over sodium sulfate
and concentrated. The crude product was dissolved in
tetrahydrofuran (10 mL), cooled to 0.degree. C. and treated with
di-tert-butyl carbonate (0.59 g, 2.69 mmol) and 10 N sodium
hydroxide (0.65 mL). The reaction was allowed to warm to room
temperature overnight. The reaction mixture was diluted with ethyl
acetate, washed with water (2.times.), brine (2.times.), dried over
sodium sulfate and concentrated. Column chromatography on silica
gel (30% ethyl acetate/hexanes) gave 0.25 g (19%). LC/MS (HPLC
method 3): t.sub.R=2.99 min, 477.05(MH).sup.+. ##STR407##
[0206] tert-Butyl
4-(((5-amino-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-c-
arboxylate. tert-Butyl
4-((3-amino-5-bromobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(220.0 mg, 0.46 mmol), 4-cyanophenylboronic acid (273.0 mg, 1.86
mmol), and tetrakis(triphenylphosphine) palladium(0) (71.7 mg,
0.046 mmol) were combined in dry tetrahydrofuran (5 mL) in a
microwave tube and sealed. The mixture was flushed with nitrogen.
To this was added potassium hydroxide (1 N in water, 1.4 mL, 1.4
mmol). The mixture was heated at 120.degree. C. for 1 h via
microwave. After cooling to room temperature, the reaction mixture
was concentrated and purified by flash chromatography on silica gel
(25% ethyl acetate/hexanes) to afford 140.0 mg (61%). LC/MS (HPLC
method 3): t.sub.R=2.85 min, 498.24(MH).sup.+. ##STR408##
[0207] tert-Butyl
4-(((5-bromo-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-c-
arboxylate. A solution of tert-Butyl
4-(((5-amino-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-c-
arboxylate (136.0 mg, 0.27 mmol) in dry acetonitrile (2.0 mL) was
added dropwise to a solution of copper (II) bromide (71.6 g, 0.32
mmol) and tert-butyl nitrite (46.0 .mu.L, 0.39 mmol) in
acetonitrile (1.0 mL) at 65.degree. C. After stirring for 30 min at
65.degree. C., the reaction mixture was cooled to room temperature,
poured into a 1 N hydrochloric acid solution, and extracted with
ethyl acetate (2.times.). The organic layers were pooled together,
washed with brine (2.times.), dried over sodium sulfate, and
concentrated. Column chromatography on silica gel (20% ethyl
acetate/hexanes) afforded 30.0 g (20%). .sup.1H-NMR (CDCl.sub.3,
300 MHz) .delta. 7.68-7.71 (m, 2H), 7.51-7.55 (m, 3H), 7.25-7.38
(m, 5H), 7.17-7.20 (m, 2H), 4.36 (s, 2H), 3.68-3.76 (m, 2H), 3.41
(s, 2H), 2.97-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.80-1.89 (m, 2H),
1.40 (s, 9H). Mass spec.: 563.12 (MH).sup.+. ##STR409##
[0208] tert-Butyl 4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate.
A flask was charged with sodium hydride (5.08 g, 127 mmol) and
dimethylformamide (100 ml) at 0.degree. C. under nitrogen.
2-(Pyridin-3-yl)acetonitrile (5 g, 42.3 mmol) was added in 25 mL of
dimethylformamide via addition funnel over 20 min. After 20 min,
tert-butyl bis(2-chloroethyl)carbamate (12.81 g, 52.9 mmol) was
added in 20 mL of dimethylformamide via addition funnel over 20
min. The reaction was allowed to stir at 0.degree. C. for 2 h and
then at 60.degree. C. for 12 h. The reaction was quenched with 10%
sodium bicarbonate (100 mL) and extracted with ethyl acetate
(5.times.100 mL). The organics were collected, washed with brine,
dried over sodium sulfate, and concentrated in vacuo. The residue
was purified via column chromatography (10% 2M ammonia in methanol,
90% dichloromethane) to yield 7.5 g (49%) of desired product. Mass
Spec.: 288.20 (MH).sup.+. LC t.sub.r=1.380 min (Phenomenex-Luna
4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min)
##STR410##
[0209]
1-(tert-Butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic
acid. A flask was charged with tert-butyl
4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate (7.5 g, 26.1 mmol)
and NaOH (50% in water, 100 mL) in ethanol (100 ml) and heated at
reflux for 6 h. The ethanol was removed, and the resulting solution
was acidified to pH=5 using concentrated hydrochloric acid. The
desired product was collected by filtration, and dried overnight to
yield 4.1 g (51%). Mass Spec. : 307.18 (MH)+. LC t.sub.r=1.31 min
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H2O/0.1%
TFA.fwdarw.90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow
rate=4 mL/min) ##STR411##
[0210] tert-Butyl
4-(hydroxymethyl)-4-(pyridin-3-yl)piperidine-1-carboxylate. A flask
was charged with
1-(tert-butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic
acid (4.0 g, 13.1 mmol) and tetrahydrofuran (25 mL). The reaction
was placed under nitrogen. To the flask was added
borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 26.1 mL,
26.1 mmol) and heated at reflux for 2 h. The reaction was cooled to
0.degree. C. and quenched with methanol (100 mL). The solution was
then concentrated in vacuo. The residue was purified via column
chromatography (5% methanol/95% dichloromethane) to yield 3.2 g
(84%). Mass Spec.: 293.26 (MH).sup.+. LC: t.sub.r=1.65 min
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow
rate=4 mL/min). ##STR412##
[0211] tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(pyridin-3-yl)piperidi-
ne-1-carboxylate. A flask was charged with
1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (2.53 g, 7.96
mmol) and tert-butyl
4-(hydroxymethyl)-4-(pyridin-3-yl)piperidine-1-carboxylate (1.1 g,
3.8 mmol) in tetrahydrofuran (10 mL) at 0.degree. C. The reaction
was treated with sodium tert-butoxide (364 mg, 3.79 mmol), stirred
at 0.degree. C. for 20 min, and treated with another aliquot of
sodium tert-butoxide (364 mg, 3.79 mmol). The reaction was allowed
to warm to room temperature for 30 min then diluted with 10% sodium
bicarbonate and extracted with ethyl acetate (2.times.). The
organic layers were pooled together, washed with brine (1.times.),
dried over sodium sulfate, and concentrated. Column chromatography
on silica gel (0%-60% ethyl acetate/hexanes) gave 1.23 g (62%).
Mass spec.: 529.12 (MH).sup.+ LC t.sub.r=2.248 min.
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow
rate=4 mL/min). ##STR413##
[0212]
3-(4-((3-Bromo-5-(trifluoromethyl)benzyloxy)methyl)-1-methylpiperi-
din-4-yl)pyridine. A flask was charged with tert-butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(pyridin-3-yl)piperidi-
ne-1-carboxylate (900 mg, 1.70 mmol) in methanol (5 mL).
Hydrochloric acid (gas) was bubbled through for 20 seconds and the
mixture was allowed to stir for 20 min. The solvent was
concentrated in vacuo. The solid white intermediate was redissolved
in dichloromethane (5 mL) and treated with formaldehyde (37 wt. %
solution in water, 1.5 mL) at 0.degree. C. After 20 min the
reaction was treated with sodium triacetoxyborohydride (1.4 g, 6.8
mmol). The reaction was stirred at 0.degree. C. for 30 min and at
room temperature for 1 h. The solvent was removed in vacuo and the
resulting residue purified via preparative HPLC to yield 330 mg
(44%) of desired product. Mass spec.: 443.03 (MH).sup.+ LC
t.sub.r=1.398 min (Phenomenex-Luna 4.6.times.50 mm S10, 10%
MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA
Gradient Time=2 min, Flow rate=4 mL/min). ##STR414##
[0213] 1-tert-Butyl 4-ethyl
4-(pyridin-4-yl)piperidine-1,4-dicarboxylate. Prepared in the same
fashion as tert-butyl
4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate. Mass Spec.:
335.01 (MH).sup.+. LC: t.sub.r=1.460 min (Phenomenex-Luna
4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min)
##STR415##
[0214] tert-Butyl
4-(hydroxymethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate. A flask
was charged with 1-tert-butyl 4-ethyl
4-(pyridin-4-yl)piperidine-1,4-dicarboxylate (250 mg, 0.748 mmol)
in tetrahydrofuran (3 mL) and cooled to -50.degree. C.
(acetonitrile/dry ice). Lithium aluminum hydride (0.785 ml, 1.570
mmol) was added dropwise, and the reaction was allowed to stir for
30 min. The flask was then warmed to room temperature and slowly
diluted with ethyl acetate (5 mL). Water (61 .mu.L) was added and
the reaction allowed to stir for 5 min. Sodium Hydroxide (1 N in
water, 120 .mu.L) was then added and the reaction allowed to stir
for 5 min. An additional portion of water (61 .mu.L) and a small
amount of sodium sulfate was added and the resulting mixture
allowed to stir for 5 min. The suspension was filtered through
celite, and the resulting pad washed with hot ethyl acetate. The
filtrate was concentrated in vacuo to yield 90 mg (41%) of desired
product. Mass Spec.: 294.05 (MH).sup.+. LC t.sub.r=1.79 min (HPLC
Method 1). ##STR416##
[0215] tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(pyridin-
-4-yl)piperidine-1-carboxylate. A flask was charged with
3'-(bromomethyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile (157
mg, 0.462 mmol) and tert-butyl
4-(hydroxymethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (90 mg,
0.308 mmol) in tetrahydrofuran (10 mL) at 0.degree. C. The reaction
was treated with potassium tert-butoxide (34.6 mg, 0.308 mmol),
stirred at 0.degree. C. for 20 min, and treated with another
aliquot of potassium tert-butoxide (34.6 mg, 0.308 mmol). The
reaction was allowed to warm to room temperature for 30 min, then
diluted with 10% sodium bicarbonate, and extracted with ethyl
acetate (2.times.). The organic layers were pooled together, washed
with brine (1.times.), dried over sodium sulfate, and concentrated.
Column chromatography on silica gel (0%.fwdarw.65% ethyl
acetate/hexanes) gave 50 mg (29%). Mass spec.: 552.18 (MH).sup.+ LC
t.sub.r=2.54 min (HPLC Method 1). ##STR417##
[0216] 1-tert-butyl 4-methyl
4-(2-fluorophenyl)piperidine-1,4-dicarboxylate. A flask was charged
with sodium hydride (2.14 g, 89.2 mmol) and dimethylformamide (70
ml) at 0.degree. C. under nitrogen. Methyl
2-(2-fluorophenyl)acetate (5 g, 29.7 mmol) was added to the flask,
and after stirring for 25 min, tert-butyl
bis(2-chloroethyl)carbamate (8.6 g, 35.6 mmol) was added. The
reaction was allowed to warm to rt and stirred overnight. The
reaction was quenched with a saturated solution of ammonium
chloride and extracted with ethyl acetate (5.times.100 mL). The
organics were collected, washed with brine, dried over sodium
sulfate, and concentrated in vacuo. The residue was purified via
silica gel chromatography (10/90.fwdarw.50/50 ethyl
acetate/hexanes) to yield 1.7 g (17%) of the desired product.
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. ppm 7.29 (m, 1H), 7.24
(m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 3.86 (m, 2H), 3.67 (m, 3H),
3.22 (m, 2H), 2.37 (m, 2H), 1.96 (m, 2H), 1.44 (s, 9H). Mass spec.:
360.22 (MNa).sup.+. LC t.sub.r=3.503 min (Phenomenex-Luna
4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min)
##STR418##
[0217]
1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)piperidine-4-carboxylic
acid. A flask was charged with 1-tert-butyl 4-methyl
4-(2-fluorophenyl)piperidine-1,4-dicarboxylate (1.7 g, 5.04 mmol)
and LiOH (2.11 g, 50.4 mmol) in 25 mL of a 4:1 THF:H2O solution.
The flask was equipped with a reflux condenser and heated to reflux
for 48 hr. The reaction was cooled to rt, and the solution was
acidified to pH=1 with 6N hydrochloric acid. The aqueous solution
was extracted with ethyl acetate, and the organic layer was
separated, washed with brine, and dried over Na.sub.2SO.sub.4. The
organic solvent was evaporated in vacuo affording 1.51 g (92%) of
the desired acid. Mass Spec.: 347.23 (MNa).sup.+. LC t.sub.r=3.253
min (Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H2O/0.1%
TFA.fwdarw.90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow
rate=4 mL/min). ##STR419##
[0218] tert-butyl
4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate. A
flask was charged with
1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)piperidine-4-carboxylic
acid (1.51 g, 4.6 mmol) and tetrahydrofuran (10 mL). The reaction
was placed under nitrogen. To the flask was added
borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 9.2 mL, 9.2
mmol). The reaction was allowed to stir at rt for 48 hr. The
reaction was cooled to 0.degree. C. and quenched with methanol (50
mL). The solution was then concentrated in vacuo. The residue was
purified via column chromatography (25% ethyl acetate/75%
hexanes.fwdarw.60% ethyl acetate/hexanes) to yield 1.0 g (70%) of
the desired alcohol. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. ppm
7.26 (m, 2H), 7.11 (m, 1H), 7.01 (m, 1H), 3.72 (m, 4H), 3.09 (m,
2H), 2.27 (m, 2H), 1.79 (m, 2H), 1.42 (s, 9H). Mass Spec.: 332.18
(MNa).sup.-. LC: t.sub.r=3.301 min (Phenomenex-Luna 4.6.times.50 mm
S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10%
H.sub.2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
##STR420##
[0219] tert-butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperi-
dine-1-carboxylate. A flask was charged with
1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47
mmol) and tert-butyl
4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.1
12 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0.degree. C. The
reaction was treated with potassium tert-butoxide (0.41 mg, 0.36
mmol), stirred at 0.degree. C. for 20 min, and treated with another
aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The
reaction was allowed to warm to room temperature and was stirred
for 16 h. The reaction mixture was evaporated in vacuo and the
crude oil was purified by silica gel chromatography (5% ethyl
acetate/95% hexanes.fwdarw.30% ethyl acetate/70% hexanes) to afford
0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH).sup.+
LC t.sub.r=4.501 min. (Phenomenex-Luna 4.6.times.50 mm S10, 10%
MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA
Gradient Time=4 min, Flow rate=4 mL/min). ##STR421##
[0220] tert-butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(2-fluor-
ophenyl)piperidine-1-carboxylate. A sealable vial was charged with
tert-butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperi-
dine-1-carboxylate (0.138 g, 0.25 mmol) and 4-cyanophenylboronic
acid (0.111 g, 0.75 mmol) in tetrahydrofuran (2 mL) at 0.degree. C.
To the reaction solution was added 1N potassium hydroxide (0.88 mL,
0.88 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.058 g,
0.05 mmol). The vial was purged with nitrogen and sealed. The
sealed vial was heated in a microwave reactor at 120.degree. C. for
2 hr. The reaction was cooled to room temperature and diluted with
4 mL ethyl acetate. The organic layer was separated, dried over
Na.sub.2SO.sub.4 and evaporated in vacuo. The crude oil was
purified by silica gel chromatography (5% ethyl acetate/95%
hexanes.fwdarw.35% ethyl acetate/65% hexanes) to afford 0.123 g
(87%) of the desired ether. Mass spec.: 591.22 (MNa).sup.+; LC
t.sub.r=4.318 min. (Phenomenex-Luna 4.6.times.50 mm S10, 10%
MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA
Gradient Time=4 min, Flow rate=4 mL/min).
EXAMPLE 1
[0221] ##STR422##
[0222]
2-Methoxy-5-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(triflu-
oromethyl)phenyl)pyrimidine. tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate (60. 0 mg, 0.11 mmol), 2-methoxy-5-pyridine boronic acid
(72.0 mg, 0.47 mmol), and tetrakis(triphenylphosphine) palladium(0)
(17.1 mg, 0.011 mmol) were combined in dry tetrahydrofuran (2 mL)
in a microwave tube and sealed. The mixture was flushed with
nitrogen then 0.35 mL of a 1 N potassium hydroxide aqueous solution
was introduced. The mixture was heated at 120.degree. C. for 1 h
via microwave. After cooling to room temperature, the reaction
mixture was concentrated and treated with a trifluoroacetic
acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent
was removed in vacuo and the resulting crude mixture passed through
a strong cation exchange column. After washing the column with
several volumes of methanol, the product was eluted by washing the
column with 2 M ammonia in methanol. Concentration and preparative
HPLC afforded 21.0 mg (42%) of the desired compound as its TFA
salt. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.57 (s, 2H), 7.54
(s, 1H), 7.25-7.31 (m, 8H), 4.40 (s, 2H), 4.03 (s, 3H), 3.40 (s,
2H), 2.83-2.88 (m, 2H), 2.64-2.69 (m, 2H), 2.10-2.18 (m, 2H),
1.77-1.86 (m, 2H). Mass spec.: 458.18 (MH).sup.+.
EXAMPLE 2
[0223] ##STR423##
[0224]
4-(5-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluorometh-
yl)phenyl)pyridin-2-yl)morpholine. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 8.49 (d, J=2.1 Hz, 1H), 8.08 (dd, J=7.0, 2.5 Hz, 1H),
7.72 (s, 1H), 7.61 (s, 1H), 7.35-7.38 (m, 3H), 7.26-7.30 (m, 3H),
7.10 (d, J=9.5 Hz, 1H), 4.48 (s, 2H), 3.86-3.88 (m, 4H), 3.71-3.73
(m, 4H), 3.42 (s, 2H), 3.28-3.31 (m, 2H), 2.86-2.90 (m, 2H),
2.39-2.42 (m, 2H), 2.27-2.33 (m, 2H). Mass spec.: 512.37
(MH).sup.+. Accurate mass spec.: m/z 512.2530 [MH].sup.+,
.DELTA.=1.0 ppm.
EXAMPLE 3
[0225] ##STR424##
[0226]
5-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-
phenyl)picolinonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
8.85 (s, 1H), 7.91 (dd, J=5.8, 2.4 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H),
7.67 (s, 1H), 7.47 (s, 1H), 7.43 (s, 1H), 7.38 (d, J=1.2 Hz, 1H),
7.36 (s, 1H), 7.30-7.33 (m, 2H), 7.17-7.20 (m, 1H), 4.48 (s, 2H),
3.49 (s, 2H), 2.91-2.94 (m, 2H), 2.74-2.79 (m, 2H), 2.19-2.22 (m,
2H), 1.88-1.93 (m, 2H). Mass spec.: 452.22 (MH).sup.+. Accurate
mass spec.: m/z 452.1945 [MH].sup.+, .DELTA.=1.0 ppm.
EXAMPLE 4
[0227] ##STR425##
[0228]
3-Chloro-4-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluo-
romethyl)phenyl)pyridine. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
8.83 (s, 1H), 8.69 (d, J=5.5 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=5.5
Hz, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.29-7.41 (m, 6H), 4.52 (s,
2H), 3.46 (s, 2H), 3.34-3.37 (m, 2H), 2.93-2.96 (m, 2H), 2.45-2.48
(m, 2H), 2.20-2.26 (m, 2H). Mass spec.: 461.32 (MH).sup.+. Accurate
mass spec.: m/z 461.1596 [MH].sup.+, .DELTA.=2.5 ppm.
EXAMPLE 5
[0229] ##STR426##
[0230]
3-Methyl-4-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluo-
romethyl)phenyl)pyridine. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
8.74 (s, 1H), 8.72 (d, J=5.8 Hz, 1H), 7.72 (d, J=5.8 Hz, 1H), 7.53
(s, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.35-7.38 (m, 2H), 7.24-7.31
(m, 3H), 4.54 (s, 2H), 3.47 (s, 2H), 3.34-3.37 (m, 2H), 2.90-2.97
(m, 2H), 2.43 (s, 3H), 2.38-2.45 (m, 2H), 2.25-2.31 (m, 2H). Mass
spec.: 441.37 (MH).sup.+. Accurate mass spec.: m/z 441.2167
[MH].sup.+, .DELTA.=3.0 ppm.
EXAMPLE 6
[0231] ##STR427##
[0232]
2-Methyl-4-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluo-
romethyl)phenyl)pyridine. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
8.81 (d, J=6.1 Hz, 1H), 7.86 (d, J=6.1 Hz, 1H), 7.78-7.80 (m, 3H),
7.56 (s, 1H), 7.38-7.41 (m, 2H), 7.28-7.32 (m, 3H), 4.54 (s, 2H),
3.47 (s, 2H), 3.33-3.35 (m, 2H), 2.90-2.96 (m, 2H), 2.83 (s, 3H),
2.41-2.44 (m, 2H), 2.29-2.35 (m, 2H). Mass spec.: 441.37
(MH).sup.+. Accurate mass spec.: m/z 441.2165 [MH].sup.+,
.DELTA.=2.6 ppm.
EXAMPLE 7
[0233] ##STR428##
[0234]
4-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-
phenyl)pyridine. .sup.1H-NMR (CD.sub.3OD, 500 MHz) .delta. 8.97 (s,
1H), 8.96 (s, 1H), 8.42 (s, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 7.98
(s, 1H), 7.75 (s, 1H), 7.41-7.51 (m, 2H), 7.41-7.44 (m, 2H),
7.28-7.31 (m, 1H), 4.65 (s, 2H), 3.61 (s, 2H), 3.36-3.38 (m, 2H),
2.95-3.00 (m, 2H), 2.56-2.59 (m, 2H), 2.24-2.29 (m, 2H).
.sup.13C-NMR (CD.sub.3OD, 126 MHz) .delta. 156.7, 142.4, 142.3,
141.9, 136.3, 132.2 (q, J=33.6 Hz), 130.4, 129.1, 127.2, 126.9,
125.3, 124.0, 124.1 (q, J=271.6 Hz), 123.9, 79.6, 71.8, 41.1, 28.9.
Mass spec.: 427.17 (MH).sup.-.
EXAMPLE 8
[0235] ##STR429##
[0236]
3'-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluoromethyl)b-
iphenyl-4-carbonitrile. .sup.1H-NMR (CD.sub.3OD, 500 MHz) .delta.
7.84-7.87 (m, 2H), 7.78-7.87 (m, 2H), 8.42 (s, 1H), 7.67 (s, 1H),
7.55 (s, 1H), 7.48-7.50 (m, 2H), 7.40-7.43 (m, 2H), 7.27-7.30 (m,
1H), 4.59 (s, 2H), 3.57 (s, 2H), 3.36-3.38 (m, 2H), 2.94-2.99 (m,
2H), 2.55-2.58 (m, 2H), 2.20-2.26 (m, 2H). .sup.13C-NMR
(CD.sub.3OD, 126 MHz) .delta. 142.2, 141.4, 141.1, 140.7, 133.0,
131.6 (q, J=32.6 Hz), 130.0, 129.0, 128.2, 127.2, 124.4 (q, J=272.6
Hz), 124.0, 123.0, 118.5. Mass spec.: 451.18(MH).sup.+.
TABLE-US-00003 TABLES 3 The following compounds were prepared by
method A. Mass HPLC retention Spec. Example Structure Method time
(MH+) 8 ##STR430## 2 1.42 451.28 9 ##STR431## 2 1.23 525.37 10
##STR432## 2 1.48 479.25 11 ##STR433## 2 1.40 475.26 12 ##STR434##
2 1.53 491.24 13 ##STR435## 2 1.51 494.25 14 ##STR436## 2 1.16
457.30 15 ##STR437## 2 1.35 477.29 16 ##STR438## 2 1.11 488.30 17
##STR439## 4 2.06 442.20 18 ##STR440## 4 2.30 477.20 19 ##STR441##
4 2.49 461.10 20 ##STR442## 4 2.31 461.20 21 ##STR443## 4 2.39
445.20 22 ##STR444## 4 2.70 495.10 23 ##STR445## 4 2.16 441.20 24
##STR446## 2 1.39 470.96 25 ##STR447## 2 1.22 440.99 26 ##STR448##
2 1.59 493.89 27 ##STR449## 2 1.55 475.98 28 ##STR450## 2 1.43
443.97 29 ##STR451## 2 1.71 459.96 30 ##STR452## 2 1.39 439.98 31
##STR453## 2 1.35 456.02 32 ##STR454## 2 1.48 439.99 33 ##STR455##
2 1.72 477.94 34 ##STR456## 2 1.53 561.90 35 ##STR457## 2 1.47
493.88 36 ##STR458## 2 1.64 563.88 37 ##STR459## 2 1.75 502.02 38
##STR460## 2 1.70 471.97 39 ##STR461## 2 1.39 440.14 40 ##STR462##
2 1.48 501.96 41 ##STR463## 2 1.28 453.98 42 ##STR464## 2 1.52
493.95 43 ##STR465## 2 1.57 454.00 44 ##STR466## 2 1.54 484.96 45
##STR467## 2 1.38 443.94 46 ##STR468## 2 1.60 475.97 47 ##STR469##
2 1.55 469.95 48 ##STR470## 2 1.31 443.92 49 ##STR471## 2 1.60
469.95 50 ##STR472## 2 1.42 493.90 51 ##STR473## 2 1.39 455.94 52
##STR474## 2 1.79 515.95 53 ##STR475## 2 1.35 459.89 54 ##STR476##
2 1.37 461.83 55 ##STR477## 2 1.43 473.86 56 ##STR478## 2 1.55
461.83 57 ##STR479## 2 1.82 467.93 58 ##STR480## 2 2.08 495.92 59
##STR481## 2 1.72 517.83 60 ##STR482## 2 1.52 453.89 61 ##STR483##
2 1.41 469.87 62 ##STR484## 2 1.84 481.92 63 ##STR485## 2 1.41
485.87 64 ##STR486## 2 1.20 441.87 65 ##STR487## 2 1.22 441.88 66
##STR488## 2 1.81 493.78 67 ##STR489## 2 1.55 509.80 68 ##STR490##
2 1.28 467.86 69 ##STR491## 2 1.25 455.88 70 ##STR492## 2 1.71
519.85 71 ##STR493## 2 1.86 583.63 72 ##STR494## 2 1.71 483.89 73
##STR495## 2 1.37 476.86 74 ##STR496## 2 1.18 455.87 75 ##STR497##
2 1.73 501.87 76 ##STR498## 2 1.65 461.85 77 ##STR499## 2 1.45
471.83 78 ##STR500## 2 1.70 467.93 79 ##STR501## 2 1.51 485.85 80
##STR502## 2 1.49 489.81 81 ##STR503## 2 1.35 450.86 82 ##STR504##
2 1.52 485.86 83 ##STR505## 2 1.45 461.84 84 ##STR506## 4 2.96
510.27 85 ##STR507## 4 2.41 468.24 86 ##STR508## 4 3.23 482.32 87
##STR509## 4 2.66 484.23 88 ##STR510## 4 3.15 490.34 89 ##STR511##
4 2.75 462.2 90 ##STR512## 4 2.74 462.2 91 ##STR513## 4 2.94 494.2
92 ##STR514## 4 2.98 454.33 93 ##STR515## 4 2.94 454.28 94
##STR516## 4 2.77 474.27 95 ##STR517## 4 2.9 458.31 96 ##STR518## 4
2.7 484.25 97 ##STR519## 4 3.02 512.3 98 ##STR520## 4 2.89 575.38
99 ##STR521## 4 2.93 532.31 100 ##STR522## 4 3.67 508.42 101
##STR523## 4 2.88 480.22 102 ##STR524## 4 3 454.33 103 ##STR525## 4
2.38 518.29 104 ##STR526## 4 2.29 472.26 105 ##STR527## 4 2.62
470.33 106 ##STR528## 4 3.34 482.34 107 ##STR529## 4 3.08 468.3 108
##STR530## 4 2.71 471.25 109 ##STR531## 4 2.73 484.32 110
##STR532## 4 3.16 560.37 111 ##STR533## 4 2.92 498.31 112
##STR534## 4 3.14 560.37 113 ##STR535## 4 2.58 471.25 114
##STR536## 4 2.24 483.29 115 ##STR537## 4 2.77 498.31 116
##STR538## 4 2.83 543.35 117 ##STR539## 4 2.99 470.33 118
##STR540## 4 2.94 470.28 119 ##STR541## 4 2.77 529.29 120
##STR542## 4 2.98 512.32 121 ##STR543## 4 2.83 498.34 122
##STR544## 4 2.76 486.27 123 ##STR545## 4 3.01 506.31 124
##STR546## 4 3.17 520.35
125 ##STR547## 4 3.01 484.33 126 ##STR548## 6 1.82 498.01 127
##STR549## 6 1.65 484.63 128 ##STR550## 6 1.43 486.96 129
##STR551## 6 1 511.02 130 ##STR552## 6 1.12 429.99 131 ##STR553## 6
1.37 495.54 132 ##STR554## 6 1.32 478.9 133 ##STR555## 6 1.75
561.9
[0237] TABLE-US-00004 TABLE 4 Mass Synthetic HPLC retention Spec.
Example Structure Method Method time (MH+) 134 ##STR556## A,D 1
2.54 474.12 135 ##STR557## A,D 1 2.40 470.30 136 ##STR558## A,D 1
2.40 458.15 137 ##STR559## A,D 1 2.49 492.05 138 ##STR560## A,D 1
2.47 458.53 139 ##STR561## A,D 1 2.46 476.18 140 ##STR562## A,D 1
2.39 488.90
EXAMPLE 141
[0238] ##STR563##
[0239]
2-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-
phenyl)pyridine. tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate (50.0 mg, 0.094 mmol), 2-tri-n-butyl stanyl-pyridine (44.2
mg, 0.12 mmol) and bis(triphenylphosphine) palladium(II) dichloride
(3.0 mg, 0.004 mmol) were combined in dry acetonitrile (2 mL) and
heated at 150.degree. C. for 1 h via microwave. After cooling to
room temperature, the reaction mixture was concentrated and treated
with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL)
for 1 h. The solvent was removed in vacuo and the resulting crude
mixture passed through a strong cation exchange column. After
washing the column with several volumes of methanol, the product
was eluted by washing the column with 2 M ammonia in methanol.
Concentration and preparative HPLC afforded 21.0 mg (41%) as its
TFA salt. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.71 (m, 1H),
8.14 (s, 1H), 7.91 (s, 1H), 7.80 (m, 1H), 7.67 (d, J=7.9 Hz, 1H),
7.43 (s, 1H), 7.31-7.38 (m, 4H), 7.27-7.29 (m, 1H), 7.19-7.22 (m,
1H), 4.47(s, 2H), 3.47 (s, 2H), 2.90-2.95 (m, 2H), 2.73-2.79 (m,
2H), 2.18-2.21 (m, 2H), 1.89-1.96 (m, 2H). Mass spec.: 427.24
(MH).sup.+. Accurate mass spec.: m/z 427.2015 [MH].sup.+,
.DELTA.=4.2 ppm. TABLE-US-00005 TABLE 5 The following compounds
were prepared by method B. HPLC retention time Mass spec. (t.sub.R,
min) Example Structure (MH).sup.+ (method 2) 142 ##STR564## 415.93
1.67 143 ##STR565## 432.86 1.46 144 ##STR566## 427.93 1.44 145
##STR567## 497.87 1.45 146 ##STR568## 429.93 1.2 147 ##STR569##
425.92 1.67 148 ##STR570## 445.9 1.71
EXAMPLE 149
[0240] ##STR571##
[0241]
4-Phenyl-4-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)-1H-tetrazo-
l-1-yl)benzyloxy)methyl)piperidine. tert-Butyl
4-phenyl-4-((3-(trifluoromethyl)-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)-
benzyloxy)methyl)piperidine-1-carboxylate (46.0 mg, 0.078 mmol) was
dissolved in a trifluoroacetic acid/methylene chloride mixture
(1:1, 2 mL) and stirred under nitrogen for 1 h. The solvent was
removed in vacuo and the resulting crude mixture passed through a
strong cation exchange column. After washing the column with
several volumes of methanol, the product was eluted by washing the
column with 2 M ammonia in methanol. Concentration afforded 29.0 mg
(77%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.61 (s, 1H), 7.58
(s, 1H), 7.3-7.33 (m, 2H), 7.21-7.26 (m, 2H), 7.12 (s, 1H),
7.02-7.06 (m, 1H), 4.50 (s, 2H), 3.48 (s, 2H), 2.89-2.93 (m, 2H),
2.72-2.77 (m, 2H), 2.19-2.22 (m, 2H), 1.84-1.89 (m, 2H),
.sup.13C-NMR (CDCl.sub.3, 125 MHz) .delta. 146.2 (q, J=42.2 Hz),
146.1, 143.8, 143.5, 133.2, 132.7 (q, J=35.6 Hz), 128.3, 127.2,
126.6, 126.5, 126.2, 122.8 (q, J=272.6 Hz), 121.1, 119.0, 116.8,
80.7, 71.1, 42.6, 41.9, 33.4. Mass spec.: 486.18 (MH).sup.-.
Accurate mass spec.: m/z 486.1739 [MH].sup.+, .DELTA.=2.1 ppm.
EXAMPLE 150
[0242] ##STR572##
[0243]
4-((2-Methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phe-
nylpiperidine. tert-Butyl
4-((2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyloxy)methyl)-4-phenylpipe-
ridine-1-carboxylate (28.0 mg, 0.057 mmol) was dissolved in a
minimum amount of ethyl acetate, followed by addition of 4 N
hydrochloric acid (1 mL). The mixture was stirred under nitrogen
for 1 h. After removing the solvents, the crude mixture was
precipitated in diethyl ether and filtered to afford 16.0 g (73%)
as its HCl salt. .sup.1H-NMR (CD.sub.3OD, 500 MHz) .delta.
7.99-8.04 (m, 2H), 7.50 (s, 1H), 7.49 (s, 1H), 7.41-7.45 (m, 3H),
7.10 (d, J=8.5 Hz, 1H), 4.51 (s, 2H), 4.43 (s, 3H), 3.88 (s, 3H),
3.55 (s, 2H), 3.35-3.37 (m, 2H), 2.94-3.09 (m, 2H), 2.45-2.54 (m,
2H), 2.31-2.37 (m, 2H). .sup.13C-NMR (CD.sub.3OD, 76 MHz) .delta.
165.3, 159.2, 141.2, 129.0, 129.1, 127.7, 127.6, 127.1, 127.0,
119.8, 110.9, 79.5, 68.0, 55.2, 41.3, 38.9, 28.8, 28.3. Mass spec.:
394.25 (MH).sup.+. Accurate mass spec.: m/z 394.2247 [MH].sup.+,
.DELTA.=4.1 ppm.
EXAMPLE 151
[0244] ##STR573##
[0245]
4-((3-(1H-Tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-ph-
enylpiperidine. tert-Butyl
4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpip-
eridine-1-carboxylate (30.0 mg, 0.058 mmol) was dissolved in a
trifluoroacetic acid/methylene chloride mixture (1:1, 1 mL) and
stirred under nitrogen for 1 h. The solvent was removed in vacuo
and the resulting crude mixture passed through a strong cation
exchange column. After washing the column with several volumes of
methanol, the product was eluted by washing the column with 2 M
ammonia in methanol. Concentration afforded 11.0 mg (45%).
LC/MS(HPLC method 3): t.sub.R=1.89 min, 418.88 (MH).sup.+.
EXAMPLE 152
[0246] ##STR574##
[0247]
3'-Chloro-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-c-
arbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.71 (m,
1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.80 (m, 1H), 7.67 (d, J=7.9 Hz,
1H), 7.43 (s, 1H), 7.31-7.38 (m, 4H), 7.27-7.29 (m, 1H), 7.19-7.22
(m, 1H), 4.47 (s, 2H), 3.47 (s, 2H), 2.90-2.95 (m, 2H), 2.73-2.79
(m, 2H), 2.18-2.21 (m, 2H), 1.89-1.96 (m, 2H). Mass spec.: 417.27
(MH).sup.+. Accurate mass spec.: m/z 417.1716 [MH].sup.+,
.DELTA.=4.2 ppm.
EXAMPLE 153
[0248] ##STR575##
[0249]
4'-Fluoro-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-ca-
rbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.65 (s, 1H),
7.41-7.44 (m, 3H), 7.32-7.37 (m, 4H), 7.21-7.26 (m, 2H), 7.13-7.16
(m, 2H), 4.40 (s, 2H), 3.45 (s, 2H), 2.91-2.95 (m, 2H), 2.74-2.79
(m, 2H), 2.19-2.22 (m, 2H), 1.88-1.93 (m, 2H). .sup.13C-NMR
(CDCl.sub.3, 126 MHz) .delta. 163.2 (d, J=248.6 Hz), 141.5, 141.0,
135.1, 129.8, 129.5, 129.1, 128.9, 128.5, 127.3, 126.4, 118.7,
116.2, 116.0, 113.1, 80.3, 72.0, 42.6, 41.9, 33.4. Mass spec.:
401.36 (MH).sup.+. Accurate mass spec.: m/z 401.2046 [MH].sup.+,
.DELTA.=4.2 ppm.
EXAMPLE 154
[0250] ##STR576##
[0251]
4'-Fluoro-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-ca-
rboxamide. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.95 (s, 1H),
7.68 (s, 1H), 7.47-7.50 (m, 2H), 7.38 (s, 1H), 7.32-7.33 (m, 4H),
7.20-7.23 (m, 1H), 7.08-7.11 (m, 2H), 4.47 (s, 2H), 3.41 (s, 2H),
3.02-3.04 (m, 2H), 2.70-2.75 (m, 2H), 2.16-2.19 (m, 4H),
.sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 169.3, 163.8 (d, J=247.6
Hz), 140.7, 139.8, 136.2, 134.3, 128.9, 128.3, 128.7, 127.2, 126.6,
125.7, 124.5, 115.9, 115.7, 79.7, 72.6, 50.7, 41.9, 31.6. Mass
spec.: 419.37 (MH).sup.-. Accurate mass spec.: m/z 419.2133
[MH].sup.+, .DELTA.=0.4 ppm.
EXAMPLE 155
[0252] ##STR577##
[0253]
4'-Fluoro-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3-ol-
. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.51-7.54 (m, 2H),
7.46-7.48 (m, 2H), 7.40-7.43 (m, 2H), 7.29-7.31 (m, 1H), 7.14-7.18
(m, 2H), 6.91-6.92 (m, 1H), 6.86 (s, 1H), 6.69 (m, 1H), 4.41 (s,
2H), 3.49 (s, 2H), 3.31 (m, 2H), 2.93-2.98 (m, 2H), 2.49-2.52 (m,
2H), 2.21-2.27 (m, 2H). Mass spec.: 392.36 (MH).sup.+. Accurate
mass spec.: m/z 392.2009 [MH].sup.+, .DELTA.=4.3 ppm.
EXAMPLE 156
[0254] ##STR578##
[0255]
3'-(((4-(2-cyano-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
400 MHz) .delta. 7.73 (d, J=8.8 Hz, 2H), 7.69 (s, 1H), 7.60 (d,
J=8.4 Hz, 2H), 7.25-7.43 (m, 5H), 4.51 (s, 2H), 3.81 (s, 2H), 3.27
m, 2H), 2.95 (m, 2H), 2.65 (m, 2H), 2.29 (m, 2H). Mass spec.:
494.16 (M+H), HPLC (method 5) 3.06 min
EXAMPLE 157
[0256] ##STR579##
[0257]
3'-(((4-(5-fluorobiphenyl-2-yl)piperidin-4-yl)methoxy)methyl)-5'-(-
trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
400 MHz) .delta. 7.73 (m, 3H), 7.58 (d, J=8.6 Hz, 2H), 7.43 (d,
J=8.3 Hz, 2H), 7.31 (M, 1H), 7.18-7.28 (M, 3H), 7.04 (m, 1H), 6.90
(d, 6.9 Hz, 2H), 6.73 (m, 1H), 4.53 (s, 2H), 3.47 (s, 2H), 3.04 (m,
2H), 2.75 (m, 2H), 2.09 (m, 2H), 1.78 (m, 2H). Mass spec. : 545.2
(M+H), HPLC (method 5) 3.57 min.
EXAMPLE 158
[0258] ##STR580##
[0259]
3'-(((4-(3-Chlorophenyl)piperidin-4-yl)methoxy)methyl)-5'-(trifluo-
romethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.75 (m, 2H), 7.68 (s, 1H), 7.61 (s, 1H), 7.44 (s, 1H),
7.37 (s, 1H), 7.21-7.30 (m, 4H), 7.16 (m, 1H), 4.48 (s, 2H), 3.43
(s, 2H), 3.32 (m, 2H), 2.88 (m, 2H), 2.42 (m, 2H), 2.21 (m, 2H).
Mass spec.: 485.17 (MH).sup.+.
EXAMPLE 159
[0260] ##STR581##
[0261]
3'-(((4-(3,4-Difluorophenyl)piperidin-4-yl)methoxy)methyl)-5'-(tri-
fluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. ppm 7.75 (m, 2H), 7.68 (s, 1H), 7.61 (m, 2H), 7.44 (s,
1H), 7.37 (s, 1H), 6.99-7.17 (br m, 3H), 4.48 (s, 2H), 3.42 (m,
2H), 3.09 (m, 2H), 2.80 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H). Mass
spec.: 487.17 (MH).sup.+.
EXAMPLE 160
[0262] ##STR582##
[0263]
3'-(((4-(4-Bromophenyl)piperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.77 (m, 2H), 7.67 (s, 1H), 7.59 (m, 2H), 7.43 (m, 4H),
7.22 (m, 2H), 4.46 (s, 2H), 3.44 (s, 2H), 2.98 (m, 2H), 2.75 (m,
2H), 2.17 (m, 2H), 1.94 (m, 2H). Mass spec.: 531.11 (MH).sup.+.
EXAMPLE 161
[0264] ##STR583##
[0265]
3'-(((4-(3-Bromophenyl)piperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.75 (m, 2H), 7.67 (s, 1H), 7.60 (m, 2H), 7.48 (s, 1H),
7.41 (m, 2H), 7.15-7.34 (m, 3H), 4.46 (s, 2H), 3.45 (s, 2H), 2.97
(m, 2H), 2.76 (m, 2H), 2.17 (m, 2H), 1.96 (m, 2H). Mass spec.:
531.11 (MH).sup.+.
EXAMPLE 162
[0266] ##STR584##
[0267]
3'-(((4-(3-Cyanophenyl)piperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. ppm 7.76 (m, 2H), 7.68 (s, 1H), 7.61 (m, 2H), 7.57-7.61 (m,
2H), 7.49 (m, 1H), 7.39-7.44 (m, 2H), 7.34 (s, 1H), 4.47 (s, 2H),
3.46 (s, 2H), 3.03 (m, 2H), 2.76 (m, 2H), 2.22 (m, 2H), 2.03 (m,
2H). Mass spec.: 476.18 (MH).sup.+.
EXAMPLE 163
[0268] ##STR585##
[0269]
(S)-3'-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5'-(trifluoromet-
hyl)biphenyl-4-carbonitrile. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. ppm 7.73 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J=8.6
Hz, 2H), 7.38 (s, 2H), 7.20-7.35 (m, 4H), 7.16 (m, 1H), 4.29 (q,
J=6.4 Hz, 1H), 3.46 (s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25 (d, J=8.9
Hz, 1H), 2.90 (m, 2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H), 1.80-1.99
(m, 2H), 1.35 (d, J=6.4 Hz, 3H). Mass spec.: 465.20 (MH).sup.+.
Accurate mass spec.: m/z 465.2136 [MH].sup.+, .DELTA.=3.8 ppm.
EXAMPLE 164
[0270] ##STR586##
[0271]
4-(((4'-Fluoro-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4--
(4-fluorophenyl)piperidine. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.63 (s, 1H), 7.46 (m, 2H), 7.40 (s, 1H), 7.28-7.37 (m,
3H), 7.15 (m, 2H), 7.00 (m, 2H), 4.45 (s, 2H), 3.44 (s, 2H), 2.91
(m, 2H), 2.74 (m, 2H), 2.14 (m, 2H), 1.91 (bs, 1H), 1.89 (m, 2H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 164.0, 162.3, 162.0,
160.4, 141.2, 140.5, 139.9, 135.8, 131.4 (q, J=33 Hz), 128.9 (m),
128.8 (m), 124.1 (q, J=273 Hz), 122.8 (q, J=3.8 Hz), 122.6 (q,
J=3.8 Hz), 116.1, 115.9, 115.1, 115.0, 79.8, 72.4, 42.6, 41.5,
33.8. Mass spec.: 462.20 (MH).sup.+. Accurate mass spec.: m/z
462.1875 [MH].sup.+, .DELTA.=4.0 ppm.
EXAMPLE 165
[0272] ##STR587##
[0273]
(.+-.)-3'-Fluoro-5'-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)biph-
enyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.71
(d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.31 (m, 4H), 7.19 (m,
1H), 7.10 (m, 1H), 7.02 (s, 1H), 6.78 (m, 1H), 4.21 (q, J=6.4 Hz,
1H), 3.28 (q.sub.AB, J.sub.AB=8.9 Hz, 2H), 2.90 (m, 2H), 2.74 (m,
2H), 2.19 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 1.83 (bs, 1H), 1.32
(d, J=6.4 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm
164.4, 162.4, 148.3, 148.2, 144.4, 144.3, 141.3, 141.2, 132.7,
128.3, 127.8, 127.4, 126.1, 120.3, 118.7, 113.2, 113.1, 113.0,
112.8, 111.7, 78.4, 77.8, 50.8, 42.8, 42.7, 41.9, 33.6, 33.3, 24.0.
Mass spec.: 415.32 (MH).sup.+. Accurate mass spec.: m/z 415.2167
[MH].sup.+, .DELTA.=4.5 ppm.
EXAMPLE 166
[0274] ##STR588##
[0275]
(.+-.)-3'-Chloro-5'-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)biph-
enyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.70
(d, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.38 (m, 1H), 7.25-7.42
(m, 4H), 7.17 (m, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 4.19 (q, J=6.4
Hz, 1H), 3.27 (q.sub.AB, J.sub.AB=8.9, 2H), 2.89 (m, 2H), 2.72 (m,
2H), 2.19 (m, 1H), 2.10 (m, 1H), 1.90 (m, 2H), 1.78 (bs, 1H), 1.31
(d, J=6.4 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm
147.5, 144.2, 141.0, 135.0, 132.7, 128.3, 127.9, 127.4, 126.4,
126.13, 126.10, 123.0, 118.8, 111.6, 78.4, 77.2, 42.79, 42.75,
41.8, 33.7, 33.3, 24.2. Mass spec.: 431.30 (MH).sup.+. Accurate
mass spec.: m/z 431.1899 [MH].sup.+, .DELTA.=2.0 ppm.
EXAMPLE 167
[0276] ##STR589##
[0277]
5-(((4-Phenylpiperidin-4-yl)methoxy)methyl)biphenyl-3,4'-dicarboni-
trile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.74-7.76 (m, 2H),
7.69 (m, 1H), 7.55-7.57 (m, 2H), 7.47 (m, 1H), 7.32-7.37 (m, 5H),
7.20-7.23 (m, 1H), 4.43 (s, 2H), 3.47 (s, 2H), 2.92-2.94 (m, 2H),
2.74-2.79 (m, 2H), 2.19-2.22 (m, 2H), 1.88-1.93 (m, 2H). Mass
spec.: 408.23 (MH).sup.+. Accurate mass spec.: m/z 408.2072
[MH].sup.+, .DELTA.=0.9 ppm.
EXAMPLE 168
[0278] ##STR590##
[0279]
3'-Methyl-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-c-
arbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.69-7.70
(m, 2H), 7.58-7.59 (m, 2H), 7.29-7.37 (m, 4H), 7.19-7.25 (m, 2H),
7.10 (m, 1H), 6.95 (m, 1H), 4.39 (s, 2H), 3.43 (s, 2H), 2.92-2.96
(m, 2H), 2.73-2.78 (m, 2H), 2.36 (s, 3H), 2.18-2.21 (m, 2H),
1.91-1.97 (m, 2H). Mass spec.: 397.40 (MH).sup.+. Accurate mass
spec.: m/z 397.2296 [MH].sup.+, .DELTA.=4.1 ppm.
EXAMPLE 169
[0280] ##STR591##
[0281]
4-(((3',5'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)me-
thoxy)methyl)-4-phenylpiperidine. .sup.1H-NMR (CD.sub.3OD, 500 MHz)
.delta. 7.76 (s, 1H), 7.56 (s, 1H), 7.48-7.49 (m, 3H), 7.41-7.44
(m, 2H), 7.25-7.31 (m, 3H), 4.56 (s, 2H), 4.04 (s, 3H), 3.35 (s,
2H), 3.35-3.36 (m, 2H), 2.94-2.99 (m, 2H), 2.55-2.58 (m, 2H),
2.18-2.24 (m, 2H). Mass spec.: 492.04 (MH).sup.+. Accurate mass
spec.: m/z 492.1976 [MH].sup.+, .DELTA.=2.9 ppm.
EXAMPLE 170
[0282] ##STR592##
[0283]
4-(((2',5'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)me-
thoxy)methyl)-4-phenylpiperidine. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.57 (s, 1H), 7.23-7.33 (m, 6H), 7.15-7.18 (m, 1H),
7.02-7.09 (m, 1H), 6.73-6.80 (m, 1H), 4.39 (s, 2H), 3.89 (s, 3H),
3.42 (s, 2H), 2.88-2.94 (m, 2H), 2.68-2.77 (m, 2H), 2.17-2.21 (m,
2H), 1.89-1.95 (m, 2H). Mass spec.: 492.20 (MH).sup.+. Accurate
mass spec.: m/z 492.1978 [MH].sup.+, .DELTA.=3.3 ppm.
EXAMPLE 171
[0284] ##STR593##
[0285]
3-Methoxy-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluo-
romethyl)biphenyl-4-carbonitrile. LC/MS: t.sub.R=2.59 min, 481.18
(MH).sup.+. Accurate mass spec.: m/z 481.2103 [MH].sup.+,
.DELTA.=0.4 ppm. (Phenomenex C18 4.6.times.50 mm, 10% MeOH/90%
H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient
time=4 min., Flow rate=4 mL/min.).
EXAMPLE 172
[0286] ##STR594##
[0287]
2,5-Difluoro-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trif-
luoromethyl)biphenyl-4-carbonitrile. LC/MS: t.sub.R=2.61 min,
487.15 (MH).sup.+. Accurate mass spec.: m/z 487.1801[MH].sup.+,
.DELTA.=1.6 ppm. (Phenomenex C18 4.6.times.50 mm, 10% MeOH/90%
H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient
time=4 min., Flow rate=4 mL/min.).
EXAMPLE 173
[0288] ##STR595##
[0289]
3'-(((4-(2-bromo-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. A solution of tert-butyl
4-(2-bromo-4-fluorophenyl)-4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl-
)methoxy)methyl)piperidine-1-carboxylate (50 mg, 0.077 mmol) in
dichloromethane (0.5 mL) and trifluoroacetic acid (2 mL) was
stirred at ambient temperature for 3 hours. The reaction was
evaporated to dryness and the resulting residue was purified by
chromatography on silica with gradient of methanol/dichloromethane
of 2% to 10%. The product
3'-(((4-(2-bromo-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5'-(triflu-
oromethyl)biphenyl-4-carbonitrile (29 mg, 69% yield) was obtained
as a clear oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.74 (d,
J=6.8 Hz, 2H), 7.68 (s, 1H), 7.58 (d, J=6.7 Hz, 2H), 7.36 (s, 1H),
7.33 (s, 1H), 7.22-7.33 (m, 2H), 7.03 (m, 1H), 4.49 (s, 2H), 3.88
(s, 2H), 3.25 (m, 2H), 2.94 (m, 2H), 2.85 (m, 2H), 2.23 (m, 2H).
Mass spec.: 547.12 (M+H), HPLC (method 5) 3.37 min.
EXAMPLE 174
[0290] ##STR596##
[0291]
4'-Cyano-N,N-dimethyl-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)b-
iphenyl-3-carboxamide. tert-Butyl
4-((3-bromo-5-(dimethylcarbamoyl)benzyloxy)methyl)-4-phenylpiperidine-1-c-
arboxylate (41.2 mg, 0.08 mmol), 4-cyanophenylboronic acid (34.3
mg, 0.23 mmol), and tetrakis(triphenylphosphine) palladium(0) (12.1
mg, 0.01 mmol) were combined in dry tetrahydrofuran (3 mL) in a
microwave tube and sealed. After flushing with nitrogen, 0.28 mL of
a 1 N potassium hydroxide aqueous solution was introduced. The
mixture was heated at 120.degree. C. for 1 h via microwave. After
cooling to room temperature, the reaction mixture was concentrated
and treated with a trifluoroacetic acid/methylene chloride mixture
(1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the
resulting crude mixture passed through a strong cation exchange
column. After washing the column with several volumes of methanol,
the product was eluted by washing the column with 2 M ammonia in
methanol and concentrated to afford 29 mg (66%). .sup.1H-NMR
(CD.sub.3OD, 500 MHz) .delta. 7.81-7.84 (m, 2H), 7.76 (s, 1H), 7.74
(s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.42-7.44 (m, 2H), 7.32-7.35
(m, 2H), 7.17-7.22 (m, 2H), 4.51 (s, 2H), 3.52 (s, 2H), 3.15 (s,
3H), 2.99 (s, 3H), 2.88-2.95 (m, 2H), 2.67-2.72 (m, 2H), 2.24-2.27
(m, 2H), 1.91-1.97 (m, 2H). .sup.13C-NMR NMR (CD.sub.3OD, 126 MHz)
.delta. 172.2, 144.9, 144.2, 140.9, 139.9, 137.3, 132.9, 128.4,
128.1, 127.4, 127.2, 126.2, 125.7, 124.7, 118.7, 111.5, 79.9, 72.2,
42.1, 41.8, 39.1, 34.7, 32.7. Mass spec.: 454.31 (MH).sup.-.
Accurate mass spec.: m/z 454.2496 [MH].sup.+, .DELTA.=0.3 ppm.
EXAMPLE 175
[0292] ##STR597##
[0293]
3'-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5'-(piperidine-1-carb-
onyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.73 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H),
7.45 (s, 1H), 7.35-7.36 (m, 2H), 7.31-7.32 (m, 3H), 7.17-7.20 (m,
2H), 4.43 (s, 2H), 3.71-3.73 (m, 2H), 3.45 (s, 2H), 3.31-3.33 (m,
2H), 2.90-2.95 (m, 2H), 2.73-2.78 (m, 2H), 2.16-2.20 (m, 2H),
1.89-1.95 (m, 2H), 1.68 (m, 4H), 1.49 (m, 2H). .sup.13C-NMR
(CDCl.sub.3, 126 MHz) .delta. 169.7, 144.8, 144.0, 140.3, 139.6,
137.6, 132.7, 128.4, 127.9, 127.3, 126.7, 126.2, 125.5, 124.7,
118.7, 111.5, 80.0, 77.7, 72.6, 50.9, 42.6, 41.9, 33.3, 27.7. Mass
spec.: 494.47 (MH).sup.+. Accurate mass spec.: m/z 494.2809
[MH].sup.+, .DELTA.=0.3 ppm.
EXAMPLE 176
[0294] ##STR598##
[0295]
3'-(Morpholine-4-carbonyl)-5'-(((4-phenylpiperidin-4-yl)methoxy)me-
thyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.73 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H),
7.47 (s, 1H), 7.29-7.37 (m, 5H), 7.17-7.20 (m, 1H), 7.16 (s, 1H),
4.44 (s, 2H), 3.41-3.78 (m, 8H), 3.46 (s, 2H), 2.89-2.93 (m, 2H),
2.72-2.77 (m, 2H), 2.16-2.19 (m, 2H), 1.88-1.93 (m, 2H).
.sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 169.8, 144.6, 144.2,
140.6, 139.9, 136.5, 132.7, 128.4, 127.9, 127.3, 127.1, 126.2,
125.6, 125.0, 118.7, 111.7, 80.2, 77.7, 72.5, 67.0, 42.7, 42.0,
33.5. Mass spec.: 496.46 (MH).sup.+.
EXAMPLE 177
[0296] ##STR599##
[0297]
4-(((4'-Fluoro-5-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpipe-
ridine. tert-Butyl
4-(((4'-fluoro-5-hydroxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine--
1-carboxylate (42.4 mg, 0.09 mmol), iodomethane (11 .mu.L, 0.17
mmol) and potassium carbonate (23.5 mg, 0.17 mmol) were combined in
dimethylformamide (2 mL). After stirring at room temperature for 16
h, the solvent was removed in vacuo and the crude product dissolved
in ethyl acetate, washed with water (2.times.), then brine
(2.times.), dried over sodium sulfate, and concentrated to afford a
precipitate which was treated with a trifluoroacetic acid/methylene
chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in
vacuo and the resulting crude mixture passed through a strong
cation exchange column. After washing the column with several
volumes of methanol, the product was eluted by washing the column
with 2 M ammonia in methanol. Concentration and preparative HPLC
afforded 22 mg (61%) as its trifluoroacetic acid salt. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 7.53-7.58 (m, 2H), 7.39-7.48 (m, 4H),
7.30-7.32 (m, 1H), 7.14-7.20 (m, 2H), 7.00-7.01 (m, 1H), 6.96 (s,
1H), 6.75 (s, 1H), 4.45 (s, 2H), 3.82 (s, 3H), 3.50 (s, 2H),
3.29-3.31 (m, 2H), 2.89-3.00 (m, 2H), 2.49-2.54 (m, 2H), 2.18-2.28
(m, 2H). Mass spec.: 406.37 (MH).sup.+. Accurate mass spec.: m/z
406.2173 [MH].sup.+, .DELTA.=2.3 ppm.
EXAMPLE 178
[0298] ##STR600##
[0299]
4-(((2',3'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)me-
thoxy)methyl)-4-phenylpiperidine. tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-car-
boxylate (150 mg, 0.28 mmol), 2,3-difluoro-4-methoxyphenylboronic
acid (139 mg, 0.84 mmol), and tetrakis(triphenylphosphine)
palladium(0) (33 mg, 0.03 mmol) were combined in dry
tetrahydrofuran (3 mL) in a microwave tube and sealed. After
flushing with nitrogen, 1.0 mL of a 1 N potassium hydroxide aqueous
solution was introduced. The mixture was heated at 120.degree. C.
for 1 h via microwave. After cooling to room temperature, the
reaction mixture was concentrated and treated with a
trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1
h. The solvent was removed in vacuo and the resulting crude mixture
passed through a strong cation exchange column. After washing the
column with several volumes of methanol, the product was eluted by
washing the column with 2 M ammonia in methanol and concentrated to
afford 45 mg (33%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.57
(s, 1H), 7.26-7.38 (m, 6H), 7.13-7.17 (m, 1H), 7.00-7.06 (m, 1H),
6.77-6.83 (m, 1H), 4.41 (s, 2H), 3.93 (s, 3H), 3.44 (s, 2H),
2.84-2.92 (m, 2H), 2.68-2.77 (m, 2H), 2.13-2.18 (m, 2H), 1.83-1.92
(m, 2H). Mass spec.: 492.01 (MH).sup.+. Accurate mass spec.: m/z
492.1978 [MH].sup.+, .DELTA.=3.3 ppm.
EXAMPLE 179
[0300] ##STR601##
[0301]
4-((3-(2-Methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)met-
hyl)-4-phenylpiperidine. tert-Butyl
4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate (48.0 mg, 0.09 mmol) was dissolved
in a minimum amount of ethyl acetate, followed by addition of 4 N
hydrochloric acid (1 mL). The mixture was stirred under nitrogen
for 1 h. After removing the solvents, the crude mixture was
precipitated in diethyl ether and filtered to afford 26.0 mg (67%)
as a white powder. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.23
(s, 1H), 8.10 (s, 1H), 7.40 (s, 1H), 7.28-7.36 (m, 4H), 7.20 (m,
1H), 4.41 (s, 2H), 4.38 (s, 3H), 3.44 (s, 2H), 2.86-2.93 (m, 2H),
2.69-2.77 (m, 2H), 2.16-2.20 (m, 2H), 1.83-1.96 (m, 2H).
.sup.13C-NMR (CDCl.sub.3, 76 MHz) .delta. 164.0, 143.4, 141.0,
131.4 (q, J=32.8 Hz), 128.3, 128.0, 127.0, 126.1, 135.5, 124.0 (q,
J=213.8 Hz), 122.6, 121.9, 79.9, 72.0, 42.3, 41.7, 39.5, 32.9. Mass
spec.: 432.20 (MH).sup.-. Accurate mass spec.: m/z 432.1994
[MH].sup.+, .DELTA.=4.0 ppm.
EXAMPLE 180
[0302] ##STR602##
[0303]
4-((3-(1-Methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)met-
hyl)-4-phenylpiperidine.
tert-Butyl4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)-
methyl)-4-phenylpiperidine-1-carboxylate (7.0 mg, 0.01 mmol) was
dissolved in a minimum amount of ethyl acetate, followed by
addition of 4 N hydrochloric acid (0.5 mL). The mixture was stirred
under nitrogen for 1 h. After removing the solvents, the crude
mixture was precipitated in diethyl ether and filtered to afford
4.0 mg (88%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.86 (s,
1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 7.33 (s, 1H),
7.27-7.29 (m, 2H), 7.20 (m, 1H), 4.49 (s, 2H), 4.06 (s, 3H), 3.48
(s, 2H), 2.93-2.96 (m, 2H), 2.74-2.77 (m, 2H), 2.20-2.22 (m, 2H),
1.89-1.94 (m, 2H). Mass spec.: 432.20 (MH).sup.+. Accurate mass
spec.: m/z 432.1994 [MH].sup.+, .DELTA.=4.4 ppm.
EXAMPLE 181
[0304] ##STR603##
[0305]
4-((3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)met-
hyl)-4-phenylpiperidine. tert-Butyl
4-((3-(5-methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4--
phenylpiperidine-1-carboxylate (40.0 mg, 0.08 mmol) was dissolved
in a minimum amount of ethyl acetate, followed by addition of 4 N
hydrochloric acid (1.5 mL). The mixture was stirred under nitrogen
for 1 h. After removing the solvents, the crude mixture was
precipitated in diethyl ether and filtered to afford 30.0 mg (93%)
as a white powder. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.58
(s, 1H), 7.53 (s, 1H), 7.31-7.35 (m, 3H), 7.22-7.26 (m, 1H),
7.08-7.11 (m, 2H), 4.49 (s, 2H), 3.43 (s, 2H), 2.86-2.90 (m, 2H),
2.71-2.75 (m, 2H), 2.52 (s, 3H), 2.17-2.20 (m, 2H), 1.84-1.87 (m,
2H). .sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 151.5, 143.9,
143.1, 134.5, 136.6 (q, J=33.6 Hz), 128.7, 128.3, 127.2, 126.3,
127.7, 125.1 (q, J=272.6 Hz), 120.4, 80.6, 71.3, 42.6, 41.9, 33.6,
33.3. Mass spec.: 432.22 (MH).sup.+.
EXAMPLE 182
[0306] ##STR604##
[0307]
4-((2-Methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzyloxy)methyl)-4-phe-
nylpiperidine. tert-Butyl
4-((2-methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzyloxy)methyl)-4-phenylpipe-
ridine-1-carboxylate (30.0 mg, 0.06 mmol) was dissolved in a
minimum amount of ethyl acetate, followed by addition of 4 N
hydrochloric acid (1 mL). The mixture was stirred under nitrogen
for 1 h. After removing the solvents, the crude mixture was
precipitated in diethyl ether and filtered to afford 18.0 mg (76%)
as a white powder. .sup.1H-NMR (CDCl.sub.3, 500 MHZ) .delta. 7.32
(s, 1H), 7.30 (s, 1H), 7.18-7.25 (m, 3H), 7.04-7.07 (m, 1H), 6.91
(d, J=8.9 Hz, 1H), 6.81 (m, 1H), 4.46 (s, 2H), 3.85 (s, 3H), 3.48
(s, 2H), 2.88-2.93 (m, 2H), 2.72-2.76 (m, 2H), 2.41 (s, 3H), 2.18
(m, 2H), 1.85-1.90 (m, 2H). .sup.13C-NMR (CDCl.sub.3, 126 MHz)
.delta. 157.5, 151.7, 144.2, 129.6, 128.2, 127.2, 126.6, 126.1,
124.6, 123.6, 110.5, 80.5, 67.0, 55.8, 42.7, 41.8, 33.6, 9.6. Mass
spec.: 394.22 (MH).sup.+. Accurate mass spec.: m/z 394.2222
[MH].sup.+, .DELTA.=4.1 ppm.
EXAMPLE 183
[0308] ##STR605##
[0309]
4-(4-Methoxy-3-(((4-phenylpiperidin-4-yl)methoxy)methyl)phenyl)pyr-
idine. tert-Butyl
4-((2-methoxy-5-(pyridin-4-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carb-
oxylate (26 mg, 0.053 mmol) was dissolved in trifluoroacetic acid
(33% in dichloromethane, 4 mL) and stirred for 1 h. The reaction
was concentrated and purified by column chromatography (5%
methanol/dichloromethane/2% trimethylamine in ethanol.fwdarw.10%
methanol/dichloromethane/2% trimethylamine in ethanol) to give 30.7
mg (quant.) as a colorless oil. The product was tainted with
trimethylamine 2,2,2-trifluoroacetate. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 13.28 (bs, 2H), 9.55 (m, 2H), 8.71 (d,
J=5.2 Hz, 2H), 7.79 (d, J=5.2 Hz, 2H), 7.60 (m, 2H), 7.34 (m, 4H),
7.26 (m, 1H), 6.94 (d, J=8.6, 1H), 4.48 (s, 2H), 3.84 (s, 3H), 3.49
(s, 2H), 3.31 (m, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta.
ppm 159.1, 154.0, 144.0, 140.5, 129.2, 128.6, 127.7, 127.4, 127.2,
126.9, 122.5, 110.8, 80.0, 67.5, 55.7, 41.2, 40.6. Mass spec.:
389.33 (MH).sup.+. Accurate mass spec.: m/z 389.2228 [MH].sup.+,
.DELTA.=0.3 ppm.
EXAMPLE 184
[0310] ##STR606##
[0311]
5-(4-Methoxy-3-(((4-phenylpiperidin-4-yl)methoxy)methyl)phenyl)pic-
olinonitrile. tert-Butyl
4-((5-(6-cyanopyridin-3-yl)-2-methoxybenzyloxy)methyl)-4-phenylpiperidine-
-1-carboxylate (46 mg, 0.090 mmol) was dissolved in trifluoroacetic
acid (33% in dichloromethane, 4 mL) and stirred for 1 h. The
reaction was concentrated and purified by column chromatography (5%
methanol/dichloromethane/2% trimethylamine in ethanol.fwdarw.10%
methanol/dichloromethane/2% trimethylamine in ethanol) to give 43.6
mg (quant.) as a colorless oil. The product was tainted with
trimethylamine 2,2,2-trifluoroacetate. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm 9.47 (bs, 1H), 9.25 (bs, 1H), 8.79 (m, 1H),
7.84 (m, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.44 (dd, J=8.5, 2.1, 1H),
7.33 (m, 5H), 7.25 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.47 (s, 2H),
3.82 (s, 3H), 3.48 (s, 2H), 3.27 (bd, 2H), 2.90 (m, 2H), 2.44 (m,
2H), 2.26 (m, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm
157.8, 149.3, 140.5, 139.5, 134.3, 131.4, 129.1, 128.5, 128.2,
127.9, 127.2, 126.8, 126.6, 117.7, 110.8, 79.9, 67.7, 55.6, 41.1,
40.6, 29.1. Mass spec.: 414.19 (MH).sup.+. Accurate mass spec.: m/z
414.2188 [MH].sup.+, .DELTA.=1.6 ppm.
EXAMPLE 185
[0312] ##STR607##
[0313]
4'-Methoxy-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4--
carbonitrile. tert-Butyl
4-(((4'-cyano-4-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-
-carboxylate (47 mg, 0.092 mmol) was dissolved in dichloromethane
(2 mL) and trifluoroacetic acid (1 mL). The reaction was stirred
for 45 min and concentrated. The residue was dissolved in methanol
and loaded onto an strong cation exchange cartridge. The cartridge
was flushed with plenty of methanol which was discarded. The
product was then eluted using 2 M ammonia in methanol. The solvent
was evaporated to give 34 mg (90%) as a colorless oil. Retention
time: 2.20 min. (Phenomenex C18 3.0.times.50 mm, 10% MeOH/90%
H.sub.2O/0.1% TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA, Gradient
time=3 min., Flow rate=4 mL/min.) Mass spec.: 413.39 (MH).sup.+.
Accurate mass spec.: m/z 413.2245 [MH].sup.+, .DELTA.=3.9 ppm.
EXAMPLE 186
[0314] ##STR608##
[0315]
3'-(((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)methyl)-5'-(trifluo-
romethyl)biphenyl-4-carbonitrile. tert-Butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluor-
ophenyl)piperidine-1-carboxylate (47.0 mg, 0.09 mmol) was treated
with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL)
for 1 h. The solvent was removed in vacuo and the resulting crude
mixture passed through a strong cation exchange column. After
washing the column with several volumes of methanol, the product
was eluted by washing the column with 2 M ammonia in methanol. The
solvents were removed in vacuo to afford 37.0 mg (92%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.75 (s, 1H), 7.73 (s, 1H), 7.66 (s,
1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.40 s, 1H),
7.30-7.33 (m, 2H), 6.96-7.00 (m, 2H), 4.46 (s, 2H), 3.44 (s, 2H),
2.87-2.91 (m, 2H), 2.70-2.75 (m, 2H), 2.11-2.14 (m, 2H), 1.87-1.90
(m, 2H). Mass spec.: 469.33 (MH).sup.+.
EXAMPLE 187
[0316] ##STR609##
[0317]
3'-(((1-Methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile.
3'-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluoromethyl)biphenyl-
-4-carbonitrile (18.3 mg, 0.04 mmol) and formaldehyde (37 wt. %
solution in water, 86.4 .mu.L, 3.22 mmol) were combined in
acetonitrile (1.0 mL) and cooled to 0.degree. C. The reaction was
treated with sodium cyanoborohydride (12.6 mg, 0.2 mmol) and a few
drops of acetic acid. The reaction was stirred at 0.degree. C. for
30 min and at room temperature for 1 h. The solvent was removed in
vacuo and the resulting crude mixture passed through a strong
cation exchange column. After washing the column with several
volumes of methanol, the product was eluted by washing the column
with 2 M ammonia in methanol. The solvents were evaporated to
afford 12.1 mg (65%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60 (m, 2H), 7.44 (s, 1H),
7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m, 2H), 7.18-7.21 (m,
1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H), 2.17-2.28 (m,
4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). Mass spec.: 465.11
(MH).sup.+.
EXAMPLE 188
[0318] ##STR610##
[0319]
4-(3-(((1-Methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluo-
romethyl)phenyl)pyridine. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta.
8.96 (s, 1H), 8.95 (s, 1H), 8.01 (s, 1H), 8.00 (s, 1H), 7.83 (s,
1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.42-7.45 (m, 2H), 7.33-7.36 (m,
3H), 4.55 (s, 2H), 3.55-3.57 (m, 2H), 3.46 (s, 2H), 2.68-2.75 (m,
2H), 2.70 (s, 3H), 2.53-2.56 (m, 2H), 2.40-2.46 (m, 2H). Mass
spec.: 441.13 (MH).sup.+.
EXAMPLE 189
[0320] ##STR611##
[0321]
3'-(((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'-
-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. 7.76-7.74 (m, 2H), 7.67 (s, 1H), 7.59-7.57 (m,
2H), 7.39-7.41 (m, 2H), 7.30-7.33 (m, 2H), 6.97-7.00 (m, 2H), 4.46
(s, 2H), 3.44 (s, 2H), 2.54-2.56 (m, 2H), 2.16-2.25 (m, 4H), 2.20
(s, 3H), 1.97-1.99 (m, 2H). Mass spec.: 483.33 (MH).sup.+.
EXAMPLE 190
[0322] ##STR612##
[0323]
3'-(((4-(3-Cyanophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. ppm 7.76 (m, 2H), 7.67 (s, 1H), 7.63 (m, 2H), 7.60
(m, 1H), 7.58 (m, 1H), 7.47 (m, 1H), 7.37-7.43 (m, 2H), 7.33 (s,
1H), 4.46 (s, 2H), 3.45 (s, 2H), 2.65 (m, 2H), 2.27 (s, 3H),
2.25-2.30 (m, 4H), 2.08 (m, 2H). Mass spec: 490.24 (MH).sup.-.
EXAMPLE 191
[0324] ##STR613##
[0325]
3'-(((4-(3,4-Difluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl-
)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. ppm 7.76 (m, 2H), 7.67 (s, 1H), 7.61
(m, 2H), 7.42 (s, 1H), 7.37 (s, 1H), 7.01-7.19 (br m, 3H), 4.47 (s,
2H), 3.43 (s, 2H), 2.53-2.57 (br m, 2H), 1.98-2.35 (m, 9H). Mass
spec.: 501.25 (MH).sup.+.
EXAMPLE 192
[0326] ##STR614##
[0327]
3'-(((4-(4-Bromophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. ppm 7.76 (m, 2H), 7.67 (s, 1H), 7.62 (m, 2H), 7.45
(s, 1H), 7.42 (s, 1H), 7.35 (m, 2H), 7.18-7.27 (m, 2H), 4.47 (s,
2H), 3.45 (s, 2H), 2.35-2.55 (br m, 2H), 1.55 (m, 9H). Mass spec.:
543.16 (MH).sup.+.
EXAMPLE 193
[0328] ##STR615##
[0329]
3'-(((4-(3-Bromophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. ppm 7.78 (m, 2H), 7.67 (s, 1H), 7.60 (m, 2H), 7.45
(m, 3H), 7.37 (s, 1H), 7.22 (s, 1H), 7.20 (s, 1H), 4.46 (s, 2H),
3.44 (s, 2H), 2.14-2.45 (br m, 7H), 1.48-1.53 (br m, 4H). Mass
spec.: 543.16 (MH).sup.+.
EXAMPLE 194
[0330] ##STR616##
[0331]
3'-(((4-(4-Cyanophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. ppm 7.78 (m, 2H), 7.60-7.69 (m, 5H), 7.45 (m, 2H),
7.28 (br m, 2H), 4.46 (s, 2H), 3.48 (s, 1H), 1.62-2.55 (br m, 12H).
Mass spec.: 490.14 (MH).sup.+.
EXAMPLE 195
[0332] ##STR617##
[0333]
3'-(((4-(3-Chlorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'-
-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. ppm 7.75 (m, 2H), 7.66 (s, 1H), 7.60 (m, 2H), 7.42
(s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.23 (m, 2H), 7.16 (m, 1H),
4.46 (s, 2H), 3.46 (s, 2H), 2.74 (br m, 1H), 1.98-2.35 (br m, 10H).
Mass spec.: 499.06 (MH).sup.+.
EXAMPLE 196
[0334] ##STR618##
[0335]
3'-(((1-Methyl-4-(3-(trifluoromethyl)phenyl)piperidin-4-yl)methoxy-
)methyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. ppm 7.74 (m, 2H), 7.66 (s, 1H), 7.58
(m, 2H), 7.54 (m, 1H), 7.42 (m, 2H), 7.35 (s, 1H), 4.45 (s, 2H),
3.48 (s, 2H), 2.66 (br m, 1H), 1.98-2.30 (br m, 10H). Mass spec.:
533.19 (MH).sup.+.
EXAMPLE 197
[0336] ##STR619##
[0337]
3'-(((4-(4-(Furan-2-yl)phenyl)-1-methylpiperidin-4-yl)methoxy)meth-
yl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. ppm 7.55-7.64 (m, 5H), 7.47-7.52 (m,
3H), 7.38 (s, 1H), 7.34 (m, 3H), 6.62 (m, 1H), 6.52 (m, 1H), 4.47
(s, 2H), 3.47 (s, 2H), 2.74-3.01 (br m, 2H), 1.98-2.30 (br m, 9H).
Mass spec.: 531.11 (MH).sup.+.
EXAMPLE 198
[0338] ##STR620##
[0339]
3'-(((4-(3-Methoxyphenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5-
'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. ppm 7.75 (m, 2H), 7.66 (s, 1H), 7.62
(m, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 7.26 (m, 1H), 6.92 (m, 1H),
6.88 (m, 1H), 6.76 (m, 1H), 4.45 (s, 2H), 3.75 (s, 3H), 3.46 (s,
2H), 2.80 (br m, 2H), 2.15-2.81 (m, 9H). Mass spec.: 495.12
(MH).sup.+.
EXAMPLE 199
[0340] ##STR621##
[0341]
4-(((4'-Fluoro-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4--
(4-fluorophenyl)-1-methylpiperidine. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.63 (s, 1H), 7.46 (m, 2H), 7.39 (s, 1H), 7.32 (m,
3H), 7.15 (m, 2H), 7.00 (m, 2H), 4.45 (s, 2H), 3.44 (s, 2H), 2.58
(m, 2H), 2.22 (s, 3H), 2.20 (m, 4H), 2.00 (m, 2H); .sup.13C NMR
(126 MHz, CDCl.sub.3) .delta. ppm 164.0, 162.3, 162.0, 160.4,
141.2, 140.4, 139.6, 135.8, 131.5, 131.2, 128.9 (m), 128.8 (m),
124.1 (q, J=273 Hz), 122.8 (q, J=3.8 Hz), 122.6 (q, J=3.8 Hz),
116.1, 115.9, 115.1, 115.0, 79.6 (br), 72.4, 51.9, 46.2, 40.4,
32.6. Mass spec.: 476.34 (MH).sup.+. Accurate mass spec.: m/z
476.2013 [MH].sup.+, .DELTA.=0.0 ppm.
EXAMPLE 200
[0342] ##STR622##
[0343]
4-(((4',5-Difluorobiphenyl-3-yl)methoxy)methyl)-1-methyl-4-phenylp-
iperidine. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.74-7.76 (m,
2H), 7.66 (s, 1H), 7.58-7.60 (m, 2H), 7.44 (s, 1H), 7.41 (s, 1H),
7.36-7.38 (m, 2H), 7.30-7.33 (m, 2H), 7.18-7.21 (m, 1H), 4.45 (s,
2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H), 2.17-2.28 (m, 4H), 2.21 (s,
3H), 1.98-2.08 (m, 2H). .sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta.
164.0 (d, J=51.8 Hz), 162.1 (d, J=52.8 Hz), 142.3, 142.0, 136.1,
128.8, 128.3, 127.4, 126.1, 121.1, 115.9, 115.7, 112.8, 112.6,
72.5, 52.1, 46.3, 40.9, 32.5. Mass spec.: 408.16 (MH).sup.+.
Accurate mass spec.: m/z 408.2157 [MH].sup.+, .DELTA.=4.4 ppm.
EXAMPLE 201
[0344] ##STR623##
[0345] 3'-Fluoro-540
-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitril-
e. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.72 (s, 1H), 7.71 (s,
1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.31-7.38 (m, 4H), 7.19-7.22 (m,
1H), 7.11-7.13 (m, 1H), 7.06 (s, 1H), 6.82-6.84 (s, 1H), 4.39 (s,
2H), 3.45 (s, 2H), 2.59-2.62 (m, 2H), 2.17-2.27 (m, 4H), 2.21 (s,
3H), 2.00-2.05 (m, 2H). Mass spec.: 415.18 (MH).sup.+.
EXAMPLE 202
[0346] ##STR624##
[0347]
4-(((4'-Methoxy-3'-methyl-5-(trifluoromethyl)biphenyl-3-yl)methoxy-
)methyl)-1-methyl-4-phenylpiperidine. .sup.1H-NMR (CD.sub.3OD, 500
MHz) .delta. 7.69 (m, 1H), 7.58 (m, 1H), 7.28-7.53 (m, 8H),
6.99-7.02 (m, 1H), 4.52 (s, 2H), 3.89 (s, 3H), 3.48 (s, 2H), 3.44
(m, 2H), 2.66-2.93 (m, 4H), 2.75 (s, 3H), 2.28 (s, 3H), 2.12-2.22
(m, 2H). Mass spec.: 484.11 (MH).sup.+. Accurate mass spec.: m/z
484.2471 [MH].sup.+, .DELTA.=1.6 ppm.
EXAMPLE 203
[0348] ##STR625##
[0349]
4-(((2',3'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)me-
thoxy)methyl)-1-methyl-4-phenylpiperidine. .sup.1H-NMR (CD.sub.3OD,
500 MHz) .delta. 7.63 (s, 1H), 7.40-7.44 (m, 4H), 7.28-7.32 (m,
2H), 7.14-7.18 (m, 2H), 7.02-7.07 (m, 1H), 4.48 (s, 2H), 3.97 (s,
3H), 3.51 (s, 2H), 2.61 (m, 2H), 2.22-2.30 (m, 4H), 2.19 (s, 3H),
2.02-2.07 (m, 2H). Mass spec.: 506.15 (MH).sup.+. Accurate mass
spec.: m/z 506.2096 [MH].sup.+, .DELTA.=4.4 ppm.
EXAMPLE 204
[0350] ##STR626##
[0351]
4-(((3',5'-difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)me-
thoxy)methyl)-1-methyl-4-phenylpiperidine. .sup.1H-NMR (CD.sub.3OD,
500 MHz) .delta. 7.73-7.75 (m, 1H), 7.57 (s, 1H), 7.43-7.50 (m,
5H), 7.21-7.33 (m, 3H), 4.55 (s, 2H), 4.04 (s, 3H), 3.49 (s, 2H),
3.46 (m, 2H), 2.84-2.90 (m, 2H), 2.76 (s, 3H), 2.70-2.73 (m, 2H),
2.10-2.23 (m, 2H). Mass spec.: 505.93 (MH).sup.+. Accurate mass
spec.: m/z 506.2116 [MH].sup.+, .DELTA.=0.5 ppm.
EXAMPLE 205
[0352] ##STR627##
[0353]
4-(((2',5'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)me-
thoxy)methyl)-1-methyl-4-phenylpiperidine. .sup.1H-NMR (CD.sub.3OD,
500 MHz) .delta. 7.65 (s, 1H), 7.40-7.42 (m, 4H), 7.28-7.33 (m,
2H), 7.03-7.20 (m, 3H), 4.48 (s, 2H), 3.95 (s, 3H), 3.50 (s, 2H),
2.65 (m, 2H), 2.30 (m, 4H), 2.18 (s, 3H), 2.04-2.08 (m, 2H). Mass
spec.: 506.19 (MH).sup.+. Accurate mass spec.: m/z 506.2110
[MH].sup.+, .DELTA.=1.7 ppm.
EXAMPLE 206
[0354] ##STR628##
[0355]
3-Methoxy-3'-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'-
-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CD.sub.3OD,
500 MHz) .delta. 7.81 (s, 1H), 7.69-7.73 (m, 1H), 7.64 (s, 1H),
7.51 (s, 1H), 7.40-7.43 (m, 2H), 7.25-7.33 (m, 4H), 7.15-7.20 (m,
1H), 4.53 (s, 2H), 4.05 (s, 3H), 3.53 (s, 2H), 2.60-2.65 (m, 2H),
2.24-2.30 (m, 4H), 2.19 (s, 3H), 2.01-2.10 (m, 2H). Mass spec.:
495.20 (MH).sup.+.
EXAMPLE 207
[0356] ##STR629##
[0357]
2,5-Difluoro-3'-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-
-5'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CD.sub.3OD, 500 MHz) .delta. 7.79-7.81 (m, 2H), 7.55-7.62 (m, 3H),
7.41-7.50 (m, 4H), 7.28-7.29 (m, 1H), 4.58 (s, 2H), 3.49 (s, 2H),
3.45-3.49 (m, 2H), 2.85-2.90 (m, 2H), 2.76 (s, 3H), 2.71-2.74 (m,
2H), 2.17-2.22 (m, 2H). Mass spec.: 501.11 (MH).sup.+. Accurate
mass spec.: m/z 501.1964 [MH].sup.+, .DELTA.=0.3 ppm.
EXAMPLE 208
[0358] ##STR630##
[0359]
(.+-.)-3'-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5'-(trifluoro-
methyl)biphenyl-4-carbonitrile. (.+-.)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate (36 mg, 0.064 mmol) was dissolved in
trifluoroacetic acid (33% in dichloromethane, 1.5 mL). The
resulting solution was stirred at room temperature for 1 h and
concentrated. The crude salt was loaded onto an SCX cartridge in
methanol. The cartridge was flushed with several volumes of
methanol which was discarded. The product was eluted with 2 M
ammonia in methanol and concentrated to give 29 mg (98%) as a
colorless film. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.73
(d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.38 (s,
2H), 7.20-7.35 (m, 4H), 7.16 (m, 1H), 4.29 (q, J=6.4 Hz, 1H), 3.46
(s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.90 (m,
2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H), 1.80-1.99 (m, 2H), 1.35 (d,
J=6.4 Hz, 3H). Mass spec.: 465.20 (MH).sup.+. Accurate mass spec.:
m/z 465.2136 [MH].sup.+, .DELTA.=3.8 ppm.
EXAMPLE 209
[0360] ##STR631##
[0361]
(.+-.)-3'-(1-((1-Methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-5'-(-
trifluoromethyl)biphenyl-4-carbonitrile. To a suspension of
(.+-.)-3'-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5'-(trifluoromethyl)-
biphenyl-4-carbonitrile (15 mg, 0.032 mmol) and sodium
cyanoborohydride (10.2 mg, 0.16 mmol) in acetonitrile (1 mL) at
0.degree. C. was added formalin (0.1 mL, 3.6 mmol). The ice bath
was removed and stirring continued for 1 h. The reaction was
concentrated and loaded onto an SCX cartridge in methanol. The
cartridge was flushed with several volumes of methanol which was
discarded. The product was eluted with 2 M ammonia in methanol and
concentrated to give 13 mg (84%) as a colorless film. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm 7.74 (m, 2H), 7.64 (s, 1H), 7.56
(m, 2H), 7.37 (s, 2H), 7.22-7.35 (m, 5H), 7.16 (m, 1H), 4.29 (q,
J=6.4 Hz, 1H), 3.32 (d, J=8.9 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.61
(m, 2H), 2.11-2.35 (m, 7H), 1.95-2.10 (m, 2H), 1.34 (m, 3H). Mass
spec.: 479.30 (MH).sup.+. Accurate mass spec.: m/z 479.2300
[MH].sup.+, .DELTA.=2.1 ppm.
EXAMPLE 210
[0362] ##STR632##
[0363]
(R)-3'-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5'-(trifluoromet-
hyl)biphenyl-4-carbonitrile. (R)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate (10 mg, 0.018 mmol) was dissolved in
trifluoroacetic acid (33% in dichloromethane, 1.5 mL). The
resulting solution was stirred at room temperature for 1 h and
concentrated. The crude salt was loaded onto an SCX cartridge in
methanol. The cartridge was flushed with several volumes of
methanol which was discarded. The product was eluted with 2 M
ammonia in methanol and concentrated to give 7.2 mg (88%) as a
colorless film. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.73
(d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.38 (s,
2H), 7.20-7.35 (m, 4H), 7.16 (m, 1H), 4.29 (q, J=6.4 Hz, 1H), 3.46
(s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.90 (m,
2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H), 1.80-1.99 (m, 2H), 1.35 (d,
J=6.4 Hz, 3H). Mass spec.: 465.20 (MH).sup.+. Accurate mass spec.:
m/z 465.2136 [MH].sup.+, .DELTA.=3.8 ppm.
EXAMPLE 211
[0364] ##STR633##
[0365]
3'-Bromo-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-ca-
rbonitrile. tert-Butyl
4-(((5-bromo-4'-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-c-
arboxylate (24.3 mg, 0.04 mmol) was treated with a trifluoroacetic
acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent
was removed in vacuo and the resulting crude mixture passed through
a strong cation exchange column. After washing the column with
several volumes of methanol, the product was eluted by washing the
column with 2 M ammonia in methanol. The solvent was evaporated and
the compound purified by column chromatography (10% ammonia in
methanol/methylene chloride) to afford 13.2 mg (72%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.71-7.73 (m, 2H), 7.31-7.37 (m, 5H),
7.28 (s, 1H), 7.20-7.22 (m, 2H), 4.38 (s, 2H), 3.44 (s, 2H),
2.91-2.94 (m, 2H), 2.74-2.78 (m, 2H), 2.16-2.20 (m, 2H), 1.89-1.93
(m, 2H). Mass spec.: 463.09 (MH).sup.+. Accurate mass spec.: m/z
463.1205 [MH].sup.+, .DELTA.=1.0 ppm.
EXAMPLE 212
[0366] ##STR634##
[0367]
6-(3-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-
phenyl)nicotinonitrile. To a solution of tert-butyl
4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)pipe-
ridine-1-carboxylate (60 mg, 0.081 mmol) and 6-bromonicotinonitrile
(16.4 mg, 0.089 mmol) in acetonitrile (1 mL) was added
bis(triphenylphosphine)palladium(II) chloride (2.28 mg, 3.25
.mu.mol). The reaction was heated at 150.degree. C. via microwave
for 1 h. The reaction was concentrated and purified by column
chromatography (12%.fwdarw.25% ethyl acetate/hexanes) gave the
Boc-protected amine: Mass spec.: 552.31 (MH).sup.+. The carbamate
was dissolved in trifluoroacetic acid (33% in dichloromethane, 1.5
mL), stirred for 1 h, and concentrated. The crude trifluoroacetic
acid salt was loaded onto a strong cation exchange cartridge which
was flushed with several volumes of methanol which were discarded.
The product was eluted using 2 M ammonia in methanol and
concentrated. The reaction was repurified by preparative HPLC
(TFA/MeOH/Water). The fraction was concentrated, loaded onto a
strong cation exchange cartridge, and flushed with several volumes
of methanol which were discarded. The product was eluted with 2 M
ammonia in methanol and concentrated to give 9 mg (25%) as a
colorless oil. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.95 (s,
1H), 8.20 (s, 1H), 8.04 (m, 1H), 7.93 (s, 1H), 7.76 (d, J=8.2 Hz,
1H), 7.49 (s, 1H), 7.30-7.45 (m, 4H), 7.22 (m, 1H), 4.48 (s, 2H),
3.48 (s, 2H), 2.94 (m, 2H), 2.77 (m, 2H), 2.21 (m, 2H), 1.94 (m,
2H). Mass spec.: 452.27 (MH).sup.+. Accurate mass spec.: m/z
452.1934 [MH].sup.+, .DELTA.=3.5 ppm.
EXAMPLE 213
[0368] ##STR635##
[0369]
3-Fluoro-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.71 (m, 1H), 7.65 (s, 1H), 7.28-7.47 (m, 8H), 7.20 (m,
1H), 4.46 (s, 2H), 3.49 (s, 2H), 2.91 (m, 2H), 2.76 (m, 2H), 2.20
(m, 2H), 1.88 (m, 2H), 1.59 (bs, 1H). Mass spec.: 469.37
(MH).sup.+. Accurate mass spec.: m/z 469.1924 [MH].sup.+,
.DELTA.=4.5 ppm.
EXAMPLE 214
[0370] ##STR636##
[0371]
2-Methyl-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.58 (s, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.33-7.44 (m, 4H),
7.20-7.31 (m, 3H), 7.10-7.18 (m, 2H), 4.44 (s, 2H), 3.46 (s, 2H),
2.90 (m, 2H), 2.75 (m, 2H), 2.22 (s, 3H), 2.19 (m, 2H), 1.88 (m,
2H), 1.59 (bs, 1H). Mass spec.: 465.31 (MH).sup.-. Accurate mass
spec.: m/z 465.2166 [MH].sup.+, .DELTA.=2.6 ppm.
EXAMPLE 215
[0372] ##STR637##
[0373]
3-Methoxy-6-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(triflu-
oromethyl)phenyl)pyridazine. To a solution of tert-butyl
4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)pipe-
ridine-1-carboxylate (100 mg, 0.135 mmol) and
3-chloro-6-methoxypyridazine (22 mg, 0.15 mmol) in acetonitrile
(1.2 mL) was added bis(triphenylphosphine)palladium(II) chloride
(3.80 mg, 5.42 .mu.mol). The reaction was heated at 150.degree. C.
via microwave for 1 h. The reaction was diluted with pentane,
filtered, and concentrated. Purification by column chromatography
(12%.fwdarw.25% ethyl acetate/hexanes) gave the Boc-protected
amine. The carbamate was dissolved in trifluoroacetic acid (33% in
dichloromethane, 1.5 mL), stirred for 1 h, and concentrated. The
reaction was purified by preparative HPLC (TFA/MeOH/Water) to give
the product as its trifluoroacetic acid salt. The salt was loaded
onto a strong cation exchange cartridge in methanol and flushed
with several volumes of methanol which were discarded. The product
was eluted with 2 M ammonia in methanol and concentrated to give 10
mg (16%). .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.20 (s, 1H),
8.06 (m, 2H), 7.61 (s, 1H), 7.49 (m, 2H), 7.42 (m, 2H), 7.34 (d,
J=9.2 Hz, 1H), 7.29 (m, 1H), 4.60 (s, 2H), 4.19 (s, 3H), 3.57 (s,
2H), 3.36 (m, 2H), 2.97 (m, 2H), 2.57 (m, 2H), 2.25 (m, 2H). Mass
spec.: 458.19 (MH).sup.+. Accurate mass spec.: m/z 458.2061
[MH].sup.+, .DELTA.=1.2 ppm.
EXAMPLE 216
[0374] ##STR638##
[0375]
3-Methyl-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.82 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.65 (s, 2H), 7.56
(m, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.41 (m, 2H), 7.28 (m, 1H),
4.57 (s, 2H), 3.56 (s, 2H), 3.36 (m, 2H), 2.97 (m, 2H), 2.63 (s,
3H), 2.56 (m, 2H), 2.22 (m, 2H). Mass spec.: 465.19 (MH).sup.+.
Accurate mass spec.: m/z 465.2152 [MH].sup.+, .DELTA.=0.4 ppm.
EXAMPLE 217
[0376] ##STR639##
[0377]
3-Chloro-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.75-7.95 (m, 3H), 7.71 (m, 1H), 7.51-7.65 (m, 2H),
7.32-7.51 (m, 4H), 7.28 (m, 1H), 4.58 (s, 2H), 3.57 (s, 2H), 3.36
(m, 2H), 2.97 (m, 2H), 2.56 (m, 2H), 2.21 (m, 2H). Mass spec.:
485.11 (MH).sup.+. Accurate mass spec.: m/z 485.1627 [MH].sup.+,
.DELTA.=4.0 ppm.
EXAMPLE 218
[0378] ##STR640##
[0379]
2,3,5,6-Tetrafluoro-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-
'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.78 (s, 1H), 7.67 (s, 1H), 7.48 (m,
3H), 7.40 (m, 2H), 7.25 (m, 1H), 4.59 (s, 2H), 3.56 (s, 2H), 3.35
(m, 2H), 2.96 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H). Mass spec.:
523.12 (MH).sup.+. Accurate mass spec.: m/z 523.1608 [MH].sup.+,
.DELTA.=2.4 ppm.
EXAMPLE 219
[0380] ##STR641##
[0381]
3,5-Difluoro-3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trif-
luoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.91 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.55 (m,
2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.29 (m, 1H), 4.59 (s, 2H), 3.57
(s, 2H), 3.36 (m, 2H), 2.97 (m, 2H), 2.57 (m, 2H), 2.21 (m, 2H).
Mass spec.: 487.16 (MH).sup.+. Accurate mass spec.: m/z 487.1792
[MH].sup.+, .DELTA.=3.4 ppm.
EXAMPLE 220
[0382] ##STR642##
[0383]
2-Chloro-5-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluo-
romethyl)phenyl)pyrimidine. .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 8.95 (s, 2H), 7.94 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H),
7.49 (m, 2H), 7.41 (m, 2H), 7.28 (m, 1H), 4.60 (s, 2H), 3.56 (s,
2H), 3.36 (m, 2H), 2.96 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H). Mass
spec.: 462.12 (MH).sup.+. Accurate mass spec.: m/z 462.1579
[MH].sup.+, .DELTA.=4.1 ppm.
EXAMPLE 221
[0384] ##STR643##
[0385]
4'-Methoxy-3'-methyl-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)b-
iphenyl-4-carbonitrile. tert-Butyl
4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carb-
oxylate (65 mg, 0.13 mmol), 4-cyanophenylboronic acid (76.4 mg,
0.52 mmol), and tetrakis(triphenylphosphine) palladium(0) (20 mg,
0.01 mmol) were combined in dry tetrahydrofuran (2 mL) in a
microwave tube and sealed. After flushing with nitrogen, 0.46 mL of
a 1 N potassium hydroxide aqueous solution was introduced. The
mixture was heated at 120.degree. C. for 1 h via microwave. After
cooling to room temperature, the reaction mixture was concentrated
and treated with a trifluoroacetic acid/methylene chloride mixture
(1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the
resulting crude mixture passed through a strong cation exchange
column. After washing the column with several volumes of methanol,
the product was eluted by washing the column with 2 M ammonia in
methanol and concentrated to afford 28 mg (51%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.69 (s, 1H), 7.68 (s, 1H), 7.55 (s,
1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.36 (s, 1H), 7.27-7.30 (m, 3H),
7.17-7.20 (m, 2H), 4.46 (s, 2H), 3.61 (s, 3H), 3.50 (s, 2H),
2.89-2.92 (m, 2H), 2.72-2.76 (m, 2H), 2.31 (s, 3H), 2.16-2.19 (m,
2H), 1.88-1.93 (m, 2H). .sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta.
157.1, 145.4, 144.4, 134.7, 132.5, 132.4, 131.7, 129.2, 128.3,
127.6, 127.4, 126.1, 125.8, 119.1, 110.6, 80.2, 68.2, 60.9, 42.7,
41.9, 33.6, 16.2. Mass spec.: 427.42 (MH).sup.+. Accurate mass
spec.: m/z 427.2378 [MH].sup.+, .DELTA.=1.8 ppm.
EXAMPLE 222
[0386] ##STR644##
[0387]
3,5-Difluoro-3'-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-
-5'-(trifluoromethyl)biphenyl-4-carbonitrile. To a solution of
tert-butyl
4-phenyl-4-((3-(tributylstannyl)-5-(trifluoromethyl)benzyloxy)methyl)pipe-
ridine-1-carboxylate (100 mg, 0.135 mmol) and
4-bromo-2,6-difluorobenzonitrile (33 mg, 0.15 mmol) in acetonitrile
(1.2 mL) was added bis(triphenylphosphine)palladium(II) chloride
(3.80 mg, 5.42 .mu.mol). The reaction was heated at 150.degree. C.
via microwave for 1 h. The reaction was diluted with pentane,
filtered, and concentrated. Purification by column chromatography
(12%.fwdarw.25% ethyl acetate/hexanes) gave the Boc-protected
amine. The carbamate was dissolved in trifluoroacetic acid (33% in
dichloromethane, 1.5 mL), stirred for 1 h, and concentrated. The
crude trifluoroacetic acid salt was dissolved in acetonitrile (2.5
mL), cooled to 0.degree. C., and treated with sodium
cyanoborohydride (25.5 mg, 0.406 mmol), and then with formalin
(0.25 mL). The crude product was purified by HPLC and concentrated.
The trifluoroacetic acid salt was loaded onto a strong cation
exchange cartridge and flushed with methanol which was discarded.
The product was eluted with 2 M ammonia in methanol and
concentrated to give 21 mg (31%). .sup.1H-NMR (CDCl.sub.3, 500 MHz)
.delta. 7.62 (s, 1H), 7.45 (s, 1H), 7.30-7.40 (m, 5H), 7.21 (m,
1H), 7.17 (s, 1H), 7.16 (s, 1H), 4.46 (s, 2H), 3.48 (s, 2H), 2.58
(m, 2H), 2.27 (m, 2H), 2.20 (s, 3H), 2.19 (m, 2H), 1.98 (m, 2H);
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta. ppm 164.1, 164.5,
162.51, 162.47, 147.7 (t, J=9.6 Hz), 141.7, 138.0 (m), 132.0 (q,
J=33 Hz), 128.8, 128.3, 127.4, 126.3, 124.9 (q, J=3.8 Hz), 123.7
(q, J=273 Hz), 122.8 (q, J=3.8 Hz), 111.01, 110.98, 110.84, 110.82,
109.1, 80.3 (br), 77.7, 72.0, 52.0, 46.3, 40.9, 32.6. Mass spec.:
501.14 (MH).sup.+. Accurate mass spec.: m/z 501.1974 [MH].sup.+,
.DELTA.=1.7 ppm.
EXAMPLE 223
[0388] ##STR645##
[0389]
2,3,5,6-Tetrafluoro-3'-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)-
methyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.55 (s, 1H), 7.50 (s, 1H), 7.36 (m,
2H), 7.25-7.32 (m, 3H), 7.13 (m, 1H), 4.46 (s, 2H), 3.47 (s, 2H),
2.57 (m, 2H), 2.26 (m, 2H), 2.19 (s, 3H), 2.18 (m, 2H), 1.98 (m,
2H). Mass spec.: 537.13 (MH).sup.+. Accurate mass spec.: m/z
537.1755 [MH].sup.+, .DELTA.=4.1 ppm.
EXAMPLE 224
[0390] ##STR646##
[0391]
3-Chloro-3'-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. 7.75 (d, J=8.2 Hz, 1H), 7.63 (m, 2H), 7.48 (dd,
J=7.9, 1.8 Hz, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.36 (m, 2H), 7.32
(m, 2H), 7.19 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.59 (m, 2H),
2.27 (m, 2H), 2.20 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H); .sup.13C
NMR (126 MHz, CDCl.sub.3) .delta. ppm 145.6, 143.8, 141.4, 138.9,
137.6, 134.5, 131.8 (q, J=33 Hz), 129.0, 128.7, 128.3, 127.4,
126.2, 126.0, 124.4 (q, J=3.8 Hz), 123.8 (q, J=273 Hz), 123.0 (q,
J=2.9 Hz), 115.9, 112.7, 80.1 (br), 77.7, 72.1, 52.0, 50.8, 46.3,
40.9, 32.5. Mass spec.: 499.14 (MH).sup.+. Accurate mass spec.: m/z
499.1776 [MH].sup.+, .DELTA.=2.4 ppm.
EXAMPLE 225
[0392] ##STR647##
[0393]
3-Methyl-3'-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'--
(trifluoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3,
500 MHz) .delta. 7.68 (d, J=8.2 Hz, 1H), 7.65 (s, 1H), 7.45 (s,
1H), 7.44 (s, 1H), 7.34-7.42 (m, 4H), 7.31 (m, 2H), 7.19 (m, 1H),
4.44 (s, 2H), 3.47 (s, 2H), 2.60 (m, 2H), 2.27 (m, 2H), 2.21 (s,
3H), 2.20 (m, 2H), 2.01 (m, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3)
.delta. ppm 144.0, 142.7, 140.9, 140.3, 133.1, 131.6 (q, J=33 Hz),
129.0, 128.3, 127.4, 126.2, 125.2, 124.0 (q, J=273 Hz), 123.8 (q,
J=3.8 Hz), 123.0 (q, J=2.9 Hz), 118.0, 112.4, 80.0 (br), 77.7,
72.3, 52.0, 46.2, 40.9, 32.4, 20.7. Mass spec.: 479.19 (MH).
Accurate mass spec.: m/z 479.2322 [MH].sup.+, .DELTA.=2.5 ppm.
EXAMPLE 226
[0394] ##STR648##
[0395]
(R)-3'-(1-((1-Methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-5'-(tri-
fluoromethyl)biphenyl-4-carbonitrile. (R)-tert-Butyl
4-((1-(4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylp-
iperidine-1-carboxylate (300 mg, 0.53 mmol) was treated with a
trifluoroacetic acid/methylene chloride mixture (1:1, 6 mL) for 1
h. The solvent was removed in vacuo and the resulting crude product
dissolved in acetonitrile (5 mL), cooled to 0.degree. C. and
treated with formaldehyde (37 wt. % solution in water, 1.1 mL). The
reaction was treated with sodium cyanoborohydride (163 mg, 2.58
mmol) and a few drops of acetic acid. The reaction was stirred at
0.degree. C. for 30 min and at room temperature for 1 h. The
solvent was removed in vacuo and the resulting crude mixture passed
through a strong cation exchange column. After washing the column
with several volumes of methanol, the product was eluted by washing
the column with 2 M ammonia in methanol. The solvents were
evaporated to afford 222 mg (73%). .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. 7.71 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.53 (s,
1H), 7.51 (s, 1H), 7.21-7.35 (m, 6H), 7.09-7.14 (m, 1H), 4.27 (q,
J=6.6 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 3.24 (d, J=8.8 Hz, 1H),
2.50-2.57 (m, 2H), 2.15 (s, 3H), 1.93-2.22 (m, 6H), 1.32 (m, 3H);
.sup.13C-NMR (CDCl.sub.3, 76 MHz) .delta. 146.5, 149.8, 140.0,
132.6, 131.4 (d, J=32.2 Hz), 128.0, 127.8, 127.7, 125.9, 123.8 (q,
J=272.4 Hz), 122.8, 122.7, 122.0, 118.5, 111.6, 51.8, 50.2, 46.1,
40.1, 32.3, 31.9, 23.9. Mass spec.: 479.19 (MH).sup.-.
EXAMPLE 227
[0396] ##STR649##
[0397]
3'-(((1-Ethyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluoro-
methyl)biphenyl-4-carbonitrile.
3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluoromethyl)biphenyl-
-4-carbonitrile (25.0 mg, 0.05 mmol) and acetaldehyde (0.25 mL,
4.31 mmol) were combined in acetonitrile (2.0 mL) and cooled to
0.degree. C. The reaction was treated with sodium cyanoborohydride
(14.0 mg, 0.23 mmol) and a few drops of acetic acid. The reaction
was stirred at 0.degree. C. for 30 min and at room temperature for
1 h. The solvent was removed in vacuo and the resulting crude
mixture passed through a strong cation exchange column. After
washing the column with several volumes of methanol, the product
was eluted by washing the column with 2 M ammonia in methanol. The
solvents were evaporated to afford 17 mg (79%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.74-7.75 (m, 2H), 7.66 (s, 1H),
7.59-7.60 (m, 2H), 7.44 (s, 1H), 7.30-7.39 (m, 5H), 7.18-7.21 (m,
1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.76 (s, 2H), 2.39-2.41 (m, 2H),
2.25-2.32 (m, 4H), 2.07-2.11 (m, 2H), 1.09 (t, J=7.0 Hz, 3H).
.sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 144.0, 141.0, 140.1,
132.8, 131.7 (q, J=32.6 Hz), 129.0, 128.5, 128.0, 127.4, 126.3,
124.0 (q, J=272.6 Hz), 123.9, 123.0, 118.7, 111.9, 72.2, 52.5,
49.5, 41.4, 32.0, 11.8. Mass spec.: 479.15 (MH).sup.+.
EXAMPLE 228
[0398] ##STR650##
[0399]
3'-(((1-Isopropyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifl-
uoromethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CDCl.sub.3, 500
MHz) .delta. 7.75 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.60 (s,
1H), 7.58 (s, 1H), 7.36-7.43 (m, 4H), 7.29-7.32 (m, 2H), 7.16-7.19
(m, 1H), 4.44 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 1H), 2.25-2.32
(m, 4H), 1.97-2.02 (m, 2H), 0.99 (s, 3H), 0.97 (s, 3H).
.sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 144.1, 141.0, 140.1,
132.8, 131.7 (q, J=32.6 Hz), 129.1, 128.3, 128.0, 127.3, 126.1,
123.4 (q, J=272.6 Hz), 123.9, 123.0, 122.9, 118.6, 112.0, 78.0,
72.3, 54.8, 45.3, 41.3, 32.8, 32.0, 18.7. Mass spec.: 493.46
(MH).sup.+. Accurate mass spec.: m/z 493.2466 [MH].sup.+,
.DELTA.=0.1 ppm.
EXAMPLE 229
[0400] ##STR651##
[0401]
3'-(((1-Benzyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluor-
omethyl)biphenyl-4-carbonitrile. .sup.1H-NMR (CD.sub.3OD, 500 MHz)
.delta. 7.84-7.86 (m, 2H), 7.81 (s, 1H), 7.74-7.76 (m, 2H), 7.61
(s, 1H), 7.50 (s, 1H), 7.42-7.43 (m, 2H), 7.25-7.33 (m, 7H),
7.19-7.20 (m, 1H), 4.51 (s, 2H), 3.43 (s, 2H), 3.42 (s, 2H),
2.63-2.65 (m, 2H), 2.26-2.30 (m, 4H), 2.05-2.07 (m, 2H). Mass
spec.: 541.23 (MH).sup.+.
EXAMPLE 230
[0402] ##STR652##
[0403]
3'-(((1-Cyclopropyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(tri-
fluoromethyl)biphenyl-4-carbonitrile. A microwave tube was charged
with
3'-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5'-(trifluoromethyl)biphenyl-
-4-carbonitrile (21.5 mg, 0.05 mmol),
(1-ethoxycyclopropoxy)trimethylsilane (96.5 .mu.L, 0.47 mmol),
sodium cyanoborohydride (15 mg, 0.24 mmol). The tube was flushed
with nitrogen and treated with methanol (2 mL) and acetic acid (3
drops). The tube was sealed and heated at 90.degree. C. for 1 h via
microwave. After cooling, the reaction was concentrated and
purified by flash chromatography on silica gel (10%
methanol/methylene chloride) to afford 13.5 mg (55%) as a colorless
oil. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 7.76 (s, 1H), 7.74
(s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H),
7.33-7.37 (m, 5H), 7.21-7.24 (m, 1H), 4.45 (s, 2H), 3.44 (s, 2H),
3.11-3.14 (m, 2H), 2.56-2.61 (m, 2H), 2.35-2.38 (m, 2H), 2.09-2.16
(m, 2H), 1.78-1.79 (m, 1H), 0.82 (m, 2H), 0.54-0.56 (m, 2H). Mass
spec.: 491.44 (MH).sup.+. Accurate mass spec.: m/z 491.2331
[MH].sup.+, .DELTA.=4.2 ppm.
EXAMPLE 231
[0404] ##STR653##
[0405]
3'-(((4-(2,4-Difluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl-
)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. Prepared by Method
A. Mass Spec: 501.27 (MH).sup.+. LC t.sub.r=1.88 min
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow
rate=4 mL/min).
EXAMPLE 232
[0406] ##STR654##
[0407]
3'-(((1-Methyl-4-(pyridin-3-yl)piperidin-4-yl)methoxy)methyl)-5'-(-
trifluoromethyl)biphenyl-4-carbonitrile. Prepared by Method A. Mass
Spec.: 466.10 (MH).sup.+. LC: t.sub.r=1.502 min (Phenomenex-Luna
4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow rate=4
mL/min).
EXAMPLE 233
[0408] ##STR655##
[0409]
3-Methyl-3'-(((1-methyl-4-(pyridin-3-yl)piperidin-4-yl)methoxy)met-
hyl)-5'-(trifluoromethyl)biphenyl-4-carbonitrile. Prepared by
Method A. Mass Spec.: 480.20 (MH).sup.+. LC t.sub.r=2.465 min
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA Gradient Time=3 min, Flow
rate=4 mL/min).
EXAMPLE 234
[0410] ##STR656##
[0411]
3'-(((1-Methyl-4-(pyridin-4-yl)piperidin-4-yl)methoxy)methyl)-5'-(-
trifluoromethyl)biphenyl-4-carbonitrile. A flask was charged with
tert-butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(pyridin-
-4-yl)piperidine-1-carboxylate (50 mg, 0.091 mmol) and
trifluoroacetic acid (1 mL, 13.0 mmol) in dichloromethane (5 mL) at
0.degree. C. under nitrogen. After 20 min the solvent was
evaporated under reduced pressure and the resulting residue dried
overnight. The resulting oil was dissolved in dichloromethane (5
mL) and treated with formaldehyde (37 wt. % solution in water, 1.0
mL) at 0.degree. C. After 20 min, the reaction was treated with
sodium triacetoxyborohydride (77 mg, 0.363 mmol). The reaction was
stirred at 0.degree. C. for 30 min and at room temperature for 1 h.
The solvent was removed in vacuo and the resulting residue purified
via preparative HPLC. The solvent was evaporated to afford 21 mg
(50%). Mass Spec: 466.10 (MH).sup.+. LC t.sub.r=2.325 min
(Phenomenex-Luna 4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1%
TFA.fwdarw.90% MeOH/10% H.sub.2O/0.1% TFA Gradient Time=4 min, Flow
rate=4 mL/min).
EXAMPLE 235
[0412] ##STR657##
[0413]
3'-(((4-(2-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-5'-
-(trifluoromethyl)biphenyl-4-carbonitrile. A flask was charged with
tert-butyl
4-(((4'-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(2-fluor-
ophenyl)piperidine-1-carboxylate (0.125 g, 0.214 mmol) in
dichloromethane (2 mL). Trifluoroacetic acid 0.5 mL was added and
the mixture was allowed to stir at room temperature for 1 hr. The
reaction mixture was concentrated in vacuo. The resulting oil was
dissolved in dichloromethane (3 mL) and 1 mL of a 37 wt %
formaldehyde solution in water. After 5 min the reaction was
treated with sodium triacetoxyborohydride (0.136 g, 0.64 mmol). The
reaction was stirred at room temperature for 16 h. The reaction was
diluted with 4 mL dichloromethane and the organic layer was
separated, dried over Na.sub.2SO.sub.4 and evaporated in vacuo. The
resulting residue was dissolved in methanol and loaded onto an SCX
cartridge. The cartridge was washed with 5 mL methanol then eluted
with 2 N NH.sub.3 in methanol. The ammonia in methanol fractions
were collected and evaporated in vacuo affording 0.093 g (90%) of
desired N-methyl piperidine. .sup.1H-NMR (CDCl.sub.3, 400 MHz)
.delta. ppm 7.73 (d, J=8.7 Hz, 2H), 7.65 (s, 1H), 7.58 (d, J=8.7
Hz, 2H), 7.41 (s, 1H), 7.35 (s, 1H), 7.32 (m, 1H), 7.16 (m, 1H),
7.09 (m, 1H), 6.91 (m, 1H), 4.46 (s, 2H), 3.69 (s, 2H), 2.57 (m,
2H), 2.37 (m, 2H), 2.24 (m, 2H), 2.21 (s, 3H), 2.00 (m, 2H). Mass
spec.: 483.3 (MH).sup.+; LC t.sub.r=3.228 min (Phenomenex-Luna
4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA Gradient Time=4 min, Flow rate=4
mL/min).
EXAMPLE 236
[0414] ##STR658##
[0415]
3'-Fluoro-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-c-
arbonitrile. tert-Butyl
4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate
(100.0 mg, 0.21 mmol), 4-cyanophenylboronic acid (93 mg, 0.63
mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.02
mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave
tube and sealed. After flushing with nitrogen, 0.7 mL of a 1 N
potassium hydroxide aqueous solution was introduced. The mixture
was heated at 120.degree. C. for 1 h via microwave. After cooling
to room temperature, the reaction mixture was concentrated and
treated with a trifluoroacetic acid/methylene chloride mixture
(1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the
resulting crude mixture passed through a strong cation exchange
column. After washing the column with several volumes of methanol,
the product was eluted by washing the column with 2 M ammonia in
methanol and concentrated to afford 48 mg (46%). .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 7.72 (s, 1H), 7.70 (s, 1H), 7.57 (s,
1H), 7.56 (s, 1H), 7.31-7.38 (m, 4H), 7.19-7.22 (m, 1H), 7.11-7.13
(m, 1H), 7.08 (s, 1H), 6.84-6.86 (s, 1H), 4.40 (s, 2H), 3.45 (s,
2H), 2.89-2.93 (m, 2H), 2.73-2.78 (m, 2H), 2.17-2.20 (m, 2H),
1.88-1.94 (m, 2H). .sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 163.3
(d, J=247.6 Hz), 144.2, 142.5, 141.2, 132.7, 128.4, 127.8, 127.3,
126.2, 121.3, 118.7, 114.2, 114.0, 113.1, 111.7, 80.1, 72.3, 42.7,
41.9, 33.6. Mass spec.: 401.28 (MH).sup.+. Accurate mass spec.: m/z
401.2026 [MH].sup.+, .DELTA.=0.8 ppm.
EXAMPLE 237
[0416] ##STR659##
[0417]
4-(((4',5-Difluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-
. .sup.1H-NMR (CDCl.sub.3, 500 MHz) .delta. 8.97 (s, 1H), 7.42-7.46
(m, 2H), 7.32-7.39 (m, 4H), 7.20-7.23 (m, 1H), 7.07-7.14 (m, 3H),
7.05 (s, 1H), 6.78-6.86 (m, 1H), 4.39 (s, 2H), 3.45 (s, 2H),
2.89-2.93 (m, 2H), 2.73-2.78 (m, 2H), 2.17-2.19 (m, 2H), 1.89-1.94
(m, 2H), .sup.13C-NMR (CDCl.sub.3, 126 MHz) .delta. 164.1 (d,
J=52.8 Hz), 162.1 (d, J=53.8 Hz), 144.3, 142.3, 142.0, 136.1,
128.8, 128.4, 127.3, 126.2, 121.2, 115.9, 115.7, 112.8, 79.9, 72.5,
42.8, 41.9, 33.6. Mass spec.: 394.3 (MH).sup.+. Accurate mass
spec.: m/z 394.1978 [MH].sup.+, .DELTA.=1.1 ppm.
EXAMPLE 238
[0418] ##STR660##
[0419]
4-((3-Bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluoroph-
enyl)-1-methylpiperidine. tert-Butyl
4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)pi-
peridine-1-carboxylate (200 mg, 0.35 mmol) was dissolved in
methanol (5 mL). Hydrochloric acid (gas) was bubbled through for 20
seconds, then removed. The reaction was allowed to stir for 20 min
and the solvent evaporated. The resulting solid was dissolved in
dichloromethane (2 mL) and treated with formaldehyde (37 wt. %
solution in water, 1.5 mL) at 0.degree. C. After 20 min the
reaction was treated with sodium triacetoxyborohydride (297 mg, 1.4
mmol). The reaction was stirred at 0.degree. C. for 30 min and at
room temperature for 1 h. The solvent was removed in vacuo and the
resulting crude mixture passed through a strong cation exchange
column. After washing the column with several volumes of methanol,
the product was eluted by washing the column with 2 M ammonia in
methanol. The solvents were evaporated to afford 142 mg (85%). Mass
Spec: 478.07 (MH).sup.+. LC t.sub.r=1.885 min (Phenomenex-Luna
4.6.times.50 mm S10, 10% MeOH/90% H.sub.2O/0.1% TFA.fwdarw.90%
MeOH/10% H.sub.2O/0.1% TFA Gradient Time=2 min, Flow rate=4
mL/min).
* * * * *