U.S. patent application number 16/454831 was filed with the patent office on 2019-10-17 for selective nr2b antagonists.
The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Imadul Islam, Dalton King, John E. Macor, Jayakumar Sankara Warrier, Jianliang Shi, Srinivasan Thangathirupathy, Lorin A. Thompson, III.
Application Number | 20190314358 16/454831 |
Document ID | / |
Family ID | 52463126 |
Filed Date | 2019-10-17 |
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United States Patent
Application |
20190314358 |
Kind Code |
A1 |
King; Dalton ; et
al. |
October 17, 2019 |
SELECTIVE NR2B ANTAGONISTS
Abstract
The disclosure generally relates to compounds of formula I,
including their salts, as well as compositions and methods of using
the compounds. The compounds are ligands of the NR2B receptor and
may be useful for the treatment of various disorders of the central
nervous system. ##STR00001##
Inventors: |
King; Dalton; (Hamden,
CT) ; Thompson, III; Lorin A.; (Cohasset, MA)
; Shi; Jianliang; (Furlong, PA) ;
Thangathirupathy; Srinivasan; (Hosur, IN) ; Sankara
Warrier; Jayakumar; (Bangalore, IN) ; Islam;
Imadul; (Richmond, CA) ; Macor; John E.;
(Washington Crossing, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Family ID: |
52463126 |
Appl. No.: |
16/454831 |
Filed: |
June 27, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16225850 |
Dec 19, 2018 |
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16454831 |
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15971067 |
May 4, 2018 |
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16225850 |
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15846672 |
Dec 19, 2017 |
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15971067 |
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15706172 |
Sep 15, 2017 |
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15846672 |
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15604904 |
May 25, 2017 |
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15706172 |
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14882041 |
Oct 13, 2015 |
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15604904 |
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14589205 |
Jan 5, 2015 |
9221796 |
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14882041 |
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61925363 |
Jan 9, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 403/04 20130101;
A61P 25/28 20180101; A61P 25/16 20180101; A61K 31/454 20130101;
A61P 25/02 20180101; A61P 25/24 20180101; A61P 25/00 20180101; A61P
25/04 20180101; C07D 401/04 20130101 |
International
Class: |
A61K 31/454 20060101
A61K031/454; C07D 403/04 20060101 C07D403/04; C07D 401/04 20060101
C07D401/04 |
Claims
1. A pharmaceutical composition comprising the compound
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This Continuation application claims the benefit of U.S.
Ser. No. 16/225,850 filed Dec. 19, 2018, now pending, which in turn
is a continuation application which claims the benefit of U.S. Ser.
No. 15/971,067 filed May 4, 2018, now abandoned, which in turn is a
Continuation application which claims the benefit of U.S. Ser. No.
15/846,672 filed Dec. 19, 2017, now abandoned, which in turn is a
Continuation application which claims the benefit of U.S. Ser. No.
15/706,172 filed Sep. 15, 2017, now abandoned, which in turn is a
Continuation application which claims the benefit of U.S. Ser. No.
15/604,904 filed May 25, 2017, now abandoned, which in turn is a
Continuation application claims the benefit of U.S. Ser. No.
14/882,041 filed Oct. 13, 2015, now abandoned, which in turn is a
Continuation application which claims the benefit of U.S. Ser. No.
14/589,205 filed Jan. 5, 2015, now U.S. Pat. No. 9,221,796, which
in turn is a Non-Provisional application which claims the benefit
of Provisional application U.S. Ser. No. 61/925,363 filed Jan. 9,
2014, now expired, hereby incorporated by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] The disclosure generally relates to compounds of formula I,
including their salts, as well as compositions and methods of using
the compounds. The compounds are ligands for the NR2B NMDA receptor
and may be useful for the treatment of various disorders of the
central nervous system.
[0003] N-Methyl-D-aspartate (NMDA) receptors are ion channels which
are gated by the binding of glutamate, an excitatory
neurotransmitter in the central nervous system. They are thought to
play a key role in the development of a number of neurological
diseases, including depression, neuropathic pain, Alzheimer's
disease, and Parkinson's disease. Functional NMDA receptors are
tetrameric structures primarily composed of two NR1 and two NR2
subunits. The NR2 subunit is further subdivided into four
individual subtypes: NR2A, NR2B, NR2C, and NR2D, which are
differentially distributed throughout the brain. Antagonists or
allosteric modulators of NMDA receptors, in particular NR2B
subunit-containing channels, have been investigated as therapeutic
agents for the treatment of major depressive disorder (G. Sanacora,
2008, Nature Rev. Drug Disc. 7: 426-437).
[0004] The NR2B receptor contains additional ligand binding sites
in addition to that for glutamate. Non-selective NMDA antagonists
such as Ketamine are pore blockers, interfering with the transport
of Ca.sup.++ through the channel. Ketamine has demonstrated rapid
and enduring antidepressant properties in human clinical trials as
an i.v. drug. Additionally, efficacy was maintained with repeated,
intermittent infusions of Ketamine (Zarate et al., 2006, Arch. Gen.
Psychiatry 63: 856-864). This class of drugs, though, has limited
therapeutic value because of its CNS side effects, including
dissociative effects.
[0005] An allosteric, non-competitive binding site has also been
identified in the N-terminal domain of NR2B. Agents which bind
selectively at this site, such as Traxoprodil, exhibited a
sustained antidepressant response and improved side effect profile
in human clinical trials as an i.v. drug (Preskorn et al., 2008, J.
Clin. Psychopharmacol., 28: 631-637, and F. S. Menniti, et al.,
1998, CNS Drug Reviews, 4, 4, 307-322). However, development of
drugs from this class has been hindered by low bioavailability,
poor pharmacokinetics, and lack of selectivity against other
pharmacological targets including the hERG ion channel. Blockade of
the hERG ion channel can lead to cardiac arrhythmias, including the
potentially fatal Torsades de pointe, thus selectivity against this
channel is critical. Thus, in the treatment of major depressive
disorder, there remains an unmet clinical need for the development
of effective NR2B-selective negative allosteric modulators which
have a favorable tolerability profile.
[0006] NR2B receptor antagonists have been disclosed in PCT
publication WO 2009/006437.
[0007] The invention provides technical advantages, for example,
the compounds are novel and are ligands for the NR2B receptor and
may be useful for the treatment of various disorders of the central
nervous system. Additionally, the compounds provide advantages for
pharmaceutical uses, for example, with regard to one or more of
their mechanism of action, binding, inhibition efficacy, target
selectivity, solubility, safety profiles, or bioavailability.
DESCRIPTION OF THE INVENTION
[0008] 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.
[0009] One aspect of the invention is a compound of formula I
##STR00002##
where: Ar.sup.1 is phenyl or indanyl and is substituted with 0-3
substituents selected from cyano, halo, alkyl, haloalkyl, and
haloalkoxy; Ar.sup.2 is phenyl substituted with 1 OH substituent
and also substituted with 0-3 substituents selected from cyano,
halo, alkyl, haloalkyl, and haloalkoxy; X is a bond or
C.sub.1-C.sub.3 alkylene; n is 1 or 2; and ring A is azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, or
homopiperazinyl and is substituted with 0-4 substituents selected
from halo, alkyl, hydroxy, or alkoxy; or a pharmaceutically
acceptable salt thereof.
[0010] Another aspect of the invention is a compound of formula I
where n is 1 and ring A is piperidinyl substituted with 0-2 halo
substituents.
[0011] Another aspect of the invention is a compound of formula I
where Ar.sup.1 is phenyl substituted with 0-3 substituents selected
from cyano, halo, alkyl, haloalkyl, and haloalkoxy.
[0012] Another aspect of the invention is a compound of formula I
where Ar.sup.2 is p-hydroxyphenyl.
[0013] Another aspect of the invention is a compound of formula I
where X is methylene.
[0014] Another aspect of the invention is the compound of formula
I:
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one or a pharmaceutically acceptable salt
thereof
##STR00003##
[0015] For a compound of formula I, the scope of any instance of a
variable substituent, including Ar.sup.1, Ar.sup.2, Ar.sup.3 X, and
n can be used independently with the scope of any other instance of
a variable substituent. As such, the invention includes
combinations of the different aspects.
[0016] 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.
"Alkynyl" means a straight or branched alkyl group composed of 2 to
6 carbons with at least one triple bond. "Cycloalkyl" means a
monocyclic ring system composed of 3 to 7 carbons. Terms with a
hydrocarbon moiety (e.g. alkoxy) include straight and branched
isomers for the hydrocarbon portion. "Halo" includes fluoro,
chloro, bromo, and iodo. "Haloalkyl" and "haloalkoxy" include all
halogenated isomers from monohalo to perhalo. "Aryl" means a
monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12
carbon atoms, or a bicyclic fused ring system wherein one or both
of the rings is a phenyl group. Bicyclic fused ring systems consist
of a phenyl group fused to a four- to six-membered aromatic or
non-aromatic carbocyclic ring. Representative examples of aryl
groups include, but are not limited to, indanyl, indenyl, naphthyl,
phenyl, and tetrahydronaphthyl. "Heteroaryl" means a 5 to 7
membered monocyclic or 8 to 11 membered bicyclic aromatic ring
system with 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. 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.
[0017] 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.
[0018] 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. The compounds
include all tautomeric forms.
[0019] The invention is intended to include all isotopes of atoms
occurring in the present compounds. Isotopes include those atoms
having the same atomic number but different mass numbers. By way of
general example and without limitation, isotopes of hydrogen
include deuterium and tritium. Isotopes of carbon include .sup.13C
and .sup.14C. Isotopically-labeled compounds of the invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described
herein, using an appropriate isotopically-labeled reagent in place
of the non-labeled reagent otherwise employed. Such compounds may
have a variety of potential uses, for example as standards and
reagents in determining biological activity. In the case of stable
isotopes, such compounds may have the potential to favorably modify
biological, pharmacological, or pharmacokinetic properties.
Synthetic Methods
[0020] Compounds of Formula I may be made by methods known in the
art including those described below and including variations within
the skill of the art. Some reagents and intermediates are known in
the art. Other reagents and intermediates can be made by methods
known in the art using readily available materials. The variables
(e.g. numbered "R" substituents) used to describe the synthesis of
the compounds are intended only to illustrate how to make the
compounds and are not to be confused with variables used in the
claims or in other sections of the specification. The following
methods are for illustrative purposes and are not intended to limit
the scope of the invention. The schemes encompass reasonable
variations known in the art.
[0021] Synthesis of the desired compounds I may begin with the
condensation of anilines/benzyl amines I with .alpha.,
.omega.-dibromoalkanoyl chlorides III to yield amides/anilides IV,
which may be cyclized to
1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V, as shown in
synthetic scheme 1.
##STR00004##
[0022] The 1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V
may be reacted with (4-oxy-phenyl)cyclic amines VI in the presence
of base to produce protected products VII, which may be subjected
to cleavage conditions appropriate for the protecting group
(PG.sub.1) to generate final products I, which may be separated
into individual enantiomers/diastereomers I*, as shown in synthetic
scheme 2.
##STR00005##
[0023] Compounds Ia may be prepared by condensing
1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V with
substituted 4(4-oxyphenyl)piperidines VIIIa-c to generate protected
intermediates IX, which may be subjected to cleavage conditions
appropriate for the protecting group (PG.sub.1) to generate final
products Ia, which may be separated into individual
enantiomers/diastereomers Ia*, as shown in synthetic scheme 3.
##STR00006##
[0024] The 4(4-oxyphenyl)piperidines VIIIa-c may be synthesized in
turn by a sequence starting with a protected tetrahydropiperidine
X, which can be hydroxylated via hydroboration/oxidation to give
the protected hydroxypiperidine XI, which may be either directly
transformed into the protected fluoropiperidine XII by treatment
with DAST or oxidized into the protected 3-oxopiperidine XIII,
which may be further transformed into protected
3,3-difluoropiperidines XIV via treatment with DAST. XI, XII, and
XIV may be transformed into VIIIa, VIIIb, and VIIIc, respectively,
by employing cleaving conditions appropriate for the protecting
group (PG.sub.2), as shown in synthetic scheme 3a.
##STR00007##
[0025] For tetrahydropyridines X which are not commercially
available may be synthesized by coupling protected bromophenols XV
with protected unsaturated piperidineboronic acids XVI, as shown in
synthetic scheme 4a.
##STR00008##
[0026] For tetrahydropyridines X which are not commercially
available may be synthesized by adding the anion generated from
protected bromophenols XV to a protected 4-piperidinone XVII to
yield 4-phenyl-4-piperidinol XVIII, which may be dehydrated under
acid conditions to yield the desired X, as shown in synthetic
scheme 4b.
##STR00009##
[0027] 1-Phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V may
be condensed with isolated individual enantiomers VIIIa-c*, which
results in diastereomers
1-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones IX*, which
may be deprotected and separated to give final products Ia*, as
shown in scheme 5.
##STR00010##
[0028] Alternatively, the backbone scaffold may be synthesized by
condensing 1-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V
with hydroxypiperidines VIIIa to yield the protected
3-fluoropiperidines IXa, which may themselves be converted to the
protected 3-fluoropiperidines IXb or oxidized to the ketones XIX,
which may be converted to the 3,3-difluoropiperidines Ixc, as shown
in scheme 6.
[0029] The final compounds can then be isolated after the
deprotection of IXa-c.
##STR00011##
DESCRIPTION OF SPECIFIC EMBODIMENTS
[0030] Abbreviations used in the schemes generally follow
conventions used in the art. Chemical abbreviations used in the
specification and examples are defined as follows: "NaHMDS" for
sodium bis(trimethylsilyl)amide; "DMF" for N,N-dimethylformamide;
"MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl;
"TFA" for trifluoroacetic acid; "DCM" for dichloromethane; "LAH"
for lithium aluminum hydride; "BOC" for t-butoxycarbonyl, "DMSO"
for dimethylsulfoxide; "h" for hours; "EtOAc" for ethyl acetate;
"THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic
acid; "Et.sub.2O" for diethyl ether; "DMAP" for
4-dimethylaminopyridine; "DCE" for 1,2-dichloroethane; "ACN" for
acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for
1-hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine,
"Nf" for CF.sub.3(CF.sub.2).sub.3SO.sub.2--; and "TMOF" for
trimethylorthoformate.
[0031] Abbreviations as used herein, are defined as follows:
"1.times." for once, "2.times." for twice, "3.times." for thrice,
".degree. C." for degrees Celsius, "eq" for equivalent or
equivalents, "g" for gram or grams, "mg" for milligram or
milligrams, "L" for liter or liters, "mL" for milliliter or
milliliters, ".mu.L" for microliter or microliters, "N" for normal,
"M" for molar, "mmol" for millimole or millimoles, "min" for minute
or minutes, "h" for hour or hours, "rt" for room temperature, "RT"
for retention time, "atm" for atmosphere, "psi" for pounds per
square inch, "conc." for concentrate, "sat" or "satd." for
saturated, "MW" for molecular weight, "mp" for melting point, "ee"
for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry,
"ESI" for electrospray ionization mass spectroscopy, "HR" for high
resolution, "HRMS" for high resolution mass spectrometry, "LCMS"
for liquid chromatography mass spectrometry, "HPLC" for high
pressure liquid chromatography, "RP HPLC" for reverse phase HPLC,
"TLC" or "tlc" for thin layer chromatography, "SFC" for
supercritical fluid chromatography, "NMR" for nuclear magnetic
resonance spectroscopy, "1H" for proton, ".delta." for delta, "s"
for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m"
for multiplet, "br" for broad, "Hz" for hertz, and "R", "S", "E",
and "Z" are stereochemical designations familiar to one skilled in
the art.
LC-MS Methods:
Method A:
[0032] Column: XBridge Phe 8, 4.6.times.30 mm, 5 .mu.m; Solvent
A=2% AcCN: 98% H2O: 10 mM NH.sub.4COOH; Solvent B=98% AcCN: 2% H2O:
10 mM NH.sub.4COOH; gradient 0-100% B over 1.5 min; 3.2 min run
time.
Method B:
[0033] Column: ZORBAX SB C18, 4.6.times.50 mm, 5 .mu.m; Solvent
A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% AcCN: 10% H2O: 0.1%
TFA; gradient 0-100% B over 2 min; 3 min run time.
Method C:
[0034] Column: ZORBAX SB AQ, 4.6.times.50 mm, 3.5 rpm; Solvent
A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% AcCN: 10% H2O: 0.1%
TFA; gradient 0-100% B over 2 min; 3 min run time.
Method D:
[0035] Column: Purospher@star RP-18, 4.times.55 mm, 3 .mu.m;
Solvent A=10% AcCN: 90% H2O: 20 mM NH4OAc; Solvent B=90% AcCN: 10%
H2O: 20 mM NH4COOH; gradient 0-100% B over 1.5 min; 3.2 min run
time.
Method E:
Column: Ascentis Express C18, 50.times.4.6 mm, 5 .mu.m; Solvent
A=2% AcCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% AcCN: 2% H2O: 10
mM NH4COOH;
[0036] gradient 0-100% B over 1.5 min.
Method F:
[0037] Column: Ascentis Express C18, 50.times.2.1 mm, 2.7 .mu.m;
Solvent A=2% AcCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% AcCN: 2%
H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min.
Method G:
[0038] Column: XBridge Phenyl, 4.6.times.150 mm, 3.5 .mu.m; Solvent
A=5% AcCN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% AcCN: 5% H2O:
0.05% TFA pH=2.5; gradient 0-100% B.
Method H:
[0039] Column: Sunfire C18, 4.6.times.150 mm, 3.5 .mu.m; Solvent
A=5% AcCN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% AcCN: 5% H2O:
0.05% TFA pH=2.5; gradient 0-100% B.
Method I:
[0040] Column: Eclipse XDB C18, 4.6.times.150 mm, 3.5 .mu.m;
Solvent A=20 mM NH4Oac in water; Solvent B=AcCN: Gradient
0-100%.
Method J:
[0041] Column: Acquity UPLC BEH C18, 50.times.2.1 mm, 1.7 .mu.m;
Solvent A=0.1% TFA in water; Solvent B: 0.1% TFA in AcCN; gradient
2-98% B over 1.6 min.
Method K:
[0042] Column: Ascentis Express C8, 50.times.2.1 mm, 2.7 .mu.m;
Solvent A=2% AcCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% AcCN: 2%
H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min).
Method L:
[0043] Column: ACE Excel 2 C18, (50.times.3.0 mm-2 .mu.m); Solvent
A=2% ACN-98% H2O: 10 mM NH4COOH; Solvent B=98% ACN:2% H2O: 10 mM
NH4COOH; gradient 0-100% B over 1.8 min) Flow=1.2 mL/min T=40 C
Method M: Column: X-Bridge BEH C18; 50.times.2.1 mm, 2.5 u; Solvent
A: 2% ACN-98% H20-0.1% TFA; Solvent B: 98% ACN-2% H20-0.1% TFA
Flow: 1.2 ml/min; T=50 C Time (min.); gradient 0-100% B over 2.6
min Method N: Column: Ascentis Express C18 4.6.times.50 mm, 2.7
.mu.m; Solvent A: 5:95 Acetonitrile:water with 10 mM NH4OAc;
Solvent B: 95:5 Acetonitrile:water with 10 mM NH4OAc; Temperature:
50.degree. C.; Gradient: 0-100% B over 4 minutes; Flow: 4.0
ml/min.
Method O:
[0044] Column: Ascentis Express C18 4.6.times.50 mm, 2.7 .mu.m;
Solvent A: 5:95 Acetonitrile:water with 0.05% TFA; Solvent B: 95:5
Acetonitrile:water with 0.05% TFA; Temperature: 50.degree. C.;
Gradient: 0-100% B over 4 minutes; Flow: 4.0 ml/min Method P:
Column: Acquity BEH C18 (2.1.times.50 mm) 1.7 u; Buffer: 10 mM
Ammonium Acetate pH 5 adjusted with HCOOH; Solvent A: Buffer: ACN
(95:5); Solvent B: Buffer: ACN (5:95); Gradient: % B: O min-5%:1.1
min-95%:1.7 min-95% Method 0: Column: Ascentis Express C18
2.1.times.50 mm, 2.7 .mu.m; Solvent A: 5:95 Acetonitrile:water with
0.1% TFA; Solvent B: 95:5 Acetonitrile:water with 0.05% TFA;
Temperature: 50.degree. C.; Gradient: 0-100% B over 3 minutes;
Flow: 1.1 ml/min Method S: Column: Xbridge C18 (50.times.2.1 mm)
2.5 u; Solvent A: 10 mM NH4COOH; Solvent B Acetonitrile, gradient
0-100% B over 1.7 minutes, 100% B for 1.5 minutes Method T: Column:
Phenomenex LUNA C18, 50.times.2, 3 um; Solvent A: 5% ACN:95%
Water:10 mM Ammonium Acetate; Solvent B: 95% ACN:5% Water:10 mM
Ammonium Acetate; Gradient: 0-100% B over 4 min Method U: Column:
PHENOMENEX-LUNA 2.0.times.50 mm 3 um; Solvent A: 95% Water:5%
methanol:0.1% TFA; Solvent B=5% Water:95% methanol:0.1% TFA;
Gradient 0-100% B over 4 min
Method V
[0045] Column: Xbridge BEH C18 (2.1.times.50 mm), 2.5 .mu.m;
Solvent A: 0.1% HCOOH/water; Solvent B: 0.07% HCOOH/acetonitrile;
Gradient 0-100% B over 1.5 min, stop time 4 min Method 100: Column:
Xbridge C.sub.18 4.6.times.50 mm, 5 .mu.m; Solvent A: water with 10
mM NH.sub.4OAc; Solvent B: methanol; Gradient: 5-95% B over 4
minutes; Flow: 4.0 ml/min.
Method 107
[0046] Column: Xbridge C.sub.18 2.1.times.50 mm, 2.5 .mu.m; Solvent
A: water with 10 mM NH.sub.4HCO.sub.3; Solvent B: Acetonitrile;
Gradient: 0-100% B over 1.7 minutes; then 100% B for 1.5 min.
Method 109
[0047] Column: Kinetex C.sub.18 2.1.times.50 mm, 2.6 .mu.m; Solvent
A: 2:98 acetonitrile/water with 10 mM ammonium formate; Solvent B:
98:2 acetonitrile/water with 10 mM ammonium formate; Gradient:
0-100% B over 1.7 minutes; then 100% B for 1.5 min.
[0048] CZ-1:
Column: Waters Aquity UPLC BEH C.sub.18 2.1.times.50 mm 1.7 .mu.m;
Solvent A: 100% water:0.05% TFA; Solvent B: 100% acetonitrile:0.05%
TFA; Gradient: 2 to 98% B over 1.5 minutes
CZ-2
[0049] Column: X-BRIDGE C.sub.18 2.1.times.50 mm, 3.5 um; Solvent
A:5% Water:95% methanol:0.1% TFA; Solvent B: 95% Water:5%
methanol:0.1% TFA; Gradient: 0 to 100% B over 4 minutes
Chiral HPLC Methods:
Method A:
[0050] Column: CHIRALPAK AD-H (250.times.4.6) mm 5 .mu.m; Mob.
Phase: 0.2% DEA in n-hexane: IPA (80:20)
Method A-2:
[0051] Column: CHIRALPAK AD-H (250.times.21) mm, 5 .mu.m; Mob.
Phase: 0.2% DEA in n-hexane: IPA (70:30)
Method A-3:
[0052] Column: CHIRALPAK AD-H (250.times.4.6) mm, 5 .mu.m; Mob.
Phase: 0.2% DEA in n-hexane: IPA (70:30)
Method A-4:
[0053] Column: CHIRALPAK AD-H (250.times.4.6) mm, 5 .mu.m; Mob.
Phase: 0.2% DEA in n-hexane: IPA (50:50)
Method B:
[0054] Column: CHIRALPAK-ASH (250.times.4.6) mm, 5 .mu.m; Mob.
Phase: 0.2% DEA in n-hexane:ethanol (70:30)
Method C:
[0055] Column: CHIRALPAK IC (250.times.4.6) mm, 5 .mu.m; Mob.
Phase: 0.1% TFA in n-hexane:ethanol (40:60)
Method D:
[0056] Column: CHIRALPAK IA (250.times.4.6) mm, 5 .mu.m; Mob.
Phase: 0.1% TFA in hexane:ethanol (50:50)
Method E:
[0057] Column: CHIRALPAK IC (250.times.4.6) mm, 5 .mu.m; Mob.
Phase: 0.05% TFA in H.sub.2O:acetonitrile (80:20)
Method F:
[0058] Column: CHIRALCEL ODH (250.times.4.6) mm, 5 .mu.m; Mob.
phase: 0.2% DEA in n-hexane:ethanol (30:70)
Method G (SFC):
[0059] Column: Lux Cellulose-2, (4.6.times.250) mm, 5 .mu.m;
co-solvent 0.3% DEA in methanol; flow rate 2.55 g/min, 15%
co-solvent, back pressure 100 bar
Method G-2 (SFC):
[0060] Column: Lux Cellulose-2, (4.6.times.250) mm, 5 .mu.m;
co-solvent 0.3% DEA in methanol, flow rate 2.55 g/min, 10%
co-solvent, back pressure 100 bar
Method H:
[0061] Column: Chiralcel OJ (21.times.250 mm) 10 .mu.m; Mob. Phase
0.1% diethylamine/heptane:ethanol (40:60)
Method H-2:
[0062] Column: Chiralcel OJ (4.6.times.100 mm) 10 .mu.m; Mob. Phase
0.1% diethylamine/heptane:ethanol (40:60)
Method H-3:
[0063] Column: Chiralcel OJ (4.6.times.250 mm) 5 .mu.m; Mob. Phase
0.1% diethylamine/hexane:ethanol (50:50)
Method H-4:
[0064] Column: Chiralcel OJ (4.6.times.250 mm) 5 .mu.m; Mob. Phase
0.2% diethylamine/hexane:ethanol (50:50)
Chiral SFC Methods:
Method A1:
[0065] Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 50; Total flow: 3 g/min; Back pressure: 93 bar.
Method A2:
[0066] Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 50; Total flow: 3 g/min; Back pressure: 100 bar;
Method A3:
[0067] Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 40; Total flow: 3 g/min; Back pressure: 101 bar
Method A4:
[0068] Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 40; Total flow: 3 g/min; Back pressure: 101 bar
Method A5:
[0069] Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 20; Total flow: 3 g/min; Back pressure: 101 bar
Method B 1:
[0070] Column: CHIRALCEL OD H; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 30; Total flow: 3 g/min; Back pressure: 100 bar
Method C1:
[0071] Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 20; Total flow: 3 g/min; Back pressure: 100 bar
Method C2:
[0072] Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 20; Total flow: 3 g/min; Back pressure: 99 bar
Method C3:
[0073] Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 40; Total flow: 3 g/min; Back pressure: 97 bar
Method C4:
[0074] Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co
Solvent %: 30; Total flow: 3 g/min; Back pressure: 102 bar
Method C5:
[0075] Column: CHIRALPAK AD H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 30; Total flow: 3 g/min; Back
pressure: 102 bar
Method C6:
[0076] Column: CHIRALPAK AD H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 45; Total flow: 3 g/min; Back
pressure: 102 bar
Method C7:
[0077] Column: CHIRALPAK AD H (250.times.21 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 45; Total flow: 60 g/min; Back
pressure: 102 bar.
Method C8:
[0078] Column: CHIRALPAK AD H (250.times.21 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 30; Total flow: 60 g/min; Back
pressure: 102 bar.
Method D:
[0079] Column: Lux Cellulose-2 (250.times.21.2) mm, 5u; Co Solvent:
0.3% DEA in methanol; Co Solvent %: 20; Total flow: 60 g/min; Back
pressure: 100 bar.
Method E:
[0080] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 60; Total flow: 3 g/min; Back
pressure: 102 bar.
Method F:
[0081] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent 30%; Total flow: 3 g/min; Back
pressure: 102 bar.
Method G:
[0082] Column: Whelk O1 (R,R), 250.times.4.6 mm, 5u; Co-solvent
0.3% DEA in methanol, cosolvent 35%; total flow 4 g/min,
backpressure 102 bar
Method H:
[0083] Column: Whelk O1 (R,R), 250.times.4.6 mm, 5u; Co-solvent
0.3% DEA in methanol, cosolvent 30%; total flow 4 g/min,
backpressure 102 bar
Method H-1:
[0084] Column: Whelk O1 (R,R), 250.times.30 mm, 5u; Co-solvent 0.3%
DEA in methanol, cosolvent 25%; total flow 120 g/min, backpressure
102 bar
Method I:
[0085] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent 35%: Total flow: 3 g/min; Back
pressure: 102 bar.
Method J:
[0086] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent 20%; Total flow: 3 g/min; Back
pressure: 102 bar.
Method K:
[0087] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent 40%; Total flow: 80 g/min; Back
pressure: 102 bar.
Method L:
[0088] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent 25%; Total flow: 100 g/min; Back
pressure: 102 bar.
Method 101:
[0089] Column: Lux Cellulose-2 (250.times.21.2) mm, 5u; Co Solvent:
0.3% DEA in methanol; Co Solvent %: 40; Total flow: 70 g/min; Back
pressure: 100 bar.
Method 104:
[0090] Column: CHIRALPAK AD H (250.times.30 mm, 5 .mu.m); Co
Solvent: 0.3% DEA in methanol; Co Solvent %: 40; Total flow: 70
g/min; Back pressure: 100 bar.
Method 105:
[0091] Column: CHIRALPAK AD H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 45; Total flow: 3 g/min; Back
pressure: 100 bar.
Method 106:
[0092] Column: CHIRALPAK AD H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 40; Total flow: 4 g/min; Back
pressure: 100 bar.
Method 108:
[0093] Column: CHIRALPAK AS H (250.times.4.6 mm, 5u); Co Solvent:
0.3% DEA in methanol; Co Solvent %: 30; Total flow: 3 g/min; Back
pressure: 100 bar.
Analytical HPLC Methods:
Method A:
[0094] Column: Waters analytical C18 Sunfire (4.6.times.150 mm, 3.5
.mu.m); Mobile phase: Buffer: 0.05% TFA in H.sub.2O pH=2.5 adjusted
with ammonia; Solvent A=buffer and acetonitrile (95:5), Solvent
B=acetonitrile and buffer (95:5); 0-15 min, 0% B.fwdarw.50% B;
15-18 min, 50% B.fwdarw.100% B; 18-23 min, 100% B; flow rate=1
mL/min; run time=28 min.
Method B:
[0095] Column: Waters analytical phenyl Xbridge column
(4.6.times.150 mm, 3.5 .mu.m); Mobile phase: Buffer: 0.05% TFA in
H.sub.2O pH=2.5 adjusted with ammonia; Solvent A=buffer and
acetonitrile (95:5), Solvent B=acetonitrile and buffer (95:5); 0-15
min, 0% B.fwdarw.50% B; 15-18 min, 50% B.fwdarw.100% B; 18-23 min,
100% B; flow rate=1 mL/min; run time=28 min.
Method C:
[0096] Column: Waters analytical C18 Sunfire (4.6.times.150 mm, 3.5
.mu.m); Mobile phase: Buffer: 0.05% TFA in H.sub.2O pH=2.5 adjusted
with ammonia; Solvent A=buffer and acetonitrile (95:5), Solvent
B=acetonitrile and buffer (95:5); 0-12 min, 10% B.fwdarw.100% B;
12-15 min, 100% B; flow rate=1 mL/min; run time=17 min.
Method D:
[0097] Column: Waters analytical phenyl Xbridge column
(4.6.times.150 mm, 3.5 .mu.m), mobile phase: Buffer: 0.05% TFA in
H.sub.2O pH=2.5 adjusted with ammonia; solvent A=buffer and
acetonitrile (95:5), Solvent B=acetonitrile and buffer (95:5); 0-12
min, 10% B.fwdarw.100% B; 12-15 min, B.fwdarw.100% B; flow rate=1
mL/min; run time=17 min.
Method E:
[0098] Column: Waters analytical phenyl Xbridge (4.6.times.150 mm,
3.5 .mu.m), Mobile phase: Solvent A=10 mM NH.sub.4HCO.sub.3 in
H.sub.2O, pH=9.5 adjusted with ammonia, Solvent B=methanol; 0-12
min, 10% B.fwdarw.100% B; 12-20 min, B.fwdarw.100% B; flow rate=1
mL/min; run time=23 min.
Method F:
[0099] Column: Waters analytical C18 Sunfire (4.6.times.150 mm, 3.5
.mu.m); Mobile phase: Buffer: 0.05% TFA in H.sub.2O pH=2.5 adjusted
with ammonia, Solvent A=buffer and acetonitrile (95:5), Solvent
B=acetonitrile and buffer (95:5); 0-25 min, 10% B.fwdarw.100% B;
25-30 min, 100% B; flow rate=1 mL/min; run time=32 min.
Method G:
[0100] Column: ECLIPSE XDB C18 (4.6.times.150 mm, 3.5 .mu.m);
Mobile phase; Solvent A=20 mM NH.sub.4OAc in H.sub.2O, Solvent
B=acetonitrile; 0-12 min, 10% B.fwdarw.100% B; 12-15 min, 100% B;
flow rate=1 mL/min; run time=18 min.
Method H:
[0101] Column: Waters analytical phenyl Xbridge (4.6.times.150 mm,
3.5 .mu.m); Mobile phase: Buffer: 0.05% TFA in H.sub.2O pH=2.5
adjusted with ammonia, solvent A=buffer and acetonitrile (95:5),
Solvent B=acetonitrile and buffer (95:5); 0-25 min, 10%
B.fwdarw.100% B; 25-30 min, 100% B; flow rate=1 mL/min; run time=32
min.
Method I:
[0102] Column: Waters analytical phenyl Xbridge (4.6.times.150 mm,
3.5 .mu.m), Mobile phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O
pH=9.5 adjusted with ammonia, B=methanol; 0-25 min, 10%
B.fwdarw.100% B; 25-30 min, B.fwdarw.100% B; flow rate=1 mL/min;
run time=30 min.
Method J:
[0103] Column: ECLIPSE XDB C.sub.18 (4.6.times.150 mm, 5 .mu.m);
Mobile phase: A=20 mM NH.sub.4OAc in H.sub.2O, B=acetonitrile; 0-25
min, 10% B.fwdarw.100% B; 25-30 min, 100% B; flow rate=1 mL/min;
run time=30 min.
Method K:
[0104] Column: Waters analytical phenyl Xbridge (4.6.times.150 mm,
3.5 .mu.m), Mobile phase: A=10 mM NH.sub.4HCO.sub.3 in H.sub.2O
pH=9.5 adjusted with ammonia, B=methanol; 0-15 min, 0% B.fwdarw.50%
B; 15-18 min, 50%-100% B; 18-23 min, 100% B; flow rate=1 mL/min;
run time=25 min.
Method L:
[0105] Column: ECLIPSE XDB C.sub.18 (4.6.times.150 mm, 5 .mu.m);
mobile phase: A=20 mM NH.sub.4OAc in H.sub.2O, B=acetonitrile; 0-15
min, 0% B.fwdarw.50% B; 15-18 min, 50%.fwdarw.100% B; 18-23 min,
100% B; flow rate=1 mL/min; run time=25 min.
Method M:
[0106] Column: Waters analytical phenyl Xbridge C.sub.18
(4.6.times.150 mm, 3.5 .mu.m), Mobile phase: A=20 mM NH4OAc in
H.sub.2O, B=acetonitrile; 0-25 min, 10% B.fwdarw.100% B; 25-30 min,
B.fwdarw.100% B; flow rate=1 mL/min; run time=30 min.
Method N:
[0107] Column: Waters analytical phenyl Xbridge C.sub.18 column
(4.6.times.150 mm, 3.5 .mu.m), Mobile phase: A=20 mM NH.sub.4OAc in
H.sub.2O, B=acetonitrile; 0-12 min, 10% B.fwdarw.100% B; 12-15 min,
B.fwdarw.100% B; flow rate=1 mL/min; run time=20 min.
Method O:
[0108] Column: Ascentis Express C.sub.18 (50.times.2.1 mm-2.7
.mu.M); Solvent A: 2% ACN-98% H20-10 mM NH.sub.4COOH, Solvent B:
98% ACN-2% H20-10 mM NH.sub.4COOH; Gradient 0-100% B over 1.7 min,
stop time 3.4 min.
Method P:
[0109] Column: XBridge Phenyl (150.times.4.6 mm) 3.5 .mu.M; Mobile
phase A:0.05% TFA in water:Acetonitrile (95:5), Mobile phase B:
Acetonitrile:0.05% TFA in water (95:5); Gradient 10-100% B over 12
min, stop time 15 min.
Method 102
[0110] Column: Ascentis Express c 18 (50.times.2.1 mm-2.7 .mu.M);
Solvent A: 5% ACN-95% H20-10 mM NH.sub.4COOH, Solvent B: 95% ACN-5%
H20-10 mM NH.sub.4COOH, Gradient from 0-100% B over 3 minutes.
Preparative HPLC Methods:
Method A:
[0111] Column: Symmetry C.sub.8 (300.times.19 mm.times.7); Mobile
phase A: 10 mM aqueous ammonium acetate, mobile phase B: methanol;
Isocratic run with 25% B in A; run time=20 minutes
Method B:
[0112] Column: Waters Xbridge C.sub.18, 19.times.150 mm, 5 .mu.m;
Guard Column: Waters XBridge C.sub.18, 19.times.10 mm, 5 .mu.m;
Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile
Phase B: 95:5 Acetonitrile:water with 10 mM NH.sub.4OAc; Gradient:
10-40% B over 25 minutes, followed by a 10 minute hold at 40% B and
5 minute hold at 100% B;
Method C:
[0113] Column: ODS (250.times.4.6 mm), 3.5u; Mobile phase A: 10 mM
ammonium acetate/water; Mobile phase B acetonitrile; gradient
50-100% B in A over 25 min
Method D:
[0114] Column: Waters Xbridge C.sub.18, 19.times.150 mm, 5 .mu.m;
Guard Column: Waters XBridge C.sub.18, 19.times.10 mm, 5 .mu.m;
Mobile Phase A: 5:95 methanol:water with 0.1% TFA; Mobile Phase B:
95:5 methanol:water with 0.1% TFA; Gradient: 10-30% B over 25
minutes, followed by a 10 minute hold at 30% B and 5 minute hold at
100% B;
Method E:
[0115] Column: Symmetry C18 (300.times.19 mm.times.7 u); Mobile
phase A 10 mM aqueous ammonium acetate, mobile phase B
acetonitrile; flow rate=16 mL/min, gradient run 20-55% B in A over
10 min; .lamda.=220 nm; run time=20 minutes
Method F:
[0116] Column: Xterra RP.sub.18 (250.times.19 mm, 5u); Mobile phase
A: 10 mM ammonium acetate pH 4.5, Mobile phase B: acetonitrile.
Flow 15 ml/min
Method 103:
[0117] Column: Sunfire C18 (150.times.4.6 mm.times.5 u); Mobile
phase A 10 mM aqueous ammonium acetate, Mobile phase B
acetonitrile; Gradient 0-100% B over 18 minutes; run time=20
minutes.
General Intermediates
1-Benzyl-3-bromopyrrolidin-2-ones/1-benzyl-3-bromopiperidin-2-ones
[0118] The synthetic intermediates in Table 1 were synthesized by a
procedure analogous to that reported in A. Kamal, et. al.,
Tetrahedron: Asymmetry, 2003, 14, 2587-2594, using substituted
benzylamines and the appropriate dibromo-alkanoyl chloride.
Representative Procedure (Intermediate 6)
Intermediate 6,
3-Bromo-1-(3-fluoro-4-methyl-benzyl)pyrrolidin-2-one
Step A
##STR00012##
[0120] To a stirring 0.degree. C. solution of
3-fluoro-4-methylbenzyl amine (2.0 g, 14 mmol) and
N-ethyl-N-isopropylpropan-2-amine (3.5 mL, 20 mmol) in
dichloromethane (30 mL) was added dropwise a solution of
2,4-dibromobutanoyl chloride (3.98 g, 15 mmol) in dichloromethane
(5 mL). After completion of the addition, the reaction was stirred
in the ice bath until all of the ice had melted, then it was
partitioned between ethyl acetate and water. The layers were
separated, the organic layer was washed with brine, and it was then
dried over magnesium sulfate. The drying agent was filtered off,
the solvent was evaporated, and the residue was dissolved in ethyl
acetate and subjected to silica gel chromatography in
10->25->100% ethyl acetate/hexane, collecting the main
component to yield 4.5 g (85%)
2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide. LCMS (method
CZ-1): RT 1.21 min, m/z 367.9 (MH.sup.+); .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.17 (t, J=7.7 Hz, 1H), 7.01-6.91 (m, 2H),
6.70 (br. s., 1H), 4.59 (dd, J=9.0, 4.9 Hz, 1H), 4.51-4.37 (m, 2H),
3.64-3.51 (m, 2H), 2.71 (dddd, J=15.0, 8.5, 6.1, 4.9 Hz, 1H), 2.51
(ddt, J=15.0, 9.2, 5.5 Hz, 1H), 2.27 (d, J=1.4 Hz, 3H).
Step B
##STR00013##
[0122] To a stirring suspension of NaH (0.76 g, 19 mmol) in
tetrahydrofuran (50 mL) was added dropwise over .about.1/2 hour a
solution of 2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide (4.5
g, 12.2 mmol) in tetrahydrofuran (30 mL) and the resulting mixture
was stirred at room temperature overnight. The reaction mixture was
then filtered and the solvent evaporated.
[0123] The residue was subjected to silica gel chromatography in
10-50% ethyl acetate/hexane, collecting 949 mg recovered starting
material and 2.28 g
3-bromo-1-(3-fluoro-4-methyl-benzyl)pyrrolidin-2-one (Intermediate
#6) as a white solid.
TABLE-US-00001 TABLE 1 Substituted
1-benzyl-3-bromo-pyrrolidin-2-ones/1-benzyl-3-
bromopiperidin-2-ones LCMS (Method) Int. RT LCMS No. Structure
(min) [M + H].sup.+ .sup.1H NMR 1 ##STR00014## (P) 0.85 272.4/
274.3 .sup.1H NMR (400 MHz, DMSO- d.sub.6) .delta. ppm 2.12-2.27
(m, 1 H) 2.56-2.68 (m, 1 H) 3.27 (dd, J = 7.78, 3.26 Hz, 2 H) 4.29-
4.38 (m, 1 H) 4.40-4.57 (m, 1 H) 4.73 (dd, J = 7.03, 3.01 Hz, 1 H)
7.04-7.35 (m, 4 H) 2 ##STR00015## (V) 2.30 268/ 270 .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 2.20- 2.30 (m, 1 H) 2.34 (s, 3
H) 2.54 (s, 1 H) 3.19 (s, 1 H) 3.36-3.45 (m, 1 H) 4.36- 4.54 (m, 3
H) 7.15 (s, 4 H) 2a ##STR00016## (K) 1.89 304/ 306 .sup.1H NMR (400
MHz, DMSO- d.sub.6) .delta. ppm 7.58 (d, J = 8.03 Hz, 2 H) 7.40 (d,
J = 8.53 Hz, 2 H) 7.03 (m, 1 H) 4.75 (dd, J = 7.53, 3.01 Hz, 1 H)
4.52- 4.59 (m, 1 H) 4.41-4.47 (m, 1 H) 3.33-3.39 (m, 1 H) 3.25-
3.32 (m, 1 H) 2.65 (dq, J = 14.62, 7.34 Hz, 1 H) 2.21 (ddt, J =
14.43, 6.65, 3.26, 3.26 Hz, 1 H) 3 ##STR00017## (P) 0.90 254.0/
256.0 300 MHz, DMSO-d6: .delta. 2.15- 2.24 (m, 1H), 2.49-2.52 (m,
1H), 3.23-3.28 (m, 2H), 4.35 (d, J = 15.00 Hz, 1H), 4.51 (d, J =
15.00 Hz, 1H), 4.74 (dd, J = 3.00, 7.20 Hz, 1H), 7.23- 7.40 (m, 5H)
4 ##STR00018## 300 MHz, DMSO-d6: .delta. 1.49 (dd, J = 3.30, 7.20
Hz, 3H), 2.11-2.18 (m, 1H), 2.49-2.63 (m, 1H), 2.95-3.03 (m, 1H),
3.38-3.41 (m, 1H), 4.71 (dd, J = 3.00, 7.20 Hz, 1H), 5.22- 5.24 (m,
1H), 7.28-7.41 (m, 5H), 5 ##STR00019## 300 MHz, DMSO-d6: .delta.
1.49 (d, J = 7.20 Hz, 3H), 2.11- 2.18 (m, 1H), 2.53-2.63 (m, 1H),
2.95-3.03 (m, 1H), 3.35- 3.41 (m, 1H), 4.70 (dd, J = 3.0, 7.20 Hz,
1H), 5.22-5.24 (m, 1H), 7.28-7.41 (m, 5H) 6 ##STR00020## (P) 0.90
286.3/ 288.3 .sup.1H NMR (400 MHz, chloroform -d) .delta. ppm 2.26
(d, J = 2.01 Hz, 5 H) 2.48-2.64 (m, 1 H) 3.20 (s, 1 H) 3.38- 3.49
(m, 1 H) 4.29-4.55 (m, 3 H) 6.92 (s, 2 H) 7.15 (s, 1 H) 7
##STR00021## 300 MHz, DMSO-d6: .delta. 1.90- 2.18 (m, 1H),
2.20-2.29 (m, 1H), 2.32-2.33 (m, 1H), 2.59- 2.62 (m, 1H), 2.88-3.01
(m, 3H), 3.21-3.25 (m, 1H), 4.74 (dd, J = 2.70, 6.90 Hz, 1H), 5.57
(t, J = 7.80 Hz, 1H), 7.08-7.11 (m, 1H), 7.23-7.32 (m, 3H) 8
##STR00022## (J) 0.92 282.0/ 284.0 9 ##STR00023## (P) 0.97 288.4/
290.3 .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.32 (d, J =
8.4, 2H), 7.20 (d, J = 8.4, 2H), 4.54 (d, J = 14, 1H), 4.48 (m,
1H), 4.74 (d, J = 14, 1H), 3.45-3.39 (m, 1H), 3.22-3.17 (m, 1H),
2.59-2.54 (m, 1H), 2.33-2.27 (m, 1H), 10 ##STR00024## (V) 1.94
306.0/ 307.9 400 MHz, MeOD: .delta. 2.34-2.29 (m, 1H), 2.67-2.72
(m, 1H), 3.39-3.32 (m, 1H), 3.52-3.46 (m, 1H), 4.42 (d, J = -15.20
Hz, 1H), 4.61 (d, J = -24.80 Hz, 2H), 7.17 (dd, J = -41.60, Hz,
2H), 7.48 (t, J = -15.60 Hz, 1H) 11 ##STR00025## (S) 1.85 289.9/
291.9 400 MHz, DMSO-d6: .delta. 7.41- 7.48 (m, 1H), 7.28-7.34 (m,
1H), 7.10-7.13 (m, 1H), 4.73- 4.76 (m, 1H), 4.36-4.50 (m, 2H),
3.27-3.31 (m, 2H), 3.36- 3.39 (m, 1H), 2.62-2.68 (m, 1H), 2.18-2.23
(m, 1H) 12 ##STR00026## (K) 1.96 320.0/ 322.0 400 MHz, DMSO-d6:
.delta. 6.98- 7.47 (m, 4H), 4.73 (dd, J = 14.00, Hz, 1H), 4.49 (d,
J = 19.60 Hz, 1H), 4.35 (d, J = 20.00 Hz, 1H), 3.22-3.29 (m, 2H),
2.56-2.68 (m, 1H), 2.15- 2.23 (m, 1H) 13 ##STR00027## (V) 3.14
282.0/ 284.0 .sup.1H NMR (400 MHz, chloroform -d) .delta. ppm 2.26
(d, J = 2.01 Hz, 5 H) 2.48-2.64 (m, 1 H) 3.20 (s, 1 H) 3.38- 3.49
(m, 1 H) 4.29-4.55 (m, 3 H) 6.92 (s, 2 H) 7.15 (s, 1 H) 14
##STR00028## (V) 2.02 302.0/ 304.0 15 ##STR00029## (F) 1.97 268.3/
270.2 .sup.1H NMR 400 MHz, MeOD: .delta. ppm 7.26-7.21 (m, 1H),
7.13- 7.05 (m, 2H), 4.62-4.53 (m, 2H), 4.35 (d, J = 14.7, 1H),
3.47-3.38 (m, 1H), 3.31-3.25 (m, 1H), 2.70-2.58 (m, 1H), 2.33-2.18
(m, 4H) 16 ##STR00030## (V) 1.73 284.0/ 286.1 .sup.1H NMR 300 MHz,
MeOD: .delta. ppm 7.22 (d, J = 6.6, 2H), 6.91 (d, J = 6.6, 2H),
4.60 (m, 1H), 4.54 (d, J = 15, 1H), 4.34 (d, J = 15, 1H), 3.78 (s,
3H), 3.46- 3.38 (m, 1H), 3.31-3.26 (m, 1H), 2.70-2.58 (m, 1H),
2.31- 2.23 (m, 1H) 17 ##STR00031## (P) 0.82/ 0.84 268.3/ 270.3
.sup.1H NMR (300 MHz, DMSO- d.sub.6) .delta. ppm 1.67-1.86 (m, 1 H)
1.90-2.19 (m, 2 H) 2.25- 2.42 (m, 1 H) 3.23-3.32 (m, 2 H) 4.41 (s,
1 H) 4.61 (s, 1 H) 4.73-4.85 (m, 1 H) 7.12- 7.44 (m, 5 H) 18
##STR00032## (P) 0.92 282.3/ 284.3 .sup.1H NMR (400 MHz, DMSO-
d.sub.6) .delta. ppm 1.67-1.84 (m, 1 H) 1.92-2.04 (m, 1 H) 2.04-
2.17 (m, 1 H) 2.29 (s, 4 H) 3.19-3.28 (m, 2 H) 4.24- 4.37 (m, 1 H)
4.53-4.64 (m, 1H) 4.72-4.82 (m, 1 H) 7.14 (d, J = 4.02 Hz, 4 H) 19
##STR00033## (P) 0.96 300.0/ 302.0 .sup.1H NMR (400 MHz, DMSO-
d.sub.6) .delta. ppm 1.65-1.85 (m, 1 H) 1.99 (s, 1 H) 2.21 (d, J =
1.51 Hz, 1 H) 2.27-2.40 (m, 3 H) 2.59-2.26 (s, 1 H) 3.24-3.32 (m,
2H) 4.36 (d, J = 15.06 Hz, 1 H) 4.57 (d, J = 15.06 Hz, 1 H) 4.79
(s, 1 H) 6.91-7.05 (m, 2 H) 7.25 (s, 1 H) 20 ##STR00034## (P) 0.99
302.3/ 304.3 .sup.1H NMR (300 MHz, DMSO- d.sub.6) .delta. ppm
1.68-1.87 (m, 1 H) 1.92-2.18 (m, 2 H) 2.22- 2.39 (m, 1 H) 3.20-3.29
(m, 2 H) 4.33-4.45 (m, 1 H) 4.53- 4.64 (m, 1 H) 4.74-4.83 (m, 1 H)
7.25-7.33 (m, 2 H) 7.35- 7.47 (m, 2 H)
Substituted (4-methoxyphenyl)cycloalkylamines
Intermediate 21: 4-(4-Methoxyphenyl)azepane
Step A tert-Butyl
4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate
##STR00035##
[0125] To a solution of 1-bromo-4-methoxybenzene (0.88 g, 4.7 mmol)
in THF (50 mL) was added n-butyllithium (2.9 mL, 4.7 mmol) at
-78.degree. C. The reaction mixture was stirred at -78.degree. C.
for 2 h, then added to a flask containing tert-butyl
4-oxoazepane-1-carboxylate (1 g, 4.7 mmol) in THF, cooled to
-78.degree. C. The reaction mixture was stirred at -78.degree. C.
for 30 min and then at 0.degree. C. for 15 min. It was then
quenched with saturated ammonium chloride solution and extracted
with ethyl acetate. The organic phase was dried over sodium
sulfate, filtered, and concentrated. The crude product was purified
by flash chromatography on silica gel using hexane/ethyl acetate as
the eluant to yield tert-butyl
4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 45%).
LCMS: R.T. 0.96 min. LCMS (ES-API), m/z 320 (M-H).
Step B 5-(4-Methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine
hydrochloride
##STR00036##
[0127] A mixture of HCl in dioxane (10 mL, 40 mmol) and tert-butyl
4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 2.1
mmol) was stirred at room temperature for 3 h. The reaction mixture
was concentrated and washed with diethyl ether and dried over
sodium sulfate to yield 0.36 g
5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride.
LCMS: R.T. 0.61 min. LCMS (ES-API), m/z 204.0 (M+H).
Step C 4-(4-Methoxyphenyl)azepane
##STR00037##
[0129] A mixture of
5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride
(0.35 g, 1.5 mmol) and 10% palladium on carbon (0.2 g) in methanol
(10 mL) was stirred overnight under balloon pressure of hydrogen.
The reaction mixture was filtered through Celite and concentrated
to yield 4-(4-methoxyphenyl)azepane (0.26 g, 1.2 mmol, 79%). LCMS:
R.T. 0.60 min. LCMS (ES-API), m/z 206.0 (M+H).
Intermediate 22: 3-(4-Methoxyphenyl)azepane
Step A tert-Butyl
3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate
##STR00038##
[0131] To a stirred solution of 1-bromo-4-methoxybenzene (0.67 mL,
5.4 mmol) in THF (50 mL) at -78.degree. C. was added n-butyllithium
(5 mL, 8 mmol) and the reaction mixture was stirred at -78.degree.
C. for 2 h. Then was added tert-butyl 3-oxoazepane-1-carboxylate
(1.14 g, 5.4 mmol) at -78.degree. C. and the reaction mixture was
warmed to room temperature over 12 h. It was then quenched with
saturated NH.sub.4Cl at 0.degree. C., and extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel
(24 g) using 10% ethyl acetate in hexane to yield tert-butyl
3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate (1.2 g, 57%) as
a colorless gum. LCMS: R.T. 1.03 min. LCMS (ES-API), m/z 204
(M-117).
Step B 6-(4-Methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine
hydrochloride
##STR00039##
[0133] A solution of tert-butyl
3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate (0.25 g, 0.78
mmol) in HCl (4M solution in dioxane) (3 mL, 12 mmol) was stirred
at room temperature for 5 h. The reaction mixture was concentrated
and the residue was triturated with diethyl ether to yield
6-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine hydrochloride
(0.18 g, 62%) as a black gum. LCMS: R.T. 0.60 min. LCMS (ES-API),
m/z 204 (M+1).
Step C 3-(4-Methoxyphenyl)azepane hydrochloride
##STR00040##
[0135] A mixture of
6-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine hydrochloride
(0.3 g, 1.251 mmol) and 10% Pd--C (0.133 g, 1.251 mmol) in methanol
(5 mL), was hydrogenated at 50 psi for 12 h. The reaction mixture
was filtered through Celite and concentrated to yield crude
3-(4-methoxyphenyl)azepane hydrochloride (0.2 g, 57%) as a black
gum, used without further purification. LCMS: RT 0.62 min. LCMS
(ES-API), m/z 206.1 (M+1).
Intermediate 24: 4-(4-Methoxyphenyl)piperidine hydrochloride
Step A tert-Butyl
4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate
##STR00041##
[0137] A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (2 g,
10.04 mmol) and diethyl ether (30 ml) was cooled to 0.degree. C.,
followed by the dropwise addition of (4-methoxyphenyl)magnesium
bromide (0.5 M in diethyl ether, 30 ml, 15 mmol). The reaction
mixture was allowed to warm to rt and stirred for 2 h. It was then
slowly quenched with 150 ml of ice cold water and then the
resulting mixture was extracted with 3.times.150 ml of DCM. The
organic layers were combined, dried, filtered, and concentrated
under vacuum. The crude product was purified by silica gel
chromatography eluting with 30:70 ethyl acetate:hexane to provide 3
g tert-butyl 4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate
(100%). LCMS: RT 1.950 min. LCMS (ES-API), m/z 305.5 (M-H). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.37 (q, J=1.0 Hz, 2H), 6.86
(q, J=1.0 Hz, 2H), 4.94 (s, 1H), 3.82 (d, J=11.5 Hz, 2H), 3.73 (s,
3H), 3.13 (br. s, 2H), 1.75 (td, J=12.9, 4.8 Hz, 2H), 1.56 (d,
J=12.3 Hz, 2H), 1.41 (s, 9H).
Step B 4-(4-Methoxyphenyl)-1,2,3,6-tetrahydropyridine
hydrochloride
##STR00042##
[0139] A mixture of tert-butyl
4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (700 mg, 2.27
mmol) from Step A and HCl in dioxane (4 ml, 16 mmol) was stirred at
rt for 3 h.
[0140] The crude mass was concentrated under vacuum and the solid
residue was washed with 3.times.10 ml of DCM to remove non-polar
impurities. The desired salt was collected as a fine solid (480 mg,
93%). LCMS: RT 1.27 min. LCMS (ES-API), m/z 190.2 (M+H). NMR:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.37 (d, J=9.0 Hz, 2H),
6.98 (d, J=9.0 Hz, 2H), 6.08-5.98 (m, 1H), 5.11 (s, 1H), 3.97 (br.
s., 1H), 3.52 (s, 1H), 3.32 (s, 3H), 2.47-2.37 (m, 1H).
Step C 4-(4-Methoxyphenyl)piperidine hydrochloride
##STR00043##
[0142] To a stirred solution of
4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine, HCl (3 g, 13.3
mmol) (from step B) in methanol (20 mL) was added 10% palladium on
carbon (1.4 g) and the reaction mixture was stirred at 20 psi of
hydrogen for 12 h. The reaction mixture was filtered through a pad
of celite, which was washed with ethyl acetate, and the combined
organic fractions were concentrated to obtain a white solid (2 g,
70% yield). LCMS (ES-API), m/z 192.1 (M+H); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.13-8.36 (m, 2H), 7.14 (d, J=8.7 Hz, 2H),
6.90 (d, J=8.7 Hz, 2H), 3.73 (s, 3H), 3.07-2.87 (m, 4H), 2.87-2.65
(m, 4H).
Intermediate 24 trans-4-(4-Methoxyphenyl)piperidin-3-ol
Step A: trans-1-Benzyl-4-(4-methoxyphenyl)piperidin-3-ol
##STR00044##
[0144] To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol)
in THF (200 mL) 0.degree. C. was added dropwise boron trifluoride
etherate (8.8 mL, 70 mmol) under a nitrogen atmosphere and the
resulting mixture was stirred for 30 minutes. Then was added
1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36
mmol) (from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100
mL of tetrahydrofuran. Stirring was continued at rt for 2 hours.
The reaction was then quenched by the dropwise addition of 100 mL
water. Next were added sequentially 100 mL ethanol, 100 mL 10%
aqueous sodium hydroxide, and hydrogen peroxide (18 mL, 18 mmol)
and the temperature was raised to reflux overnight. The reaction
mixture was diluted with saturated aqueous ammonium chloride (200
mL), and extracted with ethyl acetate (500 mL). The organic layer
was dried over Na.sub.2SO.sub.4, filtered, and evaporated under
reduced pressure to give
trans-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol,
69% yield). LCMS (Method K) RT 1.99 min; m/z 298.0 (MH.sup.+).
Step B: trans-4-(4-Methoxyphenyl)piperidin-3-ol
##STR00045##
[0146] To a solution of
trans-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in
methanol (150 mL) was added 10% Pd/C (4.8 g) and the reaction was
stirred overnight under a hydrogen atmosphere. The catalyst was
then removed by filtration through Celite and the solvent was
evaporated under reduced pressure to give (+/-)
trans-4-(4-methoxyphenyl)-piperidin-3-ol (5.1 g, 24.6 mmol, 81%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.10-7.15
(m, 2H) 6.80-6.86 (m, 2H) 4.30 (d, J=5.27 Hz, 1H) 3.37-3.43 (m, 1H)
3.04 (dd, J=11.58, 4.36 Hz, 1H) 2.86 (d, J=12.17 Hz, 1H) 2.43 (td,
J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m, 2H) 1.57-1.63 (m, 1H) 1.43-1.54
(m, 1H).
Intermediate 25. 3-(4-Methoxyphenyl)piperidine
##STR00046##
[0147] Step A: 1-Benzyl-3-(4-methoxyphenyl)piperidin-3-ol
##STR00047##
[0149] To a solution of 1-benzylpiperidin-3-one (5 g, 26 mmol) in
THF (30 mL) was added (4-methoxyphenyl)magnesium bromide (0.5 M in
ether) (66 mL, 33 mmol) at rt under a nitrogen atmosphere. The
reaction was stirred for 2 h and then diluted with sat. ammonium
chloride solution and extracted with ethyl acetate (200 mL). The
organic layer was dried over Na2SO4 and evaporated under reduced
pressure to give crude 1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol
(5.1 g, 10.29 mmol, 38.9% yield) with was used in the next step
without further purification. LCMS (Method 107): (ES-API), m/z
298.2 (M+H) RT=1.703 min.
Step B: 1-Benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
##STR00048##
[0151] To a solution of 1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol
(3.5 g, 11.8 mmol) in dioxane (20 mL) was added concentrated HCl
(3.6 mL, 43 mmol) and the reaction mixture was stirred overnight.
The solvents were evaporated under reduced pressure and the residue
was diluted with sat. bicarbonate solution (200 mL) and extracted
with ethyl acetate (200 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the
crude product which was purified via silica gel chromatography
eluting with 30% ethyl acetate in hexane to give
1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1.5 g, 4.2
mmol, 35.6% yield). LCMS (Method 107): (ES-API), m/z 280.2 (M+H)
RT=2.263 min; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.42-7.32
(m, 4H), 7.29-7.19 (m, 3H), 6.91-6.82 (m, 2H), 6.16-5.97 (m, 1H),
3.73 (s, 3H), 3.65 (d, J=2.6 Hz, 3H), 3.23 (d, J=1.9 Hz, 2H), 2.55
(s, 1H), 2.24 (d, J=3.8 Hz, 2H).
Step C: 3-(4-Methoxyphenyl)piperidine
##STR00049##
[0153] To a solution of
1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1.5 g, 5.4
mmol) in 50 mL of methanol was added 10% Pd/C (1.14 g). Hydrogen
gas was introduced via balloon and the reaction mixture was stirred
overnight at rt. The reaction mixture was then filtered through
Celite, and the filter pad was washed with additional methanol (100
mL). The filtrates were combined, and the methanol was evaporated
under reduced pressure to give 3-(4-methoxyphenyl)piperidine (950
mg, 3.73 mmol, 69.4% yield). LCMS (Method 107): (ES-API), m/z 192.2
(M+H) RT=1.497 min; .sup.1H NMR (300 MHz, DMSO-d6) .delta. 7.13
(dt, J=8.5, 2.0 Hz, 2H), 6.84 (dt, J=8.5, 2.2 Hz, 2H), 3.72 (s,
3H), 3.17 (s, 2H), 2.93 (d, J=10.6 Hz, 2H), 2.49-2.39 (m, 1H), 1.81
(d, J=1.9 Hz, 1H), 1.74-1.57 (m, 1H), 1.57-1.40 (m, 2H).
Intermediate 26 3-(4-Methoxyphenyl)azetidine
Step A. tert-Butyl
3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate
##STR00050##
[0155] To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (4
g, 23 mmol) in THF (100 mL) at 0.degree. C. was added
(4-methoxyphenyl)magnesium bromide (0.5 M in ether) (47 mL, 23
mmol). The reaction mixture was stirred for 3 h, and then a satd.
ammonium chloride solution (200 mL) was added. The mixture was
extracted with ethyl acetate (200 mL), and the organic layer was
separated, dried over Na2SO4, and evaporated under reduced pressure
to give a crude product. The product was purified by silica gel
chromatography eluting with 25% ethyl acetate in hexane to give
tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate
(2.2 g, 7.64 mmol, 32.7% yield). LCMS (Method 107): m/z 280.7 (M+H)
RT=1.929 min; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.39 (d,
J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.21 (s, 1H), 4.00 (s, 3H),
3.75 (s, 3H), 1.41 (s, 9H).
Step B tert-Butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate
##STR00051##
[0157] To a solution of tert-butyl
3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (1.1 g, 3.9
mmol) in DCM (15 mL) at 0.degree. C. was added triethylsilane (5
mL, 31 mmol) followed by TFA (1 mL, 13.8 mmol). The reaction
mixture was allowed to warm to rt and stirred overnight. The
mixture was then diluted with a satd. sodium bicarbonate solution
and extracted with DCM (100 mL). The organic layer was separated,
dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced
pressure to give a crude product which was purified by silica gel
chromatography eluting with 10% ethyl acetate in hexane to give
pure tert-butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate (380 mg,
1.37 mmol, 34.8% yield). LCMS (Method 107): (ES-API), m/z 264.0
(M+H) RT=2.128 min; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.31-7.20 (m, 2H), 6.96-6.87 (m, 2H), 4.27-4.17 (m, 2H), 3.82-3.69
(m, 6H), 1.41 (s, 9H).
Step C 3-(4-Methoxyphenyl)azetidine
##STR00052##
[0159] To a solution of tert-butyl
3-(4-methoxyphenyl)azetidine-1-carboxylate (380 mg, 1.4 mmol) in
methanol (10 mL) was added conc HCl (0.44 mL, 5.2 mmol) and the
reaction mixture was stirred at rt for 3 h. The solvents were
removed by evaporation under reduced pressure and the solid residue
was washed with diethyl ether three times (3.times.10 mL) and then
dried under reduced pressure to give 3-(4-methoxyphenyl)azetidine,
HCl (125 mg, 0.6 mmol, 41% yield). LCMS (Method 107): (ES-API), m/z
164.0 (M+H) RT=1.386 min; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.39 (br. s., 1H), 9.12 (br. s., 1H), 7.37 (dt, J=8.5, 2.5
Hz, 2H), 6.96 (dt, J=8.5, 2.5 Hz, 2H), 4.31-4.13 (m, 2H), 4.12-3.89
(m, 3H), 3.76 (s, 3H).
Intermediate 27. 4-(4-Methoxy-2-methylphenyl)piperidine, HCl
Step A. tert-Butyl
4-hydroxy-4-(4-methoxy-2-methylphenyl)piperidine-1-carboxylate
##STR00053##
[0161] A solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g,
10 mmol) in diethyl ether (100 mL) was chilled to 0.degree. C., and
a solution of (4-methoxy-3-methylphenyl)magnesium bromide (0.5 M in
ether) (20 mL, 10 mmol) was added.
[0162] The reaction mixture was allowed to warm to rt and stirred
for 12 h. The reaction mixture was then quenched with a saturated
NH.sub.4Cl solution and the mixture was diluted with ethyl acetate.
The organic layer was separated, washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, and then evaporated under reduced
pressure to provide the desired product (2.3 g, 71%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.27 (d, J=8.0 Hz, 1H), 6.75-6.61
(m, 2H), 4.83 (s, 1H), 3.85-3.77 (m, 2H), 3.71 (s, 3H), 3.17 (d,
J=5.0 Hz, 2H), 2.51 (s, 3H), 1.82-1.73 (m, 4H), 1.41 (s, 9H).
Step B. 4-(4-Methoxy-2-methylphenyl)-1,2,3,6-tetrahydropyridine
hydrochloride
##STR00054##
[0164] A solution of tert-butyl
4-hydroxy-4-(4-methoxy-2-methylphenyl)piperidine-1-carboxylate (2.3
g, 7.2 mmol) in 1,4-dioxane (20 mL) was chilled to 0.degree. C. and
treated with a solution of HCl in dioxane (4.0 M, 1.8 mL, 7.2
mmol). The reaction mixture was stirred at rt for 12 h, and then
the solvents were evaporated to provide a crude compound which was
triturated with diethyl ether to provide the desired product as a
solid (1.2 g, 82%). LC/MS (Method P) RT=0.63 min.
(M+H).sup.+=204.0; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.51-9.09 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.79-6.71 (m, 2H), 5.52
(t, J=1.5 Hz, 1H), 3.73 (s, 3H), 3.67 (br. s., 2H), 3.26 (d, J=4.5
Hz, 2H), 2.45 (d, J=1.9 Hz, 2H), 2.25 (s, 3H)
Step C. 4-(4-Methoxy-2-methylphenyl)piperidine, HCl
##STR00055##
[0166] To a solution of
4-(4-methoxy-2-methylphenyl)-1,2,3,6-tetrahydropyridine (500 mg,
2.5 mmol) in MeOH (20 mL) was added 10% Pd/C (524 mg). Hydrogen gas
was introduced under balloon pressure and the reaction mixture was
stirred vigorously for 12 h. The reaction mixture was filtered
through a glass fiber filter cartridge, and the filter pad was
washed with ethyl acetate. The combined organic layers were
evaporated under reduced pressure to give
4-(4-methoxy-2-methylphenyl)piperidine, hydrochloride (500 mg, 87%
yield). LC/MS (Method P) RT=0.63 min. (M+H).sup.+=206.1; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.21-8.25 (m, 2H), 7.05 (d,
J=8.0 Hz, 1H), 6.78-6.71 (m, 2H), 3.71 (s, 3H), 3.30 (d, J=12.0 Hz,
2H), 3.02-2.86 (m, 3H), 2.29 (s, 3H), 1.87-1.65 (m, 4H).
Intermediate 28. 4-(3-Fluoro-4-methoxyphenyl)piperidine
hydrochloride
Step A. tert-Butyl
4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate
##STR00056##
[0168] To a solution of 4-bromo-2-fluoro-1-methoxybenzene (2 g, 9.7
mmol) in tetrahydrofuran (100 mL) at -78.degree. C. was added a
solution of n-butyllithium (1.6 M in hexanes, 7.9 mL, 12.7 mmol).
The reaction mixture was stirred in the cold for 2 h, and then a
solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.94 g, 9.7
mmol) in THF (10 mL) was added dropwise. The mixture was then
allowed to warm to rt and stir for 12 h. It was quenched with a
saturated NH.sub.4Cl solution and diluted with ethyl acetate. The
organic layer was separated, washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered, and evaporated under reduced
pressure. The crude product was purified by silica gel
chromatography to provide 2.0 g (63%) of the desired compound;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.29 (dd, J=13.3, 2.3
Hz, 1H), 7.24-7.18 (m, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.09 (s, 1H),
3.85 (br. s., 2H), 3.82 (s, 3H), 1.86-1.68 (m, 2H), 1.56 (d, J=12.0
Hz, 3H), 1.46-1.38 (m, 11H).
Step B. 4-(3-Fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
hydrochloride
##STR00057##
[0170] A solution of tert-butyl
4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (0.5
g, 1.5 mmol) in 1,4-dioxane (20 mL) was chilled to 0.degree. C. and
treated with a solution of HCl in 1,4 dioxane (4.0 M, 10 mL, 40
mmol). The reaction mixture was stirred at rt for 12 h, and then
the solvents were removed to provide a crude compound which was
triturated with diethyl ether to provide the desired product as a
solid (1.2 g, 82%). LC/MS (Method 109) RT=1.798 min.
(M+H).sup.+=207.8; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.51-9.09 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.79-6.71 (m, 2H), 5.52
(t, J=1.5 Hz, 1H), 3.73 (s, 3H), 3.67 (br. s., 2H), 3.26 (d, J=4.5
Hz, 2H), 2.45 (d, J=1.9 Hz, 2H), 2.25 (s, 3H)
Step C. 4-(3-Fluoro-4-methoxyphenyl)piperidine hydrochloride
##STR00058##
[0172] To a solution of
4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (300 mg,
1.4 mmol) in MeOH (10 mL) was added Pd/C (154 mg). Hydrogen gas was
introduced under balloon pressure and the reaction mixture was
stirred vigorously for 12 h. The reaction mixture was filtered
through a glass fiber filter cartridge, and the filter pad was
washed with ethyl acetate. The combined organic layers were
evaporated under reduced pressure to give
4-(4-methoxy-2-methylphenyl)piperidine (500 mg, 87% yield). LC/MS
(Method P) RT=0.60 min. (M+H).sup.+=210.1.
Racemic
1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2-ones
[0173] Racemic
1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2-ones and
-piperidones were synthesized by condensing the lactams from Table
I with cyclic amines 21-28 in the presence of a hindered amine
base. A representative procedure follows:
Intermediate A:
1-Benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00059##
[0175] A solution of 3-bromo-1-benzyl-pyrrolidin-2-one (1.4 g, 5.1
mmol)(intermediate 3), 4-(4-methoxyphenyl)-piperidine (0.98 g, 5.1
mmol) and DIPEA (3.6 mL, 20.6 mmol) in acetonitrile (15 mL) was
heated at 90.degree. C. for 18 h. The reaction mixture was
concentrated and the residue was dissolved in ethyl acetate (150
mL), washed with water and brine, and dried over sodium sulfate.
The organic layer was concentrated to yield 2.1 g of crude product,
which was purified by flash chromatography on silica gel (24 g)
using 100% EtOAc to yield
1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (1.4
g, 71%). 1H NMR: 400 MHz, DMSO-d6: .delta. ppm 1.51-1.65 (m, 2H)
1.66-1.77 (m, 2H) 1.86-1.98 (m, 1H) 2.02-2.12 (m, 1H) 2.27-2.45 (m,
2H) 2.66-2.83 (m, 2H) 2.99-3.23 (m, 3H) 3.45-3.54 (m, 1H) 3.72 (s,
3H) 4.29-4.46 (m, 2H) 6.85 (d, J=9.04 Hz, 2H) 7.16 (d, J=9.04 Hz,
2H) 7.19-7.24 (m, 2H) 7.28 (s, 1H) 7.32-7.39 (m, 2H). LCMS: R.T.
1.76 min. LCMS (ES-API), 365.2 m/z (M+H).
Intermediate B:
1-Benzyl-3-(3-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00060##
[0177] By a procedure analogous to the synthesis of
1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,
1-benzyl-3-(3-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one was
obtained from intermediate 3 and amine 25 (1.4 g, 71%). 1H NMR: 400
MHz, DMSO-d6: .delta. ppm 1.40 (br. s., 1H) 1.47-1.61 (m, 1H)
1.63-1.82 (m, 2H) 1.90-1.96 (m, 1H) 2.00-2.11 (m, 1H) 2.20 (s, 1H)
2.61 (br. s., 3H) 2.88-2.96 (m, 1H) 3.05-3.18 (m, 2H) 3.48 (d,
J=2.01 Hz, 2H) 3.72 (d, J=1.00 Hz, 3H) 4.25-4.45 (m, 2H) 6.82-6.89
(m, 2H) 7.11-7.22 (m, 4H) 7.24-7.35 (m, 3H). LCMS: R.T. 1.75-1.76
min. LCMS (ES-API), 365.2 m/z (M+H).
[0178] The intermediates C-AJ in Table 2 were prepared by combining
1-benzyl-3-bromo-pyrrolidin-2-ones and -piperidin-2-ones from Table
1 with amines 21-28.
TABLE-US-00002 TABLE 2 Racemic
1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2- ones LCMS
R.T. LCMS Ion Int. No. Structure (min) (M + H) C ##STR00061## 1.02
399.0 D ##STR00062## 1.11 397.2 E ##STR00063## 1.04 383.2 F
##STR00064## 1.92 379.2 G ##STR00065## 2.03 393.2 H ##STR00066##
2.53 393.2 I ##STR00067## 2.42 351.2 J ##STR00068## 0.82 417.0 K
##STR00069## 0.84 413.0 L ##STR00070## 0.93 337.2 M ##STR00071##
1.10 379.0 N ##STR00072## 1.99 401.0 O ##STR00073## 2.04 399.0 P
##STR00074## 2.04 431.0 Q ##STR00075## 2.01 373.0 R ##STR00076##
1.98 355.0 S ##STR00077## 1.02 379.2 T ##STR00078## 1.0 383.2 U
##STR00079## 0.77 379.2 V ##STR00080## 1.09 397.2 W ##STR00081##
0.83 379.1 X ##STR00082## 0.81 379.1 Y ##STR00083## 0.81 391.2 Z
##STR00084## 0.79 393.2 AA ##STR00085## 0.78 397.2 AB ##STR00086##
0.81 393.2 AC ##STR00087## 0.77 379.2 AD ##STR00088## 1.08 393.6 AE
##STR00089## 1.12 411.3 AF ##STR00090## 0.79 379.6 AG ##STR00091##
1.15 413.2 AH ##STR00092## 1.89 399.1 AI ##STR00093## 1.03 369.2 AJ
##STR00094## 1.04 383.2
[0179] Final compounds were prepared via cleavage of the methoxy
group of intermediates A-AJ using boron tribromide, followed in
some cases by chiral chromatography to separate the individual
enantiomers.
Example 1
1-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00095##
[0181] To a solution of
1-(4-fluorobenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
(AJ) (3 g, 7.9 mmol) in dry dichloromethane (100 mL) under a
N.sub.2 atmosphere at -78.degree. C. was added 1 M boron tribromide
in dichloromethane (39 mL, 39 mmol) and the resulting mixture was
allowed to warm up to room temperature over 3 h, with stirring. The
reaction was quenched with water (30 mL) and the organic layer was
separated, washed with water and brine, and concentrated. The crude
product was purified by flash chromatography on silica gel using
15% EtOAc in petroleum ether to yield racemic
1-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
(2.1 g, 73%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.49-1.74 (m, 4H) 1.90-2.11 (m, 2H) 2.24-2.42 (m, 2H) 2.65-2.80 (m,
2H) 2.99-3.23 (m, 3H) 3.40-3.54 (m, 1H) 4.27-4.46 (m, 2H) 6.61-6.70
(m, 2H) 6.95-7.04 (m, 2H) 7.17-7.31 (m, 4H) 9.10-9.16 (m, 1H).
LCMS: R.T. 0.880 min. LCMS (ES-API), 369.2 m/z (M+H). A portion of
the racemate (40 mg) was separated via SFC on a Chiralpak-IA 250
mm.times.4.6 mm, 5 micron column eluting with 35% solvent B, where
solvent A=CO.sub.2 and solvent B=0.3% DEA in methanol at a total
flow of 3 mL/min. Peak 1 showed a RT of 4.35 min and Peak 2 showed
a RT of 6.29 min.
Example 2a
(S)-1-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2--
one
##STR00096##
[0183] First eluting enantiomer, Peak 1, from the chiral separation
of Example 1. Yield 11 mg. LC/MS RT=1.275 min. (M+H)+=369.2;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.47-1.59 (m, 1H)
1.65-1.75 (m, 1H) 1.84-1.96 (m, 1H) 2.03-2.12 (m, 1H) 2.24-2.43 (m,
1H) 2.63-2.72 (m, 2H) 2.72-2.85 (m, 2H) 2.96-3.05 (m, 2H) 3.09-3.23
(m, 2H) 3.41-3.54 (m, 1H) 4.23-4.50 (m, 2H) 6.58-6.71 (m, 2H)
6.96-7.10 (m, 2H) 7.15-7.21 (m, 2H) 7.26-7.34 (m, 2H) 9.06-9.19 (m,
1H).
Example 2b
(R)-1-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-o-
ne
##STR00097##
[0185] Second eluting enantiomer, Peak 2, from the chiral
separation of Example 1. Yield 13 mg. LC/MS RT=1.277 min.
(M+H).sup.+=369.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.47-1.59 (m, 1H) 1.65-1.75 (m, 1H) 1.84-1.96 (m, 1H) 2.03-2.12 (m,
1H) 2.24-2.43 (m, 1H) 2.63-2.72 (m, 2H) 2.72-2.85 (m, 2H) 2.96-3.05
(m, 2H) 3.09-3.23 (m, 2H) 3.41-3.54 (m, 1H) 4.23-4.50 (m, 2H)
6.58-6.71 (m, 2H) 6.96-7.10 (m, 2H) 7.15-7.21 (m, 2H) 7.26-7.34 (m,
2H) 9.06-9.19 (m, 1H).
Example 3
1-(4-Methylbenzyl)-3-(3-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00098##
[0187] Intermediate M (110 mg) was deprotected using the conditions
in Example 1 to yield 103 mg product. LC/MS RT=1.48, 1.51 min.
(M+H).sup.+=365; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.59-2.04 (m, 4H) 2.28 (d, J=5.52 Hz, 5H) 2.90-3.05 (m, 2H) 3.17
(s, 3H) 3.26 (d, J=6.53 Hz, 4H) 3.65-3.80 (m, 2H) 4.39 (d, J=3.01
Hz, 3H) 6.75 (d, J=8.53 Hz, 2H) 7.02-7.20 (m, 6H) 9.35-9.45 (m, 1H)
10.34-10.54 (m, 1H).
Example 4
1-(4-Fluorobenzyl)-3-(3-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00099##
[0189] Intermediate E (150 mg) was deprotected using the conditions
in Example 1 to yield 80 mg product. LC/MS (Method N) RT=1.30, 1.41
min. (M+H).sup.+=369. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.27-1.39 (m, 1H) 1.47-1.56 (m, 1H) 1.68-1.82 (m, 1H) 1.86-1.96
(m, 1H) 2.00-2.08 (m, 1H) 2.10-2.22 (m, 1H) 2.30-2.37 (m, 1H)
2.53-2.60 (m, 1H) 2.61-2.74 (m, 1H) 2.85-2.94 (m, 1H) 3.07-3.15 (m,
1H) 3.40-3.50 (m, 1H) 4.21-4.46 (m, 2H) 6.66-6.73 (m, 2H) 6.97-7.04
(m, 1H) 7.06-7.18 (m, 2H) 7.20-7.27 (m, 2H) 9.08-9.16 (m, 1H).
Example 5
1-(3,4-Difluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-o-
ne
##STR00100##
[0191] Intermediate N (150 mg) was deprotected using the conditions
in Example 1 to yield 23 mg product. LC/MS RT=1.474 min.
(M+H).sup.+=367; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.59-2.04 (m, 4H) 2.28 (d, J=5.52 Hz, 5H) 2.90-3.05 (m, 2H) 3.17
(s, 3H) 3.26 (d, J=6.53 Hz, 4H) 3.65-3.80 (m, 2H) 4.39 (d, J=3.01
Hz, 3H) 6.75 (d, J=8.53 Hz, 2H) 7.02-7.20 (m, 6H) 9.35-9.45 (m, 1H)
10.34-10.54 (m, 1H). A portion of the racemate (20 mg) was
separated via SFC on a Chiralpak-AD H 250 mm.times.4.6 mm, 5 micron
column eluting with 35% solvent B, where solvent A=CO.sub.2 and
solvent B=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1
showed a RT of 3.50 min and Peak 2 showed a RT of 7.17 min.
Example 6a
(S)-1-(3,4-Difluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-
-2-one
##STR00101##
[0193] First eluting enantiomer, Peak 1, from the chiral separation
of Example 5. Yield 1.5 mg. LC/MS RT=2.107 min. (M+H).sup.+=387;
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.69-1.85 (m, 4H)
2.03-2.26 (m, 2H) 2.38-2.50 (m, 2H) 2.73-2.80 (m, 1H) 2.90 (d,
J=11.04 Hz, 1H) 3.15-3.21 (m, 1H) 3.23-3.31 (m, 2H) 3.64 (t, J=8.78
Hz, 1H) 4.40-4.56 (m, 2H) 6.68-6.77 (m, 2H) 7.03-7.13 (m, 3H)
7.18-7.30 (m, 2H).
Example 6b
(R)-1-(3,4-Difluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-
-2-one
##STR00102##
[0195] Second eluting enantiomer, Peak 2, from the chiral
separation of Example 5. Yield 1.8 mg. LC/MS RT=2.107 min.
(M+H).sup.+=387; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.71-1.86 (m, 5H) 2.05-2.26 (m, 3H) 2.46 (td, J=10.67, 4.77 Hz, 3H)
2.75 (td, J=11.04, 3.51 Hz, 2H) 2.85-3.00 (m, 2H) 3.15-3.25 (m, 2H)
3.23-3.31 (m, 2H) 3.63-3.70 (m, 1H) 4.38-4.56 (m, 3H) 6.68-6.78 (m,
3H) 7.03-7.13 (m, 4H) 7.20-7.32 (m, 3H).
Example 7
1-(4-(Difluoromethoxy)benzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrroli-
din-2-one
##STR00103##
[0197] Intermediate P (209 mg) was deprotected using the conditions
in Example 1 to yield 33 mg product. LC/MS RT=1.474 min.
(M+H).sup.+=417; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.49-1.64 (m, 2H) 1.63-1.73 (m, 2H) 1.88-1.96 (m, 1H) 1.99-2.09 (m,
1H) 2.26-2.39 (m, 2H) 2.63-2.85 (m, 2H) 3.00-3.05 (m, 1H) 3.14 (d,
J=8.03 Hz, 2H) 3.47 (s, 1H) 4.37 (d, J=18.07 Hz, 2H) 6.63-6.72 (m,
2H) 6.97-7.38 (m, 7H) 9.11 (s, 1H).
Example 8
1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolid-
in-2-one
##STR00104##
[0199] Intermediate AH (250 mg) was deprotected using the
conditions in Example 1 to yield 36.8 mg product. LC/MS RT=0.815,
0.830 min. (M+H).sup.+=385; .sup.1H NMR (400 MHz, DMSO-d6) .delta.
ppm 1.51-1.68 (m, 2H) 1.86-1.96 (m, 1H) 2.01-2.11 (m, 1H) 2.13-2.24
(m, 1H) 2.34-2.43 (m, 0H) 2.54-2.73 (m, 1H) 2.83-2.95 (m, 1H) 3.17
(s, 5H) 3.40-3.55 (m, 3H) 4.35 (s, 3H) 6.66 (d, J=8.53 Hz, 2H) 7.01
(d, J=8.53 Hz, 2H) 7.17 (d, J=1.51 Hz, 2H) 7.26 (d, J=5.52 Hz, 2H).
A portion of the product (31 mg) was separated into the individual
diastereomers via SFC on a Chiralpak-AS H 250 mm.times.4.6 mm, 5
micron column eluting with 30% solvent B, where solvent A=CO.sub.2
and solvent B=0.3% DEA in methanol at a total flow of 3 mL/min.
Peak 1 showed a RT of 3.21 min, Peak 2 showed a RT of 3.76 min,
Peak 3 showed a RT of 5.47 min, and Peak 4 showed a RT of 4.38
min.
Example 9a
1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolid-
in-2-one
##STR00105##
[0201] First eluting diastereomer, Peak 1, from the chiral
separation of Example 8. Yield 4.5 mg. SFC (Method 108) RT=3.21
min. LC/MS RT=1.866 min. (M+H).sup.+=385; .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.29-7.33 (m, 2H), 7.07-7.12 (m, 4H), 6.75 (d,
J=8.40 Hz, 2H), 4.41 (d, J=14.80 Hz, 1H), 4.53 (d, J=14.80 Hz, 1H),
3.77-3.78 (m, 1H), 3.65-3.70 (m, 1H), 3.25-3.31 (m, 3H), 2.78 (q,
J=7.20 Hz, 2H), 2.23-2.30 (m, 3H), 2.09 (q, J=8.40 Hz, 1H),
1.75-1.78 (m, 2H).
Example 9b
1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrroli-
din-2-one
##STR00106##
[0203] Second eluting diastereomer, Peak 2, from the chiral
separation of Example 8. Yield 3.8 mg. SFC (Method 108) RT=3.76
min. LC/MS RT=1.872 min. (M+H).sup.+=385; .sup.1H NMR 400 MHz
(CD.sub.3OD) .delta. 7.28-7.31 (m, 2H), 7.05-7.10 (m, 4H), 6.73 (d,
J=8.40 Hz, 2H), 4.51 (d, J=14.80 Hz, 1H), 4.39 (d, J=14.40 Hz, 1H),
3.75-3.76 (m, 1H), 3.64-3.68 (m, 1H), 3.23-3.28 (m, 3H), 2.88 (q,
J=7.20 Hz, 1H), 2.75 (s, 1H), 2.20-2.32 (m, 3H), 1.74-1.76 (m,
1H).
Example 9c
1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrroli-
din-2-one
##STR00107##
[0205] Third eluting diastereomer, Peak 3, from the chiral
separation of Example 8. Yield 3.3 mg. SFC (Method 108) RT=5.47
min. LC/MS RT=1.866 min. (M+H).sup.+=385; .sup.1H NMR (400 MHz,
CD3OD) .delta. 7.30-7.33 (m, 2H), 7.07-7.12 (m, 4H), 6.75 (d,
J=8.40 Hz, 2H), 4.54 (d, J=14.80 Hz, 1H), 4.42 (d, J=14.80 Hz, 1H),
3.77 (q, J=4.40 Hz, 1H), 3.67-3.72 (m, 1H), 3.25-3.34 (m, 2H),
2.99-3.01 (m, 2H), 2.30-2.49 (m, 3H), 2.07-2.10 (m, 1H), 1.77-1.80
(m, 2H).
Example 9d
1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl-)piperidin-1-yl)pyrroli-
din-2-one
##STR00108##
[0207] Fourth eluting diastereomer, Peak 4, from the chiral
separation of Example 8. Yield 3.0 mg. SFC (Method 108) RT=4.38
min. LC/MS RT=1.869 min. (M+H).sup.+=385; .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.28-7.31 (m, 2H), 7.05-7.10 (m, 4H), 6.73 (d,
J=8.40 Hz, 2H), 4.52 (d, J=14.80 Hz, 1H), 4.40 (d, J=14.80 Hz, 1H),
3.75 (q, J=4.40 Hz, 1H), 3.68 (t, J=18.00 Hz, 1H), 3.23-3.31 (m,
2H), 2.98 (t, J=14.00 Hz, 2H), 2.39-2.47 (m, 2H), 2.29 (q, J=6.40
Hz, 1H), 2.07 (q, J=8.40 Hz, 1H), 1.75-1.79 (m, 2H).
Example 10
1-(3,4-Difluorobenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-on-
e
##STR00109##
[0209] Intermediate Q (150 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 95 mg product. LC/MS RT=1.245
min. (M+H).sup.+=359; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.59-1.71 (m, 1H) 1.99-2.16 (m, 1H) 3.08-3.26 (m, 9H) 3.48-3.55
(m, 2H) 3.63-3.73 (m, 2H) 4.36 (d, J=10.04 Hz, 2H) 6.70 (d, J=8.53
Hz, 2H) 7.05-7.12 (m, 1H) 7.15 (d, J=8.53 Hz, 2H) 7.22-7.33 (m, 1H)
7.37-7.47 (m, 1H) 8.90-9.52 (m, 1H).
Example 11
1-(4-Fluorobenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one
##STR00110##
[0211] Intermediate R (160 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 84 mg product. LC/MS RT=1.182
min. (M+H).sup.+=341; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.52-1.71 (m, 1H) 1.99-2.13 (m, 1H) 3.08-3.27 (m, 6H) 3.47-3.55
(m, 1H) 3.62-3.75 (m, 2H) 4.35 (d, J=11.55 Hz, 2H) 6.67-6.77 (m,
2H) 7.11-7.22 (m, 4H) 7.27 (dd, J=8.53, 5.52 Hz, 2H) 9.21 (s,
1H).
Example 12
1-Benzyl-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00111##
[0213] Intermediate A (1000 mg) was deprotected using the
conditions in Example 1 to yield a crude product which was purified
via preparative HPLC (Method B) to yield 290 mg product. LC/MS
RT=1.394 min. (M+H)+=351. 400 MHz, DMSO-d6: .delta. ppm 1.58-1.72
(m, 4H), 1.91-1.94 (m, 3H), 2.30-2.37 (m, 2H), 2.67-2.81 (m, 2H),
3.15-3.31 (m, 4H), 4.39 (q, J=50.00 Hz, 3H), 6.68 (d, J=8.40 Hz,
2H), 7.02 (d, J=8.40 Hz, 2H), 7.22-7.38 (m, 8H), 9.13 (s, 1H). Most
of the product (250 mg) was separated into the individual
enantiomers via SFC on a Chiralpak-IA 250 mm.times.4.6 mm, 5 micron
column eluting with 30% solvent B, where solvent A=CO.sub.2 and
solvent B=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1
showed a RT of 5.84 min and Peak 2 showed a RT of 8.33 min.
Example 13a
(S)-1-Benzyl-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00112##
[0215] First eluting enantiomer, Peak 1, from the chiral separation
of compound 12. Yield 88 mg. LC/MS RT=1.780 min. (M+H)+=351.2;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.74-1.84 (m,
4H) 2.02-2.12 (m, 1H) 2.15-2.23 (m, 1H) 2.47 (td, J=10.79, 4.52 Hz,
2H) 2.76 (td, J=11.04, 3.51 Hz, 1H) 2.90 (d, J=11.04 Hz, 1H)
3.12-3.20 (m, 1H) 3.21-3.29 (m, 2H) 3.64 (t, J=9.04 Hz, 1H)
4.38-4.60 (m, 2H) 6.67-6.76 (m, 2H) 7.04-7.09 (m, 2H) 7.25-7.40 (m,
5H).
Example 13b
(R)-1-Benzyl-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00113##
[0217] Second eluting enantiomer, Peak 2, from the chiral
separation of compound 12.
[0218] Yield 96 mg. LC/MS RT=1.783 min. (M+H)+=351.2; .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. ppm 1.74-1.86 (m, 4H) 2.02-2.13
(m, 1H) 2.15-2.25 (m, 1H) 2.41-2.52 (m, 2H) 2.76 (td, J=11.04, 3.51
Hz, 1H) 2.90 (d, J=11.04 Hz, 1H) 3.14-3.30 (m, 2H) 3.64 (t, J=9.04
Hz, 1H) 4.38-4.58 (m, 2H) 6.69-6.75 (m, 2H) 7.03-7.09 (m, 2H)
7.25-7.39 (m, 5H).
Example 14
1-(3-Chloro-4-methylbenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidi-
n-2-one
##STR00114##
[0220] Intermediate K (200 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 2 mg product. LC/MS RT=1.677
min. (M+H).sup.+=399.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
.delta. ppm 1.51-1.72 (m, 4H) 1.86-1.98 (m, 1H) 2.02-2.11 (m, 1H)
2.31 (s, 6H) 2.69-2.81 (m, 2H) 2.99-3.06 (m, 1H) 3.10-3.21 (m, 2H)
3.44-3.51 (m, 1H) 4.28-4.41 (m, 2H) 6.63-6.72 (m, 2H) 7.01 (s, 2H)
7.07-7.13 (m, 1H) 7.25-7.35 (m, 2H) 9.08-9.15 (m, 1H).
Example 15
1-(4-Chloro-3-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidi-
n-2-one
##STR00115##
[0222] Intermediate J (200 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 15 mg product. LC/MS RT=1.575
min. (M+H).sup.+=403.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.50-1.60 (m, 3H) 1.64-1.73 (m, 3H) 1.87-1.97 (m, 2H) 2.04-2.13
(m, 2H) 2.28-2.39 (m, 3H) 2.64-2.72 (m, 2H) 2.74-2.81 (m, 1H) 3.03
(d, J=11.55 Hz, 2H) 3.12-3.22 (m, 3H) 3.49 (t, J=8.53 Hz, 2H)
4.31-4.48 (m, 3H) 6.64-6.72 (m, 3H) 7.02 (d, J=8.53 Hz, 3H) 7.10
(dd, J=8.53, 1.51 Hz, 2H) 7.26 (dd, J=10.04, 2.01 Hz, 2H) 7.57 (t,
J=8.03 Hz, 2H) 9.12 (br. s., 1H).
Example 16
1-Benzyl-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one
##STR00116##
[0224] Intermediate L (150 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 40 mg product. LC/MS RT=1.154
min. (M+H).sup.+=323.0; .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
1.57-1.68 (m, 1H) 2.03-2.12 (m, 1H) 3.11-3.25 (m, 4H) 3.51 (t,
J=7.37 Hz, 1H) 3.62-3.74 (m, 2H) 4.28-4.44 (m, 2H) 6.67-6.74 (m,
2H) 7.13-7.38 (m, 7H) 9.23 (br. s., 1H).
Example 17
1-(4-Chlorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00117##
[0226] Intermediate C (150 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 24 mg product. LC/MS RT=1.576
min. (M+H).sup.+=385; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.57-1.73 (m, 1H) 2.19-2.33 (m, 2H) 2.62 (d, J=7.93 Hz, 4H)
2.77 (d, J=18.51 Hz, 3H) 3.09-3.21 (m, 3H) 3.40-3.46 (m, 1H) 4.36
(s, 2H) 6.63-6.77 (m, 2H) 7.00 (d, J=8.69 Hz, 2H) 7.15-7.26 (m, 2H)
7.33-7.49 (m, 2H) 9.03-9.34 (m, 1H). The racemic product was
separated into the individual enantiomers via SFC on a Chiralpak-IA
250 mm.times.4.6 mm, 5 micron column eluting with 30% solvent B,
where solvent A=CO.sub.2 and solvent B=0.3% DEA in methanol at a
total flow of 3 mL/min. Peak 1 showed a RT of 5.94 min and Peak 2
showed a RT of 10.59 min.
Example 18a
(S)-1-(4-Chlorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-o-
ne
##STR00118##
[0228] First eluting enantiomer, Peak 1, from the chiral separation
of compound 17. Yield 3.9 mg. LC/MS RT=2.315 min. (M+H)+=385.0;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.68-1.85 (m,
4H) 1.99-2.09 (m, 1H) 2.16-2.24 (m, 1H) 2.37-2.50 (m, 2H) 2.70-2.79
(m, 1H) 2.86-2.95 (m, 1H) 3.23-3.32 (m, 3H) 3.56-3.66 (m, 1H)
4.37-4.45 (m, 1H) 4.48-4.58 (m, 1H) 6.71 (d, J=8.53 Hz, 2H)
7.01-7.13 (m, 2H) 7.20-7.30 (m, 2H) 7.36 (s, 2H).
Example 18b
(R)-1-(4-Chlorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-o-
ne
##STR00119##
[0230] Second eluting enantiomer, Peak 2, from the chiral
separation of compound 17.
[0231] Yield 4.7 mg. LC/MS RT=2.350 min. (M+H).sup.+=385.2; .sup.1H
NMR (400 MHz, methanol-d4) .delta. ppm 1.68-1.85 (m, 4H) 1.99-2.09
(m, 1H) 2.16-2.24 (m, 1H) 2.37-2.50 (m, 2H) 2.70-2.79 (m, 1H)
2.86-2.95 (m, 1H) 3.23-3.32 (m, 3H) 3.56-3.66 (m, 1H) 4.37-4.45 (m,
1H) 4.48-4.58 (m, 1H) 6.71 (d, J=8.53 Hz, 2H) 7.01-7.13 (m, 2H)
7.20-7.30 (m, 2H) 7.36 (s, 2H).
Example 19
1-(3-Fluoro-4-methylbenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidi-
n-2-one
##STR00120##
[0233] Intermediate D (120 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 18 mg product. LC/MS RT=1.552
min. (M+H).sup.+=383.0; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 1.48-1.92 (m, 4H) 2.21 (d, J=1.13 Hz, 4H) 2.27-2.38 (m, 2H)
2.68-2.86 (m, 1H) 2.97-3.18 (m, 2H) 3.41-3.65 (m, 1H) 4.21-4.48 (m,
2H) 6.56-6.74 (m, 2H) 6.89-7.11 (m, 4H) 7.21-7.35 (m, 1H).
Example 20
1-(3-Fluoro-4-methylbenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-
-2-one
##STR00121##
[0235] Intermediate A1 (120 mg) was deprotected using the
conditions in Example 1 to yield a crude product which was purified
via preparative HPLC (Method B) to yield 35 mg product. LC/MS
RT=1.400 min. (M+H)+=355.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.59-1.68 (m, 1H) 2.02-2.12 (m, 1H) 2.21 (d, J=2.01 Hz,
3H) 3.06-3.15 (m, 2H) 3.22-3.33 (m, 2H) 3.51 (s, 2H) 3.62-3.76 (m,
3H) 4.33 (d, J=14.56 Hz, 2H) 6.61-6.77 (m, 2H) 6.87-7.02 (m, 2H)
7.09-7.21 (m, 2H) 7.25 (s, 1H). A portion of the product (25 mg)
was separated into the individual enantiomers via SFC on a
Chiralpak-IA 250 mm.times.4.6 mm, 5 micron column eluting with 40%
solvent B, where solvent A=CO.sub.2 and solvent B=0.3% DEA in
methanol at a total flow of 4 mL/min. Peak 1 showed a RT of 1.81
min and Peak 2 showed a RT of 2.38 min.
Example 21a
(R)-1-(3-Fluoro-4-methylbenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrol-
idin-2-one
##STR00122##
[0237] First eluting enantiomer, peak 1, from the chiral separation
of Example 20. Yield 5.6 mg. LC/MS RT=2.056 min. (M+H).sup.+=355.0;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.65-1.82 (m,
1H) 2.26 (d, J=2.01 Hz, 4H) 3.29 (d, J=16.56 Hz, 1H) 3.43-3.51 (m,
2H) 3.71 (s, 1H) 3.76-3.84 (m, 1H) 3.89-4.02 (m, 1H) 4.42 (d,
J=17.07 Hz, 2H) 6.65-6.79 (m, 2H) 6.94-7.05 (m, 2H) 7.14-7.27 (m,
3H).
Example 21b
(S)-1-(3-Fluoro-4-methylbenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrol-
idin-2-one
##STR00123##
[0239] Second eluting enantiomer, peak 2, from the chiral
separation of Example 20. Yield 4.1 mg. LC/MS RT=2.043 min.
(M+H).sup.+=355.0; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
ppm 1.65-1.82 (m, 1H) 2.26 (d, J=2.01 Hz, 4H) 3.29 (d, J=16.56 Hz,
1H) 3.43-3.51 (m, 2H) 3.71 (s, 1H) 3.76-3.84 (m, 1H) 3.89-4.02 (m,
1H) 4.42 (d, J=17.07 Hz, 2H) 6.65-6.79 (m, 2H) 6.94-7.05 (m, 2H)
7.14-7.27 (m, 3H).
Example 22
3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
##STR00124##
[0241] Intermediate F (1000 mg) was deprotected using the
conditions in Example 1 to yield a crude product which was purified
via preparative HPLC (Method B) to yield 98 mg product. LC/MS
RT=1.544 min. (M+H).sup.+=365; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.48-1.81 (m, 4H) 1.84-2.16 (m, 2H) 2.28 (s, 5H)
2.60-2.88 (m, 2H) 2.95-3.25 (m, 3H) 3.40-3.55 (m, 1H) 4.21-4.46 (m,
2H) 6.62-7.18 (m, 8H) 9.12 (br. s., 1H). The racemate was separated
into the individual enantiomers via SFC on a Chiralpak-IA 250
mm.times.4.6 mm, 5 micron column eluting with 30% solvent B, where
solvent A=CO.sub.2 and solvent B=0.3% DEA in methanol at a total
flow of 3 mL/min. Peak 1 showed a RT of 6.67 min and Peak 2 showed
a RT of 9.74 min.
Example 23a
(S)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-o-
ne
##STR00125##
[0243] First eluting enantiomer, peak 1, from the chiral separation
of Example 22. Yield 6 mg. LC/MS RT=1.849 min. (M+H).sup.+=365.2 1H
NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.79 (ddd, J=9.91,
6.15, 4.02 Hz, 4H) 1.99-2.13 (m, 1H) 2.14-2.23 (m, 1H) 2.33 (s, 3H)
2.46 (d, J=4.02 Hz, 2H) 2.75 (d, J=3.51 Hz, 1H) 2.83-2.93 (m, 1H)
3.10-3.30 (m, 3H) 3.62 (t, J=8.78 Hz, 1H) 4.31-4.55 (m, 2H)
6.67-6.77 (m, 2H) 7.02-7.10 (m, 2H) 7.17 (br. s., 0H).
Example 23b
(R)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-o-
ne
##STR00126##
[0245] Second eluting enantiomer, peak 2, from the chiral
separation of Example 22. Yield 34 mg. LC/MS RT=1.841 min.
(M+H).sup.+=365.2 1H NMR (400 MHz, methanol-d4) .delta. ppm
1.66-1.84 (m, 4H) 2.01-2.21 (m, 2H) 2.33 (s, 3H) 2.36-2.49 (m, 2H)
2.73 (br. s., 1H) 2.86 (br. s., 1H) 3.06-3.28 (m, 3H) 3.30-3.33 (m,
1H) 3.60 (s, 1H) 4.30-4.53 (m, 2H) 6.72 (d, J=8.53 Hz, 2H) 7.05 (d,
J=8.03 Hz, 2H) 7.10-7.22 (m, 4H).
Example 24
1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00127##
[0246] Step A.
1-(4-Methoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00128##
[0248] A mixture of
1-(4-methoxybenzyl)-3-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)py-
rrolidin-2-one (G) (400 mg, 1.02 mmol), MeOH (4 ml) and ethanol (8
ml) was flushed with nitrogen, followed by the addition of 10% Pd/C
(108 mg).
[0249] Then the mixture was stirred overnight at rt and 25 psi
hydrogen pressure. The catalyst was removed by filtration through
Celite and the filtrate was concentrated under vacuum. Yield: 400
mg. LCMS (method F) RT 2.36 min, m/z 395.2 (MH.sup.+).
Step B.
1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidi-
n-2-one
[0250] The product from step A was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 60 mg of the titled compound
of Example 24. LC/MS RT=1.012 min. (M+H).sup.+=367.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.44-1.61 (m, 2H) 1.66-1.77 (m,
2H) 1.91 (s, 2H) 1.99-2.09 (m, 1H) 2.23-2.41 (m, 2H) 2.60-2.80 (m,
2H) 3.08 (s, 3H) 3.42-3.52 (m, 1H) 3.91 (s, 1H) 4.20-4.34 (m, 2H)
6.60-6.77 (m, 4H) 7.02 (d, J=8.03 Hz, 4H) 9.10 (s, 1H) 9.34 (s,
1H). A portion of the product (50 mg) was separated into the
individual enantiomers via SFC on a Chiralpak-IA 250 mm.times.4.6
mm, 5 micron column eluting with 30% solvent B, where solvent
A=CO.sub.2 and solvent B=0.3% DEA in methanol at a total flow of 3
mL/min. Peak 1 showed a RT of 5.12 min and Peak 2 showed a RT of
6.47 min.
Example 25a
(S)-1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2--
one
##STR00129##
[0252] First eluting enantiomer, peak 1, from the chiral separation
of Example 24. Yield 18 mg. LC/MS RT=1.546 min. (M+H).sup.+=367.2
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.66-1.83 (m,
4H) 1.96-2.21 (m, 2H) 2.38-2.51 (m, 2H) 2.73 (td, J=11.04, 3.51 Hz,
1H) 2.83-2.95 (m, 1H) 3.08-3.31 (m, 3H) 3.60 (t, J=8.78 Hz, 1H)
4.23-4.46 (m, 2H) 6.65-6.82 (m, 4H) 7.00-7.17 (m, 4H).
Example 25b
(R)-1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2--
one
##STR00130##
[0254] Second eluting enantiomer, peak 2, from the chiral
separation of Example 24. Yield 20 mg. LC/MS RT=1.544 min.
(M+H).sup.+=367.2 .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
ppm 1.66-1.84 (m, 4H) 1.98-2.08 (m, 1H) 2.11-2.21 (m, 1H) 2.38-2.49
(m, 2H) 2.74 (td, J=11.04, 3.51 Hz, 1H) 2.89 (d, J=2.01 Hz, 1H)
3.08-3.30 (m, 3H) 3.60 (t, J=8.53 Hz, 1H) 4.23-4.35 (m, 1H)
4.40-4.48 (m, 1H) 6.67-6.80 (m, 4H) 7.02-7.17 (m, 4H).
Example 26
1-(3,4-Dimethylbenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-o-
ne
##STR00131##
[0256] Intermediate H (200 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 21 mg product. LC/MS RT=1.669
min. (M+H).sup.+=379.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.54-1.62 (m, 2H) 1.90 (d, J=13.05 Hz, 3H) 2.03-2.13 (m, 1H)
2.65-2.81 (m, 2H) 2.96-3.03 (m, 1H) 3.10 (s, 2H) 3.45 (s, 1H) 3.74
(s, 3H) 4.20-4.41 (m, 2H) 4.74 (s, 1H) 6.84-6.95 (m, 2H) 7.11-7.24
(m, 3H) 7.26-7.36 (m, 2H) 7.49 (dd, J=8.28, 1.25 Hz, 2H).
Example 27
3-(3-(4-Hydroxyphenyl)azetidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
##STR00132##
[0258] Intermediate I (110 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 44 mg product. LC/MS RT=1.341
min. (M+H).sup.+=337.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.56-1.66 (m, 1H) 2.08 (s, 1H) 2.29 (s, 3H) 3.11 (d, J=1.51 Hz,
3H) 3.23 (s, 2H) 3.46-3.53 (m, 1H) 3.61-3.75 (m, 2H) 4.31 (d,
J=13.05 Hz, 2H) 6.65-6.75 (m, 2H) 7.05-7.20 (m, 6H) 9.19-9.27 (m,
1H). A portion of the product (34 mg) was separated into the
individual enantiomers via SFC on a Lux Cellulose 2 250
mm.times.4.6 mm, 5 micron column eluting with 40% solvent B, where
solvent A=CO.sub.2 and solvent B=0.3% DEA in methanol at a total
flow of 3 mL/min. Peak 1 showed a RT of 4.65 min and Peak 2 showed
a RT of 3.54 min.
Example 28a
(S)-3-(3-(4-Hydroxyphenyl)azetidin-1-yl)-1-(4-methylbenzyl-)pyrrolidin-2-o-
ne
##STR00133##
[0260] First eluting enantiomer, peak 1, from the chiral separation
of Example 27. Yield 8 mg. LC/MS RT=1.683 min. (M+H).sup.+=337.2
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.68-1.81 (m,
1H) 2.18-2.24 (m, 1H) 2.33 (s, 4H) 3.13-3.30 (m, 2H) 3.47 (s, 2H)
3.66-3.75 (m, 1H) 3.78-3.85 (m, 1H) 3.90-4.00 (m, 1H) 4.41 (d,
J=7.03 Hz, 2H) 6.76 (d, J=8.53 Hz, 2H) 7.08-7.22 (m, 6H).
Example 28b
(R)-3-(3-(4-Hydroxyphenyl)azetidin-1-yl)-1-(4-methylbenzyl)-pyrrolidin-2-o-
ne
##STR00134##
[0262] Second eluting enantiomer, peak 2, from the chiral
separation of Example 27. Yield 6 mg. LC/MS RT=1.683 min.
(M+H)+=337.2 .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
1.71-1.81 (m, 1H) 2.19-2.26 (m, 1H) 2.33 (s, 3H) 3.04 (s, 1H)
3.15-3.26 (m, 1H) 3.24 (s, 2H) 3.45-3.58 (m, 2H) 3.68-3.73 (m, 1H)
3.78-3.85 (m, 1H) 3.91-4.00 (m, 1H) 4.41 (d, J=7.03 Hz, 2H)
6.67-6.80 (m, 2H) 7.10-7.22 (m, 6H).
Example 29
1-Benzyl-3-(4-(4-hydroxy-2-methylphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00135##
[0264] Intermediate S (200 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 30 mg product. LC/MS RT=1.47
min. (M+H)+=365.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.47-1.67 (m, 4H) 1.84-1.98 (m, 1H) 2.01-2.13 (m, 1H) 2.20 (s, 3H)
2.27-2.39 (m, 1H) 2.67-2.82 (m, 1H) 2.99-3.07 (m, 2H) 3.08-3.22 (m,
1H) 3.43-3.54 (m, 2H) 4.29-4.47 (m, 2H) 6.53 (s, 2H) 6.95-7.01 (m,
1H) 7.17-7.27 (m, 2H) 7.25-7.32 (m, 1H) 7.35 (d, J=7.53 Hz, 2H)
8.98 (s, 1H).
Example 30
1-Benzyl-3-(4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00136##
[0266] Intermediate T (200 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 38 mg product. LC/MS RT=1.46
min. (M+H)+=369 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.47-1.60 (m, 2H) 1.65-1.75 (m, 2H) 1.89-1.97 (m, 1H) 2.02-2.13 (m,
1H) 2.23-2.43 (m, 2H) 2.64-2.73 (m, 1H) 2.76-2.82 (m, 1H) 2.98-3.06
(m, 1H) 3.09-3.22 (m, 2H) 3.48 (s, 2H) 4.35 (s, 1H) 4.28-4.37 (s,
1H) 6.80-6.89 (m, 2H) 6.94-7.03 (m, 1H) 7.17-7.25 (m, 2H) 7.25-7.31
(m, 1H) 7.34 (d, J=7.53 Hz, 2H).
Example 31
1-(4-Fluorobenzyl)-3-(3-(4-hydroxyphenyl)azepan-1-yl)pyrrolidin-2-one
##STR00137##
[0268] Intermediate V (120 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 19 mg product. LC/MS RT=1.56
min. (M+H).sup.+=383; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.48-1.85 (m, 6H) 2.02-2.19 (m, 1H) 2.59-2.84 (m, 4H) 2.93-3.12
(m, 3H) 3.51-3.66 (m, 1H) 4.20-4.43 (m, 2H) 6.59-6.72 (m, 2H)
6.93-7.03 (m, 2H) 7.05-7.16 (m, 2H) 7.17-7.25 (m, 2H) 8.98-9.15 (m,
1H).
Example 32
3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin-2-on-
e
##STR00138##
[0270] Intermediate W (220 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 41 mg product. LC/MS RT=1.45
min. (M+H).sup.+=365.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 10.00 (q, J=7.20 Hz, 3H), 1.62 (t, J=46.00 Hz, 2H), 1.68 (d,
J=1.20 Hz, 2H), 1.97-2.19 (m, 1H), 2.22-2.40 (m, 2H), 2.78 (t,
J=7.60 Hz, 3H), 2.89-3.19 (m, 2H), 3.31 (d, J=3.60 Hz, 1H),
3.38-3.45 (m, 2H), 3.47-3.61 (m, 3H), 5.28 (d, J=6.80 Hz, 1H),
6.65-6.68 (m, 2H), 6.99-7.02 (m, 2H), 7.25-7.28 (m, 3H), 7.33-7.37
(m, 2H). A portion of the product (34 mg) was separated into the
individual diastereomers via SFC on a Chiralpak-IA 250 mm.times.4.6
mm, 5 micron column eluting with 40% solvent B, where solvent
A=CO.sub.2 and solvent B=0.3% DEA in methanol at a total flow of 4
mL/min. Peak 1 showed a RT of 2.70 min and Peak 2 showed a RT of
4.03 min.
Example 33a
(S)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin--
2-one
##STR00139##
[0272] First eluting diastereomer, peak 1, from the chiral
separation of Example 32. Yield 6 mg. LC/MS RT=2.28 min.
(M+H).sup.+=365.0; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.44
(d, J=7.2, 3H), 1.50-1.56 (m, 2H), 1.66 (m, 2H), 1.84 (m, 1H),
2.00-2.15 (m, 1H), 2.30-2.33 (m, 2H), 2.66 (m, 1H), 2.74 (m, 1H),
2.88-2.95 (m, 1H), 2.95-3.05 (m, 1H), 3.21 (m, 1H), 3.45 (t, J=8.8,
1H), 5.25 (d, J=7.2, 1H), 6.67 (dd, J=2, 6.8, 2H), 7.01 (d, J=8.4,
2H), 7.25-7.29 (m, 3H), 7.34-7.38 (m, 2H), 9.1 (s, 1H).
Example 33b
(R)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin--
2-one
##STR00140##
[0274] Second eluting diastereomer, peak 2, from the chiral
separation of Example 32.
[0275] Yield 8 mg. LC/MS RT=2.29 min. (M+H).sup.+=365.2; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.47 (d, J=7.20 Hz, 3H),
1.51-1.58 (m, 2H), 1.66-1.69 (m, 2H), 1.89-2.02 (m, 1H), 2.02-2.19
(m, 1H), 2.29-2.35 (m, 2H), 2.62-2.73 (m, 1H), 2.75-2.83 (m, 2H),
2.97-3.15 (m, 1H), 3.60 (t, J=8.80 Hz, 1H), 5.28-5.30 (m, 1H), 6.67
(dd, J=2.00, 6.80 Hz, 2H), 7.02 (d, J=8.40 Hz, 2H), 7.25-7.29 (m,
3H), 7.34-7.38 (m, 2H), 9.10 (s, 1H).
Example 34
1-(2,3-Dihydro-1H-inden-1-yl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrroli-
din-2-one
##STR00141##
[0277] Intermediate Y (280 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 7 mg product. LC/MS RT=1.52
min. (M+H).sup.+=377; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.56-1.59 (m, 2H), 1.69-1.72 (m, 2H), 1.83-2.11 (m, 3H),
2.33-2.50 (m, 3H), 2.77-3.04 (m, 6H), 3.11-3.18 (m, 4H), 3.49 (t,
J=8.40 Hz, 1H), 5.60 (t, J=8.00 Hz, 1H), 6.68 (dd, J=2.00, 6.60 Hz,
2H), 7.01-7.04 (m, 3H), 7.20-7.29 (m, 3H).
Example 35
1-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)azepan-1-yl)pyrrolidin-2-one
##STR00142##
[0279] Intermediate AA (110 mg) was deprotected using the
conditions in Example 1 to yield a crude product which was purified
via preparative HPLC (Method B) to yield 25 mg product. LC/MS
RT=1.50 min. (M+H).sup.+=383; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.67-1.81 (m, 7H), 2.15-2.20 (m, 1H), 2.65-2.70 (m,
3H), 2.79-2.92 (m, 2H), 3.09-3.02 (m, 1H), 3.13-3.18 (m, 2H),
3.58-3.61 (m, 2H), 4.35 (t, J=3.20 Hz, 2H), 6.65 (dd, J=3.60, 6.40
Hz, 2H), 6.97-6.99 (m, 2H), 7.15-7.19 (m, 2H), 7.24-7.28 (m,
2H)
Example 36
3-(4-(4-Hydroxyphenyl)azepan-1-yl)-1-(4-methylbenzyl)-pyrrolidin-2-one
##STR00143##
[0281] Intermediate AB (100 mg) was deprotected using the
conditions in Example 1 to yield a crude product which was purified
via preparative HPLC (Method B) to yield 14 mg product. LC/MS
RT=1.60 min. (M+H)+=379.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.50-89.00 (m, 7H), 2.13 (s, 1H), 2.28 (s, 3H), 2.71
(s, 1H), 2.84 (s, 2H), 3.12 (s, 3H), 3.62 (s, 1H), 4.35 (d, J=14.00
Hz, 2H), 6.66 (d, J=8.00 Hz, 2H), 6.99 (d, J=8.00 Hz, 2H), 7.14 (t,
J=12.00 Hz, 5H), 9.06 (s, 1H).
Example 37
1-Benzyl-3-(4-(4-hydroxyphenyl)azepan-1-yl)pyrrolidin-2-one
##STR00144##
[0283] Intermediate AC (90 mg) was deprotected using the conditions
in Example 1 to yield a crude product which was purified via
preparative HPLC (Method B) to yield 15 mg product. LC/MS RT=1.44
min. (M+H)+=365.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.70-1.85 (m, 8H), 2.19-2.25 (m, 1H), 2.66-2.71 (m, 3H), 2.79-2.93
(m, 2H), 2.96-3.15 (m, 1H), 3.14-3.20 (m, 3H), 3.61 (t, J=4.00 Hz,
3H), 4.37 (t, J=7.20 Hz, 4H), 6.65 (dd, J=2.00, 8.60 Hz, 2H), 6.98
(d, J=8.40 Hz, 2H), 7.20-7.33 (m, 3H), 7.35-7.37 (m, 2H).
Example 38
4-(4-Hydroxyphenyl)-1'-(4-methylbenzyl)-[1,3'-bipiperidin]-2'-one
##STR00145##
[0284] Step A.
4-(4-Methoxyphenyl)-1'-(4-methylbenzyl)-[1,3'-bipiperidin]-2'-one
##STR00146##
[0286] Intermediate AD (130 mg) was hydrogenated as in Example 24
to yield 130 mg
4-(4-methoxyphenyl)-1'-(4-methylbenzyl)-[1,3'-bipiperidin]-2'-one.
LCMS (method) RT 1.08 min, m/z 393.6 (MH.sup.+).
Step B.
4-(4-Hydroxyphenyl)-1'-(4-methylbenzyl)-[1,3'-bipiperidin]-2'-one
[0287] The intermediate
(4-(4-methoxyphenyl)-1'-(4-methylbenzyl)-[1,3'-bipiperidin]-2'-one)
(130 mg) was deprotected using the conditions in Example 1 to yield
a crude product which was purified via preparative HPLC (Method B)
to yield 28 mg of the titled compound of Example 38. LC/MS RT=1.42
min. (M+H).sup.+=379.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.79-2.07 (m, 6H) 2.29 (s, 5H) 2.65-2.79 (m, 1H) 3.10-3.31 (m,
7H) 4.26-4.37 (m, 1H) 4.46 (s, 1H) 4.57-4.70 (m, 1H) 6.73 (d,
J=8.53 Hz, 2H) 7.04 (d, J=8.53 Hz, 2H) 7.18 (s, 4H) 9.16-9.34 (s,
1H) 9.56-9.72, (s, 1H).
Example 39
1'-(3-Fluoro-4-methylbenzyl)-4-(4-hydroxyphenyl)-[1,3'-bipiperidin]-2'-one
##STR00147##
[0288] Step A.
1'-(3-Fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3'-bipiperidin]-2'-on-
e
##STR00148##
[0290] Intermediate AE (100 mg) was hydrogenated as in Example 24
to yield .about.100 mg crude
1'-(3-fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3'-bipiperidin]-2'-on-
e as a 2:1 mixture with unreacted starting material. LCMS (method)
RT 1.12 min, m/z 411.3 (MH.sup.+), 1.16 min, m/z 409.2 (MH.sup.+-
H.sub.2).
Step B.
1'-(3-Fluoro-4-methylbenzyl)-4-(4-hydroxyphenyl)-[1,3'-bipiperidin-
]-2'-one
[0291] The intermediate
1'-(3-fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3'-bipiperidin]-2'-on-
e (100 mg) was deprotected using the conditions in Example 1 to
yield a crude product which was purified via preparative HPLC
(Method B) to yield 25 mg of the titled compound of Example 39.
LC/MS RT=1.52 min. (M+H).sup.+=399 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.40-1.91 (m, 8H) 2.12-2.26 (m, 3H)
2.29-2.49 (m, 2H) 2.75-2.93 (m, 2H) 2.98-3.27 (m, 4H) 4.36-4.59 (m,
2H) 6.59-6.75 (m, 2H) 6.92-7.07 (m, 4H) 7.19-7.31 (m, 1H) 9.00-9.20
(m, 1H).
Example 40
1'-Benzyl-4-(4-hydroxyphenyl)-[1,3'-bipiperidin]-2'-one
##STR00149##
[0292] Step A.
1'-Benzyl-4-(4-methoxyphenyl)-[1,3'-bipiperidin]-2'-one
##STR00150##
[0294] Intermediate AF (100 mg) was hydrogenated as in Example 24
to yield .about.100 mg crude
1'-benzyl-4-(4-methoxyphenyl)-[1,3'-bipiperidin]-2'-one. LCMS
(method) RT 0.79 min, m/z 379.6 (MH.sup.+)
Step B. 1'-Benzyl-4-(4-hydroxyphenyl)-[1,3'-bipiperidin]-2'-one
[0295] The crude crude
1'-benzyl-4-(4-methoxyphenyl)-[1,3'-bipiperidin]-2'-one from step A
was deprotected as in example 1 to yield a crude product which was
purified via preparative HPLC (Method B) to yield 75 mg of the
titled compound of Example 40.
[0296] LC/MS RT=1.27 min. (M+H).sup.+=365.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.46-1.60 (m, 2H) 1.63-1.90 (m, 5H)
2.31-2.48 (m, 2H) 2.80-2.91 (m, 2H) 3.18 (s, 6H) 4.43-4.61 (m, 2H)
6.68 (d, J=8.53 Hz, 2H) 7.02 (d, J=8.53 Hz, 2H) 7.21-7.29 (m, 3H)
7.34 (d, J=7.53 Hz, 2H). A portion (63 mg) was separated into the
separate enantiomers via SFC on a Chiralpak-OD-H 250 mm.times.4.6
mm, 5 micron column eluting with 30% solvent B, where solvent
A=CO.sub.2 and solvent B=0.3% DEA in methanol at a total flow of 3
mL/min. Peak 1 showed a RT of 4.50 min and Peak 2 showed a RT of
5.86 min.
Example 41a
1'-Benzyl-4-(4-hydroxyphenyl)-[1,3'-bipiperidin]-2'-one
##STR00151##
[0298] First eluting enantiomer, peak 1, from the chiral separation
of Example 40. Yield 11 mg. LC/MS RT=1.94 min. (M+H)+=365.2 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.44-1.59 (m, 2H) 1.61-1.73
(m, 3H) 1.85 (s, 3H) 2.50 (br. s, 2H) 2.79-2.90 (m, 2H) 3.02-3.29
(m, 3H) 4.47 (s, 1H) 4.54 (s, 1H) 6.67 (d, J=8.53 Hz, 2H) 7.02 (d,
J=8.53 Hz, 2H) 7.19-7.40 (m, 5H) 8.87-9.09 (m, 1H).
Example 41b
1'-Benzyl-4-(4-hydroxyphenyl)-[1,3'-bipiperidin]-2'-one
##STR00152##
[0300] Second eluting enantiomer, peak 2, from the chiral
separation of Example 40. Yield 7 mg. LC/MS RT=1.94 min.
(M+H).sup.+=365.2 1H NMR (300 MHz, DMSO-d6) .delta. ppm 1.54 (br.
s., 2H) 1.65 (d, J=10.95 Hz, 3H) 1.82 (d, J=15.11 Hz, 3H) 2.44 (br.
s., 2H) 2.85 (br. s., 2H) 3.02-3.20 (m, 3H) 3.25 (dd, J=9.82, 6.04
Hz, 2H) 4.35-4.50 (m, 1H) 4.52-4.67 (m, 1H) 6.57-6.72 (m, 2H)
6.94-7.08 (m, 2H) 7.18-7.31 (m, 3H) 7.34-7.36 (2, m), 8.89-9.24 (m,
1H).
Example 42
1'-(4-Chlorobenzyl)-3-(4-hydroxyphenyl)-[1,3'-bipiperidin]-2'-one
##STR00153##
[0302] Intermediate AG (120 mg) was deprotected using the
conditions in Example 1 to yield a crude product which was purified
via preparative HPLC (Method B) to yield one pair of racemic
diastereomers (out of two possible pairs). Yield 19 mg. LC/MS
RT=1.56 min. (M+H).sup.+=399 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.60-1.72 (m, 1H) 1.78-1.89 (m, 3H) 1.93-2.08 (m, 3H)
2.22-2.36 (m, 1H) 3.05-3.20 (m, 3H) 3.22-3.38 (m, 5H) 4.17-4.31 (m,
1H) 4.44-4.54 (m, 1H) 4.58-4.71 (m, 1H) 6.67-6.78 (m, 2H) 7.01-7.14
(m, 2H) 7.24-7.38 (m, 2H) 7.34-7.49 (m, 2H) 9.23-9.41 (m, 1H)
9.60-9.76 (m, 1H).
Example 43
(R)-1-(3,4-Dihydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidi-
n-2-one
##STR00154##
[0303] Step A. (R)-tert-Butyl
(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate
##STR00155##
[0305] To a 0.degree. C. solution of
(3,4-dimethoxyphenyl)methanamine (2 g, 12 mmol) in DCM (20 mL) was
added sequentially
(R)-2-((tert-butoxycarbonyl)amino)-4-(methylthio)butanoic acid
(3.28 g, 13.2 mmol), PyBOP (6.85 g, 13.2 mmol) and DIPEA (4.18 mL,
23.92 mmol). The reaction mixture was stirred and allowed to warm
up to ambient temperature over 2 h. The reaction was then quenched
by the addition of water and the mixture was extracted twice with
100 mL DCM. The organic fraction was washed with 50 mL water, 50 mL
brine, and the layers were separated. The organic fraction was
dried over sodium sulfate, filtered, and evaporated. The residue
was purified via silica gel chromatography, eluting with 30% ethyl
acetate/petroleum ether. Yield 3.5 gms (R)-tert-butyl
(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate.
LCMS (Method F) RT 2.3 min, m/z 399.2 (MH.sup.+); .sup.1H NMR (400
MHz, chloroform-d) .delta. 1.41 (s, 9H), 1.91-1.98 (m, 1H), 2.07
(s, 3H), 2.10-2.14 (m, 1H), 2.47-2.61 (m, 2H), 3.65 (s, 6H),
4.25-4.27 (br s, 1H), 4.33-4.42 (m, 2H), 5.16 (br s, 1H), 6.47 (br
s, 1H), 6.80 (s, 3H).
Step B.
(R)-(3-(tert-butoxycarbonylamino)-4-(3,4-dimethoxybenzylamino)-4-o-
xobutyl)dimethylsulfonium iodide
##STR00156##
[0307] A mixture of (R)-tert-butyl
(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate
(2 g, 5 mmol) and methyl iodide (24 ml, 381 mmol) was stirred at RT
for 48 hrs. The solvent was then evaporated off and the residue was
triturated with ether and dried under high vacuum. Yield 2 g. LCMS
(Method J) RT 0.64 min, m/z 413.1 (M+); .sup.1H NMR (400 MHz,
chloroform-d) .delta. 1.40 (s, 9H), 2.08-2.21 (br s, 1H), 2.55-2.70
(br s, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.70-3.80 (br s, 1H), 3.85
(s, 3H), 3.89 (s, 3H), 4.34 (m, 2H), 4.45-4.55 (br s, 1H), 6.07 (d,
J=6.8, 1H) 6.79 (d, J=8, 1H), 6.91 (m, 1H), 7.26 (s, 1H), 8.16 (s,
1H). The crude reaction product was used directly in the next
step.
Step C. (R)-tert-Butyl
(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate
##STR00157##
[0309] To a 0.degree. C. solution of
(R)-(3-((tert-butoxycarbonyl)amino)-4-((3,4-dimethoxybenzyl)amino)-4-oxob-
utyl)dimethylsulfonium, iodide salt (2 g, 3.7 mmol) in THF (50 mL)
was added LHMDS (3.7 mL, 3.7 mmol) dropwise. The reaction was
stirred at 0.degree. C. for a further 2 hrs. Then was added
saturated ammonium chloride solution and water. The mixture was
extracted with 100 mL ethyl acetate. The layers were separated and
the organic fraction was washed with water and brine. It was then
dried over sodium sulfate, filtered, and evaporated. The residue
was purified via silica gel chromatography using 50% ethyl
acetate/petroleum ether.
[0310] Yield 0.8 gms (R)-tert-butyl
(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate. LCMS
(method P) RT 0.82 min, m/z 351.2 (MH.sup.+); .sup.1H NMR (400 MHz,
chloroform-d) .delta. 1.45 (s, 9H), 1.78-1.86 (m, 1H), 2.57-2.60
(br s, 1H), 3.15-3.23 (m, 2H), 3.68 (s, 6H), 4.12-4.25 (br s, 1H),
4.40 (m, 2H), 5.14 (br s, 1H), 6.75-6.82 (m, 3H).
Step D. (R)-3-Amino-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one
##STR00158##
[0312] To a 0.degree. C. solution of (R)-tert-butyl
(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate (0.7 g, 2
mmol) in dioxane (2 mL) was added dropwise HCl (1 mL, 12 mmol). The
solution was allowed to warm up to RT with stirring over 2 h. It
was then concentrated under vacuum and the residue was triturated
with diethyl ether.
[0313] Yield 400 mg crude
(R)-3-amino-1-(3,4-dimethoxybenzyl)-pyrrolidin-2-one. LCMS (Method
J) RT 0.5 min, m/z 251.1 (MH.sup.+), .sup.1H NMR (400 MHz,
chloroform-d) .delta. 2.48 (br s, 4H), 3.35 (br s, 2H), 3.70 (s,
3H), 3.8-3.95 (m, 6H), 4.4 (br s, 3H), 6.76 (br s, 3H), 8.81 (br s,
3H).
Step E.
(R)-1-(3,4-Dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)p-
yrrolidin-2-one
##STR00159##
[0315] To a solution of
(R)-3-amino-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one (0.4 g, 1.6
mmol) in acetonitrile (10 mL) was added
2-(4-methoxyphenyl)propane-1,3-diyl dimethanesulfonate (0.8 g, 1.8
mmol) (prepared as in GAG Sulyok et al; J Med Chem 2001, 44,
1938-1950 and N Rios-Lombardia et al, J Org Chem 2011, 76,
5709-5718) and DIPEA (0.84 mL, 4.8 mmol). The reaction mixture was
heated at 100.degree. C. overnight. The mixture was then
concentrated in vacuo, diluted with water, and extracted with 100
mL ethyl acetate. The organic layer was washed with water and
brine, then dried over sodium sulfate. The drying agent was
filtered off, the solvent was removed under vacuum and the residue
was purified via silica gel chromatography using 20% ethyl
acetate/pet ether to yield 200 mg
(R)-1-(3,4-dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolid-
in-2-one. LCMS (method J) RT 0.71 min, m/z 425.2 (MH.sup.+),
.sup.1H NMR (300 MHz, chloroform-d) .delta. 1.82-1.89 (m, 4H),
2.02-2.16 (m, 2H), 2.44-2.51 (m, 2H), 2.81 (m, 1H), 2.96 (m, 1H),
3.08-3.23 (m, 3H), 3.62 (m, 1H), 3.80 (s, 3H), 3.88 (s, 3H), 3.89
(s, 3H), 4.34 (d, J=14, 1H), 4.51 (d, J=14, 1H), 6.81 (s, 3H),
6.84-6.89 (m, 2H), 7.14-7.14 (m, 2H).
Step F.
(R)-1-(3,4-Dihydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)p-
yrrolidin-2-one
[0316] To a 0.degree. C. solution of
(R)-1-(3,4-dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolid-
in-2-one (0.03 g, 0.07 mmol) in DCM (5 mL) was added dropwise boron
tribromide (0.07 mL, 0.07 mmol). The solution was allowed to warm
up to RT with stirring over 3 h. The reaction was then quenched by
the addition of saturated sodium bicarbonate solution (10 mL). The
mixture was then extracted with DCM (100 mL) and washed with water
(50 mL) and brine (50 mL). The organic fraction was dried over
sodium sulfate, filtered, and concentrated under vacuum. The
residue was subjected to preparative HPLC (method B) to yield 5.6
mg of the titled compound of Example 43, as a pale yellow solid.
LCMS (method N) RT 0.93 min (99% AP) m/z 383.0 (MH.sup.+); .sup.1H
NMR (400 MHz, DMSO-d.sub.6) ppm 1.45-1.65 (m, 4H), 1.66-1.75 (m,
1H), 1.88-1.92 (m, 1H), 2.32-2.36 (m, 2H), 2.67-2.68 (m, 2H),
3.04-3.31 (m, 3H), 4.06-4.25 (m, 2H), 6.46-6.49 (m, 1H), 6.60-6.68
(m, 4H), 7.00-7.03 (m, 2H), 8.79 (s, 1H), 8.89 (s, 1H), 9.11 (s,
1H).
Example 44 (Enantiomer-1 and Enantiomer-2)
1-(4-Fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrr-
olidin-2-one
##STR00160##
[0317] Step A. (.+-.)-rel-(3S,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-(4-nitrobenzoyloxy)piperidine-1-carboxylate
##STR00161##
[0319] A mixture of diethylazodicarboxylate (12.9 mL, 81 mmol of
40% toluene solution), triphenyl phosphine (22 mL, 83 mmol),
4-nitrobenzoic acid (6.97 g, 42 mmol) and 200 mL tetrahydrofuran
was stirred for 10 min under an Ar atmosphere. Then was added a
solution of tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (Example
56, step D, 8 g, 20.9 mmol) in tetrahydrofuran (100 mL) and the
resulting mixture was stirred at rt overnight. It was then diluted
with water and extracted twice with 50 mL ethyl acetate. The
combined organic fractions were dried over Na.sub.2SO.sub.4,
filtered, and evaporated to dryness. The residue was purified via
silica gel chromatography (750 gm column, eluting with 0-50% ethyl
acetate/hexane) to yield 6 gms (.+-.)-rel-(3S,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-(4-nitrobenzoyloxy)piperidine-1-carboxylate.
LCMS (Method F) RT 2.68 min (87% AP), m/z 476.8
(MH.sup.+-t-butyl).
Step B. (.+-.)-rel-(3S,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
##STR00162##
[0321] To a suspension of KOH (5.06 g, 90 mmol), water (60 ml) and
tetrahydrofuran (200 ml) was added tert-butyl
4-(4-(benzyloxy)phenyl)-3-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate
(6 g, 11.3 mmol) and the reaction mixture was stirred at room
temperature overnight. It was then diluted with 200 mL water and
extracted twice with 200 mL ethyl acetate. The organic layer was
washed with 1.5 N HCl solution and was then dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The crude
product 4 g, (.+-.)-rel-(3S,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate), was
used in the next step without further purification. LCMS (method F)
RT 2.44 min (95% AP), m/z 382 (M-H) (negative mode); .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.29-7.44 (m, 5H), 7.71 (d,
J=8.4, 2H), 6.91 (d, J=8.4, 2H), 5.06 (s, 2H), 4.45 (br s, 1H),
3.80-4.20 (m, 2H), 3.70 (br s, 1H), 2.60-3.05 (m, 3H), 1.95-2.20
(m, 1H), 1.35 (s, 9H).
Step C. (.+-.)-rel-(3S,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol,
hydrochloride
##STR00163##
[0323] To a solution of tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (100 mg,
0.26 mmol) in 10 mL diethyl ether was added 4 M HCl in dioxane (1.3
mL, 5.2 mmol) and the resulting mixture was stirred at rt
overnight.
[0324] The solvent was evaporated off and the residue triturated
with ether. Yield 80 mg (88%), LCMS (Method J) RT 0.73 min (92%
AP), m/z 284.2 (MH.sup.+), .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 7.30-7.45 (m, 5H), 7.27 (d, J=8.4, 2H), 6.97 (d, J=8.7,
2H), 5.09 (s, 2H), 4.09 (s, 1H), 3.44 (d, J=12.6, 2H), 3.32-3.29
(m, 1H), 3.08-3.20 (m, 1H), 2.95 (d, J=12.6, 1H), 2.48-2.58 (m,
1H), 1.82 (d, J=13.2, 1H).
Step D.
(.+-.)-rel-3-((3S,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-
-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one
##STR00164##
[0326] To a mixture of
(.+-.)-rel-(3S,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol, HCl (260
mg, 0.81 mmol), 3-bromo-1-(4-fluorobenzyl)pyrrolidin-2-one (442 mg,
1.63 mmol, Intermediate 3) and DMF (3 mL) was added triethylamine
(0.57 mL, 4 mmol) and the reaction mixture was heated in the
microwave for 1 hour at 120.degree. C. The reaction mixture was
cooled, diluted with water, and twice extracted with 20 mL ethyl
acetate. The combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The residue
was subjected to preparative HPLC (method F), collecting two
racemic diastereomers D1 (90 mg) and D2 (100 mg). The relative
stereochemistry of D1 and D2 was not determined. Data for D1 (first
eluting diastereomer): LCMS (method E) RT 2.90 min, m/z 475
(MH.sup.+), .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.47-7.37 (m, 4H), 7.36-7.25 (m, 3H), 7.23-7.15 (m, 4H), 6.93-6.89
(m, 2H), 5.08 (s, 2H), 4.37 (d, J=14.1 Hz, 2H), 3.84 (d, J=7.5 Hz,
1H), 3.72-3.66 (m, 1H), 3.49 (s, 1H), 3.16 (d, J=19.6 Hz, 2H),
3.07-3.00 (m, 1H), 2.89 (s, 1H), 2.80-2.74 (m, 1H), 2.59-2.53 (m,
1H), 2.38-2.30 (m, 1H), 2.19-2.06 (m, 2H), 1.88 (s, 1H), 1.53-1.44
(m, 1H). Data for D2 (second eluting diastereomer): LCMS (method E)
RT 2.37 min, m/z 475 (MH.sup.+), .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.47-7.37 (m, 4H), 7.35-7.25 (m, 3H),
7.22-7.16 (m, 4H), 6.93-6.89 (m, 2H), 5.08 (s, 2H), 4.44-4.30 (m,
2H), 3.99 (d, J=7.5 Hz, 1H), 3.72 (d, J=7.5 Hz, 1H), 3.51 (t, J=8.5
Hz, 1H), 3.21-3.10 (m, 2H), 2.97-2.92 (m, 1H), 2.85-2.80 (m, 2H),
2.54 (br. s., 1H), 2.47 (s, 1H), 2.16-2.06 (m, 2H), 1.92 (s, 1H),
1.48-1.42 (m, 1H).
Step E.
(.+-.)-rel-1-(4-fluorobenzyl)-3-((3S,4R)-3-hydroxy-4-(4-hydroxyphe-
nyl)piperidin-1-yl)pyrrolidin-2-one
##STR00165##
[0328] A mixture of
3-(4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorobenzyl)-py-
rrolidin-2-one (D2 from step E, 85 mg, 0.18 mmol), methanol (5 mL),
and 38 mg 10% Pd/C was stirred in a pressure vessel overnight under
125 psi hydrogen pressure. The catalyst was removed by filtration
through Celite and the filtrate was evaporated to dryness to yield
70 mg of racemic
1-(4-fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)py-
rrolidin-2-one. LCMS (method J) RT=0.63 (52% AP), 0.66 (31% AP)
min, m/z 385.4 (MH.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.27-7.28 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (d, J=8.4,
2H), 6.45 (d, J=8.4, 2H), 4.39 (d, J=15, 1H), 4.32 (d, J=15, 1H),
3.74-3.76 (m, 1H), 3.66 (m, 1H), 3.47 (m, 1H), 3.10-3.18 (m, 2H),
3.01 (m, 1H), 2.85-2.88 (m, 1H), 2.76 (m, 1H), 2.30-2.40 (m, 1H),
2.06-2.11 (m, 2H), 1.80-1.95 (m, 1H), 1.46 (d, J=12, 1H). The
complete relative stereochemistry was not determined.
Step F.
1-(4-Fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-
-yl)pyrrolidin-2-one
[0329] The product from Step E,
1-(4-fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrroli-
din-2-one (70 mg, 0.182 mmol), was separated via SFC (method C-3)
into two enantiomers, Example 44 E-1 (12 mg) and E-2 (10 mg). E-1
was re-purified via preparative HPLC (method B). The absolute
configurations were not determined. Data for E-1: LCMS (method N)
RT 1.34 min (99% AP), m/z 385.0 (MH.sup.+), Chiral SFC (method C-3)
RT 3.2 min; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
1.59-1.68 (m, 1H) 2.02-2.35 (m, 3H) 2.50-2.70 (m, 2H) 2.79-2.91 (m,
2H) 3.04-3.12 (m, 1H) 3.22-3.30 (m, 2H) 3.73 (s, 1H) 3.84 (br. s.,
1H) 4.39-4.47 (m, 1H) 4.51-4.60 (m, 1H) 6.71-6.77 (m, 2H) 7.06-7.18
(m, 4H) 7.32 (dd, J=8.78, 5.27 Hz, 2H). Data for E-2: LCMS (method
F) RT 1.97 min (95% AP), m/z 385.0 (MH.sup.+), Chiral SFC (method
C-3) RT 7.4 min; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
ppm 1.59-1.68 (m, 1H) 2.02-2.35 (m, 3H) 2.50-2.70 (m, 2H) 2.79-2.91
(m, 2H) 3.04-3.12 (m, 1H) 3.22-3.30 (m, 2H) 3.73 (s, 1H) 3.84 (br.
s., 1H) 4.39-4.47 (m, 1H) 4.51-4.60 (m, 1H) 6.71-6.77 (m, 2H)
7.06-7.18 (m, 4H) 7.32 (dd, J=8.78, 5.27 Hz, 2H).
Example 45 (Peak-1, Peak-2, Peak-3, Peak-4)
(S)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-f-
luoro-4-methylbenzyl)pyrrolidin-2-one and
(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00166##
[0330]
(S)-3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-
-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00167##
[0331] Step A. tert-butyl
4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate
##STR00168##
[0333] A stirred solution of tert-butyl
4-oxopiperidine-1-carboxylate (4.5 g, 22.6 mmol) in diethyl ether
(100 mL) at 0.degree. C. was treated with a solution of
(3-fluoro-4-methoxyphenyl)magnesium bromide (49.7 mL, 24.8 mmol,
0.5 M in tetrahydrofuran). The reaction mixture was allowed to warm
to rt and was stirred at for 12 h. It was then diluted with 100 mL
water and the layers were separated. The aqueous layer was
extracted three times with 150 mL of ethyl acetate and the combined
organic layers were dried over anhydrous sodium sulfate, filtered,
and evaporated. The residue was purified by silica gel
chromatography (120 g column) eluting with 30% ethyl acetate in
petroleum ether to obtain 6.5 g of tert-butyl
4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate as a
clear liquid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.33-1.47 (m, 11H) 1.52-1.61 (m, 2H) 1.69-1.84 (m, 2H) 3.03-3.22
(m, 2H) 3.77-3.89 (m, 6H) 5.09 (s, 1H) 7.10 (s, 1H) 7.17-7.26 (m,
1H) 7.25-7.33 (m, 1H).
Step B. 4-(3-Fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
hydrochloride
##STR00169##
[0335] To a stirred solution of tert-butyl
4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (6.5
g, 20 mmol) in 1,4-dioxane (100 mL) at 0.degree. C. was added 50 mL
of 1M HCl (dioxane solution) and the mixture was allowed to warm to
rt and stirred for 12 h. The solvent was then removed under reduced
pressure. The residue was triturated with ethyl acetate to obtain
4.5 g crude 4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
hydrochloride as a solid which was isolated by filtration and used
without further purification. LCMS (Method P) RT 0.57 min, m/z 208
(M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
2.37-2.61 (m, 2H), 3.12-3.38 (m, 3H) 3.80-3.94 (m, 3H) 3.95-4.12
(m, 2H) 7.10-7.29 (m, 1H) 7.33-7.44 (m, 1H) 7.51 (dd, J=13.05, 2.51
Hz, 1H) 9.27-9.63 (m, 2H).
Step C. tert-Butyl
4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00170##
[0337] To a stirring solution of
4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
hydrochloride (4.5 g, 18.5 mmol) and triethylamine (7.7 mL, 55
mmol) in DCM (30 mL) at 0.degree. C. was added 5.6 mL (24 mmol) of
di-tert-butyl dicarbonate. The mixture was allowed to warm to rt
and was stirred for 12 h. It was then diluted with DCM (100 mL) and
water (100 mL) and the layers were separated. The aqueous layer was
again extracted with DCM and the combined organic layers were
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated under reduced pressure to obtain crude tert-butyl
4-(3-fluoro-4-methoxyphenyl)-5,6-dihydro-pyridine-1(2H)-carboxylate
(6 g) as a liquid which was purified using an 80 g silica gel
column eluting with 17%-30% ethyl acetate/petroleum ether to obtain
4.5 g of the pure product as a liquid. LCMS (Method P) RT=1.21 min,
m/z 252 (M+H.sup.+-t-butyl); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.39-1.48 (m, 9H) 2.37-2.46 (m, 2H) 3.52 (s, 2H)
3.77-3.89 (m, 3H) 3.95-4.09 (m, 2H) 6.07-6.16 (m, 1H) 7.06-7.17 (m,
1H) 7.18-7.24 (m, 1H) 7.26-7.35 (m, 1H).
Step D. (.+-.)-rel-(3S,4S)-tert-butyl
4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate
##STR00171##
[0339] To a suspension of NaBH.sub.4 (0.37 g, 9.8 mmol) in
tetrahydrofuran (50 mL) was added BF.sub.3.OEt.sub.2 (1.3 mL, 10
mmol) at 0.degree. C. The reaction mixture was warmed to rt for 1 h
and then re-cooled to 0.degree. C. Tert-butyl
4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate
(1 g, 3.3 mmol) in tetrahydrofuran (10 mL) was then added. The
resulting mixture was allowed to warm to rt over 2 h. It was then
re-cooled to 0.degree. C. and water (4 mL), ethanol (4 mL), 30%
H.sub.2O.sub.2 (3 mL, 29.4 mmol) and a NaOH solution (4 mL, 3.25
mmol) were added sequentially and the final mixture was heated to
65.degree. C. for 12 h. It was cooled to room temperature, and 50
mL water and 200 mL ethyl acetate were added. The layers were
separated and the aqueous layer was twice extracted with 150 mL of
ethyl acetate. The combined organic layers were washed with 1N HCl
followed by brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure
to obtain 2 g of crude (.+-.)-rel-(3S,4S)-tert-butyl
4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate as a
brown gum. The crude compound was purified on a 40 g silica gel
column eluting with 30% ethyl acetate in petroleum ether to obtain
450 mg of the pure product as a liquid. LCMS (Method P) RT 0.98
min, m/z 252 (M+H.sup.+-t-butyl), 270 (M+H.sup.+-t-butyl,
--H.sub.2O); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.42
(s, 9H) 1.46-1.58 (m, 1H) 1.61-1.71 (m, 1H) 2.32-2.48 (m, 2H)
2.62-2.77 (m, 1H) 3.34-3.47 (m, 1H) 3.80 (s, 3H) 3.91-4.01 (m, 1H)
4.05-4.14 (m, 1H) 4.82 (s, 1H) 6.96-7.02 (m, 1H) 7.03-7.13 (m,
2H).
Step E. (.+-.)-rel-(3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate
##STR00172##
[0341] A stirred solution of trans-tert-butyl
4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate (100
mg, 0.31 mmol) in DCM (15 mL) at -78.degree. C. was treated
dropwise with DAST (0.08 mL, 0.6 mmol). The resulting mixture was
stirred at -78.degree. C. for 90 min. It was then quenched with ice
water, warmed to rt, and extracted with DCM (50 mL). The organic
layer was separated, washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure
to obtain 70 mg of (.+-.)-rel-(3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate. LCMS
(Method P) RT 1.11, 1.13 min, m/z 313
(M+H.sup.++CH.sub.3CN-t-butyl). Three batches of product
(.about.210 mg total) were combined and subjected to HPLC
purification (Method A) to give 140 mg
(.+-.)-rel-(3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.43 (s, 9H)
1.55-1.67 (m, 1H) 1.74-1.82 (m, 1H) 2.72-2.90 (m, 3H) 3.82 (s, 3H)
3.89-4.03 (m, 1H) 4.24-4.34 (m, 1H) 4.50-4.71 (m, 1H) 7.09 (d,
J=1.51 Hz, 2H) 7.18-7.28 (m, 1H).
Step F. (3R,4R)-tert-Butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate and
(3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate
##STR00173##
[0343] The purified product from step F was subjected to chiral SFC
(method D) to afford the two separate enantiomers (E-1 and E-2).
Data for E-1 (3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate:
chiral HPLC (method G) RT=2.45 min, 100% AP; LCMS (Method J)
RT=1.04 min, m/z=252 (M+H+-HF, -t-butyl), 272 (M+H.sup.+-t-butyl);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.02-7.11 (m,
3H) 4.36-4.59 (m, 2H) 4.07-4.16 (m, 1H) 3.87 (s, 3H) 2.76-2.95 (m,
3H) 1.82-1.93 (m, 1H) 1.64-1.76 (m, 1H) 1.51 (s, 9H). Data for E-2
(3R,4R)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate:
chiral HPLC (method G) RT=2.82 min, 96.9% AP; LCMS (Method J)
RT=1.04 min, m/z=252 (M+H+-HF, -t-butyl), 272 (M+H.sup.+-t-butyl);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.05 (m, 3H)
4.39-4.60 (m, 2H) 4.07-4.16 (m, 1H) 3.87 (s, 3H) 2.76-2.94 (m, 3H)
1.84-1.91 (m, 1H) 1.63-1.76 (m, 1H) 1.51 (s, 9H).
Step G. (3S,4S)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine,
hydrochloride
##STR00174##
[0345] To a stirring solution of (3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (E-1,
the first eluting enantiomer from step F, 44 mg, 0.134 mmol) in
1,4-dioxane (3 mL) at 0.degree. C. was added 2 mL (8 mmol) of 4 M
HCl in dioxane, and the resulting mixture was stirred at rt for 12
h. The solvent was removed under reduced pressure to afford
(3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine
hydrochloride (30 mg) as a white solid which was used without
further purification. LCMS (Method J) RT=0.60 min, m/z 228.2
(M+H.sup.+). .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
7.01-7.19 (m, 3H) 4.88-4.99 (m, 1H) 4.71-4.83 (m, 1H) 3.89 (s, 3H)
3.67-3.78 (m, 1H) 3.40-3.53 (m, 1H) 3.00-3.25 (m, 3H) 2.12-2.27 (m,
1H) 1.93-2.08 (m, 1H).
Step H.
3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1--
(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00175##
[0347] A mixture of
(3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine
hydrochloride (30 mg, 0.11 mmol, from step G),
3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.19
mmol, intermediate 6) and DIPEA (0.02 mL, 0.11 mmol) in DMF (3 mL)
was heated to 120.degree. C. for 90 min in a microwave reactor. The
reaction mixture was cooled to rt and the solvent was removed under
reduced pressure to obtain 60 mg of
3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluo-
ro-4-methylbenzyl)-pyrrolidin-2-one (diastereomeric pair), which
was used in the next step without purification. LCMS (Method P)
RT=1.12 min, m/z 433 (M+H.sup.+).
Step I.
3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1--
(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00176##
[0349] To a stirring solution of
3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluo-
ro-4-methylbenzyl)pyrrolidin-2-one (60 mg, 0.14 mmol,
diastereomeric mixture from step H) in 10 mL of DCM at -78.degree.
C. was added 2.5 mL of boron tribromide (2.5 mmole) and the mixture
allowed to warm to rt and stirred for 3 h. The reaction mixture was
then cooled to 0.degree. C. and quenched with saturated NaHCO.sub.3
solution. The mixture was then diluted with DCM and the organic
layer was separated and evaporated under reduced pressure. The
crude compound was purified by preparative HPLC to give
3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-
-fluoro-4-methyl-benzyl)pyrrolidin-2-one (20 mg, 0.047 mmol, 34%
yield) (diastereomeric pair). LCMS (Method Q) RT=1.17 min, m/z
419.0 (M+H.sup.+).
Step J.
(S)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl-
)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one and
(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one
[0350] The product mixture from step I was subjected to chiral
separation via SFC method C-6 to give two homochiral products:
Example 45, P-1 (4.1 mg) and Example 45, P-2 (7.3 mg). Data for P-1
(S)-3-(3S,4S)-(3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one: HPLC (Method C) RT=7.09 min
(Method D) RT=7.88 min; LCMS (Method F) RT=2.1 min, m/z 419
(M+H.sup.+). Chiral HPLC (Method C-6) RT=2.87 min; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.76-1.94 (m, 2H) 1.99-2.12 (m,
1H) 2.14-2.24 (m, 1H) 2.25-2.29 (m, 3H) 2.39-2.50 (m, 1H) 2.52-2.71
(m, 2H) 2.94-3.06 (m, 1H) 3.07-3.19 (m, 1H) 3.22-3.31 (m, 2H)
3.69-3.80 (m, 1H) 4.38-4.68 (m, 3H) 6.81-7.04 (m, 5H) 7.19-7.29 (m,
1H). Data for P-2
(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one: HPLC (Method C) RT=7.10 min
(Method D) RT=7.88 min; LCMS (Method F) RT=2.098 min, m/z 419
(M+H.sup.+). Chiral HPLC (Method C-6) RT=5.33 min; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.72-1.90 (m, 2H) 2.02-2.14 (m,
1H) 2.15-2.23 (m, 1H) 2.23-2.29 (m, 3H) 2.38-2.49 (m, 1H) 2.53-2.72
(m, 2H) 2.73-2.82 (m, 1H) 3.22-3.32 (m, 2H) 3.38-3.47 (m, 1H)
3.59-3.64 (m, 1H) 3.69-3.76 (m, 1H) 4.38-4.54 (m, 2H) 4.60-4.71 (m,
1H) 6.85-7.04 (m, 5H) 7.20-7.28 (m, 1H).
Step K. (3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine
hydrochloride
##STR00177##
[0352] To a stirring solution of (3R,4R)-tert-butyl
3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (38
mg, 0.12 mmol, E-2, the second eluting enantiomer from step F) in 3
mL of 1,4-dioxane at 0.degree. C. was added 2 mL of 4M HCl in
1,4-dioxane (8 mmol) and the mixture was allowed to warm up to rt
over 12 h. The solvent was removed under reduced pressure to obtain
(3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine
hydrochloride (30 mg) as a semi-solid which was used without
further purification. LCMS (Method K) RT=0.59 min, m/z 228, m/z 419
(M+H.sup.+); .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
6.99-7.22 (m, 3H) 4.73-4.84 (m, 1H) 3.89 (s, 3H) 3.67-3.78 (m, 2H)
3.41-3.52 (m, 1H) 3.00-3.25 (m, 3H) 2.09-2.26 (m, 1H) 1.88-2.08 (m,
1H).
Step L.
3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1--
(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00178##
[0354] A mixture of
(3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine
hydrochloride (30 mg, 0.114 mmol, from step K),
3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.189
mmol, intermediate 6) and DIPEA (0.020 mL, 0.114 mmol) in DMF (3
mL) was heated to 120.degree. C. for 90 min in the a microwave
reactor. The solvent was then removed under reduced pressure to
obtain 60 mg of
3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluo-
ro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) which was
used in the next step without further purification. LCMS (Method P)
RT=1.12 min, m/z 433 (M+H.sup.+).
Step M.
3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1--
(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00179##
[0356] To a stirred solution of
3-((3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluo-
ro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair from step
L, 50 mg, 0.12 mmol) in DCM (5 mL) at -78.degree. C. was added
boron tribromide (2 mL, 2 mmol, 1 M in DCM) and the resulting
mixture was stirred at rt for 3 h. The solvent was evaporated and
the residue subjected to preparative HPLC (method D) to yield 20 mg
(0.04 mmol, 37%) of
3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluo-
ro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair). LCMS
(Method K) RT 1.16 min; m/z 419 (M+H.sup.+); .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. ppm 7.22-7.29 (m, 1H) 6.90-7.09 (m, 5H)
4.88-4.96 (m, 1H) 4.49-4.53 (m, 2H), 4.12-4.25 (m, 1H), 4.35-4.42
(m, 1H) 3.98-4.02 (m, 1H) 3.34-3.48 (m, 4H) 3.14-3.21 (m, 1H)
2.98-3.07 (m, 1H) 2.46-2.56 (m, 1H) 2.20-2.30 (m, 5H) 1.98-2.12 (m,
1H).
Step N.
(S)-3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl-
)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one
[0357] The product mixture from step M was subjected to chiral
separation via SFC (method C-6) to give two homochiral products:
Example 45, P-3 (3.6 mg) and Example 45, P-4 (2.2 mg). Data for P-3
(S)-3-(3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-f-
luoro-4-methylbenzyl)pyrrolidin-2-one: HPLC (Method C) RT=7.03 min
(Method D) RT=8.3 min, LCMS (Method F) RT=2.10 min, m/z 419.2
(M+H.sup.+), Chiral HPLC (Method C-6) RT=3.6 min; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.73-1.90 (m, 2H) 2.02-2.24 (m,
2H) 2.25-2.31 (m, 3H) 2.39-2.48 (m, 1H) 2.52-2.71 (m, 2H) 2.74-2.82
(m, 1H) 3.13-3.30 (m, 2H) 3.38-3.47 (m, 1H) 3.67-3.76 (m, 1H)
4.37-4.70 (m, 4H) 6.82-7.04 (m, 5H) 7.18-7.28 (m, 1H). Data for P-4
(R)-3-((3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3--
fluoro-4-methylbenzyl)pyrrolidin-2-one: HPLC (Method C) RT=7.05 min
(Method D) RT=8.33 min, LCMS (Method F) RT=2.10 min, m/z 419.2
(M+H.sup.+), Chiral HPLC (Method C-6) RT=5.44 min; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.67-1.93 (m, 2H) 2.01-2.13 (m,
1H) 2.14-2.23 (m, 1H) 2.25-2.28 (m, 3H) 2.39-2.51 (m, 1H) 2.52-2.72
(m, 2H) 2.97-3.07 (m, 1H) 3.09-3.18 (m, 1H) 3.22-3.32 (m, 2H)
3.68-3.78 (m, 1H) 4.38-4.55 (m, 2H) 4.58-4.70 (m, 1H) 6.84-7.05 (m,
5H) 7.19-7.28 (m, 1H).
Example 46 (Peak-1, Peak-2, Peak-3, Peak-4)
(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenz-
yl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
##STR00180##
[0358]
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-met-
hylbenzyl)pyrrolidin-2-one and
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
##STR00181##
[0359] Step A.
(.+-.)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol
##STR00182##
[0361] To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol)
in THF (200 mL) at 0.degree. C. under a nitrogen atmosphere was
added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the
resulting mixture was stirred for 30 minutes. Then
1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36
mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100
mL of tetrahydrofuran was added. The mixture was allowed to warm to
rt and stirred for 2 h. The reaction was then quenched by the
dropwise addition of 100 mL of water. Next were added sequentially
100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide
solution, and 30% hydrogen peroxide (18 mL, 180 mmol) and the
mixture was stirred at reflux temperature overnight. The reaction
mixture was then allowed to cool, diluted with saturated aqueous
ammonium chloride (200 mL), and extracted with ethyl acetate (500
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and evaporated under reduced pressure to give
(.+-.)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5
g, 24.6 mmol, 69% yield) which was used without further
purification. LCMS (Method K) RT 1.99 min; m/z 298.0
(M+H.sup.+).
Step B. (.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol
##STR00183##
[0363] To a solution of
(.+-.)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g,
30 mmol) in methanol (150 mL) was added 10% Pd/C (4.8 g) and the
reaction mixture was stirred overnight under a hydrogen atmosphere.
The catalyst was then removed by filtration through Celite and the
solvent was evaporated under reduced pressure to give
(.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6
mmol, 81% yield) which was used without further purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.10-7.15 (m, 2H)
6.80-6.86 (m, 2H) 4.30 (d, J=5.27 Hz, 1H) 3.37-3.43 (m, 1H) 3.04
(dd, J=11.58, 4.36 Hz, 1H) 2.86 (d, J=12.17 Hz, 1H) 2.43 (td,
J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m, 2H) 1.57-1.63 (m, 1H) 1.43-1.54
(m, 1H).
Step C. (.+-.)-rel-(3S,4S)-tert-butyl
4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
##STR00184##
[0365] To a solution of
(.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5 g, 21.7
mmol) in DCM (150 mL) at -10.degree. C. under nitrogen was added a
1 M solution of boron tribromide in DCM (109 mL, 109 mmol). The
reaction mixture was allowed to warm to rt, stirred for 2 h, and
then rechilled to 0.degree. C. and quenched by the addition of a
saturated aqueous sodium bicarbonate solution (300 mL). The aqueous
layer was washed with 250 mL of DCM and then to it was added 200 mL
10% aqueous NaOH, followed by 9.5 g (43.5 mmol) of di-t-butyl
dicarbonate and the resulting mixture was stirred for an additional
2 h. The mixture was then extracted with 200 mL ethyl acetate and
the organic layer was separated, dried over Na.sub.2SO.sub.4,
filtered, and evaporated under reduced pressure to
(.+-.)-rel-(3S,4S)-tert-butyl
4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
(6.5 g, 12 mmol, 56% yield) which was used without further
purification. LCMS (Method K) RT 2.33 min, m/z 282 (M+H.sup.+-2
t-butyl), 370; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.27
(d, J=8.66 Hz, 2H) 7.08 (d, J=8.66 Hz, 2H) 4.85 (d, J=5.65 Hz, 1H)
4.13 (d, J=8.41 Hz, 1H) 3.97 (d, J=10.48 Hz, 1H) 3.45 (tt, J=10.27,
5.19 Hz, 1H) 1.67 (d, J=3.39 Hz, 1H) 1.50-1.59 (m, 1H) 1.49 (s,
11H).
Step D. (.+-.)-rel-(3S,4S)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate
##STR00185##
[0367] To a solution of (.+-.)-rel-(3S,4S)-tert-butyl
4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
(6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of
potassium carbonate (83 mmol) and the reaction mixture was stirred
at rt for 5 h. The organic solvent was removed under reduced
pressure and the residue was partitioned between 1N HCl (300 mL)
and ethyl acetate (300 mL). The layers were separated and the
organic layer was dried over Na.sub.2SO.sub.4 and evaporated under
reduced pressure to give (.+-.)-rel-(3S,4S)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 15
mmol, 92% yield) which was used without further purification. LCMS
(method F) RT 1.85 min, m/z 238 (M+H.sup.+-t-butyl), 279
(M+H.sup.+-t-butyl+CH.sub.3CN), .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.01 (d, J=8.53 Hz, 2H) 6.66 (d, J=8.53 Hz, 2H) 4.70
(d, J=5.02 Hz, 1H) 4.09 (br. s., 1H) 3.94 (d, J=11.55 Hz, 1H)
3.35-3.41 (m, 1H) 2.66-2.77 (m, 1H) 2.29-2.39 (m, 1H) 1.63 (dd,
J=13.30, 3.26 Hz, 1H) 1.44-1.52 (m, 1H) 1.42 (s, 9H).
Step E. (3S,4S)-tert-Butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and
(3R,4R)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate
##STR00186##
[0369] (.+-.)-rel-(3S,4S)-tert-Butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 17
mmol, from step D) was subjected to chiral SFC separation (method
C-5) to yield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0% yield) and
E-2 (2.4 g, 8.18 mmol, 48.0% yield). Data for E-1: chiral HPLC
(method A5) retention time 3.42 min. Data for E-2: chiral HPLC
(method A5) retention time 4.2 min.
Step F. (3R,4R)-tert-Butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
##STR00187##
[0371] A mixture of (3R,4R)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (620 mg, 2.1
mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and
benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt
for 16 h. The solvent was removed by evaporation and the residue
was treated with 50 mL of water. The aqueous mixture was then
extracted 4 times with 50 mL of chloroform. The combined organic
phases were dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to yield 750 mg of (3R,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate which was
used without further purification. LCMS (method F) RT 2.28 min,
m/z=310 (M+H.sup.+-t-butyl-water), 328 (M+H.sup.+-t-butyl).
Step G. (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol
hydrochloride
##STR00188##
[0373] A mixture of (3R,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg,
2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCl in dioxane was
stirred at rt for 2 h. The reaction was then evaporated to dryness
to yield 550 mg of (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol
hydrochloride which was used without further purification. LCMS
(method J) RT 0.70 min, m/z 284 (M+H.sup.+).
Step H.
3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-m-
ethylbenzyl)pyrrolidin-2-one
##STR00189##
[0375] A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one
(Intermediate 2, 220 mg, 0.82 mmol),
(3R,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262
mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was
stirred at 60.degree. C. for 1 h, 80.degree. C. for 1 h,
100.degree. C. for 1 h and 120.degree. C. for 1 h. The reaction
mixture was then allowed to cool, diluted with 40 mL of water and
extracted four times with 50 mL of chloroform. The combined organic
layers were washed with 60 mL brine, dried over anhydrous sodium
sulfate, filtered, and evaporated to yield 382 mg of
3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(-
4-methylbenzyl)pyrrolidin-2-one which was used without further
purification. LCMS (method J) (main component of a mixture) RT 2.23
min, m/z 471 (M+H.sup.+).
Step I.
3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-me-
thylbenzyl)pyrrolidin-2-one
##STR00190##
[0377] A solution of
3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)py-
rrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to
0.degree. C. was treated dropwise with DAST (0.32 mL, 2.4 mmol)
over 3 min. The reaction mixture was then allowed to warm to rt and
was stirred for 2 h. The reaction was then quenched with 50 mL of
10% aqueous sodium bicarbonate solution and extracted 4 times with
40 mL of DCM. The combined organic layers were washed with 50 mL of
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum to yield 382 mg of
3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one as a mixture of two diastereomers and
rearrangement products which was used without further purification.
LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473
(M+H.sup.+).
Step J.
3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methyl-
benzyl)pyrrolidin-2-one
##STR00191##
[0379] A mixture of
3-((3R,4R)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbe-
nzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was
flushed with nitrogen, followed by the addition of 172 mg of 10%
Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi
hydrogen pressure. The reaction was then transferred to a 100 mL
autoclave and stirred at 7 kg/cm.sup.2 hydrogen pressure for 4
days. The catalyst was removed by filtration through Celite and the
solvent was evaporated off. The crude product was subjected to HPLC
purification (method B) to yield 77.3 mg
3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-methylbenzyl-
)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15
min, m/z 383.0 (M+H.sup.+).
Step K.
(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-me-
thylbenzyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
[0380] The diastereomeric mixture from step J was separated by SFC
method C-7 to yield homochiral Examples 46 P-1 (29.3 mg) and P-2
(32.8 mg). Data for P-1
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-m-
ethylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z
383.2 (M+H.sup.+), 405.2 (M+Na.sup.+); HPLC (method B) RT 8.24 min
(98.8% AP); HPLC (method C) RT 6.52 min (99.1% AP); Chiral HPLC
(method C-6) RT 4.1 min; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. ppm 1.76-1.86 (m, 2H) 2.07 (d, J=8.53 Hz, 1H) 2.13-2.21 (m,
1H) 2.34 (s, 3H) 2.43 (s, 0H) 2.55-2.60 (m, 1H) 2.65-2.70 (m, 1H)
2.75 (br. s., 1H) 3.20-3.30 (m, 2H) 3.38-3.45 (m, 1H) 3.70 (t,
J=8.78 Hz, 1H) 4.44 (t, J=79.81 Hz, 3H) 4.63-4.71 (m, 1H) 6.70-6.80
(m, 2H) 7.07-7.15 (m, 2H) 7.07-7.12 (m, 1H) 7.13-7.22 (m, 4H);
.sup.19F NMR .delta. ppm -184.171. Data for P-2:
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2
(M+H.sup.+), 405.2 (M+Na.sup.+); HPLC (method B) RT 8.29 min (99.7%
AP); HPLC (method C) RT 6.52 min (99.8% AP); Chiral HPLC (method
C-6) RT 6.92 min; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
ppm 1.80-1.90 (m, 2H) 2.07 (d, J=8.03 Hz, 1H) 2.19 (s, 1H) 2.34 (s,
3H) 2.41-2.48 (m, 1H) 2.66 (d, J=4.52 Hz, 2H) 2.95-3.03 (m, 1H)
3.10-3.18 (m, 1H) 3.20-3.30 (m, 2H) 3.68-3.78 (m, 1H) 4.38 (s, 1H)
4.51 (d, J=14.56 Hz, 2H) 6.70-6.80 (m, 2H) 7.05-7.13 (m, 2H)
7.13-7.22 (m, 4H); .sup.19F NMR .delta. ppm -184.311.
Step L. (3S,4S)-tert-Butyl
3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate
##STR00192##
[0382] To a solution of (3S,4S)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (400 mg, 1.36
mmol, the first eluting enantiomer E-1 from step E) in DCM (5 mL)
cooled to 0.degree. C. was added dropwise DAST (0.54 mL, 4.1 mmol)
over 10 min. The mixture was allowed to warm up to rt and was
stirred for 2 h. The reaction was slowly quenched with 50 mL of a
10% aqueous sodium bicarbonate solution and extracted four times
with 50 mL of DCM. The combined organic layers were washed with 75
mL of brine, dried, and concentrated under vacuum to yield 390 mg
of (3S,4S)-tert-butyl
3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate which was used
without further purification. LCMS (Method Q) RT 0.92 min, m/z
240.1 (M+H.sup.+).
Step M. 4-((3S,4S)-3-Fluoropiperidin-4-yl)phenol hydrochloride
##STR00193##
[0384] A mixture of (3S,4S)-tert-butyl
3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (390 mg, 1.3
mmol) and 4M HCl in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL)
was stirred at rt for 2 hr. It was then concentrated to dryness,
washed with 10 mL of 5% DCM/diethyl ether mixture and the solid was
isolated by filtration. Yield: 260 mg of
4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride; LCMS
(method Q) RT 0.46 min, mz 196.1 (M+H.sup.+).sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.57 (br. s., 4H), 8.92-8.68 (m, 1H), 7.14
(d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.82-6.73 (m, 2H),
5.07-4.85 (m, 1H), 3.77-3.36 (m, 9H), 3.32-3.22 (m, 2H), 3.13-2.85
(m, 5H), 2.06-1.88 (m, H).
Step N.
3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methyl-
benzyl)pyrrolidin-2-one
##STR00194##
[0386] A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (200
mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and
4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg,
0.75 mmol) in DMF (3 mL) was heated to 120.degree. C. in a
microwave reactor for 1.5 h. The mixture was allowed to cool and
was then mixed with 60 mL water and extracted 5 times with 40 mL of
DCM. The combined organic extracts were washed with 80 mL of brine,
dried over anhydrous sodium sulfate, filtered, and evaporated to
give 265 mg of
3-((3S,4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-1-yl)-1-(4-methylbenzyl-
)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method
P) RT 0.92 min m/z 383.4 (M+H.sup.+).
Step O.
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-me-
thylbenzyl)pyrrolidin-2-one and
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
[0387] A portion of the diastereomer mixture from step N (130 mg)
was subjected to chiral purification via SFC (method C-7) to give
homochiral Examples 46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for
P-3
(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one: LCMS (Method F) RT=2.10 min, m/z 383.2
(M+H.sup.+); HPLC (Method C) RT 6.54 min, (Method D) RT 8.20 min;
chiral HPLC (method C-6) RT 3.42 min; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. ppm 1.76-1.86 (m, 2H) 2.06 (d, J=8.53 Hz,
1H) 2.10-2.21 (m, 1H) 2.34 (s, 3H) 2.40-2.48 (m, 1H) 2.53-2.60 (m,
1H) 2.61-2.70 (m, 2H) 2.95-3.01 (m, 1H) 3.01 (s, 2H) 3.10-3.16 (m,
1H) 3.18-3.28 (m, 2H) 3.72 (s, 1H) 4.35-4.41 (m, 1H) 4.46-4.70 (m,
2H) 6.72-6.80 (m, 2H) 7.05-7.23 (m, 6H). Data for P-4
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methy-
lbenzyl)pyrrolidin-2-one: LCMS (Method F) RT 2.11 min, m/z 383.2
(M+H.sup.+); HPLC (Method C) RT 6.50 min, (Method D) RT 8.21 min;
chiral HPLC (method C-6) RT 6.31 min; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. ppm 1.81 (dd, J=7.28, 2.76 Hz, 2H) 2.06
(d, J=9.04 Hz, 2H) 2.33 (s, 3H) 2.43 (s, 1H) 2.55 (br s, 1H) 2.66
(d, J=40.16 Hz, 2H) 2.75-2.80 (m, 1H) 2.96-3.10 (m, 2H) 3.20-3.28
(m, 2H) 3.41 (d, J=5.52 Hz, 1H) 3.66-3.75 (m, 1H) 4.31-4.41 (m, 1H)
4.46-4.71 (m, 2H) 6.76 (d, J=8.53 Hz, 2H) 7.05-7.23 (m, 6H).
Example 47
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-m-
ethylbenzyl)pyrrolidin-2-one,
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one,
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one, and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one
##STR00195##
[0388] Step A.
(.+-.)-rel-1-(3-Fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyp-
henyl)piperidin-1-yl)pyrrolidin-2-one
##STR00196##
[0390] To a solution of
3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (Intermediate
6, 200 mg, 0.7 mmol) and
(.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (145 mg, 0.7
mmol, from Example 46, step B) in acetonitrile (15 mL) was added
triethylamine (0.1 mL, 0.7 mmol) and the resulting mixture was
heated in the microwave at 100.degree. C. for 1 h. The cooled
reaction mixture was diluted with a saturated ammonium chloride
solution and extracted with ethyl acetate (100 mL). The organic
layer was separated, dried over Na2SO4, filtered, and evaporated
under reduced pressure to give
(.+-.)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-met-
hoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.51 mmol, 73%
yield, mixture of 4 diastereoisomers), which was used directly in
the next step. LCMS (Method F) RT 1.99 min m/z 413.2
(M+H.sup.+).
Step B.
(.+-.)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-h-
ydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00197##
[0392] To a solution of
(.+-.)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyp-
henyl)piperidin-1-yl)pyrrolidin-2-one (300 mg, 0.73 mmol) in DCM
(20 mL) under nitrogen at -10.degree. C. was added boron tribromide
(0.17 mL, 1.8 mmol) and the reaction mixture was stirred at rt for
1 h. The reaction was then quenched with saturated sodium
bicarbonate solution and extracted with 200 mL of ethyl acetate.
The organic layer was separated, dried over Na.sub.2SO.sub.4,
filtered, and evaporated under reduced pressure to give
(.+-.)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyp-
henyl)piperidin-1-yl)pyrrolidin-2-one (290 mg, 0.36 mmol, 50%
yield, mixture of 4 diastereoisomers); LCMS (Method F) RT 1.854 min
m/z 399.2 (M+H.sup.+).
Step C.
(.+-.)-rel-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)--
1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
##STR00198##
[0394] To a solution of
(.+-.)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyp-
henyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.7 mmol) in DCM (20
mL) was added DAST (0.5 mL, 3.5 mmol) and the reaction mixture was
stirred under nitrogen for 1 h. The reaction was then quenched by
the addition of 100 mL of a saturated sodium bicarbonate solution
and the mixture was diluted with 100 mL of ethyl acetate. The
organic layer was separated, dried over Na.sub.2SO.sub.4, filtered,
and evaporated under reduced pressure. The residue was subjected to
preparative HPLC (method B) to yield 22 mg of
(.+-.)-rel-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylbenzyl)pyrrolidin-2-one as a mixture of 4
diastereomers. LCMS (method P) RT 1.64 min; m/z=401.0
(M+H.sup.+).
Step D.
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylbenzyl)pyrrolidin-2-one,
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one,
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one, and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one
[0395] The compound
(.+-.)-rel-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylbenzyl)pyrrolidin-2-one (85 mg, 0.212 mmol) isolated
from Step C was separated into the homochiral Examples 47 P-1, P-2,
P-3, and P-4 via chiral SFC (method I): Data for P-1
(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)-pyrrolidin-2-one: LCMS (Method F) RT 2.03 min, m/z
401 (M+H.sup.+); HPLC (Method A) RT=6.73 min (96.8% AP), (method B)
RT=7.719 min (97% AP); Chiral SFC (Method E) RT 5.17 min (100% AP);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.84 (dd,
J=7.28, 3.26 Hz, 2H) 2.01-2.27 (m, 5H) 2.39-2.68 (m, 3H) 2.97-3.06
(m, 1H) 3.15 (s, 1H) 3.22-3.30 (m, 1H) 3.73 (t, J=8.78 Hz, 1H)
4.38-4.71 (m, 3H) 6.73-6.79 (m, 2H) 6.93-7.03 (m, 2H) 7.08-7.16 (m,
1H) 7.23 (t, J=7.53 Hz, 1H). Data for P-2
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluor-
o-4-methylbenzyl)-pyrrolidin-2-one: LCMS (Method F) RT 2.30 min,
m/z 401 (M+H.sup.+); HPLC (Method A) RT=6.71 min (99% AP), Method B
RT=7.73 min (98.1% AP); Chiral SFC (Method E) RT 6.21 min (96.5%
AP); .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.74-1.86
(m, 2H) 2.03-2.13 (m, 1H) 2.15-2.27 (m, 4H) 2.43 (td, J=10.04, 4.52
Hz, 1H) 2.50-2.71 (m, 2H) 2.76 (d, J=1.51 Hz, 1H) 3.20-3.30 (m, 2H)
3.38-3.46 (m, 1H) 3.71 (t, J=9.04 Hz, 1H) 4.37-4.70 (m, 3H)
6.72-6.78 (m, 2H) 6.92-7.02 (m, 2H) 7.09-7.13 (m, 1H) 7.23 (t,
J=7.78 Hz, 1H). Data for P-3
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)-pyrrolidin-2-one: LCMS (Method F) RT 2.04 min, m/z
401 (M+H.sup.+); HPLC (Method A) RT=6.68 min (98% AP), (Method B)
RT=7.70 min (99.2% AP); Chiral SFC (Method E) RT 7.22 min (98.5%
AP); .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.74-1.86
(m, 2H) 2.02-2.27 (m, 5H) 2.43 (td, J=10.04, 5.02 Hz, 1H) 2.50-2.72
(m, 3H) 2.73-2.82 (m, 3H) 3.23-3.30 (m, 2H) 3.38-3.46 (m, 1H) 3.71
(t, J=8.78 Hz, 1H) 4.36-4.72 (m, 4H) 6.73-6.79 (m, 2H) 6.94-7.02
(m, 2H) 7.08-7.14 (m, 2H) 7.23 (t, J=7.78 Hz, 1H). Data for P-4
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT: 2.03 min, m/z
401 (M+H.sup.+). HPLC (Method A) RT=6.71 min (90% AP); (Method B)
RT=7.68 min (91.5% AP); Chiral SFC (Method E) RT 7.89 min (97% AP);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.78-1.88 (m,
2H) 2.09 (d, J=8.53 Hz, 1H) 2.26 (d, J=2.01 Hz, 4H) 2.40-2.47 (m,
1H) 2.66 (d, J=4.52 Hz, 2H) 2.96-3.06 (m, 1H) 3.15 (s, 1H)
3.21-3.30 (m, 2H) 3.73 (s, 1H) 4.37-4.69 (m, 3H) 6.72-6.79 (m, 2H)
6.94-7.03 (m, 2H) 7.07-7.13 (m, 1H) 7.23 (t, J=7.53 Hz, 1H).
Step E. (3R,4R)-4-(4-Hydroxyphenyl)piperidin-3-ol hydrochloride
##STR00199##
[0397] To a solution of (3R,4R)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.5 g, 5.1
mmol, E-2 from example 46 step E) in methanol (50 mL) under
nitrogen was added 12.8 mL of 4 M HCl in dioxane and the reaction
was stirred for 1 h at rt. The mixture was then evaporated under
reduced pressure to dryness and the residue was washed twice with
20 mL of diethyl ether. The solid residue was dried under vacuum to
give (3R,4R)-4-(4-hydroxyphenyl)-piperidin-3-ol hydrochloride E-2a
(950 mg, 4.1 mmol). LCMS (method F) RT: 0.17 min, m/z 194
(M+H.sup.+). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.74-1.93 (m, 2H) 2.61-2.68 (m, 1H) 2.81-2.93 (m, 1H) 3.21-3.33 (m,
2H) 3.78-3.90 (m, 1H) 6.72 (d, J=8.53 Hz, 2H) 7.00 (d, J=8.53 Hz,
2H) 9.14-9.25 (m, 1H) 9.27-9.44 (m, 1H).
Step F.
1-(3-Fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxypheny-
l)piperidin-1-yl)pyrrolidin-2-one
##STR00200##
[0399] To a solution of racemic
3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (1.5 g, 5.2
mmol, Intermediate 6) and
(3R,4R)-4-(4-hydroxyphenyl)piperidin-3-ol, HCl (1.2 g, 5.2 mmol) in
acetonitrile (20 mL) was added triethylamine (2.2 mL, 15.7 mmol)
and the resulting mixture was heated for 5 h at 60.degree. C. The
reaction mixture was then evaporated and the residue was diluted
with saturated ammonium chloride solution and extracted with 200 mL
of ethyl acetate. The layers were separated and the organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
evaporated to yield
1-(3-fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-pipe-
ridin-1-yl)pyrrolidin-2-one (1.9 g, 4 mmol) as a mixture of two
diastereomers. LCMS (method F) RT 1.93 min, m/z 399
(M+H.sup.+).
Step G.
3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-
-4-methylbenzyl)pyrrolidin-2-one
##STR00201##
[0401] To a solution of
1-(3-fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-pipe-
ridin-1-yl)pyrrolidin-2-one (from step F, 1.9 g, 4.8 mmol) in DCM
(35 mL) at 0.degree. C. was added DAST (3.2 mL, 23.8 mmol) under
nitrogen. The reaction mixture was allowed to warm to rt and
stirred for 2 h, and then diluted with saturated bicarbonate
solution and extracted with 200 mL of DCM. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced
pressure to give a crude product which was purified via preparative
HPLC (method J) to yield
3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-meth-
ylbenzyl)pyrrolidin-2-one (1.1 g, 2.6 mmol) as a pair of
diastereomers. LCMS (Method F) RT: 2.13 min, m/z 401.
(M+H).sup.+.
Step H,
(R)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylbenzyl)pyrrolidin-2-one
[0402] The mixture of diastereomers of
3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-meth-
ylbenzyl)pyrrolidin-2-one (1.1 g) from step G was separated by
chiral SFC chromatography (method J). The second-eluting isomer,
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one, was isolated (355 mg) and its data
was consistent with those of Example 47, P-4. LCMS (Method F) RT
2.14 min, m/z 401 (M+H.sup.+); HPLC (Method A) RT 6.70 min (99.6%
AP), (Method B) RT 8.16 min (99.7% AP); Chiral SFC (Method E) RT
7.62 (100% AP); .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
1.85 (dd, J=7.28, 2.76 Hz, 2H) 2.09 (d, J=8.03 Hz, 1H) 2.13-2.27
(m, 4H) 2.45 (s, 1H) 2.51-2.60 (m, 1H) 2.61-2.71 (m, 1H) 2.98-3.06
(m, 1H) 3.15 (s, 1H) 3.23-3.30 (m, 1H) 3.62 (s, 1H) 3.69-3.77 (m,
1H) 4.39-4.70 (m, 4H) 6.72-6.80 (m, 2H) 6.95-7.03 (m, 2H) 7.09-7.15
(m, 2H) 7.24 (t, J=7.78 Hz, 1H).
Example 48 (Peak 1, Peak 2, Peak 3, Peak 4)
(S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-
-yl)pyrrolidin-2-one,
(S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one,
(R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one, and
(R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one
##STR00202##
[0403] Step A.
(.+-.)-rel-1-(4-Fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one
##STR00203##
[0405] To a solution of 3-bromo-1-(4-fluorobenzyl)pyrrolidin-2-one
(Intermediate 1, 300 mg, 1.1 mmol) and
trans-4-(4-methoxyphenyl)piperidin-3-ol (from Example 46, step B,
240 mg, 1.16 mmol) in acetonitrile (10 mL) was added triethylamine
(560 mg, 5.5 mmol) and the mixture was heated at 120.degree. C. in
a microwave reactor for 1 h. The reaction mixture was then diluted
with water and extracted with 100 mL of ethyl acetate. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated
under reduced pressure to give
(.+-.)-rel-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one (450 mg, 0.7 mmol) as a mixture of
four diastereomers which was used without further purification.
LCMS (Method S) RT 1.89 min, m/z 399.1 (M+H.sup.+).
Step B.
(.+-.)-rel-3-((3S,4S)-3-Fluoro-4-(4-methoxyphenyl)piperidin-1-yl)--
1-(4-fluorobenzyl)pyrrolidin-2-one
##STR00204##
[0407] To a solution of
1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)p-
yrrolidin-2-one from step B (2.5 g, 6.3 mmol) in 50 mL DCM was
added DAST (4.1 mL, 31 mmol) and the reaction was stirred at
ambient temperature for 1 h. The reaction was then quenched with a
sat. bicarbonate solution (200 mL) and the mixture was extracted
with 200 mL of DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure.
The residue was purified via silica gel chromatography eluting with
28% ethyl acetate in hexane to give
(.+-.)-rel-3-((3S,4S)-3-fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fl-
uorobenzyl)pyrrolidin-2-one (900 mg, 1.6 mmol) as a mixture of four
diastereomers. LCMS (method P) RT 0.89 min, m/z 401.2
(M+H.sup.+).
Step C.
3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoro-
benzyl)pyrrolidin-2-one
##STR00205##
[0409] To a solution of
(trans-3-fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrr-
olidin-2-one (700 mg, 1.75 mmol) in 50 mL of DCM at 0.degree. C.
was added BBr.sub.3 (0.3 mL, 3.5 mmol). The reaction mixture was
allowed to warm up to room temperature over 1 h. The mixture was
then diluted with a sat. bicarbonate solution and extracted with
200 mL of DCM. The organic layer was dried over Na2SO4, filtered,
and evaporated under reduced pressure.
[0410] The residue was purified by preparative HPLC (method A) to
yield 120 mg of
3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-flu-
orobenzyl)pyrrolidin-2-one as a mixture of four diastereomers. LCMS
(method N) RT 1.45 min, m/z 387.0 (M+H.sup.+).
Step D.
(S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one,
(S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one,
(R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one, and
(R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one
[0411] The diastereomeric mixture from step C was separated via
chiral SFC (method F) into the 4 homochiral diastereomers, Example
48 P-1, P-2, P-3, and P-4. Data for P-1
(S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 3.32 min, 100% AP;
HPLC (Method A) RT 6.53 min, 96.0% AP, (Method B) RT 6.7 min, 96.3%
AP; LCMS (Method F) RT 2.02 min, m/z 387.0 (M+H.sup.+); .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. ppm 7.32 (dd, J=8.78, 5.27 Hz,
2H) 7.07-7.14 (m, 4H) 6.76 (d, J=8.53 Hz, 2H) 4.41-4.56 (m, 2H)
3.74 (t, J=8.78 Hz, 1H) 3.23-3.31 (m, 2H) 3.10-3.17 (m, 1H) 3.01
(d, J=11.04 Hz, 1H) 2.88 (d, J=7.03 Hz, 1H) 2.66 (td, J=10.04, 4.52
Hz, 1H) 2.57 (dd, J=10.54, 6.53 Hz, 1H) 2.40-2.49 (m, 1H) 2.16-2.25
(m, 1H) 2.03-2.13 (m, 1H) 1.80-1.88 (m, 2H). Data for P-2
(S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 4.15 min, 99.7% AP;
HPLC (Method A) RT 6.52 min, 98.1% AP, (Method B) RT 6.92 min,
98.6% AP; LCMS (Method F) RT 2.03 min, m/z 387.0 (M+H.sup.+);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.29-7.34 (m,
2H) 7.07-7.14 (m, 4H) 6.76 (d, J=9.04 Hz, 2H) 3.71 (t, J=8.78 Hz,
1H) 3.39-3.45 (m, 1H) 3.24-3.31 (m, 2H) 2.74-2.80 (m, 1H) 2.64-2.72
(m, 1H) 2.57 (dd, J=10.54, 6.02 Hz, 1H) 2.43 (td, J=10.04, 5.02 Hz,
1H) 2.15-2.25 (m, 1H) 2.05-2.14 (m, 1H) 1.77-1.85 (m, 2H). Data for
P-3
(R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 4.56 min, 97.4% AP;
HPLC (Method A) RT 6.53 min, 96.0% AP, (Method B) RT 6.94 min,
96.4% AP; LCMS (Method F) RT 2.02 min, m/z 387.0 (M+H.sup.+);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.29-7.34 (m,
2H) 7.07-7.13 (m, 4H) 6.74-6.78 (m, 2H) 4.40-4.55 (m, 2H) 3.71 (t,
J=9.04 Hz, 1H) 3.38-3.45 (m, 1H) 3.23-3.31 (m, 2H) 2.76 (br. s.,
1H) 2.64-2.72 (m, 1H) 2.57 (dd, J=10.54, 6.02 Hz, 1H) 2.43 (td,
J=10.04, 5.02 Hz, 1H) 2.16-2.25 (m, 1H) 2.05-2.14 (m, 1H) 1.77-1.87
(m, 2H). Data for P-4
(R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin--
1-yl)pyrrolidin-2-one: Chiral SFC (Method F) RT 5.57 min, 99.9% AP;
HPLC (Method A) RT 6.55 min, 99.9% AP, (Method B) RT 6.90 min,
99.9% AP; LCMS (Method F) RT 2.03 min, m/z 387.0 (M+H.sup.+);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.32 (dd,
J=8.78, 5.27 Hz, 2H) 7.07-7.14 (m, 4H) 6.76 (d, J=8.53 Hz, 2H)
4.41-4.56 (m, 3H) 3.74 (t, J=8.53 Hz, 1H) 3.24-3.32 (m, 2H)
3.10-3.17 (m, 1H) 2.66 (td, J=9.91, 4.77 Hz, 1H) 2.57 (dd, J=10.54,
6.53 Hz, 1H) 2.41-2.49 (m, 1H) 2.16-2.24 (m, 1H) 2.04-2.12 (m, 1H)
1.80-1.88 (m, 2H).
Example 49 (Peak-1 and Peak-2)
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-m-
ethylphenyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one
##STR00206##
[0412] Step A. (3R,4R)-tert-Butyl
3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate
##STR00207##
[0414] To a solution of (3R,4R)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (M G
Bursavich et al; Organic Letters 2001, 3, 2317, 150 mg, 0.51 mmol)
in 5 mL of DCM at -78.degree. C. under nitrogen was added DAST (0.2
mL, 1.5 mmol). The mixture was allowed to warm up to rt with
stirring over 3 h. To the mixture was added 100 mL of ethyl acetate
and the organic layer was separated, washed with a saturated
NaHCO.sub.3 solution, and then evaporated under vacuum. The residue
was purified via silica gel chromatography eluting with 0-100%
ethyl acetate/hexanes to give (3R,4R)-tert-butyl
3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41
mmol); LCMS (Method T) RT 3.09 min, m/z 294.3. (M-H).sup.-; .sup.1H
NMR (500 MHz, chloroform-d) .delta. 7.11 (d, J=8.5 Hz, 2H), 6.93
(br. s., 1H), 6.89-6.82 (m, 2H), 4.56-4.47 (m, 1H), 4.45-4.38 (m,
1H), 4.16 (d, J=7.2 Hz, 1H), 2.89-2.69 (m, 3H), 1.89-1.83 (m, 1H),
1.76-1.65 (m, 1H), 1.53 (s, 9H).
Step B. 4-((3R,4R)-3-Fluoropiperidin-4-yl)phenol
trifluoroacetate
##STR00208##
[0416] To a solution of (3R,4R)-tert-butyl
3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41
mmol) in 1.5 mL DCM at rt was added TFA (0.5 mL, 6.5 mmol), and the
mixture was stirred for 3 h. The mixture was then concentrated in
vacuo to dryness to yield 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol
trifluoroacetate (126 mg, 0.41 mmol), which was used directly in
step D.
Step C. 3-Bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one
##STR00209##
[0418] To a solution of 2,4-dibromobutanoyl chloride (10 g, 38
mmol) in 100 mL of DCM at 0.degree. C. under nitrogen was added
3-fluoro-4-methylaniline (5.21 g, 42 mmol) followed by Et.sub.3N
(6.3 mL, 45 mmol). The mixture was stirred at rt for 2 h, then
concentrated in vacuo. The residue was dissolved in diethyl ether,
then hexanes was added and a solid precipitated. The solid was
removed by filtration and discarded. The filtrate was then
concentrated in vacuo to give a dry residue. To a solution of this
residue in 100 mL DMF at 0.degree. C. under nitrogen was slowly
added 60% NaH (1.82 g, 45 mmol). The mixture was stirred and
allowed to warm up to rt over 30 min. The reaction mixture was
slowly poured into 400 mL of ice water and allowed to stand
overnight. A solid formed, and was filtered off and dried, then
purified via silica gel chromatography eluting with 0-50% ethyl
acetate/hexanes to give racemic
3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (5.6 g, 20.6
mmol). LCMS (method U) RT 3.41 min, m/z 273.97 (M+H.sup.+). .sup.1H
NMR (500 MHz, chloroform-d) .delta. 7.50 (dd, J=11.7, 2.2 Hz, 1H),
7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (dd, J=7.0, 2.9 Hz, 1H),
4.03 (ddd, J=9.8, 7.9, 6.8 Hz, 1H), 3.82 (ddd, J=10.0, 7.7, 2.7 Hz,
1H), 2.75 (dq, J=14.6, 7.5 Hz, 1H), 2.48 (ddt, J=14.3, 6.7, 2.7 Hz,
1H), 2.28 (d, J=1.7 Hz, 3H).
Step D.
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylphenyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one
[0419] To a solution of 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol
trifluoroacetate, from step B (120 mg, 0.39 mmol) in DMF (2.0 mL)
was added K.sub.2CO.sub.3 (134 mg, 0.97 mmol) and racemic
3-bromo-1-(3-fluoro-4-methyl-phenyl)pyrrolidin-2-one (106 mg, 0.39
mmol, from step C). The mixture was heated to 60.degree. C. and
stirred for 30 min. It was then allowed to cool to rt and stirred
overnight, followed by the addition of 50 mL of EtOAc, which
induced precipitation of a solid. The solid was removed by
filtration and discarded, and the filtrate was concentrated in
vacuo. The residue was purified via silica gel chromatography
eluting with a gradient of 0-100% ethyl acetate/hexanes to give 110
mg of (R and S)
3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-meth-
ylphenyl)pyrrolidin-2-one) as a mixture of two diastereomers. A
portion (35 mg) of the diastereomer mixture was separated (chiral
HPLC method H) into homochiral example 49 P-1 (14 mg) and P-2 (14
mg). Data for P-1
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 6.97
min, 98% AP; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
7.60-7.52 (m, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.76
(d, J=8.5 Hz, 2H), 4.72-4.65 (m, 1H), 4.63-4.55 (m, 1H), 3.84 (d,
J=9.2 Hz, 4H), 3.51-3.44 (m, 1H), 2.87-2.80 (m, 1H), 2.76-2.68 (m,
1H), 2.64-2.54 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.30 (m, 1H), 2.26
(d, J=1.4 Hz, 3H), 2.24-2.18 (m, 1H), 1.84 (br s, 3H). Data for P-2
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(3-fluoro-4-
-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 8.84
min, 99.3% AP; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.56
(dd, J=12.0, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.12 (d, J=8.4 Hz,
2H), 6.80-6.73 (m, 2H), 4.70-4.63 (m, 1H), 4.60-4.54 (m, 1H),
3.88-3.77 (m, 5H), 3.23-3.17 (m, 2H), 3.07 (d, J=10.7 Hz, 2H),
2.75-2.68 (m, 2H), 2.64-2.48 (m, 4H), 2.33 (dd, J=6.6, 2.4 Hz, 2H),
2.26 (d, J=1.5 Hz, 5H), 2.21 (dd, J=12.7, 9.6 Hz, 2H), 1.90-1.83
(m, 4H).
Example 50 (Peak-1, Peak-2, Peak-3, and Peak 4)
(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-flu-
orophenyl)-ethyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)pyrrolidin-2-one
##STR00210##
[0420]
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-
-(4-fluorophenyl)ethyl)pyrrolidin-2-one and
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)-ethyl)pyrrolidin-2-one
##STR00211##
[0421] Step A.
2,4-Dibromo-N--((S)-1-(4-fluorophenyl)ethyl)butanamide
##STR00212##
[0423] To a stirred solution of (S)-1-(4-fluorophenyl)ethanamine
(3.2 g, 23 mmol) in diethyl ether (50 mL) and triethylamine (9.6
mL, 69 mmol) at 0.degree. C. was added 2,4-dibromobutanoyl chloride
(7.3 g, 27.6 mmole) and the mixture was allowed to warm to rt and
stirred for 12 h. A solid formed which was removed by filtration,
washed with ethyl acetate, and then discarded. The combined
filtrates were evaporated under reduced pressure and the residue
was subjected to silica gel chromatography eluting with 20-30%
ethyl acetate/petroleum ether yielding 4.5 g of
2,4-dibromo-N--((S)-1-(4-fluorophenyl)ethyl)butanamide as a brown
solid. LCMS (method O) RT=0.99 min, m/z 366, 368, 370 (M+H.sup.+,
M+H.sup.++2, M+H.sup.++4); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.25-1.44 (m, 3H) 2.27-2.46 (m, 2H) 3.46-3.58 (m, 2H)
4.55-4.66 (m, 1H) 4.81-5.00 (m, 1H) 7.03-7.24 (m, 2H) 7.30-7.45 (m,
2H) 8.89 (d, J=8.03 Hz, 1H).
Step B. 3-Bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one
##STR00213##
[0425] To a stirred solution of
2,4-dibromo-N--((S)-1-(4-fluorophenyl)ethyl)butanamide (3 g, 8.2
mmol) in tetrahydrofuran (50 mL) at 0.degree. C. was added NaH
(1.29 g, 32 mmol) and the mixture was allowed to warm to rt and
stirred for 3 h. The mixture was then poured into ice-cold water
and diluted with ethyl acetate. The organic phase was separated,
washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure yielding 1.6 g of
liquid. The residue was purified by silica gel chromatography
eluting with 30% ethyl acetate/petroleum ether to obtain 1 g of
3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one as a brown
solid (mixture of two diastereomers). LCMS (method O) RT 0.83/0.86
min, mz 286/288 (M+H.sup.+), 308 (M+Na.sup.+); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.50 (d, J=7.03 Hz, 3H) 2.08-2.25
(m, 1H) 2.57-2.69 (m, 1H) 2.99 (d, J=10.04 Hz, 1H) 3.35-3.44 (m,
1H) 4.71 (dd, J=7.03, 3.01 Hz, 1H) 5.13-5.30 (m, 1H) 7.21 (t,
J=9.04 Hz, 2H) 7.30-7.42 (m, 2H).
Step C. tert-Butyl
4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00214##
[0427] To a stirring mixture of tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (16.45 g, 53 mmol), dimethoxyethane (200 mL) and water
(50 mL) was added 1-(benzyloxy)-4-bromobenzene (14 g, 53 mmol),
sodium carbonate (16.9 g, 160 mmol) and
bis-(triphenylphosphine)palladium(II) chloride (1.867 g, 2.66 mmol)
at rt. The reaction mixture was purged with nitrogen for 15 min,
then heated at 80.degree. C. for 4 h. The mixture was allowed to
cool to rt and then was filtered through Celite and diluted with
200 mL of water. The mixture was then extracted three times with
200 mL of ethyl acetate and the combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The
residue was subjected to silica gel chromatography eluting with 20%
ethyl acetate/petroleum ether to obtain 16 g of tert-butyl
4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (16
g, 82% yield) as an off-white solid. LCMS (method O) RT 1.32 min,
m/z 366 (M+H.sup.+); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.47 (s, 9H), 2.42 (d, J=1.50 Hz, 2H), 3.52 (t, J=11.40 Hz, 2H),
3.97 (s, 2H), 5.11 (s, 2H), 6.04 (s, 1H), 6.98 (d, J=9.00 Hz, 2H),
7.30-7.46 (m, 7H).
Step D. (.+-.)-rel-(3S,4S)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
##STR00215##
[0429] To a stirring mixture of NaBH.sub.4 (0.93 g, 24.6 mmol) in
THF (25 mL) cooled to 0.degree. C. was added boron trifluoride
etherate (3.2 mL, 25 mmol) and the mixture was allowed to warm up
to rt over 1 h. It was then re-cooled to 0.degree. C. and to it was
added a solution of tert-butyl
4-(4-(benzyloxy)-phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3
g, 8.2 mmol) in THF (10 mL). The resulting mixture was allowed to
warm up to rt over 2 h. The reaction mixture was cooled again to
0.degree. C. and H.sub.2O (10 mL), ethanol (10 mL), 10 M NaOH (10
mL) and H.sub.2O.sub.2 (8 mL, 26 mmol) were sequentially added. The
final mixture was heated to 65.degree. C. overnight. After cooling,
the reaction was quenched with water and the mixture was extracted
with ethyl acetate (2.times.100 mL).
[0430] The combined organic layers were dried over Na.sub.2SO.sub.4
and concentrated in vacuo yielding 2.7 g of
(.+-.)-rel-(3S,4S)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (82%
yield) as off-white solid. LCMS (method O) RT 2.41 min, m/z 382
(M-H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.41 (s, 9H),
1.63 (m, 1H), 1.67 (m, 1H), 2.67 (m, 1H), 3.37-3.41 (m, 1H), 3.92
(m, 1H), 4.10 (m, 1H), 4.73 (d, J=2.4, 1H), 5.07 (s, 2H), 6.91 (d,
J=9, 2H), 7.14 (d, J=9, 2H), 7.31-7.44 (m, 4H).
Step E. (3S,4S)-tert-Butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate and
(3R,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate
##STR00216##
[0432] To a solution of racemic trans-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (1 g, 2.6
mmol, from step D) in DCM (15 mL) cooled to 0.degree. C. was added
DAST (1.7 mL, 13 mmol) and the mixture was stirred at 0.degree. C.
for 15 min. The reaction was then quenched by the addition of ice
water and the mixture was extracted twice with 20 mL of DCM. The
combined organic layers were dried over anhydrous Na2SO4, filtered
and concentrated to a pale yellow solid (1 g). The two desired
products were separated from a complex mixture via chiral SFC
(method D) to afford E-1 (0.13 g) and E-2 (0.14 g). Data for E-1
(3S,4S)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate: LCMS
(method P) RT 1.35 min, m/z 330.4 (M-C4H8); chiral HPLC (method
G-2) RT 5.8 min; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.42
(s, 9H), 1.56-1.61 (m, 1H), 1.74-1.78 (m, 1H), 2.73-2.84 (m, 3H),
3.94 (d, J=12.30 Hz, 1H), 4.25 (d, J=18.00 Hz, 1H), 4.43-4.64 (m,
1H), 5.08 (s, 2H), 6.95 (d, J=8.70 Hz, 2H), 7.23 (d, J=8.70 Hz,
2H), 7.32-7.46 (m, 5H). Data for E-2 (3R,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate: LCMS
(method P) RT 1.35 min, m/z 330.4 (M-C.sub.4Hs); chiral HPLC
(method G-2) RT 6.51 min; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.42 (s, 9H), 1.56-1.61 (m, 1H), 1.74-1.78 (m, 1H),
2.73-2.84 (m, 3H), 3.94 (d, J=12.30 Hz, 1H), 4.25 (d, J=18.00 Hz,
1H), 4.43-4.64 (m, 1H), 5.08 (s, 2H), 6.95 (d, J=8.70 Hz, 2H), 7.23
(d, J=8.70 Hz, 2H), 7.32-7.46 (m, 5H).
Step F. (3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidine
hydrochloride
##STR00217##
[0434] To a solution of (3R,4R)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (0.12 g,
0.31 mmol, E-2 from step E) in 1,4-dioxane (3 mL) was added a 4 M
HCl in dioxane solution (2 mL, 8 mmol) and the reaction mixture was
stirred at rt overnight. The solvent was then evaporated and the
solid was triturated with ethyl acetate and dried to afford E-2a
(3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride
(0.09 g, 83% yield) as an off-white solid. LCMS (method O) RT: 0.95
min m/z 286 (M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.92-1.92 (m, 1H), 2.29-2.33 (m, 1H), 3.04-3.14 (m, 3H),
3.45-3.60 (m, 2H), 4.83-4.95 (m, 1H), 5.10 (s, 2H), 7.01-7.04 (m,
2H), 7.25-7.31 (m, 2H), 7.32-7.46 (m, 5H), 9.09 (s, 1H).
Step G. 4-((3R,4R)-3-Fluoropiperidin-4-yl)phenol hydrochloride
##STR00218##
[0436] To a solution of
(3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride
(0.09 g, 0.28 mmol, E-2a from step F) in methanol (3 mL) was added
10% Pd/C (0.09 g) and the mixture was stirred at rt under hydrogen
balloon pressure for 12 h.
[0437] The mixture was then filtered through Celite and
concentrated to afford E-2b
4-((3R,4R)-3-fluoropiperidin-4-yl)phenol hydrochloride (0.06 g, 77%
yield) as brown solid. LCMS (method P) RT 0.5 min; m/z 196
(M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.90-1.94 (m,
2H), 2.90-3.03 (m, 3H), 3.27-3.35 (m, 1H), 3.57-3.61 (m, 1H),
4.79-4.97 (m, 1H), 6.75 (d, J=8.40 Hz, 2H), 7.05 (d, J=8.80 Hz,
2H), 9.28 (s, 1H), 9.35 (s, 1H).
Step H.
(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)--
1-(4-fluorophenyl)-ethyl)pyrrolidin-2-one and
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)pyrrolidin-2-one
[0438] A mixture of
3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (mixture of
diastereomers from step B) (60 mg, 0.21 mmol),
4-((3R,4R)-3-fluoropiperidin-4-yl)phenol hydrochloride (20.5 mg,
0.1 mmol, E-2b from step G) and DIPEA (0.1 mL, 0.6 mmol) in DMF (1
mL) was heated in a microwave reactor at 120.degree. C. for 90 min.
The mixture was allowed to cool and the solvent was then removed
under reduced pressure. The diastereomeric products were then
separated via preparative HPLC (method B), yielding homochiral
examples 50 P-1 (2.4 mg) and P-2 (9.5 mg). Data for P-1
(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-((S)-1-(4-f-
luorophenyl)ethyl)pyrrolidin-2-one: LCMS (method N) RT 1.60 min,
m/z 401 (M+H.sup.+), (method O) RT 1.02 min, m/z 401 (M+H.sup.+);
.sup.1H NMR (400 MHz, methanol-d4) .delta. ppm 7.30-7.43 (m, 2H)
7.05-7.15 (m, 4H) 6.75 (d, J=8.53 Hz, 2H) 5.36-5.46 (m, 1H)
4.46-4.69 (m, 1H) 3.64-3.75 (m, 1H) 3.34-3.42 (m, 2H) 3.01-3.10 (m,
1H) 2.48-2.78 (m, 3H) 2.33-2.43 (m, 1H) 2.10-2.24 (m, 1H) 1.90-2.04
(m, 1H) 1.71-1.84 (m, 2H) 1.55 (d, J=7.53 Hz, 3H). Data for P-2
(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)-pyrrolidin-2-one: LCMS (method N) RT 1.63 min,
m/z 401 (M+H.sup.+), (method O) RT 1.05 min, m/z 401 (M+H.sup.+);
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.30-7.42 (m,
2H) 7.06-7.16 (m, 4H) 6.67-6.80 (m, 2H) 5.36-5.50 (m, 1H) 4.60-4.72
(m, 1H) 4.50-4.59 (m, 1H) 3.59-3.70 (m, 1H) 3.40-3.54 (m, 2H)
3.08-3.18 (m, 1H) 2.87-3.05 (m, 2H) 2.51-2.72 (m, 2H) 2.39-2.49 (m,
1H) 2.00-2.20 (m, 2H) 1.75-1.90 (m, 2H) 1.50-1.64 (m, 3H).
Step I. (3S,4S)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidine
hydrochloride
##STR00219##
[0440] To a solution of (3S,4S)-t-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (0.12 g,
0.31 mmol, E-1 from step E) in 1,4-dioxane (3 mL) was added a 4 M
HCl in dioxane solution (2 mL, 8 mmol) and the reaction mixture was
stirred at rt overnight. The mixture was concentrated in vacuo and
the solid was triturated with ethyl acetate and dried to afford
E-1a (3S,4S)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine
hydrochloride (0.09 g, 88% yield) as an off-white solid. LCMS
(method P) RT 0.95 min, m/z 286 (M+H.sup.+); 400 MHz, DMSO-d6:
.delta. 1.94-1.96 (m, 2H), 2.97-3.04 (m, 3H), 3.38-3.62 (m, 2H),
4.84-4.95 (m, 1H), 5.10 (s, 2H), 7.00-7.03 (m, 2H), 7.17-7.20 (m,
2H), 7.31-7.46 (m, 5H), 9.30 (s, 1H).
Step J. ((3S,4S)-3-Fluoropiperidin-4-yl)phenol
##STR00220##
[0442] A mixture of
(3S,4S)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride
(0.09 g, 0.28 mmol, E-1a from step I) in methanol (3 mL) was added
10% Pd/C (0.09 g) and the reaction mixture was stirred at rt under
hydrogen balloon pressure for 12 h.
[0443] The mixture was filtered through Celite and concentrated in
vacuo to afford E-1b ((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.05
g, 68.7% yield) as an off-white solid. LCMS (method P) RT 0.50 min,
m/z 196 (M+H.sup.+); .sup.1H NMR (400 MHz DMSO-d.sub.6) .delta.
1.90-1.94 (m, 2H), 2.91-3.05 (m, 3H), 3.24-3.27 (m, 1H), 3.59-3.62
(m, 1H), 4.78-4.97 (m, 1H), 6.71-6.76 (m, 2H), 6.99-7.06 (m, 2H),
9.27 (s, 1H), 9.36 (s, 1H).
Step K.
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)--
1-(4-fluorophenyl)ethyl)pyrrolidin-2-one and
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)-ethyl)pyrrolidin-2-one
[0444] To a solution of ((3S,4S)-3-fluoropiperidin-4-yl)phenol
(0.02 g, 0.1 mmol, E-1b from step J) in DMF (2 mL) was added DIPEA
(0.05 mL, 0.31 mmol) followed by
3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.059 g,
0.21 mmol, mixture of diastereomers from step B), and the mixture
was then heated to 120.degree. C. in a microwave reactor for 90
min. The mixture was allowed to cool and then the diastereomeric
products were subjected to preparative HPLC (method B) to afford
homochiral examples 50 P-3 (2.7 mg, 6% yield) and P-4 (8.2 mg,
19.8% yield). Data for P-3
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-
-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one: pale yellow solid; LCMS
(method N) RT 1.60 min, m/z 401 (M+H.sup.+); .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 1.56 (d, J=7.20 Hz, 3H), 1.81-1.85 (m,
2H), 2.16-2.22 (m, 1H), 2.42-2.44 (m, 1H), 2.51-2.67 (m, 2H),
3.06-3.09 (m, 3H), 3.35-3.40 (m, 2H), 3.70-3.75 (m, 1H), 4.35-4.70
(m, 1H), 5.42 (q, J=7.20 Hz, 1H), 6.74-6.76 (m, 2H), 7.09-7.14 (m,
4H), 7.37-7.41 (m, 2H). Data for P-4
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)-pyrrolidin-2-one: pale yellow solid; LCMS (method
N) RT 1.63 min, m/z 401 (M+H.sup.+); .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 1.59 (d, J=7.20 Hz, 3H), 1.81-1.84 (m,
2H), 2.08-2.16 (m, 2H), 2.42-2.43 (m, 1H), 2.51-2.59 (m, 1H),
2.65-2.72 (m, 1H), 2.73-2.81 (m, 1H), 2.92-2.95 (m, 1H), 3.34-3.37
(m, 2H), 3.61-3.66 (m, 1H), 4.50-4.71 (m, 1H), 5.43 (q, J=6.80 Hz,
1H), 6.75-6.77 (m, 2H), 7.09-7.13 (m, 4H), 7.35-7.38 (m, 2H).
Example 51 (Peak-1, Peak-2, Peak-3, and Peak-4)
(S)-3-((R)-3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenz-
yl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one, and
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
##STR00221##
[0445] Step A. 1-Benzyl-4-(4-methoxyphenyl)piperidin-4-ol
##STR00222##
[0447] To a solution of 1-bromo-4-methoxybenzene (5 g, 27 mmol) in
THF (100 mL) at -78.degree. C. was added a solution of 1.6 M
N-butyl lithium/hexanes (18.4 mL, 29.4 mmol), and the reaction
mixture was stirred for 1 hr. Then a solution of
1-benzylpiperidin-4-one (4.81 g, 25.4 mmol) in 50 mL of THF was
added. After the addition, the mixture was allowed to warm up to rt
and was stirred for 1 h. The reaction was then quenched by the
addition of 100 mL of 1.5 M aqueous HCl and the mixture was
extracted with 200 mL of ethyl acetate. The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to
yield 7.1 g (72% yield) of
1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol. LCMS (method F) RT 2.19
min, 81% AP, m/z 298.4 (M+H.sup.+), .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.23-7.39 (m 8.5H), 6.94 (m, 0.5H), 6.84-6.94
(m, 2H), 4.66 (s, 1H), 3.74 (s, 0.8H), 3.72 (s, 3H), 3.32 (s, 2H),
2.50-2.67 (m, 2H), 2.34-2.45 (m, 3H), 1.83-1.90 (m, 2H), 1.55 (d,
J=11, 2H).
Step B. 1-Benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
##STR00223##
[0449] To a solution of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol
(7 g, 23.5 mmol) in DCM (150 mL) was added trifluoroacetic acid
(2.68 g, 23.5 mmol) and the reaction mixture was stirred at rt
overnight. The mixture was then evaporated under reduced pressure
and partitioned between 500 mL saturated aqueous sodium bicarbonate
and 500 mL of ethyl acetate. The organic layer was separated, dried
over Na.sub.2SO.sub.4, filtered, and evaporated under reduced
pressure to yield
1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (5.9 g, 88%
yield). LCMS (method F) RT 2.84 min, 100% AP, m/z 280.4
(M+H.sup.+).
Step C.
(.+-.)-rel-(3S,4S)-1-Benzyl-4-(4-methoxyphenyl)piperidin-3-ol
##STR00224##
[0451] To a suspension of NaBH.sub.4 (2.7 g, 72 mmol) in THF (150
mL) at -10.degree. C. was added boron trifluoride etherate (9.1 mL,
72 mmol) and the solution was stirred for 15 minutes. Then a
solution of 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
(10 g, 36 mmol) in 100 mL tetrahydrofuran was added and the mixture
was stirred for an additional hour. Next were sequentially added 25
mL of water, 25 mL of 10% aqueous sodium hydroxide, 50 mL of
ethanol, and 12.8 mL of 30% aqueous hydrogen peroxide (125 mmol)
and the final mixture was heated to reflux overnight. The mixture
was allowed to cool and was then diluted with 200 mL of water and
extracted with 300 mL of ethyl acetate. The organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered, and evaporated
under reduced pressure. The residue was triturated with diethyl
ether to yield 7.5 g (57%)
(.+-.)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol. LCMS
(method A) RT 2.03 min, 81.5% AP, m/z 298.4 (M+H.sup.+), .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.28-7.35 (m, 5H) 7.14 (d,
J=8.69 Hz, 2H) 6.83 (d, J=8.69 Hz, 2H) 4.43 (d, J=6.04 Hz, 1H) 3.51
(d, J=19.26 Hz, 4H) 3.33 (s, 3H) 2.97 (dd, J=10.01, 3.59 Hz, 1H)
2.81 (d, J=10.95 Hz, 1H) 2.19-2.29 (m, 1H) 1.96-1.98 (m, 1H) 1.78
(t, J=10.20 Hz, 1H) 1.58-1.68 (m, 2H).
Step D. (.+-.)-rel-(3S,4S)-4-(4-Methoxyphenyl)piperidin-3-ol
##STR00225##
[0453] To a solution of
(.+-.)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (7 g,
23.5 mmol) in methanol (100 mL) was added 10% Pd/C (3.76 g) and the
reaction mixture was stirred overnight under a hydrogen atmosphere
(balloon pressure). The catalyst was removed by filtration through
Celite and the solvent was evaporated under reduced pressure to
give (.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.8 g,
89% yield). LCMS (method F) RT 1.485 (61.5% AP) m/z 207.8
(M+H.sup.+), 1.536 (29.7% AP), m/z 207.8 (M+H.sup.+); .sup.1H NMR
(DMSO-d6) .delta. 7.133 (d, J=7, 2H), 6.83 (d, J=7, 2H), 4.31 (br
s, 1H), 3.7 (s, 3H), 3.02 (m, 1H), 2.86 (d, J=12, 1H), 2.45 (m,
1H), 2.22-2.39 (m, 2H), 1.62-1.61 (m, 1H), 1.610-1.46 (m, 1H).
Step E.
(.+-.)-rel-3-((3R,4R)-3-Hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-
-1-(4-methylbenzyl)pyrrolidin-2-one
##STR00226##
[0455] A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one
(Intermediate 2, 450 mg, 1.68 mmol),
(.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (313 mg, 1.5
mmol) and triethylamine (23 mL, 16.8 mmol) was stirred at
60.degree. C. for 1 h, followed by heating at 85.degree. C. for 1
h, 120.degree. C. for 1 h and at 140.degree. C. for 1 h. The
mixture was cooled and then quenched with 40 mL of water and
extracted with 3.times.50 mL of chloroform. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated
under vacuum. The residue was purified via silica gel
chromatography (24 g column, gradient of 0-80% ethyl
acetate/petroleum ether) to yield 375 mg of
(.+-.)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-m-
ethylbenzyl)pyrrolidin-2-one as a mixture of four diastereomers.
LCMS (method F) RT 1.84 min (74% AP), m/z 395.2 (M+H.sup.+);
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.31-7.41 (m, 8H)
6.86 (d, J=9.07 Hz, 2H) 4.66 (s, 1H) 3.73 (s, 3H) 3.49 (s, 2H) 2.59
(d, J=10.58 Hz, 2H) 2.32-2.47 (m, 3H) 1.89 (td, J=12.65, 4.53 Hz,
2H) 1.56 (d, J=11.71 Hz, 2H).
Step F.
4-(4-Methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)pip-
eridin-3-one
##STR00227##
[0457] A mixture of DMSO (0.17 mL, 2.46 mmol) and DCM (4 mL) was
cooled to -78.degree. C., and oxalyl chloride (0.2 mL, 2.3 mmol)
was added dropwise over 2 min. Following the addition, the mixture
was stirred at the same temperature for 10 min. To the reaction was
then added dropwise
(.+-.)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-m-
ethylbenzyl)pyrrolidin-2-one (375 mg, 0.95 mmol, mixture of four
diastereomers from step E) in DCM over 5 min. The mixture was
stirred for 1 h, and then triethylamine (1 mL, 7.6 mmol) was added
and the mixture was stirred for 15 min, slowly warmed to rt, and
then extracted with 3.times.40 mL of DCM. The combined organic
layers were washed with 50 mL of brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to yield
345 mg of
4-(4-methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin--
3-one (as a mixture of 4 diastereomers), which was used directly in
the next step. LCMS (method) RT 1.12 min, m/z 393 (M+H.sup.+), 411
(M+H.sup.++18), 1.18 min, m/z 393 (M+H.sup.+).
Step G.
3-(3,3-Difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenz-
yl)pyrrolidin-2-one
##STR00228##
[0459] A mixture of
4-(4-methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin--
3-one (370 mg, 0.94 mmol) and DCM (5 mL) was cooled to 0.degree.
C., followed by the drop-wise addition of DAST (0.62 mL, 4.7 mmol)
over 2 minutes.
[0460] The mixture was warmed to rt and stirred overnight. The
reaction was then quenched with 50 mL of aqueous sodium bicarbonate
and extracted with 3.times.50 mL of DCM.
[0461] The combined organic layers were washed with 50 mL of brine,
separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under vacuum to yield 380 mg of
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrr-
olidin-2-one (as a mixture of 4 diastereomers), which was used
directly in the next step. LCMS (method J) RT 1.32 min (29% AP),
m/z 397, 478, 1.36 min (45% AP), m/z 415.2 (M+H.sup.+).
Step H.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenz-
yl)pyrrolidin-2-one
##STR00229##
[0463] A mixture of
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrr-
olidin-2-one (230 mg, 0.55 mmol) and 4 mL DCM was cooled to
-78.degree. C., followed by the dropwise addition of boron
tribromide (0.05 mL, 0.55 mmol).
[0464] The mixture was then allowed to warm up to rt over 4 h. The
reaction was then quenched with 50 mL of 10% aqueous sodium
bicarbonate and extracted with 4.times.50 mL DCM. The combined
organic fractions were dried over Na2SO4, filtered, and
concentrated. The residue was subjected to preparative HPLC (method
B) to afford 28.1 mg
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrr-
olidin-2-one as a mixture of 4 diastereomers. LCMS (method N) RT
1.59 min, m/z 401 (M+H.sup.+).
Step I.
(S)-3-((R)-3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-me-
thylbenzyl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one, and
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
[0465] A mixture of 4 diastereomers of
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrr-
olidin-2-one from step H (34 mg) was separated via chiral SFC
(method K) to yield homochiral Examples 51 P-1 (6.8 mg), P-2 (3.7
mg), P-3 (3.7 mg), and P-4 (4.5 mg) which include
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one, and
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one. The absolute and relative stereochemical
configurations were not determined. The compounds were arbitrarily
designated as P-1, P-2, P-3, and P-4 based on their order of
elution during the chiral separation. Data for P-1: .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta.=7.19-7.11 (m, 6H), 6.76-6.72
(m, 2H), 4.51-4.36 (m, 2H), 3.70 (t, J=8.8 Hz, 1H), 3.30-3.20 (m,
2H), 3.16-3.07 (m, 3H), 2.98-2.84 (m, 1H), 2.53 (t, J=1.0 Hz, 1H),
2.34 (s, 3H), 2.28-2.13 (m, 2H), 2.03 (s, 1H), 1.88-1.80 (m, 1H);
.sup.19F NMR (methanol-d.sub.4) .delta. s -102.58, s -103.22, s
-115.114, s -115.753; HPLC (method D) RT 8.21 min, 97.5% AP,
(method C) RT 8.0 min, 97.6% AP; LCMS (method P) RT 2.37 min, m/z
401 (M+H.sup.+); chiral SFC (method C-5) RT 5.56 min, 100% AP. Data
for P-2: .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.=7.18-7.12
(m, 6H), 6.77-6.73 (m, 2H), 4.44 (q, J=1.0 Hz, 2H), 3.68 (t, J=8.8
Hz, 1H), 3.41-3.35 (m, 1H), 3.31-3.20 (m, 2H), 3.01-2.83 (m, 3H),
2.72-2.60 (m, 1H), 2.34 (s, 3H), 2.27-2.11 (m, 2H), 2.08-1.96 (m,
1H), 1.82 (tdd, J=2.5, 5.0, 13.1 Hz, 1H); .sup.19F NMR
(methanol-d.sub.4) .delta. s -102.461, s -103.102, s -114.549, s
-115.189; HPLC (method D) RT 8.33 min, 98.3% AP, (method C) RT 8.21
min, 98.2% AP; LCMS (method P) RT 2.37 min, m/z 401 (M+H.sup.+);
chiral SFC (method C-5) RT 7.39 min, 99.7% AP. Data for P-3:
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.78-1.87 (m,
1H) 1.98-2.08 (m, 1H) 2.14-2.27 (m, 2H) 2.34 (s, 3H) 2.60-2.72 (m,
1H) 2.83-3.01 (m, 3H) 3.21-3.31 (m, 2H) 3.35-3.41 (m, 1H) 3.68 (t,
J=8.78 Hz, 1H) 4.44 (q, J=1.00 Hz, 2H) 6.72-6.76 (m, 2H) 7.11-7.18
(m, 6H); .sup.19F NMR (377 MHz, methanol-d.sub.4) .delta. s
-102.457, s -103.097, s -114.554, s -115.194; HPLC (method D) RT
8.34 min, 98.6% AP, (method C) RT 8.21 min, 99% AP; LCMS (method P)
RT 2.29 min, m/z 401 (M+H.sup.+); chiral SFC (method C-5) RT 10.1
min, 97.8% AP. Data for P-4: .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. ppm 1.80-1.90 (m, 1H) 2.03 (s, 1H)
2.13-2.29 (m, 2H) 2.34 (s, 3H) 2.53 (t, J=1.00 Hz, 1H) 2.85-3.00
(m, 1H) 3.07-3.18 (m, 3H) 3.20-3.31 (m, 2H) 3.71 (t, J=8.78 Hz, 1H)
4.44 (q, J=1.00 Hz, 2H) 6.73-6.78 (m, 2H) 7.12-7.19 (m, 6H);
.sup.19F NMR (methanol-d.sub.4) .delta. s -102.579, s -103.217, s
-115.087, s -115.726; HPLC (method D) RT 8.2 min, 96.4% AP, (method
C) RT 8.0 min, 96.5% AP; LCMS (method P) RT 2.21 min, m/z 401
(M+H.sup.+); chiral SFC (method C-5) RT 13.6 min, 100% AP.
Example 52 (Peak-1, Peak-2, Peak-3, and Peak-4)
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-m-
ethylbenzyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)-pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one, and
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one
##STR00230##
[0466] Step A. tert-Butyl
4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate
##STR00231##
[0468] To a solution of DMSO (3.7 mL, 52 mmol) in 50 mL of DCM
under nitrogen at -78.degree. C. was added oxalyl chloride (4.45
mL, 51 mmol). The mixture was stirred for 10 minutes after the
completion of the addition. Then a solution of
(.+-.)-rel-(3S,4S)-tert-butyl
4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (from
Example 50, step D, 6.5 g, 17 mmol) in 50 mL of DCM was added and
the mixture was stirred in the cold for a further 90 minutes. The
reaction was then quenched by the addition of 11.8 mL of
triethylamine (85 mmol) and allowed to warm up to rt. The mixture
was then partitioned between 200 mL brine and 200 mL DCM. The
layers were separated, and the organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated.
[0469] The residue was subjected to column chromatography on 48 g
of basic alumina eluting with 8% ethyl acetate/hexanes to afford
4.7 g (67%) of racemic tert-butyl
4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate. LCMS (method
F) RT 2.376 min, m/z 381.2 (M+); chiral SFC (method G) RT 4.54 min
(46.9% AP, 4.93 min (49.7% AP). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.30-7.40 (m, 5H), 7.07 (d, J=7 Hz, 2H) 6.94 (d, J=7), 2H;
5.08 (s, 2H), 4.10 (d, J=17.6, 1H), 3.97 (d, J=17.6, 1H), 3.77 (m,
2H), 3.43 (br s, 1H), 2.16 (m, 2H), 1.42 (s, 9H).
Step B. tert-Butyl
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate
##STR00232##
[0471] To a solution of tert-butyl
4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate (4.7 g, 12.3
mmol) in 100 mL DCM at 0.degree. C. was added DAST (8.1 mL, 62
mmol) and the reaction mixture was stirred for 1 h. It was then
allowed to warm to rt and partitioned between saturated sodium
bicarbonate and 200 mL of DCM. The layers were separated and the
organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford 4.2 g (68%) of racemic tert-butyl
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate. LCMS
(method P) RT 1.16 min, m/z 348.1 (M-t-butyl+H).sup.+.
Step C. 4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidine
##STR00233##
[0473] To a solution of t-butyl
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate (5.2
g, 12.9 mmol) in MeOH (100 mL) was added 4 M HCl/dioxane (32.2 mL,
130 mmol) and the reaction mixture was stirred at rt for 5 h. The
mixture was then evaporated under reduced pressure, and the residue
was diluted with a saturated sodium bicarbonate solution and
extracted with 200 mL of ethyl acetate. The layers were separated
and the organic phase was dried over Na.sub.2SO.sub.4, filtered,
and concentrated under vacuum. The residue was subjected to
preparative HPLC (method C) to afford 2.5 grams (63%) of racemic
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine. LCMS (method F) RT
2.044 min, m/z 304 (M+H.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.31-7.48 (m, 5H) 7.21 (d, J=8.53 Hz, 2H) 6.98 (d,
J=9.04 Hz, 2H) 5.10 (s, 2H) 3.05-3.20 (m, 2H) 2.98 (d, J=13.05 Hz,
1H) 2.74-2.87 (m, 1H) 2.60 (t, J=11.55 Hz, 1H) 1.88-2.00 (m, 4H)
1.72 (d, J=13.05 Hz, 1H), .sup.19F NMR (377 MHz, DMSO-d.sub.6)
.delta. -102.276, -102.900, -115.135, -115.759.
Step D.
3-(4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidin-1-yl)-1-(3-fluoro-
-4-methylbenzyl)pyrrolidin-2-one
##STR00234##
[0475] To a mixture of
3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (0.51 g, 1.8
mmol, Intermediate 6) and
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.3 g, 1 mmol, from
step C) was added triethylamine (0.69 mL, 4.9 mmol) and the
resulting mixture was heated in a sealed tube at 120.degree. C. for
1 h. The reaction mixture was allowed to cool and then diluted with
water and the mixture was extracted with ethyl acetate. The organic
layer was separated, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue (0.45
grams, 64%, mixture of 4 diastereoisomers) was used directly in the
next step without further purification, LCMS (method P) RT 1.19
min, m/z 509 (M+H.sup.+).
Step E.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-m-
ethylbenzyl)pyrrolidin-2-one
##STR00235##
[0477] To a stirred solution of
3-(4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidin-1-yl)-1-(3-fluoro-4-meth-
ylbenzyl)pyrrolidin-2-one (0.45 g, 0.89 mmol, mixture of
diastereomers from step D) in MeOH (8 mL) at rt was added 0.56 g of
10% Pd/C and the reaction mixture was stirred at rt under a
hydrogen atmosphere overnight. The catalyst was removed by
filtration through Celite and the solvent was removed in vacuo. The
residue was subjected to HPLC purification (method E) to yield 200
mg of
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbe-
nzyl)pyrrolidin-2-one as a mixture of four diastereoisomers.
Step F.
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylbenzyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)-pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one, and
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one
[0478] The mixture of diastereomers of
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbe-
nzyl)pyrrolidin-2-one (0.1 g, 0.239 mmol) from step E was subjected
to chiral SFC purification to afford homochiral Examples 52 P-1
(12.8 mg), P-2 (13.7 mg), P-3 (6.7 mg), and P-4 (13.1 mg) which
include
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)-pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one, and
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylbenzyl)pyrrolidin-2-one. The absolute and relative
stereochemical configurations were not determined. The compounds
were arbitrarily designated as P-1, P-2, P-3, and P-4 based on
their order of elution during the chiral separation. Data for P-1:
yellow solid; LCMS (method F) RT 2.05 min, 100% AP, m/z 419.2
(M+H.sup.+); HPLC (method A) RT 8.45 min 98.2% AP, (method B) RT
8.56 min, 97.8% AP; chiral SFC (method C-5) RT 4.52 min, 100% AP;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 7.23 (t, J=7.8 Hz,
1H), 7.15 (d, J=8.0 Hz, 2H), 7.03-6.93 (m, 2H), 6.75 (d, J=8.5 Hz,
2H), 4.52-4.36 (m, 2H), 3.71 (t, J=8.8 Hz, 1H), 3.31-3.23 (m, 3H),
3.19-3.12 (m, 2H), 3.11-3.07 (m, 1H), 3.00-2.83 (m, J=13.2, 4.7,
4.7 Hz, 1H), 2.53 (t, J=11.0 Hz, 1H), 2.26 (d, J=1.5 Hz, 3H),
2.25-2.21 (m, 1H), 2.20-2.13 (m, 1H), 2.11-1.99 (m, 1H), 1.89-1.78
(m, 1H); .sup.19F NMR (377 MHz, chloroform-d) 6-133.04 (s, 1F),
-133.68 (s, 1F), -145.26 (s, 1F), -145.90 (s, 1F), -147.99 (s, 1F).
Data for P-2: yellow solid; LCMS (method F) RT 2.05 min, 95.8% AP,
m/z 419.2 (M+H.sup.+); HPLC (method A) RT 8.64 min 97.8% AP,
(method B) RT 8.71 min, 97.6% AP; chiral SFC (method C-5) RT 6.35
min, 95.4% AP; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 7.23
(t, J=7.8 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.04-6.92 (m, 2H),
6.81-6.70 (m, 2H), 4.53-4.35 (m, 2H), 3.69 (t, J=8.8 Hz, 1H),
3.46-3.35 (m, 2H), 3.31-3.22 (m, 2H), 3.04-2.94 (m, 2H), 2.93-2.83
(m, 2H), 2.74-2.58 (m, 1H), 2.28-2.25 (m, 3H), 2.25-2.15 (m, 2H),
1.87-1.78 (m, 1H); .sup.19F NMR (377 MHz, chloroform-d) 6-132.68
(s, 1F), -133.32 (s, 1F), -144.55 (s, 1F), -145.19 (s, 1F), -147.96
(s, 1F). Data for P-3: yellow solid; LCMS (method F) RT 2.05 min,
92.1% AP, m/z 419.2 (M+H.sup.+); HPLC (method A) RT 8.70 min 97.3%
AP, (method B) RT 8.64 min, 97.1% AP; chiral SFC (method C-5) RT
8.81 min, 98.2% AP; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
7.24 (t, J=7.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.05-6.91 (m, 2H),
6.81-6.68 (m, 2H), 4.45 (dd, J=30.5, 14.5 Hz, 2H), 3.69 (t, J=8.8
Hz, 1H), 3.46-3.36 (m, 2H), 3.31-3.22 (m, 2H), 3.05-2.94 (m, 2H),
2.93-2.81 (m, 2H), 2.75-2.56 (m, J=8.0, 8.0 Hz, 1H), 2.27 (d, J=1.5
Hz, 3H), 2.25-2.11 (m, 1H), 2.05 (dd, J=13.3, 8.3 Hz, 1H),
1.90-1.76 (m, 1H); .sup.19F NMR (377 MHz, chloroform-d) 6-132.68
(s, 1F), -133.32 (s, 1F), -144.53 (s, 1F), -145.17 (s, 1F), -147.94
(s, 1F). Data for P-4: yellow solid; LCMS (method F) RT 2.05 min,
94.5% AP, m/z 419.2 (M+H.sup.+); HPLC (method A) RT 8.45 min 96.9%
AP, (method B) RT 8.56 min, 97.0% AP; chiral SFC (method C-5) RT
12.13 min, 99.4% AP; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 7.23 (t, J=7.8 Hz, 1H), 7.19-7.11 (m, J=8.5 Hz, 2H),
7.04-6.92 (m, 2H), 6.81-6.71 (m, J=8.5 Hz, 2H), 4.53-4.35 (m, 2H),
3.72 (t, J=8.8 Hz, 1H), 3.32-3.22 (m, 2H), 3.20-3.07 (m, 3H),
3.04-2.82 (m, 1H), 2.53 (t, J=11.3 Hz, 1H), 2.26 (d, J=1.5 Hz, 3H),
2.25-2.12 (m, 2H), 2.12-2.01 (m, 2H), 1.92-1.78 (m, 1H); .sup.19F
NMR (377 MHz, chloroform-d) 6-133.04 (s, 1F), -133.68 (s, 1F),
-145.25 (s, 1F), -145.89 (s, 1F), -147.99 (s, 1F).
Example 53 (Peak-1 and Peak-2)
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)--
benzyl)pyrrolidin-2-one
##STR00236##
[0479] Step A.
2,4-Dibromo-N-(4-(trifluoromethyl)benzyl)butanamide
##STR00237##
[0481] To a solution of (4-(trifluoromethyl)phenyl)methanamine (3
g, 17 mmol) in diethyl ether (60 mL) under nitrogen at 0.degree. C.
was added 2,4-dibromobutanoyl chloride (2.3 mL, 17 mmol) and the
reaction mixture was stirred for 1 h at rt. The mixture was then
diluted with water and extracted with 200 mL of ethyl acetate. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated under reduced pressure to afford
2,4-dibromo-N-(4-(trifluoromethyl)benzyl)-butanamide (6.5 g, 87%).
LCMS (method F) RT 2.01 min, m/z 434.8, 483.8; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 2.39-2.47 (m, 2H) 3.50-3.67 (m, 2H)
4.41 (dd, J=13.05, 6.02 Hz, 2H) 4.59-4.64 (m, 1H) 7.49 (d, J=7.53
Hz, 2H) 7.71 (d, J=8.03 Hz, 2H) 9.06 (s, 1H).
Step B. 3-Bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one
##STR00238##
[0483] To a suspension of
2,4-dibromo-N-(4-(trifluoromethyl)benzyl)butanamide (6.8 g, 16.9
mmol) in tetrahydrofuran (200 mL) was added NaH (1.35 g, 34 mmol)
and the reaction was stirred at rt for 4 h. The reaction mixture
was then diluted with water and twice extracted with 30 mL of ethyl
acetate. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The residue
was purified by silica gel chromatography eluting with 0-40% ethyl
acetate/hexanes to afford 2.8 g of
3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (48%). LCMS
(method Q) RT 0.90 min, m/z 322.1 (M+H.sup.+); .sup.1H NMR (400
MHz, chloroform-d) .delta. 12.39 (d, J=8.0 Hz, 2H), 12.16 (d, J=8.0
Hz, 2H), 9.46-9.38 (m, 1H), 9.25 (d, J=1.8 Hz, 2H), 8.27-8.17 (m,
1H), 7.99 (s, 1H), 7.43-7.31 (m, 1H), 7.14-7.05 (m, 1H).
Step C. (R)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine and
(S)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine
##STR00239##
[0485] Racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (2.2
g, 7.3 mmol, from Example 52, step C) was submitted to chiral
separation (method H-4) and the chirally pure fractions were
collected and evaporated under reduced pressure to give E1 (850 mg,
2.77 mmol, 38.3% yield) and E2 (780 mg, 2.55 mmol, 35.1% yield)
(R)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine and
(S)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (absolute
configuration not assigned). Data for E-1: LCMS (method F) RT 2.16
min, m/z 304 (M+H.sup.+); Chiral HPLC (method H-3) RT 11.1 min,
100% AP; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.72 (d,
J=13.55 Hz, 1H) 1.94 (dd, J=12.55, 4.02 Hz, 1H) 2.60 (t, J=12.05
Hz, 1H) 2.74-2.88 (m, 1H) 2.98 (d, J=12.55 Hz, 1H) 3.04-3.20 (m,
2H) 5.10 (s, 2H) 6.95-7.02 (m, 2H) 7.21 (d, J=8.53 Hz, 2H)
7.30-7.50 (m, 5H); .sup.19F NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
-102.275, -102,900, -115.135, -115.759. Data for E-2: LCMS (method
F) RT 2.16 min, m/z 304 (M+H.sup.+); Chiral HPLC (method H-3) RT
18.28 min, 99.7% AP; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.72 (d, J=12.55 Hz, 1H) 1.94 (dd, J=13.05, 4.02 Hz, 1H)
2.55-2.64 (m, 1H) 2.74-2.88 (m, 1H) 2.98 (d, J=13.05 Hz, 1H)
3.05-3.20 (m, 2H) 5.10 (s, 2H) 6.95-7.00 (m, 2H) 7.21 (d, J=8.53
Hz, 2H) 7.30-7.49 (m, 5H): .sup.19F NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm -102.276, -102-900, -115.134, -115.748.
Step D. 4-(3,3-Difluoropiperidin-4-yl)phenol
##STR00240##
[0487] A mixture of 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine
(E-2 from Step C, above, 1 g, 3.3 mmol) and methanol (15 mL) was
flushed with nitrogen, followed by the addition of 10% Pd/C (0.7
g). The reaction mass then stirred overnight at rt under 160 psi of
hydrogen pressure in a 100 mL autoclave. The catalyst was then
removed by filtration through Celite and the filtrate was
concentrated under vacuum. A yield of 0.65 g (78%) of E-2a
4-(3,3-difluoropiperidin-4-yl)phenol was obtained. LCMS (method Q)
RT 0.47 min, m/z 214.1 (M+H.sup.+).
Step E.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoro-
methyl)benzyl)pyrrolidin-2-one
##STR00241##
[0489] A mixture of 4-(3,3-difluoropiperidin-4-yl)phenol (200 mg,
0.94 mmol, E-2a from step D),
3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (604 mg, 1.9
mmol), triethylamine (0.65 mL, 4.7 mmol), and 2 mL of DMF was
heated in a microwave reactor at 120.degree. C. for 1 h. The cooled
reaction mixture was partitioned between water and 30 mL of ethyl
acetate, and the aqueous phase was again extracted with 30 mL of
ethyl acetate. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford 150 mg of
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-
-benzyl)pyrrolidin-2-one (0.33 mmol, 35%, 2 diastereoisomers) which
was purified and separated in step F. LCMS (method J) RT 0.8 min
(60% AP), m/z 455.4 (M+H.sup.+).
Step F.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoro-
methyl)-benzyl)pyrrolidin-2-one
[0490] The product
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-
-benzyl)pyrrolidin-2-one (150 mg, 0.33 mmol), from step E was
separated via SFC (method C-7) to give the separated diastereomers,
which were individually purified via preparative HPLC (method B) to
give homochiral Examples 53 P-1 (40.8 mg) and P-2 (39.3 mg). The
products differ at the lactam 3-position stereocenter; however, the
relative stereochemical configurations were not determined. Data
for P-1: pale yellow solid. LCMS (method N) RT 1.70 min (99.7% AP),
m/z 455.0 (M+H.sup.+); .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta.=7.69 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.15 (d,
J=8.0 Hz, 2H), 6.80-6.71 (m, 2H), 4.58 (d, J=16.6 Hz, 2H), 3.75 (s,
1H), 3.30-3.25 (m, 2H), 3.23-3.09 (m, 3H), 3.02-2.85 (m, 1H),
2.59-2.50 (m, 1H), 2.33-2.03 (m, 3H), 1.91-1.80 (m, 1H). .sup.19F
NMR (400 MHz, methanol-d.sub.4) .delta. -64.073, -102.629,
-103.268, -115.125, -115.764. Data for P-2: pale yellow solid. LCMS
(method N) RT 1.71 min (99.7% AP), m/z 455.0 (M+H.sup.+); .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta.=7.69 (d, J=8.0 Hz, 2H),
7.49 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 6.79-6.72 (m, 2H),
4.65-4.52 (m, 2H), 3.72 (t, J=9.0 Hz, 1H), 3.47-3.38 (m, 1H),
3.31-3.26 (m, 1H), 3.03-2.84 (m, 3H), 2.74-2.61 (m, 1H), 2.31-2.01
(m, 3H), 1.88-1.80 (m, 1H). .sup.19F NMR (400 MHz,
methanol-d.sub.4) .delta. -64.074, -102.511, -103.151, -114.583,
-115.225.
Example 54 (Peak-1, Peak-2, Peak-3, and Peak-4)
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenz-
yl)pyrrolidin-2-one,
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one,
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one, and
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one
##STR00242##
[0491] Step A. (3S,4S)-4-(4-Methoxyphenyl)piperidin-3-ol and
(3R,4R)-4-(4-methoxyphenyl)piperidin-3-ol
##STR00243##
[0493] Racemic (.+-.)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol
(2.6 g, 12.54 mmol, from Example 51, step D) was subjected to SFC
chiral purification (Method H-1), which gave enantiomers E-1 (680
mg) and E-2 (720 mg), (3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol and
(3R,4R)-4-(4-methoxyphenyl)piperidin-3-ol (absolute configurations
not assigned). Data for E-1, 1st eluting isomer: Chiral SFC (method
H) RT 2.57 min; 98% AP; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.13 (d, J=9 Hz, 2H) 6.84 (d, J=9 Hz, 2H) 4.43 (br. s., 1H)
3.72 (s, 3H) 3.43 (d, J=10.54 Hz, 2H) 3.08 (dd, J=11.80, 4.77 Hz,
1H) 2.92 (d, J=12.05 Hz, 1H) 2.28-2.39 (m, 2H) 1.47-1.68 (m, 2H).
Data for E-2, 2nd eluting isomer: Chiral SFC (method H) RT 3.18
min; 94.3% AP; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.13
(d, J=9 Hz, 2H) 6.85 (d, J=8 Hz, 2H) 4.58 (br. s., 1H) 3.72 (s, 3H)
3.43 (br d, 3H) 3.11 (m, 2H) 2.61 (m, 1H) 2.28-2.39 (m, 2H)
1.47-1.68 (m, 2H).
Step B.
1-(4-Fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-
-1-yl)pyrrolidin-2-one
##STR00244##
[0495] To a mixture of 3-bromo-1-(4-fluorobenzyl)pyrrolidin-2-one
(Intermediate 1, 200 mg, 0.74 mmol),
trans-4-(4-methoxyphenyl)piperidin-3-ol (152 mg, 0.74 mmol, E-2
from step A) and acetonitrile (15 mL) was added triethylamine (0.5
mL, 3.7 mmol) and the resulting mixture was heated at 100.degree.
C. for 1 h. The reaction was then diluted with water and extracted
with ethyl acetate (100 mL). The layers were separated, and the
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated under reduced pressure to afford
1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-
-1-yl)pyrrolidin-2-one (mixture of 2 diastereomers, 320 mg, 73.%
yield). LCMS (method F) RT 1.706 min (67% AP) m/z 399.4
(M+H.sup.+).
Step C.
1-(1-(4-Fluorobenzyl)-2-oxopyrrolidin-3-yl)-4-(4-methoxyphenyl)pip-
eridin-3-one
##STR00245##
[0497] To a mixture of DMSO (0.14 mL, 2 mmol) and DCM (20 mL) at
-78.degree. C. under nitrogen was added oxalyl chloride (0.18 mL, 2
mmol) and the reaction mixture was stirred for 10 min. Then
1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)-piperidin-1-yl)-
pyrrolidin-2-one (320 mg, 0.8 mmol) was added and the reaction was
stirred for one hour at same temperature. Triethylamine (0.56 mL, 4
mmol) was then added, and the reaction mixture was allowed to warm
to rt. The mixture was then partitioned between water (100 mL) and
DCM (200 mL). The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure
to give afford the crude product, which was taken on to step D
without further purification. LCMS (method Q) RT 0.68 min (47% AP),
m/z 397.1 (M+H.sup.+).
Step D.
3-(3,3-Difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenz-
yl)pyrrolidin-2-one
##STR00246##
[0499] To a solution of
1-(1-(4-fluorobenzyl)-2-oxopyrrolidin-3-yl)-4-(4-methoxyphenyl)piperidin--
3-one (350 mg, 0.88 mmol) in 15 mL of DCM at -10.degree. C. was
added DAST (0.58 mL, 4.4 mmol) and the reaction was stirred under
nitrogen for 1 h. The mixture was then diluted with a saturated
sodium bicarbonate solution (100 mL) and extracted with 250 mL of
DCM. The organic layer was separated, dried over Na2SO4, filtered,
and evaporated under reduced pressure to yield
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrr-
olidin-2-one (mixture of diastereomers), which was used in step E
without further purification. LCMS (method F) RT 1.939 min, 55.8%
AP, m/z 381.2, 471.2.
Step E.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenz-
yl)pyrrolidin-2-one
##STR00247##
[0501] To a solution of
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrr-
olidin-2-one (200 mg, 0.48 mmol, mixture of diastereomers from step
D) in DCM (15 mL) at -10.degree. C. was added boron tribromide
(0.05 mL, 0.48 mmol) and the reaction mixture was stirred under
nitrogen for one hour. The mixture was then diluted with a satd.
sodium bicarbonate solution and extracted with 100 mL of DCM. The
organic layer was separated, dried over Na.sub.2SO.sub.4, filtered,
and evaporated under reduced pressure. The residue was purified via
preparative HPLC (method D) to yield
3-(3,3-difluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-fluorobenzyl)pyr-
rolidin-2-one (mixture of 4 diastereomers, 34 mg, 17% yield). LCMS
(method N) RT 1.497 min, m/z 405.0 (M+H.sup.+).
Step F.
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fl-
uorobenzyl)pyrrolidin-2-one,
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one,
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one, and
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one
[0502] The diastereomeric mixture of
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrr-
olidin-2-one (32 mg, 0.08 mmol, from step E) was purified by SFC
(method C-8) to obtain homochiral Examples 54 P-1 (5.2 mg), P-2
(5.2 mg), P-3 (5.4 mg), and P-4 (5.4 mg),
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one,
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one,
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one, and
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluoroben-
zyl)pyrrolidin-2-one. The absolute and relative stereochemical
configurations were not determined. The compounds were arbitrarily
designated as P-1, P-2, P-3, and P-4 based on their order of
elution during the chiral separation. The presence of 4 instead of
2 diastereoisomers implies racemization of the starting homochiral
piperidine during the course of the synthesis. Data for P-1: HPLC
(method D) RT 7.87 min, 95.8% AP, (method A) RT 7.58 min, 97.5% AP;
LCMS (method F) RT 2.05 min, 100% AP, m/z 405.0 (M+H.sup.+); chiral
SFC (method C-5) RT 4.77 min; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. ppm 7.32 (dd, J=8.78, 5.27 Hz, 2H)
7.06-7.17 (m, 4H) 6.72-6.77 (m, 2H) 4.40-4.53 (m, 2H) 3.71 (t,
J=8.78 Hz, 1H) 3.22-3.31 (m, 2H) 3.07-3.18 (m, 3H) 2.85-2.99 (m,
1H) 2.52 (t, J=11.29 Hz, 1H) 1.99-2.31 (m, 3H) 1.84 (ddt, J=13.30,
4.77, 2.26, 2.26 Hz, 1H). Data for P-2: HPLC (method D) RT 7.89
min, 100% AP, (method A) RT 7.77 min, 95.1% AP; LCMS (method F) RT
2.04 min, 100% AP, m/z 405.0 (M+H.sup.+); chiral SFC (method C-5)
RT 6.6 min; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
7.31 (dd, J=8.78, 5.27 Hz, 2H) 7.06-7.17 (m, 4H) 6.75 (d, J=8.53
Hz, 2H) 4.47 (q, J=15.06 Hz, 2H) 3.68 (t, J=9.04 Hz, 1H) 3.35-3.42
(m, 1H) 3.22-3.30 (m, 1H) 2.82-3.02 (m, 3H) 2.59-2.74 (m, 1H)
1.98-2.28 (m, 3H) 1.82 (ddt, J=13.18, 4.64, 2.38, 2.38 Hz, 1H).
Data for P-3: HPLC (method D) RT 7.99 min, 100% AP, (method A) RT
7.77 min, 96.3% AP; LCMS (method F) RT 2.04 min, 100% AP, m/z 405.0
(M+H.sup.+); chiral SFC (method C-5) RT 7.25 min; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 7.31 (dd, J=8.78, 5.27 Hz, 2H)
7.06-7.17 (m, 4H) 6.72-6.78 (m, 2H) 4.40-4.53 (m, 2H) 3.68 (t,
J=9.04 Hz, 1H) 3.34-3.43 (m, 1H) 3.21-3.30 (m, 1H) 2.77-3.01 (m,
3H) 2.60-2.72 (m, 1H) 1.98-2.29 (m, 3H) 1.82 (ddt, J=13.30, 4.77,
2.26, 2.26 Hz, 1H). Data for P-4: HPLC (method A) RT 7.58 min,
96.9% AP; LCMS (method F) RT 2.04 min, 100% AP, m/z 405.0
(M+H.sup.+); chiral SFC (method C-5) RT 10.3 min; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 7.32 (dd, J=8.78, 5.27 Hz, 2H)
7.06-7.17 (m, 4H) 6.75 (d, J=8.53 Hz, 2H) 4.39-4.54 (m, 2H) 3.71
(t, J=8.78 Hz, 1H) 3.24-3.30 (m, 1H) 3.07-3.18 (m, 3H) 2.85-2.99
(m, 1H) 2.52 (t, J=11.29 Hz, 1H) 1.98-2.30 (m, 3H) 1.84 (ddt,
J=13.36, 4.83, 2.45, 2.45 Hz, 1H).
Example 55 (Peak-1, Peak-2, Peak-3, and Peak-4)
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-m-
ethylphenyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one, and
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one
##STR00248##
[0503] Step A. (3R,4R)-tert-Butyl
3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate
##STR00249##
[0505] To a solution of (3R,4R)-tert-butyl
3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (490 mg, 1.67
mmol, procedure from WO 2000/63173) in DMF (6 mL) was added
K.sub.2CO.sub.3 (577 mg, 4.2 mmol) followed by methyl iodide (0.52
mL, 8.4 mmol) at rt. The mixture was stirred at rt for 18 h. It was
then diluted with 50 mL ethyl acetate and the solids were removed
by filtration. The solvent was then evaporated under vacuum and the
residue was purified via silica gel chromatography (hexanes-100%
EtOAc) to yield (3R,4R)-tert-butyl
3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (450 mg, 88%
yield). LCMS (method T) RT 3.068 min, m/z 306.3 (M-H).sup.-;
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.15 (d, J=8.7 Hz, 2H),
6.87 (d, J=8.7 Hz, 2H), 4.40-4.30 (m, 1H), 4.25-4.05 (m, 1H), 3.78
(s, 3H), 3.64-3.52 (m, 1H), 2.77-2.66 (m, 1H), 2.65-2.51 (m, 1H),
2.45 (br. s., 1H), 2.26-2.10 (m, 1H), 1.76 (d, J=2.7 Hz, 1H),
1.71-1.60 (m, 1H), 1.48 (s, 9H).
Step B. tert-Butyl
4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate
##STR00250##
[0507] To a solution of (3R,4R)-tert-butyl
3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (180 mg, 0.59
mmol) in DCM (3 mL) at 0.degree. C. under N.sub.2 was added
Dess-Martin Periodinane (373 mg, 0.88 mmol). The mixture was
allowed to warm to rt and stirred for 3 h. The reaction mixture was
directly purified via silica gel chromatography eluting with 30%
EtOAc in hexanes to afford tert-butyl
4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate (155 mg, 87%
yield). Subsequent results revealed that the 4R stereochemistry is
lost in this reaction and the racemic product was obtained. .sup.1H
NMR (500 MHz, chloroform-d) .delta. 7.09-7.03 (m, 2H), 6.93-6.87
(m, 2H), 4.24 (d, J=18.0 Hz, 1H), 4.11-4.02 (m, 1H), 3.80 (s, 3H),
3.61 (dd, J=11.9, 5.6 Hz, 1H), 3.56-3.46 (m, 1H), 2.34-2.16 (m,
2H), 1.50 (s, 9H).
Step C. tert-butyl
3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate
##STR00251##
[0509] To a solution of tert-butyl
4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate (90 mg, 0.3 mmol,
from step B) in DCM (5 mL) at -78.degree. C. under N.sub.2 was
added DAST (0.16 mL, 1.18 mmol). The mixture was stirred from
-78.degree. C. to rt over 1 h, then allowed to stand in the
refrigerator overnight. It was then concentrated and tert-butyl
3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate (65 mg,
67.4% yield) was isolated which was used without further
purification. LCMS (method U) m/z 350.2 (M+Na); .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.39 (d, J=8.7 Hz, 2H), 6.95-6.86 (m,
3H), 4.10 (br. s., 2H), 3.83 (s, 3H), 3.82 (s, 1H), 3.64-3.58 (m,
2H), 3.06-2.93 (m, 1H), 2.57-2.45 (m, 2H), 1.50 (s, 9H).
Step D. 3,3-Difluoro-4-(4-methoxyphenyl)piperidine
trifluoroacetate
##STR00252##
[0511] To a solution of (R)-t-butyl
3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate (65 mg,
0.2 mmol) in DCM (0.8 mL) was added TFA (0.4 mL, 5.2 mmol) at rt.
The mixture was stirred for 2 h, then concentrated to dryness in
vacuo to afford crude 3,3-difluoro-4-(4-methoxyphenyl)piperidine
trifluoroacetate (67.8 mg, 0.2 mmol, 100% yield), which was used in
step G without further purification.
Step E.
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-m-
ethylphenyl)pyrrolidin-2-one
##STR00253##
[0513] To a solution of 3,3-difluoro-4-(4-methoxyphenyl)piperidine
trifluoroacetate (67 mg, 0.2 mmol) in DMF (0.8 mL) was added
3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (from Example
49, step C, 96 mg, 0.35 mmol) and DIPEA (0.1 mL, 0.6 mmol). The
mixture was stirred at rt for 18 h, then raised to 80.degree. C.
for 2 h. The mixture was cooled, the solvent was removed under
vacuum and the residue was purified via silica gel chromatography,
eluting with a gradient from 0 to 100% ethyl acetate in hexanes to
yield 62 mg of
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylph-
enyl)pyrrolidin-2-one (along with 20 mg of the sideproduct,
1-(3-fluoro-4-methylphenyl)-3-hydroxypyrrolidin-2-one). LCMS
(method U) RT 3.755 min, m/z 419.3 (M+H.sup.+); .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.51 (d, J=11.9, 2H), m 7.26-7.26 (3H),
m 7.20 (1H), 6.90 (d, J=8.7) 3.82 (s, 3H), 3.65-3.78 (m, 3H),
3.2-3.45 (m, 3H), 2.87-3.00 (m, 1H), 2.72-2.85 (m, 0.4H), 2.65 (t,
0.5H), 2.37-2.48 (m, 1H), 2.27 (s, 3H), 2.1-2.25 (m, 2H), 1.87-1.95
(m, 1H). Chiral HPLC (method A-2) revealed that the chirality
present in the starting material for step A had been lost.
Step F.
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fl-
uoro-4-methylphenyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one, and
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one
[0514] To a solution of
3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylph-
enyl)pyrrolidin-2-one (62 mg, 0.15 mmol) in DCM (0.8 mL) at
-78.degree. C. under N.sub.2 was added boron tribromide (0.04 mL,
0.44 mmol). The reaction was warmed to rt and stirred for a further
2 h. It was then quenched with several drops of EtOH, and 50 mL of
EtOAc was added. After stirring at rt for 1 h, the solid was
removed by filtration and washed with MeOH. The filtrates were
combined and concentrated. The residue was purified via silica gel
chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to
give a mixture containing all four diastereomers, which were
separated via chiral HPLC (method A-2) to give homochiral Examples
55 P-1, P-2, P-3, and P-4,
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one,
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one, and
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4--
methylphenyl)pyrrolidin-2-one. The absolute and relative
stereochemical configurations were not determined. The compounds
were arbitrarily designated as P-1, P-2, P-3, and P-4 based on
their order of elution during the chiral separation. Data for P-1:
7.3 mg; LCMS (method U) RT 2.19 min (82% AP), m/z 405.1, 427.3
(M+H.sup.+, M+Na.sup.+); chiral HPLC (method A-3) RT 6.28 min,
98.1% AP; .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.49 (dd,
J=11.8, 1.8 Hz, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.24-7.16 (m, 3H),
6.83 (d, J=8.4 Hz, 2H), 3.84-3.71 (m, 3H), 3.37 (t, J=9.2 Hz, 1H),
3.31-3.22 (m, 1H), 3.14 (d, J=10.8 Hz, 1H), 3.00-2.88 (m, 1H),
2.87-2.77 (m, 1H), 2.50-2.40 (m, 1H), 2.28 (s, 3H), 2.25-2.11 (m,
3H), 1.94-1.86 (m, 1H). Data for P-2: 4.4 mg; LCMS (method U) RT
2.19 min (86% AP), m/z 405.2, 427.2 (M+H.sup.+, M+Na.sup.+); chiral
HPLC (method A-3) RT 8.77 min, 78.4% AP; .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.50 (dd, J=11.9, 2.1 Hz, 1H), 7.28-7.24 (m,
1H), 7.24-7.15 (m, 3H), 6.85 (d, J=8.4 Hz, 2H), 3.83-3.68 (m, 3H),
3.43-3.19 (m, 2H), 2.99-2.87 (m, 1H), 2.87-2.76 (m, 1H), 2.62 (t,
J=11.5 Hz, 1H), 2.49-2.39 (m, 1H), 2.27 (s, 3H), 2.25-2.12 (m, 2H),
1.96-1.85 (m, 2H). Data for P-3: 2.0 mg; LCMS (method U) RT 2.20
min (76% AP), m/z 405.2, 427.2 (M+H.sup.+, M+Na.sup.+); chiral HPLC
(method A-3) RT 11.46 min, 76.3% AP; .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.50 (dd, J=11.7, 2.1 Hz, 1H), 7.26 (dd,
J=8.5, 2.4 Hz, 1H), 7.24-7.16 (m, 3H), 6.83 (d, J=8.5 Hz, 2H),
3.83-3.71 (m, 3H), 3.36 (br. s., 1H), 3.31-3.22 (m, 1H), 3.15 (br.
s., 1H), 3.00-2.88 (m, 1H), 2.82 (dd, 1H), 2.50-2.42 (m, 1H), 2.28
(s, 3H), 2.25-2.12 (m, 3H), 1.95-1.86 (m, 1H). Data for P-4: 7.1
mg; LCMS (method U) RT 2.19 min (84% AP), m/z 405.2, 427.2
(M+H.sup.+, M+Na.sup.+); chiral HPLC (method A-3) RT 12.58 min,
89.5% AP; .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.49 (dd,
J=11.9, 1.8 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.24-7.14 (m, 3H),
6.83 (d, J=8.4 Hz, 2H), 3.83-3.70 (m, 3H), 3.43-3.19 (m, 3H),
2.99-2.87 (m, 1H), 2.63 (t, J=11.4 Hz, 1H), 2.49-2.39 (m, 1H), 2.27
(s, 3H), 2.25-2.12 (m, 3H), 1.95-1.86 (m, 1H).
Example 56
Example 56 (Peak-1, Peak-2, Peak-3, and Peak-4)
(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-flu-
orophenyl)ethyl)pyrrolidin-2-one,
(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)pyrrolidin-2-one,
(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)pyrrolidin-2-one, and
(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fl-
uorophenyl)ethyl)pyrrolidin-2-one
##STR00254##
[0515] Step A. (R)-4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidine
and (S)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine
##STR00255##
[0517] Racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine
(Example 52, step C, 5 g) was separated using chiral HPLC (method
H-3) to yield both pure enantiomers E-1 (1.5 g, 4.94 mmol, 39.5%
yield) and E-2 (1.4 g, 4.62 mmol, 36.8% yield). The absolute
configurations were not assigned. Data for E-1: Chiral SFC (method
C-6) RT 3.58 min, 100% AP; LCMS (method F) RT 2.32 min, 100% AP,
m/z 304.0 (M+H.sup.+); HPLC (method H) RT 6.746 min, 91.2% AP;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) d ppm 1.72 (d, J=13.55 Hz, 1H)
1.94 (dd, J=12.55, 4.02 Hz, 1H) 2.60 (t, J=12.05 Hz, 1H) 2.74-2.88
(m, 1H) 2.98 (d, J=12.55 Hz, 1H) 3.04-3.20 (m, 2H) 5.10 (s, 2H)
6.95-7.02 (m, 2H) 7.21 (d, J=8.53 Hz, 2H) 7.30-7.50 (m, 5H).
[0518] Data for E-2: Chiral SFC (method C-6) RT 6.56 min, 99.3% AP;
LCMS (method F) RT 2.32 min, 97.5% AP, m/z 304.0 (M+H.sup.+); HPLC
(method H) RT 6.767 min, 91.7% AP. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.72 (d, J=13.55 Hz, 1H) 1.94 (dd,
J=12.55, 4.02 Hz, 1H) 2.60 (t, J=12.05 Hz, 1H) 2.74-2.88 (m, 1H)
2.98 (d, J=12.55 Hz, 1H) 3.04-3.20 (m, 2H) 5.10 (s, 2H) 6.95-7.02
(m, 2H) 7.21 (d, J=8.53 Hz, 2H) 7.30-7.50 (m, 5H).
Step B. 4-(3,3-Difluoropiperidin-4-yl)phenol
##STR00256##
[0520] To a stirred solution of
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.6 g, 2 mmol) (E-2
from step A) in 20 mL methanol at rt was added 10% Pd/C (0.21 g)
and the reaction mixture was allowed to stir under 8 kPa of
hydrogen pressure for 4 h.
[0521] The catalyst was removed by filtration and the mixture was
concentrated under vacuum. The residue was triturated with ether
and the solid was isolated by filtration to yield 0.4 g of E-2a
4-(3,3-difluoropiperidin-4-yl)phenol (homochiral), which was used
directly in the next step. LCMS (method P) RT 0.53 min, m/z 214.4
(M+H.sup.+).
Step C.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-flu-
orophenyl)ethyl)pyrrolidin-2-one
[0522] A mixture of
3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (from
Example 50, step B) (0.145 g, 0.51 mmol),
4-(3,3-difluoropiperidin-4-yl)phenol (0.06 g, 0.28 mmol, E-2a from
Example 56 step B) and 0.2 mL of triethylamine (1.4 mmol) was
heated at 120.degree. C. for 1 h. The cooled reaction mixture was
partitioned between water and ethyl acetate. The organic phase was
washed with water and brine, and then it was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophen-
yl)ethyl)pyrrolidin-2-one as a pair of diastereomers. These
diastereomers were separated via preparative HPLC (method B) to
yield
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophen-
yl)ethyl)pyrrolidin-2-one homochiral Examples 56 P-1 (10.7 mg) and
P-2 (5.5 mg). The relative and absolute configurations of Examples
56 P-1 and P-2 were not determined and are arbitrarily named P-1
and P-2 based on the order of elution during the HPLC purification.
Data for P-1: pale yellow solid; LCMS (method O) RT 1.21 min (95.8%
AP) m/z 419.0 (M+H.sup.+); .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. ppm 1.55 (m, 3H) 1.78-1.90 (m, 1H), 1.90-2.01 (M, 1H),
2.1-2.2 (m, 1H), 2.21-2.35 (m, 1H), 2.49 (m, 1H), 2.80-2.99 (m,
1H), 3.01-3.10 (m, 4H), 3.33-3.38 (m, 3H), 3.63 (t, 1H), 5.40 (m,
1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H), 7.38-7.41 (m, 2H); .sup.19F
NMR .delta. ppm -76.948, -102.623, -103.262, -115.103, -115.743,
-117.043. Data for P-2: solid; LCMS (methods N, O) 99% AP; .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.59 (d, J=7.03 Hz, 3H)
1.79-1.90 (m, 1H) 2.01-2.23 (m, 3H) 2.62-2.72 (m, 1H) 2.86-3.19 (m,
5H) 3.40-3.74 (m, 2H) 4.36-4.56 (m, 1H) 5.28-5.48 (m, 1H) 6.76 (d,
J=9.04 Hz, 2H) 7.08-7.19 (m, 4H) 7.30-7.42 (m, 2H); .sup.19F NMR
.delta. ppm -76.938, -102.480, -012.630, -103.120, -103.146,
-103.269, -114.559, -115.124, -115.199, -115.763, -116.990,
-117.049.
Step D. 4-(3,3-Difluoropiperidin-4-yl)phenol
##STR00257##
[0524] To a stirred solution of
4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.6 g, 2 mmol, E-1
from step A) in MeOH (20 mL) at rt was added 10% Pd/C (0.21 g) and
the reaction mixture was allowed to stir under 8 kPa of hydrogen
pressure for 4 h. The catalyst was removed by filtration through
Celite and the filtrate was concentrated under vacuum to afford 0.4
g of homochiral E-1a 4-(3,3-difluoropiperidin-4-yl)phenol. LCMS
(method P) RT 0.55 min (74% AP), m/z 214.4 (M+H.sup.+).
Step E.
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-flu-
orophenyl)ethyl)pyrrolidin-2-one
[0525] To a mixture of
3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.134 g,
0.47 mmol, from Example 50, step B) and
4-(3,3-difluoropiperidin-4-yl)phenol (0.05 g, 0.23 mmol, E-1a from
Example 56, step D) was added triethylamine (0.16 mL, 1.2 mmol) and
the resulting mixture was heated at 120.degree. C. for 1 h. After
cooling, the reaction was partitioned between ethyl acetate and
water. The layers were separated and the organic phase was washed
with water and brine, then dried over Na.sub.2SO.sub.4, filtered,
and concentrated under vacuum. The residue was purified via
preparative HPLC (method B) to yield the homochiral Examples 56 P-3
and P-4
3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophen-
yl)ethyl)pyrrolidin-2-one diastereomers. The relative and absolute
configurations of Examples 56 P-3 and P-4 were not determined and
are arbitrarily named P-3 and P-4 based on the order of elution
during the HPLC purification. Data for P-3: 11.5 mg pale yellow
solid, LCMS (method O) RT 1.23 min (99.8% AP), m/z 419.0
(M+H.sup.+); .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
1.55 (d, J=7.2, 3H), 1.83 (m, 1H), 1.91-1.99 (m, 1H), 2.10-2.30 (m,
2H), 2.57-2.64 (q, 1H), 2.82-3.95 (m, 3H), 3.07-3.20, (m, 1H),
3.33-3.42 (m, 2H), 3.67 (t, J=9, 1H), 5.40 (d, J=7.2, 1H), 6.75 (m,
2H), 7.09-7.15 (m, 4H), 7.37-7.41 (m, 2H); .sup.19F NMR .delta. ppm
-102.515, -103.158, -114.576, -115.216, -117.070. Data for P-4:
13.7 mg pale yellow solid; LCMS (method O) RT 1.215 min (100% AP),
m/z 419.0 (M+H.sup.+); .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. ppm 1.59 (d, J=6.4, 3H), 1.80-1.90 (m, 1H), 2.01-2.29 (m,
3H), 2.53 (t, 1H), 2.81-2.97 (m, 3H), 3.01-3.25 (m, 3H), 3.34-3.43
(m, 1H), 3.64 (t, J=8.8, 1H), 5.42 (d, J=7.2, 1H), 6.74-6.77 (m,
2H), 7.09-7.16 (m, 4H), 7.35-7.38 (m, 2H); .sup.19F NMR .delta. ppm
-102.632, -103.271, -115.162, -115.801, -116.989.
General Procedure A: Used for Preparation of Examples 57-73
##STR00258##
[0527] To a microwave vial containing
4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (25 mg, 0.128 mmol, E-1b
from Example 50, step J) and the corresponding lactam bromide
(0.256 mmol, compound LB) was added DMF (1 mL) and triethylamine
(0.09 mL, 0.64 mmol). The vial was capped and the reaction mixture
was heated to 110.degree. C. using microwave irradiation for 1 h.
LC/MS data were collected using method 100. The samples were
directly purified by preparative HPLC under conditions B. Products
were a mixture of diastereoisomers. In some cases, the
diastereomers were further separated into the individual homochiral
components under the conditions reported in the specific
examples.
Example 57
(S)-1-Benzyl-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrroli-
din-2-one
##STR00259##
[0528] and
Example 58
(R)-1-Benzyl-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrroli-
din-2-one
##STR00260##
[0530] A diastereomeric mixture of
1-benzyl-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-
-2-one (prepared using general procedure A) was separated by SFC
(method C-6) to afford the titled compounds of Examples 57 and 58.
Data for Example 57: SFC (Method 105) RT=3.06 min. LC/MS RT=2.01
min, (M+H)+=369.2; .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm
1.78-1.88 (m, 2H) 2.04-2.12 (m, 1H) 2.20 (ddd, J=16.56, 12.80, 3.26
Hz, 1H) 2.41-2.51 (m, 1H) 2.55-2.62 (m, 1H) 2.67 (dt, J=9.79, 5.15
Hz, 2H) 3.01 (d, J=7.03 Hz, 1H) 3.12-3.18 (m, 1H) 3.22-3.29 (m, 1H)
3.75 (t, J=8.53 Hz, 1H) 4.51-4.61 (m, 2H) 4.67 (dt, J=10.04, 5.02
Hz, 1H) 6.70-6.83 (m, 2H) 7.07-7.14 (m, 2H) 7.27-7.33 (m, 3H)
7.34-7.41 (m, 2H). Data for Example 58: SFC (Method 105) RT=5.76
min. LC/MS RT=2.01 min, (M+H)+=369.2; .sup.1H NMR (400 MHz,
methanol-d4) .delta. ppm 1.78-1.89 (m, 2H) 2.08 (dd, J=13.30, 8.78
Hz, 2H) 2.15-2.21 (m, 1H) 2.43 (dt, J=10.29, 4.89 Hz, 2H) 2.51-2.60
(m, 2H) 2.63-2.71 (m, 2H) 2.77 (br. s., 2H) 3.23-3.29 (m, 2H)
3.36-3.47 (m, 2H) 3.72 (t, J=8.78 Hz, 1H) 4.40-4.48 (m, 2H) 4.54
(s, 1H) 6.71-6.80 (m, 2H) 7.07-7.14 (m, 2H) 7.20-7.33 (m, 3H)
7.34-7.41 (m, 2H).
Example 59
3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)p-
yrrolidin-2-one
##STR00261##
[0532] A diastereomeric mixture of
3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)-
pyrrolidin-2-one (Example 59) was prepared using general procedure
A. Data for Example 59: LC/MS RT=1.612 min, (M+H)+=383.0 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.23-7.06 (m,
6H), 6.73-6.67 (m, 2H), 4.66-4.42 (m, 2H), 4.33-4.26 (m, 1H),
3.64-3.55 (m, 1H), 3.43-3.36 (m, 1H), 3.19-3.04 (m, 3H), 2.77-2.65
(m, 2H), 2.57-2.53 (m, 1H), 2.36-2.23 (m, 4H), 2.15-2.05 (m, 1H),
1.98-1.86 (m, 1H), 1.77-1.56 (m, 1H).
Example 60
3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)p-
yrrolidin-2-one
##STR00262##
[0534] A diastereomeric mixture of
3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)-
pyrrolidin-2-one was prepared using general procedure A. Data for
Example 60: LC/MS RT=1.628 min, (M+H)+=383.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.27-7.20 (m, 1H), 7.09 (d,
J=8.5 Hz, 3H), 7.05-6.98 (m, 2H), 6.73-6.67 (m, 2H), 4.66-4.42 (m,
1H), 4.41-4.26 (m, 2H), 3.61-3.53 (m, 1H), 3.44-3.34 (m, 1H),
3.21-3.08 (m, 3H), 2.95 (d, J=11.1 Hz, 1H), 2.76-2.65 (m, 2H),
2.57-2.53 (m, 1H), 2.35-2.24 (m, 5H), 2.16-2.05 (m, 1H), 1.98-1.86
(m, 1H), 1.78-1.55 (m, 2H).
Example 61
1-(4-(Difluoromethoxy)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piper-
idin-1-yl)pyrrolidin-2-one
##STR00263##
[0536] A diastereomeric mixture of
1-(4-(difluoromethoxy)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)pipe-
ridin-1-yl)pyrrolidin-2-one was prepared using general procedure A.
Data for Example 61: LC/MS RT=1.594 min, (M+H)+=435.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.41-7.01 (m, 7H),
6.73-6.67 (m, 2H), 4.66-4.44 (m, 1H), 4.44-4.30 (m, 2H), 3.61-3.53
(m, 1H), 3.43-3.35 (m, 1H), 3.23-3.09 (m, 3H), 2.95 (d, J=10.0 Hz,
0H), 2.76-2.63 (m, 2H), 2.56 (d, J=4.6 Hz, 0H), 2.35-2.24 (m, 1H),
2.15-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.78-1.56 (m, 2H).
Example 62
(S)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-((3S,4S)-3-fluoro-4-(4-hydrox-
yphenyl)-piperidin-1-yl)pyrrolidin-2-one
##STR00264##
[0537] and
Example 63
(R)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-((3S,4S)-3-fluoro-4-(4-hydrox-
yphenyl)-piperidin-1-yl)pyrrolidin-2-one
##STR00265##
[0539] A diastereomeric mixture of
1-(3-chloro-4-(difluoromethoxy)phenyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyph-
enyl)piperidin-1-yl)pyrrolidin-2-one (prepared using general
procedure A) was separated by SFC (method 101) to afford the titled
compounds of Examples 62 and 63. Data for Example 62: SFC (Method
106) RT=3.78 min.
[0540] LC/MS (Method O): RT=2.177 min, (M+H)+=455.0; .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. ppm 1.28-1.35 (m, 3H) 1.83-1.91
(m, 2H) 2.19-2.28 (m, 1H) 2.32-2.43 (m, 2H) 2.49-2.63 (m, 2H) 2.73
(td, J=10.04, 4.52 Hz, 1H) 2.98-3.12 (m, 2H) 3.20-3.29 (m, 1H)
3.76-3.91 (m, 3H) 4.69 (dt, J=10.04, 5.02 Hz, 1H) 6.64-6.90 (m, 3H)
7.10-7.19 (m, 2H) 7.35 (d, J=9.04 Hz, 1H) 7.62 (dd, J=9.04, 3.01
Hz, 1H) 8.01 (d, J=2.51 Hz, 1H). Data for Example 63: SFC (Method
106) RT=5.03 min. LC/MS (Method O): RT=2.189 min, (M+H)+=455.0;
.sup.1H NMR (400 MHz, methanol-d4) .delta. ppm 1.25 (t, J=7.28 Hz,
3H) 1.80-1.90 (m, 2H) 2.22-2.39 (m, 3H) 2.45-2.63 (m, 3H) 2.81-2.95
(m, 4H) 3.44-3.54 (m, 2H) 3.78-3.92 (m, 3H) 4.69-4.77 (m, 2H) 6.76
(d, J=9.04 Hz, 3H) 7.13 (d, J=8.53 Hz, 2H) 7.30-7.38 (m, 1H)
7.56-7.65 (m, 1H) 8.01 (d, J=2.51 Hz, 1H).
Example 64
(S)-1-(4-Chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1--
yl)pyrrolidin-2-one
##STR00266##
[0541] and
Example 65
(R)-1-(4-Chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1--
yl)pyrrolidin-2-one
##STR00267##
[0543] A diastereomeric mixture of
1-(4-Chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-
pyrrolidin-2-one (prepared using general procedure A) was separated
by SFC (method 104) to afford the titled compounds of Example 64
and 65. Data for Example 64: SFC (Method 106) RT=4.24 min. LC/MS
(Method O): RT=2.10 min, (M+H)+=403.2; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.42-7.35 (m, 2H), 7.32-7.25 (m, 2H),
7.15-7.08 (m, 2H), 6.79-6.72 (m, 2H), 4.59-4.38 (m, 3H), 3.74 (t,
J=8.8 Hz, 1H), 3.30-3.23 (m, 2H), 3.18-3.10 (m, 1H), 3.02 (d,
J=11.0 Hz, 1H), 2.67 (dt, J=4.8, 9.9 Hz, 1H), 2.57 (dd, J=6.5, 10.5
Hz, 1H), 2.49-2.41 (m, 1H), 2.26-2.03 (m, 2H), 1.88-1.80 (m, 2H).
Data for Example 65: SFC (Method 106) RT=7.88 min. LC/MS (Method
O): RT=2.10 min, (M+H)+=403.2; .sup.1H NMR (400 MHz, methanol-d4)
.delta.=7.41-7.35 (m, 2H), 7.32-7.25 (m, 2H), 7.14-7.08 (m, 2H),
6.79-6.73 (m, 2H), 4.58-4.40 (m, 3H), 3.72 (t, J=8.8 Hz, 1H),
3.46-3.40 (m, 1H), 3.30-3.24 (m, 2H), 2.80-2.75 (m, 1H), 2.74-2.52
(m, 2H), 2.44 (dt, J=4.5, 10.0 Hz, 1H), 2.27-2.05 (m, 2H),
1.88-1.77 (m, 2H).
Example 66
(S)-1-(4-Chloro-3-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one
##STR00268##
[0544] and
Example 67
(R)-1-(4-Chloro-3-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one
##STR00269##
[0546] A diastereomeric mixture of
1-(4-chloro-3-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one (prepared using general procedure A) was
separated by SFC (method 105) to afford the titled compounds of
Example 66 and 67. Data for Example 66: SFC (Method 105) RT=6.59
min. LC/MS (Method O): RT=2.122 min, (M+H)+=421.2; .sup.1H NMR (400
MHz, methanol-d4) .delta. ppm 1.77-1.88 (m, 2H) 2.04-2.16 (m, 1H)
2.18-2.26 (m, 1H) 2.49-2.61 (m, 2H) 2.67-2.79 (m, 2H) 3.43-3.52 (m,
2H) 3.60-3.64 (m, 1H) 3.70-3.75 (m, 1H) 4.43-4.53 (m, 2H) 4.57-4.60
(m, 2H) 6.74-6.80 (m, 2H) 7.03-7.15 (m, 3H) 7.17-7.24 (m, 1H)
7.45-7.52 (m, 1H). Data for Example 67: SFC (Method 105) RT=3.51
min. LC/MS (Method O): RT=2.124 min, (M+H)+=421.2; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.84 (d, J=4.02 Hz, 2H) 2.10
(dd, J=13.05, 8.53 Hz, 1H) 2.22 (dd, J=12.55, 3.51 Hz, 1H)
2.42-2.50 (m, 1H) 2.68 (td, J=9.79, 4.52 Hz, 1H) 3.04 (d, J=13.05
Hz, 1H) 3.13-3.19 (m, 1H) 3.38 (br. s., 1H) 3.75 (t, J=8.53 Hz, 1H)
4.45-4.53 (m, 2H) 4.58 (s, 1H) 6.74-6.81 (m, 2H) 7.12 (d, J=8.53
Hz, 3H) 7.20 (dd, J=10.04, 2.01 Hz, 1H) 7.44-7.53 (m, 1H).
Example 68
3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(1-phenylethyl)py-
rrolidin-2-one
##STR00270##
[0548] The titled compound of Example 68 was prepared using the
general procedure A. Only one diastereomer was isolated after
purification. Data for Example 68: LC/MS RT=1.60 min, (M+H)+=383.0;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.39-7.33
(m, 2H), 7.31-7.25 (m, 3H), 7.09 (d, J=8.5 Hz, 2H), 6.72-6.68 (m,
2H), 5.29 (q, J=7.4 Hz, 1H), 4.66-4.46 (m, 1H), 3.50 (t, J=8.5 Hz,
1H), 3.44-3.35 (m, 2H), 2.84-2.62 (m, 3H), 2.35-2.23 (m, 1H), 2.06
(dd, J=4.3, 8.3 Hz, 1H), 1.91 (dd, J=8.3, 12.3 Hz, 1H), 1.76-1.68
(m, 1H), 1.59 (dd, J=4.3, 12.8 Hz, 1H), 1.48 (d, J=7.0 Hz, 2H).
Example 69
1-(3,4-Difluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1--
yl)pyrrolidin-2-one
##STR00271##
[0550] The titled compound of example 69 was prepared as a mixture
of diastereomers using general procedure A. Data for Example 69:
LC/MS RT=1.568 min, (M+H)+=405.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.47-7.38 (m, 1H), 7.32-7.25
(m, 1H), 7.09 (d, J=8.0 Hz, 3H), 6.73-6.68 (m, 2H), 4.66-4.41 (m,
1H), 4.37 (d, J=4.0 Hz, 2H), 3.63-3.54 (m, 1H), 3.44-3.35 (m, 1H),
3.16 (s, 3H), 2.99-2.92 (m, 1H), 2.76-2.65 (m, 2H), 2.57-2.54 (m,
1H), 2.35-2.23 (m, 1H), 2.08 (s, 1H), 2.00-1.88 (m, 1H), 1.80-1.54
(m, 2H).
Example 70
1-(3,4-Dichlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1--
yl)pyrrolidin-2-one
##STR00272##
[0552] The titled compound of example 70 was prepared as a mixture
of diastereomers using the general procedure A. Data for Example
70: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.63
(dd, J=0.8, 8.4, 1H), 7.50 (s, 1H), 7.22 (dd, J=1.2, 8, 1H), 7.08
(d, J=8.4, 2H), 6.90 (dd, J=2, 6.4, 2H), 4.60 (m, 1H), 4.45 (m,
1H), 4.39 (m, 1H), 3.58 (m, 1H), 3.40 (m, 1H), 3.30-3.10 (m, 3H),
2.69 (m, 2H), 2.35-2.21 (m, 1H), 2.10 (m, 1H), 1.95 (m, 1H), 1.70
(m, 1H), 1.60 (m, 1H).
Example 71
(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoro-
methyl)-benzyl)pyrrolidin-2-one
##STR00273##
[0553] and
Example 72
(R)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoro-
methyl)benzyl)-pyrrolidin-2-one
##STR00274##
[0555] A diastereomeric mixture of
3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromet-
hyl)benzyl)-pyrrolidin-2-one (prepared using general procedure A)
was separated by SFC (method 105) to afford the titled compounds of
Example 71 and 72. Data for Example 71: SFC (Method 105) RT=2.31
min. LC/MS (Method 0): RT=2.233 min, (M+H)+=437.2; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 7.68 (d, J=8.16 Hz, 2H) 7.48 (d,
J=8.03 Hz, 2H) 7.08-7.15 (m, 2H) 6.70-6.78 (m, 2H) 4.50-4.70 (m,
3H) 3.76 (t, J=8.88 Hz, 1H) 3.12-3.18 (m, 1H) 2.99-3.07 (m, 1H)
2.68 (td, J=9.91, 4.77 Hz, 1H) 2.53-2.62 (m, 1H) 2.42-2.50 (m, 1H)
2.17-2.27 (m, 1H) 2.04-2.16 (m, 1H) 1.80-1.88 (m, 1H). Data for
Example 72: SFC (Method 105) RT=3.31 min. LC/MS (Method O):
RT=2.208 min, (M+H)+=437.2; .sup.1H NMR (400 MHz, methanol-d4)
.delta. ppm 7.68 (d, J=8.09 Hz, 3H) 7.48 (d, J=8.03 Hz, 3H)
7.09-7.14 (m, 4H) 6.71-6.79 (m, 2H) 4.51-4.71 (m, 3H) 3.74 (t,
J=8.97 Hz, 1H) 3.41-3.47 (m, 1H) 2.74-2.83 (m, 0H) 2.65-2.73 (m,
1H) 2.51-2.62 (m, 1H) 2.44 (td, J=9.99, 4.80 Hz, 1H) 2.17-2.27 (m,
1H) 2.05-2.16 (m, 1H) 1.76-1.87 (m, 2H).
Example 73
1-(3-Chloro-4-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperid-
in-1-yl)pyrrolidin-2-one
##STR00275##
[0557] The titled compound of example 73 was prepared as a mixture
of diastereomers using general procedure A. Data for Example 73:
LC/MS RT=1.674 min, (M+H)+=421.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.20 (s, 1H), 7.48-7.36 (m, 2H), 7.29-7.21
(m, 1H), 7.09 (d, J=8.5 Hz, 2H), 6.73-6.67 (m, 2H), 4.38 (d, J=4.0
Hz, 3H), 3.64-3.53 (m, 1H), 3.44-3.35 (m, 1H), 3.16 (s, 3H),
2.99-2.91 (m, 1H), 2.76-2.63 (m, 2H), 2.36-2.22 (m, 1H), 2.08 (s,
1H), 2.00-1.85 (m, 1H), 1.79-1.52 (m, 2H).
General Procedure B: Used for Preparation of Examples 74-89
##STR00276##
[0559] To a microwave vial containing
4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (23 mg, 0.12 mmol, E-2b
from Example 50, Step G) and the corresponding lactam bromide (0.21
mmol, compound LB) was added DMF (1 mL) and triethylamine (0.08 mL,
0.59 mmol). The vial was capped and the reaction mixture was heated
to 110.degree. C. using microwave irradiation for 1 h. LC/MS data
were collected using method 100. The samples were directly purified
by preparative HPLC under conditions B. Products are a mixture of
diastereoisomers. In some cases, the diastereo-isomers were further
separated into the individual homochiral components under the
conditions reported in the specific examples.
Example 74
(S)-1-Benzyl-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrroli-
din-2-one
##STR00277##
[0560] and
Example 75
(R)-1-Benzyl-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrol-
idin-2-one
##STR00278##
[0562] A diastereomeric mixture of
1-benzyl-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-
-2-one (prepared using general procedure B) was separated by SFC
(method 105) to afford the titled compounds of Example 74 and 75.
Data for Example 74: SFC (Method 105) RT=3.59 min. LC/MS (Method
O): RT=2.099 min, (M+H)+=369.2; .sup.1H NMR (400 MHz, methanol-d4)
.delta. ppm 7.26-7.40 (m, 5H) 7.08-7.13 (m, 2H) 6.71-6.79 (m, 2H)
4.40-4.71 (m, 3H) 3.68-3.75 (m, 1H) 3.38-3.45 (m, 1H) 3.22-3.31 (m,
2H) 2.74-2.81 (m, 1H) 2.64-2.72 (m, 1H) 2.51-2.63 (m, 1H) 2.43 (td,
J=10.01, 4.83 Hz, 1H) 2.14-2.24 (m, 1H) 2.02-2.13 (m, 1H) 1.75-1.87
(m, 2H). Data for Example 75: SFC (Method 105) RT=6.2 min. LC/MS
(Method O): RT=2.091 min, (M+H)+=369.2; .sup.1H NMR (400 MHz,
methanol-d4) .delta. ppm 7.25-7.39 (m, 5H) 7.03-7.14 (m, 2H)
6.70-6.84 (m, 2H) 4.38-4.72 (m, 3H) 3.74 (t, J=8.82 Hz, 1H)
3.22-3.30 (m, 2H) 3.10-3.18 (m, 1H) 2.94-3.05 (m, 2H) 2.66 (td,
J=9.91, 4.77 Hz, 1H) 2.51-2.60 (m, 1H) 2.40-2.49 (m, 1H) 2.14-2.25
(m, 1H) 1.99-2.12 (m, 1H) 1.79-1.89 (m, 2H).
Example 76
3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)p-
yrrolidin-2-one
##STR00279##
[0564] The titled compound of example 76 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
76: LC/MS RT=1.588 min, (M+H)+=383.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.56-1.78 (m, 2H) 1.87-1.97 (m, 1H) 2.08
(s, 1H) 2.23-2.35 (m, 5H) 2.64-2.79 (m, 2H) 3.04-3.18 (m, 3H)
3.36-3.44 (m, 1H) 3.60 (d, J=7.03 Hz, 1H) 4.27-4.34 (m, 1H)
4.43-4.65 (m, 2H) 6.66-6.73 (m, 2H) 7.06-7.22 (m, 6H) 9.20 (s,
1H).
Example 77
3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)p-
yrrolidin-2-one
##STR00280##
[0566] The titled compound of example 77 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
77: LC/MS RT=1.600 min, (M+H)+=383.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.57-1.76 (m, 2H) 1.86-1.98 (m, 1H) 2.08
(s, 1H) 2.29 (s, 2H) 2.65-2.76 (m, 1H) 3.09-3.21 (m, 2H) 3.57 (d,
J=7.53 Hz, 1H) 4.25-4.41 (m, 2H) 4.44-4.69 (m, 1H) 6.66-6.74 (m,
2H) 6.98-7.04 (m, 2H) 7.09 (d, J=8.53 Hz, 3H) 7.20-7.28 (m, 1H)
9.21 (s, 1H).
Example 78
1-(4-(Difluoromethoxy)benzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piper-
idin-1-yl)pyrrolidin-2-one
##STR00281##
[0568] The titled compound of example 78 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
78: LC/MS RT=1.565 min, (M+H)+=435.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.53-1.75 (m, 2H) 1.86-1.97 (m, 1H)
2.04-2.14 (m, 1H) 2.20-2.35 (m, 1H) 2.63-2.78 (m, 1H) 3.06-3.24 (m,
2H) 3.51-3.61 (m, 1H) 4.37 (d, J=12.55 Hz, 2H) 4.46-4.66 (m, 1H)
6.70 (d, J=8.53 Hz, 1H) 6.99-7.11 (m, 1H) 7.13-7.23 (m, 1H)
7.26-7.32 (m, 1H) 7.40 (s, 1H) 9.21 (s, 1H).
Example 79
1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphe-
nyl)-piperidin-1-yl)pyrrolidin-2-one
##STR00282##
[0570] The titled compound of example 79 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
79: LC/MS RT=1.762 min, (M+H)+=455.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.59-1.80 (m, 2H) 2.01-2.14 (m, 1H)
2.20-2.27 (m, 1H) 2.30-2.41 (m, 1H) 2.72-2.80 (m, 1H) 3.17 (s, 1H)
3.69-3.84 (m, 3H) 4.41-4.69 (m, 1H) 6.62-6.75 (m, 2H) 6.98-7.27 (m,
4H) 7.35-7.45 (m, 2H) 7.64 (d, J=3.51 Hz, 1H) 8.03 (t, J=2.51 Hz,
1H) 9.13-9.30 (m, 1H).
Example 80
(S)-1-(4-Chlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1--
yl)pyrrolidin-2-one
##STR00283##
[0571] and
Example 81
(R)-1-(4-Chlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1--
yl)pyrrolidin-2-one
##STR00284##
[0573] A diastereomeric mixture of
1-(4-chlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-
pyrrolidin-2-one (prepared using general procedure B) was separated
by SFC (method 105) to afford the titled compounds of Example 80
and 81. Data for Example 80: SFC (Method 105) RT=4.58 min. LC/MS
(Method 0): RT=2.216 min, (M+H)+=403.2; .sup.1H NMR (400 MHz,
methanol-d4) .delta. ppm 1.76-1.89 (m, 2H) 2.06-2.27 (m, 3H)
2.40-2.55 (m, 2H) 2.65-2.70 (m, 1H) 2.77 (d, J=10.54 Hz, 1H)
3.39-3.46 (m, 2H) 3.62 (s, 1H) 3.72 (t, J=8.78 Hz, 2H) 4.36-4.60
(m, 4H) 6.74-6.78 (m, 2H) 7.11 (d, J=8.53 Hz, 2H) 7.24-7.30 (m, 2H)
7.35-7.41 (m, 2H). Data for Example 81: SFC (Method 105) RT=9.5
min. LC/MS (Method O): RT=2.233 min, (M+H)+=403.2; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.84 (d, J=3.51 Hz, 2H) 2.45
(dd, J=14.81, 11.29 Hz, 1H) 2.68 (dd, J=10.04, 4.52 Hz, 1H)
2.97-3.06 (m, 2H) 3.10-3.16 (m, 2H) 3.25-3.31 (m, 2H) 3.62 (s, 1H)
4.49 (d, J=19.58 Hz, 3H) 4.66 (dd, J=10.04, 5.02 Hz, 2H) 6.72-6.79
(m, 2H) 7.12 (d, J=8.53 Hz, 2H) 7.26-7.32 (m, 2H) 7.35-7.40 (m,
2H).
Example 82
(S)-1-(4-Chloro-3-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one
##STR00285##
[0574] and
Example 83
(R)-1-(4-Chloro-3-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one
##STR00286##
[0576] A diastereomeric mixture of
1-(4-chloro-3-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one (prepared using general procedure B) was
separated by SFC (method 106) to afford the titled compounds of
Example 82 and 83. Data for Example 82: SFC (Method 106) RT=3.9
min. LC/MS (Method O): RT=2.081 min, (M+H)+=421.2; .sup.1H NMR (400
MHz, methanol-d4) .delta. ppm 7.44-7.50 (m, 1H) 7.16-7.21 (m, 1H)
7.08-7.14 (m, 1H) 6.72-6.81 (m, 2H) 4.42-4.71 (m, 4H) 3.69-3.75 (m,
1H) 3.40-3.47 (m, 1H) 3.25-3.31 (m, 1H) 2.74-2.80 (m, 1H) 2.64-2.72
(m, 1H) 2.53-2.62 (m, 1H) 2.39-2.48 (m, 1H) 2.17-2.27 (m, 1H)
2.04-2.16 (m, 1H) 1.77-1.87 (m, 2H). Data for Example 83: SFC
(Method 106) RT=7.05 min. LC/MS (Method O): RT=2.210 min,
(M+H)+=421.2; .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm
7.45-7.50 (m, 1H) 7.17-7.22 (m, 1H) 7.08-7.14 (m, 2H) 6.73-6.78 (m,
2H) 4.43-4.70 (m, 3H) 3.71-3.78 (m, 1H) 3.25-3.31 (m, 1H) 3.10-3.18
(m, 1H) 2.98-3.08 (m, 1H) 2.62-2.71 (m, 1H) 2.52-2.61 (m, 1H)
2.39-2.49 (m, 1H) 2.17-2.27 (m, 1H) 2.03-2.15 (m, 1H) 1.79-1.90 (m,
2H).
Example 84
3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethy-
l)pyrrolidin-2-one
##STR00287##
[0578] The titled compound of example 84 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
84: LC/MS RT=1.574 min, (M+H)+=383.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.48 (d, J=7.53 Hz, 3H) 1.84-1.94 (m, 1H)
2.00-2.13 (m, 1H) 2.23-2.31 (m, 1H) 2.66-2.75 (m, 1H) 2.81 (dt,
J=9.66, 7.72 Hz, 1H) 2.95 (d, J=9.04 Hz, 1H) 3.12-3.19 (m, 1H) 3.51
(t, J=8.53 Hz, 1H) 4.42-4.62 (m, 1H) 5.26-5.32 (m, 1H) 6.67-6.74
(m, 2H) 7.07-7.11 (m, 2H) 7.25-7.31 (m, 3H) 7.33-7.39 (m, 2H) 9.20
(s, 1H).
Example 85
1-(3,4-Difluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-
-yl)pyrrolidin-2-one
##STR00288##
[0580] The titled compound of example 85 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
85: LC/MS RT=1.540 min, (M+H)+=405.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.51-1.78 (m, 2H) 1.86-2.01 (m, 1H) 2.08
(s, 1H) 2.22-2.35 (m, 1H) 2.71 (br. s., 2H) 3.09-3.24 (m, 3H)
3.54-3.64 (m, 1H) 4.37 (d, J=4.02 Hz, 2H) 4.43-4.69 (m, 1H) 6.70
(d, J=8.53 Hz, 2H) 7.09 (d, J=8.53 Hz, 3H) 7.24-7.32 (m, 1H) 7.43
(s, 1H) 9.20 (s, 1H).
Example 86
1-(3,4-Dichlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-
-yl)pyrrolidin-2-one
##STR00289##
[0582] The titled compound of example 86 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
86: LC/MS RT=1.768 min, (M+H)+=437.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.51-1.76 (m, 2H) 1.85-2.00 (m, 1H)
2.05-2.15 (m, 1H) 2.21-2.34 (m, 1H) 2.66-2.75 (m, 2H) 3.07-3.25 (m,
3H) 3.37 (s, 1H) 3.59 (d, J=6.53 Hz, 1H) 4.39 (d, J=5.52 Hz, 2H)
4.43 (s, 1H) 6.67-6.74 (m, 2H) 7.09 (d, J=8.53 Hz, 2H) 7.20-7.28
(m, 1H) 7.50 (t, J=2.01 Hz, 1H) 7.62 (dd, J=8.03, 1.00 Hz, 1H) 9.21
(s, 1H).
Example 87
(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoro-
methyl)benzyl)-pyrrolidin-2-one
##STR00290##
[0583] and
Example 88
(R)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoro-
methyl)benzyl)-pyrrolidin-2-one
##STR00291##
[0585] A diastereomeric mixture of
3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromet-
hyl)benzyl)-pyrrolidin-2-one (prepared using general procedure B)
was separated by SFC (method 106) to afford the titled compounds of
Example 87 and 88. Data for Example 87: SFC (Method 106) RT=2.09
min. LC/MS (Method O): RT=2.14 min, (M+H)+=437.2; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta.=7.69 (d, J=8.0 Hz, 2H), 7.49 (d,
J=8.0 Hz, 2H), 7.15-7.09 (m, 2H), 6.80-6.72 (m, 2H), 4.71-4.51 (m,
3H), 3.74 (t, J=9.0 Hz, 1H), 3.48-3.41 (m, 1H), 3.30-3.25 (m, 2H),
2.83-2.75 (m, 1H), 2.73-2.65 (m, 1H), 2.62-2.52 (m, 1H), 2.45 (dt,
J=4.5, 10.0 Hz, 1H), 2.28-2.07 (m, 2H), 1.88-1.77 (m, 2H). Data for
Example 88: SFC (Method 106) RT=3.19 min. LC/MS (Method O): RT=2.13
min, (M+H)+=437.2; .sup.1H NMR (400 MHz, methanol-d4)
.delta.=7.72-7.66 (m, 2H), 7.53-7.45 (m, 2H), 7.16-7.08 (m, 2H),
6.80-6.72 (m, 2H), 4.69-4.49 (m, 3H), 3.81-3.72 (m, 1H), 3.32-3.26
(m, 2H), 3.19-3.11 (m, 1H), 3.09-3.00 (m, 1H), 2.74-2.65 (m, 1H),
2.62-2.53 (m, 1H), 2.51-2.42 (m, 1H), 2.28-2.18 (m, 1H), 2.16-2.04
(m, 1H), 1.90-1.79 (m, 2H).
Example 89
1-(3-Chloro-4-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperid-
in-1-yl)pyrrolidin-2-one
##STR00292##
[0587] The titled compound of example 89 was prepared as a mixture
of diastereomers using the general procedure B. Data for Example
89: LC/MS RT=1.645 min, (M+H)+=421.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.49-1.79 (m, 2H) 1.86-1.99 (m, 2H) 2.08
(s, 2H) 2.21-2.35 (m, 2H) 2.65-2.76 (m, 2H) 3.16 (s, 4H) 3.36-3.44
(m, 1H) 3.54-3.64 (m, 1H) 4.38 (d, J=4.02 Hz, 2H) 4.44-4.68 (m, 1H)
6.70 (d, J=8.53 Hz, 2H) 7.09 (d, J=8.53 Hz, 2H) 7.21-7.27 (m, 1H)
7.40 (s, 2H) 9.20 (s, 1H).
General Procedure C: Used for Preparation of Examples 90-117
##STR00293##
[0589] To a microwave vial containing
4-(3,3-difluoropiperidin-4-yl)phenol HCl (30 mg, 0.14 mmol, E-1a
from Example 56, Step D) and the appropriate lactam bromide (0.28
mmol, compound LB) was added DMF (1 mL) and triethylamine (0.1 mL,
0.7 mmol). The vial was capped and the reaction mixture was heated
to 120.degree. C. using microwave irradiation for 1 h. LC/MS data
were collected using method 100. The samples were directly purified
by preparative HPLC under conditions B. Products are a mixture of
diastereoisomers. In some cases, the diastereo-isomers were further
separated into the individual homochiral components under the
conditions reported in the specific examples. Assignment of lactam
stereochemistry followed biological activity but was not rigorously
determined chemically, therefore individual compounds are
identified by the retention time in SFC. The absolute configuration
of the homochiral 4-(3,3-difluoropiperidin-4-yl)phenol used has not
been determined.
Example 90
1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)-
piperidin-1-yl)pyrrolidin-2-one
##STR00294##
[0591] The titled compound of example 90 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
90: LC/MS RT=1.769 min, (M+H)+=473.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.31 (s, 1H), 8.03 (t, J=3.0 Hz, 1H),
7.68-7.62 (m, 1H), 7.44-7.07 (m, 4H), 6.72 (d, J=8.0 Hz, 2H), 3.80
(d, J=10.0 Hz, 3H), 3.17 (d, J=5.0 Hz, 2H), 3.06-2.85 (m, 2H),
2.73-2.60 (m, 1H), 2.48-2.43 (m, 1H), 2.35-2.22 (m, 1H), 2.13-1.93
(m, 4H), 1.81-1.70 (m, 1H).
Example 91 (Peak-1)
1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-on-
e
##STR00295##
[0592] and
Example 91 (Peak-2)
1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-on-
e
##STR00296##
[0594]
1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolid-
in-2-one was prepared as a mixture of diastereomers using the
general procedure C. The mixture of diastereomers was separated
into the individual homochiral compounds of example 91 P-1 and P-2
by SFC using method 105. The relative and absolute configurations
of were not determined and are arbitrarily named P-1 and P-2 based
on the order of elution during the SFC purification. Data for
Example 91, P-1: SFC (Method 105) RT=5.29 min. LC/MS (Method O):
RT=2.103 min, (M+H)+=387.2; .sup.1H NMR (400 MHz, methanol-d4)
.delta. ppm 7.26-7.39 (m, 5H) 7.15 (d, J=8.35 Hz, 2H) 6.73-6.77 (m,
2H) 4.41-4.59 (m, 3H) 3.69 (t, J=8.85 Hz, 1H) 3.36-3.42 (m, 1H)
3.22-3.30 (m, 2H) 3.06 (d, J=7.28 Hz, 1H) 2.84-3.01 (m, 3H)
2.60-2.73 (m, 1H) 1.98-2.28 (m, 3H) 1.82 (ddt, J=13.18, 4.76, 2.38,
2.38 Hz, 1H). Data for Example 91, P-2: SFC (Method 105) RT=5.18
min. LC/MS (Method O): RT=2.117 min, (M+H)+=387.2; .sup.1H NMR (400
MHz, methanol-d4) .delta. ppm 7.26-7.39 (m, 5H) 7.15 (d, J=8.41 Hz,
2H) 6.73-6.77 (m, 2H) 4.41-4.57 (m, 2H) 3.72 (t, J=8.82 Hz, 1H)
3.22-3.30 (m, 1H) 3.03-3.18 (m, 4H) 2.86-3.00 (m, 1H) 2.53 (t,
J=11.39 Hz, 1H) 1.99-2.30 (m, 3H) 1.80-1.88 (m, 1H).
Example 92
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrro-
lidin-2-one
##STR00297##
[0596] The titled compound of example 92 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
92: LC/MS RT=1.609 min, (M+H)+=401.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.30 (d, J=1.5 Hz, 1H), 7.22-7.07 (m, 6H),
6.71 (d, J=8.0 Hz, 2H), 4.48-4.42 (m, 1H), 4.35-4.28 (m, 1H), 3.62
(d, J=9.0 Hz, 1H), 3.19-3.04 (m, 4H), 3.02-2.78 (m, 2H), 2.69-2.54
(m, 1H), 2.45-2.32 (m, 1H), 2.25 (d, J=1.0 Hz, 3H), 2.18-2.07 (m,
1H), 1.94 (d, J=17.1 Hz, 2H), 1.80-1.69 (m, 1H).
Example 93
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrro-
lidin-2-one
##STR00298##
[0598] The titled compound of example 93 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
93: LC/MS RT=1.622 min, (M+H)+=401.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.30 (s, 1H), 7.27-7.20 (m, 1H), 7.09 (d,
J=8.0 Hz, 3H), 7.06-6.99 (m, 2H), 6.72 (d, J=8.0 Hz, 2H), 4.40-4.28
(m, 2H), 4.11-4.05 (m, 1H), 3.60 (d, J=8.5 Hz, 1H), 3.39-3.34 (m,
1H), 3.23-2.77 (m, 6H), 2.69-2.54 (m, 1H), 2.45-2.32 (m, 1H), 2.29
(s, 3H), 2.19-2.08 (m, 1H), 2.04-1.85 (m, 2H), 1.79-1.69 (m,
1H).
Example 94
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(difluoromethoxy)b-
enzyl)-pyrrolidin-2-one
##STR00299##
[0600] The titled compound of example 94 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
94: LC/MS RT=1.595 min, (M+H)+=453.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.30 (d, J=1.0 Hz, 1H), 7.42-7.02 (m, 8H),
6.71 (d, J=8.0 Hz, 2H), 4.43-4.32 (m, 2H), 3.60 (d, J=8.0 Hz, 1H),
3.40-3.33 (m, 1H), 3.24-3.04 (m, 3H), 3.02-2.76 (m, 2H), 2.69-2.54
(m, 1H), 2.43-2.31 (m, 1H), 2.20-2.07 (m, 1H), 2.03-1.85 (m, 1H),
1.79-1.69 (m, 1H).
Example 95 (Peak-1)
(3S)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-
pyrrolidin-2-one
##STR00300##
[0601] and
Example 95 (Peak-2)
(3R)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-
pyrrolidin-2-one
##STR00301##
[0603]
1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-y-
l)pyrrolidin-2-one was prepared as a mixture of diastereomers using
the general procedure C. The mixture of diastereomers was separated
into the individual homochiral compounds of example 95 P-1 and P-2
by SFC (method 105). The stereochemical configurations were not
determined and are arbitrarily named P-1 and P-2. Data for Example
95, P-1: SFC (Method 105) RT=5.29 min. LC/MS (Method O): RT=2.062
min, (M+H)+=421.2; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta.=7.41-7.35 (m, 2H), 7.32-7.26 (m, 2H), 7.15 (d, J=8.5 Hz,
2H), 6.79-6.73 (m, 2H), 4.55-4.40 (m, 2H), 3.69 (t, J=8.8 Hz, 1H),
3.43-3.37 (m, 1H), 3.31-3.24 (m, 2H), 3.01-2.84 (m, 3H), 2.73-2.58
(m, 1H), 2.28-2.01 (m, 3H), 1.83 (ddd, J=2.0, 1H). Data for Example
95, P-2: SFC (Method 105) RT=8.79 min. LC/MS (Method O): RT=2.059
min, (M+H)+=421.2; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta.=7.40-7.34 (m, 2H), 7.32-7.26 (m, 2H), 7.15 (d, J=8.5 Hz,
2H), 6.78-6.73 (m, 2H), 4.55-4.39 (m, 2H), 3.72 (t, J=8.8 Hz, 1H),
3.62 (s, 1H), 3.30-3.24 (m, 2H), 3.20-3.07 (m, 3H), 2.98-2.86 (m,
1H), 2.53 (s, 1H), 2.30-2.02 (m, 3H), 1.86 (br. s., 1H).
Example 96 (Peak-1)
(3S)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one
##STR00302##
[0604] and
Example 96 (Peak-2)
(3R)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one
##STR00303##
[0606]
1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)pipe-
ridin-1-yl)pyrrolidin-2-one was prepared as a mixture of
diastereomers using the general procedure C. The mixture of
diastereomers was separated into the individual homochiral
compounds of example 96 P-1 and P-2 by SFC (method 105). The
stereochemical configurations were not determined and are
arbitrarily named P-1 and P-2. Data for Example 96, P-1: SFC
(Method 105) RT=5.13 min. LC/MS (Method O): RT=2.214 min,
(M+H)+=439.0; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
1.47-1.51 (m, 1H) 1.84 (d, J=13.05 Hz, 1H) 2.05-2.31 (m, 3H)
2.54-2.66 (m, 1H) 2.83-3.02 (m, 3H) 3.29-3.32 (m, 1H) 3.39-3.56 (m,
2H) 3.65-3.74 (m, 1H) 4.41-4.55 (m, 2H) 6.71-6.78 (m, 2H) 7.07-7.35
(m, 4H) 7.46-7.52 (m, 1H). Data for Example 96, P-2: SFC (Method
105) RT=7.15 min. LC/MS (Method O): RT=2.211 min, (M+H)+=439.0;
.sup.1H NMR (400 MHz, methanol-d4) .delta. ppm 1.81-1.92 (m, 1H)
2.01-2.30 (m, 3H) 2.46-2.58 (m, 1H) 3.03-3.11 (m, 1H) 3.10-3.21 (m,
2H) 3.24-3.32 (m, 1H) 3.72 (t, J=8.78 Hz, 1H) 4.42-4.56 (m, 2H)
6.72-6.79 (m, 2H) 7.09-7.23 (m, 4H) 7.43-7.51 (m, 1H).
Example 97
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluorobenzyl)p-
yrrolidin-2-one
##STR00304##
[0608] The titled compound of example 97 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
97: LC/MS RT=1.569 min, (M+H)+=423.0; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.30 (d, J=1.0 Hz, 1H), 7.46-7.37 (m, 1H),
7.33-7.25 (m, 1H), 7.09 (d, J=8.5 Hz, 3H), 6.71 (d, J=8.5 Hz, 2H),
4.37 (s, 2H), 3.65-3.57 (m, 1H), 3.43-3.35 (m, 1H), 3.27-3.04 (m,
4H), 3.03-2.76 (m, 2H), 2.63-2.58 (m, 1H), 2.44-2.32 (m, 1H),
2.21-2.07 (m, 1H), 2.04-1.87 (m, 2H), 1.79-1.69 (m, 1H).
Example 98
1-(3,4-Dichlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)p-
yrrolidin-2-one
##STR00305##
[0610] The titled compound of example 98 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
98: LC/MS RT=1.843 min, (M+H)+=454.9; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.33-9.28 (m, 1H), 7.62 (dd, J=1.3, 8.3 Hz,
1H), 7.50 (t, J=1.8 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.5
Hz, 2H), 6.71 (d, J=8.5 Hz, 2H), 4.39 (s, 2H), 4.11-4.05 (m, 1H),
3.65-3.57 (m, 1H), 3.17 (d, J=5.0 Hz, 4H), 3.03-2.76 (m, 2H),
2.42-2.31 (m, 1H), 2.21-2.07 (m, 1H), 1.90 (s, 2H), 1.79-1.69 (m,
1H).
Example 99 (Peak-1)
(3S)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromet-
hyl)benzyl)-pyrrolidin-2-one
##STR00306##
[0611] and
Example 99 (Peak-2)
(3S)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromet-
hyl)benzyl)-pyrrolidin-2-one
##STR00307##
[0613]
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluorom-
ethyl)benzyl)-pyrrolidin-2-one was prepared as a mixture of
diastereomers using the general procedure C. The mixture of
diastereomers was separated into the individual homochiral
compounds of example 99 P-1 and P-2 by SFC using method 100. The
relative and absolute configurations of were not determined and are
arbitrarily named P-1 and P-2 based on the order of elution during
the SFC purification. Data for Example 99, P-1: SFC (Method 105)
RT=2.8 min. LC/MS (Method O): RT=2.156 min, (M+H)+=455.2; .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.80-1.86 (m, 1H)
2.02-2.32 (m, 3H) 2.61-2.74 (m, 1H) 2.84-3.06 (m, 3H) 3.23-3.30 (m,
1H) 3.38-3.46 (m, 1H) 3.71 (t, J=8.78 Hz, 1H) 4.50-4.64 (m, 2H)
6.71-6.79 (m, 2H) 7.15 (d, J=8.53 Hz, 2H) 7.49 (d, J=8.03 Hz, 2H)
7.68 (d, J=8.53 Hz, 2H). Data for Example 99, P-2: SFC (Method 105)
RT=3.36 min. LC/MS (Method O): RT=2.152 min, (M+H)+=455.2; .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.27-1.37 (m, 1H)
2.02-2.30 (m, 3H) 2.54 (t, J=11.04 Hz, 1H) 3.07-3.20 (m, 4H)
3.24-3.30 (m, 2H) 3.35-3.56 (m, 1H) 3.74 (t, J=8.78 Hz, 1H)
4.55-4.60 (m, 2H) 6.72-6.79 (m, 2H) 7.15 (d, J=8.53 Hz, 2H) 7.49
(d, J=8.03 Hz, 2H) 7.68 (d, J=8.03 Hz, 2H).
Example 100
1-(3-Chloro-4-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-
-yl)pyrrolidin-2-one
##STR00308##
[0615] The titled compound of example 100 was prepared as a mixture
of diastereomers using the general procedure C. Data for Example
100: LC/MS RT=1.726 min, (M+H)+=439.0; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.47-7.42 (m, 1H), 7.30-7.23 (m, 2H),
7.18-7.12 (m, 2H), 6.79-6.72 (m, 2H), 4.52-4.41 (m, 2H), 3.75-3.66
(m, 1H), 3.30-3.26 (m, 1H), 3.20-3.08 (m, 2H), 3.01-2.83 (m, 2H),
2.71-2.49 (m, 1H), 2.33-2.07 (m, 3H), 1.89-1.79 (m, 1H).
General Procedure D. Used for Preparation of Examples 101-139
##STR00309##
[0617] To a microwave vial containing
4-(3,3-difluoropiperidin-4-yl)phenol (25 mg, 0.12 mmol, E-2a,
Example 56, step B) and the appropriate lactam bromide (0.29 mmol,
LB) was added DMF (1 mL) and triethylamine (0.08 mL, 0.6 mmol). The
vial was capped and the reaction mixture was heated to 120.degree.
C. using microwave irradiation for 1 h. LC/MS data were collected
using method 100. The samples were directly purified by preparative
HPLC under conditions B. Products are a mixture of
diastereoisomers. In some cases, the diastereoisomers were further
separated into the individual homochiral components under the
conditions reported in the specific examples. Assignment of lactam
stereochemistry could be inferred through biological activity, but
was not unambiguously determined. Individual compounds are
identified by the retention time during SFC. The absolute
configuration of the homochiral
4-(3,3-difluoropiperidin-4-yl)phenol used has not been
determined.
Example 101 (Peak-1)
(3S)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyph-
enyl)-piperidin-1-yl)pyrrolidin-2-one
##STR00310##
[0618] and
Example 101 (Peak-2)
(3R)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyph-
enyl)-piperidin-1-yl)pyrrolidin-2-one
##STR00311##
[0620]
1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxy-
phenyl)piperidin-1-yl)pyrrolidin-2-one was prepared as a mixture of
diastereomers using the general procedure D. The mixture of
diastereomers was separated into the individual homochiral
compounds of example 101 P-1 and P-2 by SFC using method 106. The
relative and absolute configurations of were not unambiguously
determined and are arbitrarily named P-1 and P-2 based on the order
of elution during the SFC purification. Data for Example 101, P-1:
SFC (Method 106) RT=2.79 min; LC/MS (Method O): RT=2.208 min,
(M+H)+=473.0; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
1.89 (br. s., 1H) 2.15-2.25 (m, 2H) 2.35-2.47 (m, 2H) 2.58-2.66 (m,
2H) 3.09-3.29 (m, 4H) 3.74-3.92 (m, 3H) 6.65-7.04 (m, 3H) 7.16 (d,
J=8.53 Hz, 1H) 7.34 (d, J=9.04 Hz, 1H) 7.57-7.67 (m, 1H) 8.00 (d,
J=2.51 Hz, 1H). Data for Example 101, P-2: SFC (Method 106) RT=3.36
min; LC/MS (Method O): RT=2.210 min, (M+H)+=473.0; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. ppm 1.85 (d, J=13.05 Hz, 1H)
2.12-2.27 (m, 2H) 2.34-2.44 (m, 1H) 2.68-2.82 (m, 2H) 2.87-3.10 (m,
4H) 3.48-3.53 (m, 1H) 3.78-3.89 (m, 3H) 6.61-6.91 (m, 3H) 7.16 (d,
J=8.53 Hz, 2H) 7.35 (d, J=9.04 Hz, 1H) 7.61 (dd, J=9.04, 2.51 Hz,
1H) 8.00 (d, J=3.01 Hz, 1H).
Example 102 (Peak-1)
(3S)-1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-
-2-one
##STR00312##
[0621] and
Example 102 (Peak-2)
(3R)-1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-
-2-one
##STR00313##
[0623]
1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolid-
in-2-one was prepared as a mixture of diastereomers using the
general procedure D. The mixture of diastereomers was separated
into the individual homochiral compounds of example 102 P-1 and P-2
by SFC using method 105. The relative and absolute configurations
of were not unambiguously determined and are arbitrarily named P-1
and P-2 based on the order of elution during the SFC purification.
Data for Example 102, P-1: SFC (Method 105) RT=2.62 min; LC/MS
(Method O): RT=2.106 min, (M+H)+=387.2; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.41-7.26 (m, 5H), 7.15 (d, J=8.5 Hz,
2H), 6.79-6.72 (m, 2H), 4.58-4.41 (m, 2H), 3.72 (t, J=8.8 Hz, 1H),
3.30-3.23 (m, 2H), 3.19-3.08 (m, 3H), 3.00-2.86 (m, 1H), 2.54 (t,
J=11.5 Hz, 1H), 2.30-2.01 (m, 3H), 1.85 (tdd, J=2.4, 4.6, 13.1 Hz,
1H). Data for Example 102, P-2: LC/MS RT=1.633 min; (M+H)+=401.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=9.33-9.28 (m, 1H), 7.19
(d, J=1.5 Hz, 6H), 6.75-6.67 (m, 2H), 4.50-4.41 (m, 1H), 4.35-4.25
(m, 1H), 3.69-3.53 (m, 1H), 3.22-3.02 (m, 3H), 2.94-2.80 (m, 1H),
2.46-2.32 (m, 1H), 2.25 (s, 4H), 2.17-2.06 (m, 1H), 1.99-1.65 (m,
3H).
Example 103
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrro-
lidin-2-one
##STR00314##
[0625] The titled compound of example 100 was prepared as a mixture
of diastereomers using the general procedure D. Data for Example
103: LC/MS RT=1.633 min; (M+H)+=401.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.33-9.28 (m, 1H), 7.19 (d, J=1.5 Hz, 6H),
6.75-6.67 (m, 2H), 4.50-4.41 (m, 1H), 4.35-4.25 (m, 1H), 3.69-3.53
(m, 1H), 3.22-3.02 (m, 3H), 2.94-2.80 (m, 1H), 2.46-2.32 (m, 1H),
2.25 (s, 4H), 2.17-2.06 (m, 1H), 1.99-1.65 (m, 3H).
Example 104
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrro-
lidin-2-one
##STR00315##
[0627] The titled compound of example 104 was prepared as a mixture
of diastereomers using the general procedure D. Data for Example
104: LC/MS RT=1.647 min; (M+H)+=401.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.31 (s, 1H), 7.27-7.19 (m, 1H), 7.12-6.99
(m, 5H), 6.72 (d, J=8.0 Hz, 2H), 4.42-4.24 (m, 2H), 3.60 (d, J=9.0
Hz, 1H), 3.22-3.03 (m, 3H), 2.92-2.56 (m, 2H), 2.29 (s, 3H), 2.13
(br. s., 1H), 1.93 (br. s., 2H), 1.79-1.68 (m, 1H).
Example 105
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(difluoromethoxy)b-
enzyl)-pyrrolidin-2-one
##STR00316##
[0629] The titled compound of example 105 was prepared as a mixture
of diastereomers using the general procedure D. Data for Example
105: LC/MS RT=1.622 min; (M+H)+=453.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.31 (s, 1H), 7.47-7.24 (m, 3H), 7.22-7.00
(m, 6H), 6.72 (d, J=8.5 Hz, 2H), 4.44-4.31 (m, 2H), 3.60 (d, J=8.0
Hz, 1H), 3.23-3.05 (m, 4H), 3.00-2.77 (m, 2H), 2.44-2.31 (m, 1H),
2.17-2.06 (m, 1H), 1.94 (d, J=17.1 Hz, 2H), 1.79-1.69 (m, 1H).
Example 106 (Peak-1)
(3S)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-
pyrrolidin-2-one
##STR00317##
[0630] and
Example 106 (Peak-2)
(3R)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-
pyrrolidin-2-one
##STR00318##
[0632]
1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-y-
l)pyrrolidin-2-one was prepared as a mixture of diastereomers using
the general procedure D. The mixture of diastereomers was separated
into the individual homochiral compounds of example 106 P-1 and P-2
by SFC using method 106. The relative and absolute configurations
were not determined and are arbitrarily named P-1 and P-2 based on
the order of elution during the SFC purification. Data for Example
106, P-1: SFC (Method 106) RT=3.14 min; LC/MS (Method O): RT=2.127
min, (M+H)+=421.2; .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm
7.35-7.41 (m, 2H) 7.26-7.31 (m, 2H) 7.15 (d, J=8.35 Hz, 2H)
6.73-6.78 (m, 2H) 4.40-4.54 (m, 2H) 3.69-3.75 (m, 1H) 3.61-3.62 (m,
0H) 3.45-3.50 (m, 1H) 3.23-3.31 (m, 1H) 3.09-3.20 (m, 3H) 2.86-3.05
(m, 1H) 2.49-2.58 (m, 1H) 2.00-2.31 (m, 3H) 1.79-1.90 (m, 1H). Data
for Example 106, P-2: SFC (Method 106) RT=4.29 min; LC/MS (Method
O): RT=2.128 min, (M+H)+=421.2; .sup.1H NMR (400 MHz, methanol-d4)
.delta. ppm 7.34-7.41 (m, 2H) 7.24-7.30 (m, 2H) 7.15 (d, J=8.35 Hz,
2H) 6.73-6.78 (m, 2H) 4.48 (q, J=14.87 Hz, 2H) 3.69 (t, J=8.85 Hz,
1H) 3.62 (s, 1H) 3.38-3.49 (m, 1H) 3.23-3.31 (m, 1H) 3.06 (q,
J=7.26 Hz, 1H) 2.84-3.01 (m, 2H) 2.60-2.73 (m, 1H) 1.98-2.31 (m,
3H) 1.79-1.89 (m, 1H).
Example 107 (Peak-1)
(3S)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one
##STR00319##
[0633] and
Example 107 (Peak-2)
(3R)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one
##STR00320##
[0635]
1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)pipe-
ridin-1-yl)pyrrolidin-2-one was prepared as a mixture of
diastereomers using the general procedure D. The mixture of
diastereomers was separated into the individual homochiral
compounds of example 107 P-1 and P-2 by SFC using method 105. The
relative and absolute configurations were not determined and are
arbitrarily named P-1 and P-2 based on the order of elution during
the SFC purification. Data for Example 107, P-1: SFC (Method 105)
RT=2.85 min; LC/MS (Method O): RT=2.093 min, (M+H)+=439.0; .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.85 (ddt, J=13.18,
4.64, 2.38, 2.38 Hz, 1H) 2.03-2.31 (m, 3H) 2.53 (t, J=11.29 Hz, 1H)
3.05-3.12 (m, 1H) 3.13-3.18 (m, 2H) 3.26-3.31 (m, 2H) 3.72 (t,
J=8.78 Hz, 1H) 4.41-4.54 (m, 2H) 6.73-6.79 (m, 2H) 7.08-7.23 (m,
4H) 7.48 (t, J=8.03 Hz, 1H). Data for Example 107, P-2: SFC (Method
105) RT=3.99 min; LC/MS (Method Q): RT=1.648 min, (M+H)+=439.0;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 1.85 (ddt,
J=13.18, 4.64, 2.38, 2.38 Hz, 1H) 2.03-2.31 (m, 3H) 2.53 (t,
J=11.29 Hz, 1H) 3.05-3.12 (m, 1H) 3.13-3.18 (m, 2H) 3.26-3.31 (m,
2H) 3.72 (t, J=8.78 Hz, 1H) 4.41-4.54 (m, 2H) 6.73-6.79 (m, 2H)
7.08-7.23 (m, 4H) 7.48 (t, J=8.03 Hz, 1H).
Example 108 (Peak-1)
(3S)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluoroben-
zyl)-pyrrolidin-2-one
##STR00321##
[0636] and
Example 108 (Peak-2)
(3R)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluoroben-
zyl)-pyrrolidin-2-one
##STR00322##
[0638]
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluorob-
enzyl)pyrrolidin-2-one was prepared as a mixture of diastereomers
using the general procedure D. The mixture of diastereomers was
separated into the individual homochiral compounds of example 108
P-1 and P-2 by SFC using method 105. The relative and absolute
configurations were not determined and are arbitrarily named P-1
and P-2 based on the order of elution during the SFC purification.
Data for Example 108, P-1: SFC (Method 105) RT=2.27 min; LC/MS
(Method O): RT=2.149 min, (M+H)+=423.2; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.32-7.19 (m, 2H), 7.18-7.08 (m, 3H),
6.79-6.72 (m, 2H), 4.60-4.40 (m, 2H), 3.72 (t, J=9.0 Hz, 1H),
3.30-3.24 (m, 2H), 3.20-3.05 (m, 3H), 3.00-2.85 (m, 1H), 2.53 (t,
J=11.0 Hz, 1H), 2.30-2.02 (m, 3H), 1.85 (tdd, J=2.4, 4.6, 13.2 Hz,
1H). Data for Example 108, P-2: SFC (Method 105) RT=2.85 min; LC/MS
(Method O): RT=2.182 min, (M+H)+=423.2; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.34-7.07 (m, 5H), 6.76 (d, J=8.5 Hz,
2H), 4.53-4.39 (m, 2H), 3.69 (t, J=9.0 Hz, 1H), 3.46-3.38 (m, 1H),
3.30-3.24 (m, 2H), 3.02-2.83 (m, 3H), 2.73-2.59 (m, 1H), 2.29-2.03
(m, 3H), 1.88-1.79 (m, 1H).
Example 109
1-(3,4-Dichlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)p-
yrrolidin-2-one
##STR00323##
[0640] The titled compound of example 109 was prepared as a mixture
of diastereomers using the general procedure D. Data for Example
109: LC/MS RT=1.833 min, (M+H)+=454.9; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=9.31 (s, 1H), 7.62 (dd, J=1.5, 8.0 Hz, 2H),
7.51 (d, J=1.5 Hz, 1H), 7.23 (dd, J=2.0, 8.0 Hz, 1H), 7.09 (d,
J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 4.39 (s, 2H), 4.09 (q, J=5.5
Hz, 1H), 3.23-3.13 (m, 4H), 2.94-2.83 (m, 1H), 2.43-2.34 (m, 1H),
2.21-2.09 (m, 2H), 2.01-1.70 (m, 3H).
Example 110
3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)b-
enzyl)-pyrrolidin-2-one
##STR00324##
[0642] The titled compound of example 110 was prepared as a mixture
of diastereomers using the general procedure D. Data for Example
110: LC/MS RT=1.789 min, (M+H)+=455.0; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.69 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0
Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.79-6.73 (m, 2H), 4.60 (s, 2H),
3.81 (s, 2H), 3.77-3.68 (m, 1H), 3.46-3.40 (m, 1H), 3.30-3.26 (m,
1H), 3.21-3.09 (m, 2H), 3.02-2.86 (m, 2H), 2.74-2.51 (m, 1H), 2.06
(s, 3H), 1.90-1.80 (m, 1H).
Example 111
1-(3-Chloro-4-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-
-yl)pyrrolidin-2-one
##STR00325##
[0644] The titled compound of example 110 was prepared as a mixture
of diastereomers using the general procedure D. Data for Example
110: LC/MS RT=1.744 min, (M+H)+=439.0; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta.=7.47-7.41 (m, 1H), 7.28-7.24 (m, 2H),
7.18-7.12 (m, 2H), 6.76 (d, J=9.0 Hz, 2H), 4.52-4.39 (m, 2H), 3.70
(q, J=9.4 Hz, 1H), 3.45-3.37 (m, 1H), 3.30-3.25 (m, 1H), 3.21-3.08
(m, 2H), 3.01-2.85 (m, 2H), 2.69 (d, J=10.5 Hz, 1H), 2.53 (t,
J=11.3 Hz, 1H), 2.30-2.03 (m, 3H), 1.85 (tdd, J=2.3, 4.8, 13.2 Hz,
1H).
Example 112 (Peak-1)
(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenz-
yl)pyrrolidin-2-one
##STR00326##
[0645] and
Example 112 (Peak-2)
(R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenz-
yl)pyrrolidin-2-one
##STR00327##
[0646] Step A.
(S)-3-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-one
##STR00328##
[0648] A stirred solution of commercial
(S)-3-hydroxypyrrolidin-2-one (5 g, 50 mmol) in DCM (198 ml) was
treated with DMAP (0.2 g, 1.63 mmol), imidazole (6.73 g, 99 mmol),
and TBDMS-Cl (8.94 g, 59 mmol). The reaction mixture was stirred at
rt for 16h, and then was washed with a satd. NaHCO.sub.3 solution.
The organic layer was concentrated and the crude reaction product
was purified by silica gel chromatography, eluting with 50% ethyl
acetate in petroleum ether. The desired product was isolated as a
white solid (8.1 g, 76%). LC/MS (M+H)+=216.2; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 6.40 (br. s., 1H), 4.26 (t, J=7.8 Hz, 1H),
3.42-3.34 (m, 1H), 3.29-3.21 (m, 1H), 2.36 (dtd, J=12.7, 7.3, 3.3
Hz, 1H), 2.07-1.96 (m, 1H), 0.91 (s, 9H), 0.15 (d, J=7.0 Hz,
6H).
Step B.
(S)-3-((tert-Butyldimethylsilyl)oxy)-1-(4-methylbenzyl)pyrrolidin--
2-one
##STR00329##
[0650] (S)-3-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-one (5 g,
23.22 mmol) was dissolved in anhydrous THF (46.4 ml) and the
reaction mixture was cooled to 0.degree. C. under a nitrogen
atmosphere. Sodium hydride (1.393 g, 34.8 mmol) was then added in
one portion and the reaction mixture was allowed to stir for 5 min
before the dropwise addition of 1-(bromomethyl)-4-methylbenzene
(5.37 g, 29 mmol) in anhydrous THF (46 ml). The reaction was
allowed to stir at 0.degree. C. for 5 min, then the cooling bath
was removed and mixture was allowed to warm to rt overnight. The
reaction was cautiously quenched with water (100 mL) and then
extracted with ethyl acetate (3.times.100 mL). The combined organic
layers were then washed with brine (200 mL) and dried (MgSO4).
Evaporation of the solvent in vacuo gave the crude product (9.6 g,
oil) which was then purified by silica gel chromatography (330 g of
silica) eluting with a gradient of 0% to 20% ethyl acetate in
hexanes to provide 6.53 g (88%) of the desired product. LC/MS
(Conditions B) RT=4.320 min, (M+H)+=320.3; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.15 (s, 4H), 4.42 (s, 2H), 4.37 (t, J=7.6
Hz, 1H), 3.32-3.18 (m, 1H), 3.10 (dt, J=9.7, 7.5 Hz, 1H), 2.36 (s,
3H), 2.29 (dtd, J=12.6, 7.6, 3.1 Hz, 1H), 1.97-1.84 (m, 1H), 0.95
(s, 9H), 0.20 (d, J=10.3 Hz, 6H).
Step C. (S)-3-Hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one
##STR00330##
[0652] HCl (4 M in 1,4-dioxane, 25.5 ml, 102 mmol) was added in one
portion to a solution of
(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methylbenzyl)pyrrolidin-2-one
(6.53 g, 20.4 mmol) in anhydrous DCM (20.44 ml) at rt. A slight
exotherm was noted. The reaction mixture was allowed to stir at rt
for 2 h and then evaporated in vacuo. The residue was taken up in
DCM (100 mL) and washed with a satd. sodium bicarbonate solution
(100 mL) and brine (50 mL), and then the solution was dried over
MgSO4 and concentrated to a residue. The crude product was purified
by silica gel chromatography (120 g of silica) eluting with a
gradient of 40% to 100% ethyl acetate in hexanes to provide 3.73 g
(89%) of the desired product. LC/MS (Conditions B) RT=2.338 min,
(M+H)+=206.2; .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.26-7.02
(m, 4H), 4.43 (d, J=3.5 Hz, 2H), 4.41-4.37 (m, 1H), 3.66 (d, J=2.6
Hz, 1H), 3.34-3.05 (m, 2H), 2.41 (dddd, J=12.8, 8.4, 6.6, 2.2 Hz,
1H), 2.34 (s, 3H), 1.93 (dq, J=12.8, 8.8 Hz, 1H).
Step D. (S)-1-(4-Methylbenzyl)-2-oxopyrrolidin-3-yl
methanesulfonate
##STR00331##
[0654] Triethylamine (0.51 ml, 3.6 mmol) was added to a cooled
solution of (S)-3-hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one (0.5
g, 2.4 mmol) in anhydrous DCM (12.2 ml) at 0.degree. C. under a
nitrogen atmosphere. Methanesulfonyl chloride (0.2 ml, 2.6 mmol)
was then added dropwise and the reaction was allowed to stir at
0.degree. C. for 15 min before quenching with a satd. sodium
bicarbonate solution (10 mL). The mixture was allowed to warm to rt
and the aqueous layer was separated and extracted with DCM
(2.times.). The combined organic layers were dried over MgSO.sub.4
and evaporated in vacuo to give a white solid (0.73 g) which was
then purified by silica gel chromatography (40 g of silica) eluting
with a gradient of 0% to 50% ethyl acetate in hexanes to provide
0.63 g (91%) of the desired product as a white solid.
Step E. cis-tert-Butyl
4-(4-(benzyloxy)phenyl)-3-fluoro-4-hydroxypiperidine-1-carboxylate
##STR00332##
[0656] To a cloudy solution of tert-butyl
4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate
(Example 50, step C, 2.8 g, 7.7 mmol) in acetonitrile (30 mL) and
water (8 mL) was added 1.2 eq. of Selectfluor at rt. After stirring
at rt for 1 h, another 0.5 eq. of Selectfluor was added, and the
mixture was stirred at 50.degree. C. for 30 min. A saturated
NaHCO.sub.3 solution (100 mL) was added and the mixture was
extracted with 3.times.150 mL of EtOAc. The combined organic layers
were concentrated. The residue was dissolved in 20 mL of
CH.sub.2Cl.sub.2. Triethylamine (3.20 mL, 23 mmol) was added
followed by di-tertbutyldicarbonate (4.45 mL, 19.15 mmol). The
mixture was stirred at rt for 2 h, and then the mixture was
concentrated. The residue was purified via silica gel
chromatography (80 g of silica) eluting with a gradient of 0 to
100% ethyl acetate in hexanes. The first eluting spot was isolated
to give cis-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoro-4-hydroxypiperidine-1-carboxylate
(2.0 g, 5 mmol, 65% yield). LC/MS (Conditions CZ-1,
M-t-butyl+AcCN+H).sup.+=387.2. (M-t-butyl+AcCN)+=369.25. RT 1.392
min; .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.55-7.31 (m, 7H),
7.09-6.90 (m, 2H), 5.09 (s, 2H), 5.05-4.93 (m, 1H), 4.89 (br. s.,
1H), 4.31 (br. s., 1H), 3.92 (br. s., 1H), 3.29 (br. s., 1H),
3.25-3.04 (m, 1H), 2.00-1.86 (m, 1H), 1.83 (br. s., 1H), 1.55-1.45
(m, 9H).
Step F. tert-Butyl
4-(4-(benzyloxy)phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate
##STR00333##
[0658] To a solution of cis-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoro-4-hydroxypiperidine-1-carboxylate
(2.0 g, 5 mmol) in CH.sub.2Cl.sub.2 (25 mL) was added 6 mL of TFA
dropwise at rt. The mixture was stirred at rt for 2 h. Another 8 mL
of TFA was added. After stirring for 1 h, 3 mL more of TFA was
added. The mixture was concentrated to dryness in vacuo at rt, then
10 mL of CH.sub.2Cl.sub.2 and Et.sub.3N (4.2 mL, 30 mmol) were
added followed by bis-(tert)butyldicarbonate (3.5 mL, 15 mmol) and
the resulting mixture was stirred for 16 h. The mixture was
concentrated and directly purified via silica gel chromatography
(40 g of silica) eluting with a gradient of 0-20% ethyl acetate in
hexanes to provide racemic tert-butyl
4-(4-(benzyloxy)phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate
(1.35 g, 3.5 mmol, 70.7% yield), LC/MS (Conditions CZ-1,
M-Boc+AcCN+H)+=325.25. (M-t-butyl+AcCN+H)+=369.25. RT 1.504 min;
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.48-7.38 (m, 6H),
7.38-7.32 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.34-6.16 (m, 1H),
5.45-5.20 (m, 1H), 5.10 (s, 2H), 4.61-4.37 (m, 2H), 3.81 (br. s.,
1H), 3.39-3.24 (m, 1H), 1.59 (s, 3H), 1.52 (s, 9H).
Step G. cis-tert-Butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate
##STR00334##
[0660] To 10% Pd/C (220 mg) under nitrogen was added a soln of
tert-butyl
4-(4-(benzyloxy)-phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate
(1.35 g, 3.5 mmol) in ethyl acetate (20 mL). The mixture was
stirred at rt under a hydrogen atmosphere at balloon pressure for
45 min. The Pd/C was removed by filtration, and the filtrate was
concentrated. The residue was purified via silica gel
chromatography (40 g of silica gel) eluting with a gradient of
0-100% ethyl acetate in hexanes to give the product cis-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (1.05 g,
2.7 mmol, 77% yield). LC/MS (Conditions CZ-1) (M-t-butyl,
AcCN+H)+=371.25. RT=1.504 min; .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.45 (d, J=7.6 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34 (t,
J=7.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 6.96 (ddd, J=8.9, 2.7, 2.0
Hz, 2H), 5.07 (s, 2H), 4.79-4.60 (m, 1H), 4.55-4.23 (m, 2H),
3.08-2.81 (m, 2H), 2.75 (ddd, J=36.0, 13.4, 3.1 Hz, 1H), 2.21 (qd,
J=12.9, 4.3 Hz, 1H), 1.69 (d, J=11.7 Hz, 1H), 1.59 (s, 3H), 1.51
(s, 9H). The structure of this compound was verified by
single-crystal X-ray analysis.
Step H. cis-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidine
##STR00335##
[0662] To a solution of cis-tert-butyl
4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (400 mg,
1.04 mmol) in CH.sub.2Cl.sub.2 (4 mL) was dropwise added TFA (1 mL,
13 mmol) at rt. The mixture was stirred at rt for 2 h and then
concentrated. To the residue was added 50 mL of saturated aqueous
sodium bicarbonate and the mixture was extracted with 3.times.60 mL
of CH.sub.2Cl.sub.2. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to dryness to yield
270 mg cis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (0.95 mmol,
91%). (M+H).sup.+=286.25. .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.49-7.38 (m, 4H), 7.34 (t, J=7.5 Hz, 1H), 7.26-7.20 (m,
J=8.5 Hz, 2H), 7.01-6.93 (m, 2H), 5.08 (s, 2H), 4.70 (d, J=49.0 Hz,
1H), 3.38 (t, J=12.5 Hz, 1H), 3.25 (dt, J=13.4, 2.0 Hz, 1H), 2.93
(d, J=14.3 Hz, 1H), 2.90-2.68 (m, 3H), 2.09 (qd, J=12.9, 4.1 Hz,
1H), 1.69 (d, J=14.3 Hz, 1H).
Step I. cis-4-(3-Fluoropiperidin-4-yl)phenol
##STR00336##
[0664] To 10% Pd/C (40 mg) under nitrogen was added a solution of
cis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (140 mg, 0.49 mmol)
in IPA (4 mL). The mixture was stirred under a hydrogen atmosphere
using balloon pressure at rt for 2 h. The Pd/C was removed by
filtration through a glass fiber filter. The filtrate was
concentrated to give cis-4-(3-fluoropiperidin-4-yl)phenol (90 mg,
0.46 mmol, 94% yield). LC/MS (Method J, M+H).sup.+=196.25, RT=0.706
min; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.14 (d, J=8.4
Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 4.63 (d, J=48.4 Hz, 1H), 3.30-3.22
(m, 1H), 3.15 (dt, J=13.1, 2.0 Hz, 1H), 2.95-2.66 (m, 3H), 2.12
(qd, J=13.0, 4.2 Hz, 1H), 1.64 (dd, J=13.4, 3.0 Hz, 1H).
Step J.
(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-me-
thylbenzyl)pyrrolidin-2-one and
(R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one
##STR00337##
[0666] To a solution of cis-4-(3-fluoropiperidin-4-yl)phenol (60
mg, 0.31 mmol) in 1.0 mL of CH.sub.3CN and DIPEA (0.2 mL, 1.2 mmol)
at 80.degree. C. was added a solution of
(S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (87
mg, 0.3 mmol) in 0.5 mL of CH.sub.3CN over 1.5 h. The mixture was
then stirred at 80.degree. C. for 16 h. The mixture was allowed to
cool to rt and then concentrated. The residue was purified via
silica gel chromatography (4 g of silica) eluting with a gradient
of 0-100% EtOAc in hexanes to give a mixture of two diastereomers,
which were further separated via chiral HPLC under the following
conditions: Chiralcel OD column (21.times.250 mm, 10.mu.) eluting
with an isocratic mixture of 30% B where solvent A=0.1%
diethylamine in n-heptane and solvent B=100% ethanol. The absolute
stereochemistry of the 2 products has not been assigned and is
shown and named for convenience. The first eluting isomer (Example
112, P-1) was
(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one (33.8 mg, 0.086 mmol, 28% yield). .sup.1H NMR
(500 MHz, methanol-d.sub.4) .delta. 7.21-7.07 (m, 6H), 6.78-6.68
(m, 2H), 4.70 (d, J=48.8 Hz, 1H), 4.41 (dd, J=58.0, 14.5 Hz, 2H),
3.61 (t, J=8.8 Hz, 1H), 3.30-3.03 (m, 5H), 2.77-2.60 (m, 1H), 2.51
(t, J=11.1 Hz, 1H), 2.32 (s, 3H), 2.31-2.15 (m, 2H), 2.01 (dq,
J=13.2, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 2.6 Hz, 1H), (M+H)+=383.25.
HPLC RT under separation conditions=8.87 min. The second eluting
isomer (Example 112, P-2) was
(R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylben-
zyl)pyrrolidin-2-one (35.2 mg, 0.084 mmol, 27.3% yield), .sup.1H
NMR (500 MHz, methanol-d.sub.4) .delta. 7.19-7.08 (m, 6H), 6.74 (d,
J=8.4 Hz, 2H), 4.66 (d, J=47.9 Hz, 1H), 4.41 (dd, J=53.7, 14.8 Hz,
2H), 3.58 (t, J=8.8 Hz, 1H), 3.42 (t, J=10.8 Hz, 1H), 3.30-3.14 (m,
2H), 3.05-2.88 (m, 2H), 2.79-2.51 (m, 2H), 2.33 (s, 3H), 2.31-2.13
(m, 2H), 2.06-1.90 (m, 1H), 1.67 (d, J=10.8 Hz, 1H), (M+H)+=383.25.
HPLC RT under separation conditions=11.97 min.
Example 113
1-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperazin-1-yl)pyrrolidin-2-one
##STR00338##
[0668] A mixture of intermediate 1 (150 mg),
4-(piperazin-1-yl)phenol (262 mg), and triethylamine (0.820 mL) in
acetonitrile (10 mL) was heated in a sealed vial at 145.degree. C.
for 1 h. The crude reaction was allowed to cool to rt and was
diluted with dichloromethane (2 mL). The crude mixture was purified
using silica gel column chromatography (50-100% ethyl
acetate/hexanes, then 10% methanol/ethyl acetate) to afford
1-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperazin-1-yl)pyrrolidin-2-one
(300 mg, 54% yield) as a light brown powder. LC/MS (M+H)+=351.3;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H), 7.77-7.56
(m, 2H), 7.47-7.30 (m, 2H), 7.19-7.08 (m, 1H), 6.94 (d, J=8.4 Hz,
2H), 6.70-6.59 (m, 2H), 3.76-3.66 (m, 2H), 3.58 (t, J=9.0 Hz, 1H),
2.95 (d, J=11.1 Hz, 1H), 2.71 (d, J=11.0 Hz, 1H), 2.58-2.52 (m,
1H), 2.38 (d, J=7.0 Hz, 2H), 2.26-2.10 (m, 2H), 2.05-1.95 (m, 1H),
1.54 (t, J=7.9 Hz, 2H), 1.46-1.30 (m, 1H), 1.21-1.02 (m, 2H).
Example 114 (Peak-1)
(R)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)pi-
peridin-1-yl)pyrrolidin-2-one
##STR00339##
[0669] and
Example 114 (Peak-2)
(S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)pi-
peridin-1-yl)pyrrolidin-2-one
##STR00340##
[0670] Step A.
(S)-3-(tert-Butyldimethylsilyloxy)pyrrolidin-2-one
##STR00341##
[0672] 4-Dimethylaminopyridine (0.199 g, 1.63 mmol), imidazole
(6.73 g, 99 mmol) and TBDMS-Cl (20.6 ml, 59.3 mmol) was added to a
stirred solution of (S)-3-hydroxypyrrolidin-2-one (5.0 g, 49.5
mmol) in DCM (198 ml) at RT. The reaction mixture was stirred for
24 h and then diluted with water. The mixture was extracted with
DCM. The combined organic layers were washed with saturated aqueous
sodium bicarbonate solution, dried over sodium sulfate, filtered
and concentrated in vacuo. The crude product was purified using
silica gel column chromatography (50-80% EtOAc/hexanes) to afford
(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (10.4 g, 97%
yield) as a white solid: .sup.1H NMR (500 MHz, chloroform-d)
.delta. 6.15 (br. s., 1H), 4.28 (t, J=7.6 Hz, 1H), 3.40 (dddd,
J=9.7, 8.5, 3.1, 1.2 Hz, 1H), 3.28 (dt, J=9.6, 7.4 Hz, 1H), 2.39
(dtd, J=12.7, 7.3, 3.1 Hz, 1H), 2.10-2.02 (m, 1H), 0.97-0.92 (m,
9H), 0.20-0.14 (m, 6H).
Step B.
(S)-3-(tert-Butyldimethylsilyloxy)-1-(4-(difluoromethyl)benzyl)pyr-
rolidin-2-one
##STR00342##
[0674] A 60% dispersion of sodium hydride in mineral oil (232 mg,
5.31 mmol) was added to a stirred solution of
(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (762 mg, 3.54
mmol) in THF (7 mL) at 0.degree. C. After 15 min, a solution of
1-(bromomethyl)-4-(difluoromethyl)benzene (980 mg, 4.43 mmol) in
THF (7 mL) was added to the reaction mixture. The resulting mixture
was stirred at RT for 6 h. The reaction was quenched with pellets
of ice. The resulting mixture was extracted with EtOAc. The
combined organic layers were washed with water, dried over sodium
sulfate, filtered and concentrated in vacuo. The crude reaction
mixture was purified using silica gel column chromatography (0-30%
EtOAc/hexanes) to afford
(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolid-
in-2-one (440 mg, 35% yield) as a white solid: LCMS (M+H)+356.3;
.sup.1H NMR (500 MHz, chloroform-d) .delta. 7.49 (d, J=8.1 Hz, 2H),
7.35 (d, J=7.9 Hz, 2H), 6.65 (br. t, J=1.0 Hz, 1H), 4.56-4.44 (m,
2H), 4.38 (t, J=7.5 Hz, 1H), 3.27 (ddd, J=9.7, 8.7, 3.4 Hz, 1H),
3.13 (dt, J=9.7, 7.4 Hz, 1H), 2.36-2.27 (m, 1H), 1.98-1.90 (m, 1H),
0.96 (br. s., 9H), 0.22-0.20 (m, 3H), 0.20-0.18 (m, 3H).
Step C.
(S)-1-(4-(Difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one
##STR00343##
[0676] A solution of 4 M HCl in dioxane (0.62 mL, 2.5 mmol) was
added to a stirred solution of
(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolid-
in-2-one (440 mg, 1.24 mmol) in dichloromethane (1.24 mL) at RT.
The reaction mixture was stirred for 2 h. The reaction mixture was
concentrated in vacuo to afford
(S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg,
quantitative yield): LC-MS (M+H)+242.1.
Step D. (S)-1-(4-(Difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl
methanesulfonate
##STR00344##
[0678] Triethylamine (0.319 mL, 2.29 mmol) and methansulfonyl
chloride (0.131 mL, 1.68 mmol) was added to a stirred solution of
(S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg,
1.53 mmol) in dichloromethane (7.63 mL) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 1 h. The resulting
mixture was diluted with water and the aqueous mixture was
extracted with dichloromethane. The combined organic layers were
washed with 10% sodium bicarbonate solution, dried over sodium
sulfate, filtered, and concentrated in vacuo. The crude material
was purified using silica gel column chromatography (0-100% EtOAc).
The pure fractions were combined and concentrated in vacuo to
afford 1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl
methanesulfonate (322 mg, 66% yield) as a white solid: LC-MS
(M+H)+320.1; .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.53 (d,
J=7.9 Hz, 2H), 7.38-7.33 (m, 2H), 6.67 (br. t, J=1.0 Hz, 1H), 5.27
(dd, J=8.2, 7.5 Hz, 1H), 4.60-4.49 (m, 2H), 3.41-3.35 (m, 1H), 3.33
(s, 3H), 3.27 (dt, J=9.9, 7.3 Hz, 1H), 2.64-2.55 (m, 1H), 2.27
(ddt, J=13.9, 8.9, 7.1 Hz, 1H).
Step E.
(R)-1-(4-(Difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyp-
henyl)piperidin-1-yl)pyrrolidin-2-one (Peak 1) and
(S)-1-(4-(Difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)p-
iperidin-1-yl)pyrrolidin-2-one (Peak 2)
##STR00345##
[0680] A solution of
(S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl
methanesulfonate (500 mg, 1.57 mmol) in 5.0 mL of acetonitrile was
added dropwise over 1.5 h to a stirred mixture of
4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg,
1.57 mmol, from example 46, step M) and N,N-diisopropylethylamine
(1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at
85.degree. C. After complete addition, the reaction mixture was
stirred at 85.degree. C. for 16 h. The resulting mixture was
concentrated in vacuo. The residue was purified using silica gel
column chromatography (0-100% EtOAc/hexanes) to afford a
diastereomeric mixture of
1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piper-
idin-1-yl)pyrrolidin-2-one (235 mg, 35% yield) due to partial
epimerization. A sample of the diastereomeric mixture (780 mg) was
separated by preparative chiral SFC (column=Lux Cellulose-2
(21.times.250 mm, 5 .mu.m); isocratic solvent=20% methanol (with 15
mM ammonia)/80% CO.sub.2; temp=35.degree. C.; flow rate=60 mL/min;
injection volume=1.0 mL (.about.20 mg/mL in MeOH) stacked @ 13 min
intervals; .lamda.=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to
afford 389 mg of Example 114, P-1 and 242 mg of Example 114, P-2.
Data for Example 114, P-1: LC-MS m/z 419.3 (M+H.sup.+); .sup.1H NMR
(500 MHz, chloroform-d) .delta. 7.50 (d, J=7.9 Hz, 2H), 7.34 (d,
J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t,
J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz,
1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H),
2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H),
2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m,
2H)). The relative and absolute configuration of Example 114, P-1
was confirmed by single crystal X-ray analysis. Data for Example
114, P-2: LC-MS m/z 419.3 (M+H.sup.+); .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.50 (d, J=7.9 Hz, 2H), 7.35 (d, J=7.9 Hz,
2H), 7.15 (d, J=8.4 Hz, 2H), 6.87-6.81 (m, 2H), 6.65 (t, J=56.5 Hz,
1H), 4.95 (s, 1H), 4.74-4.42 (m, 3H), 3.66 (t, J=8.9 Hz, 1H),
3.28-3.15 (m, 3H), 3.07-2.99 (m, 1H), 2.72-2.58 (m, 2H), 2.49-2.40
(m, 1H), 2.20-2.12 (m, 1H), 2.04 (dq, J=13.0, 8.7 Hz, 1H),
1.93-1.87 (m, 2H).
Example 115
(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(4-m-
ethylbenzyl)pyrrolidin-2-one
##STR00346##
[0681] Step A. tert-Butyl
4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00347##
[0683] A solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.0 g,
17.8 mmol) and tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (6.60 g, 21.3 mmol) in acetonitrile (50 mL) was
degassed for 5 min. To this was added water (50 mL),
Na.sub.2CO.sub.3 (5.66 g, 53.4 mmol) and Pd(Ph.sub.3P).sub.4 (1.23
g, 1.07 mmol) and the reaction was further degassed for 10 min. It
was then heated to 80.degree. C. for 16 h. The reaction cooled to
rt, poured into water, and extracted with EtOAc. The combined
organic layers were, dried with magnesium sulfate, filtered through
celite, and concentrated in vacuo to afford a brown oil. The oil
was purified using silica gel column chromatography (0-30%
EtOAc/hexanes) to afford 1-butyl
4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate
(5.63 g, 83% yield): LC-MS [M+H].sup.+-tBu+ACN=369.2; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.51-7.27 (m, 6H), 7.25-7.13 (m,
2H), 6.12 (br. s., 1H), 5.19 (s, 2H), 3.97 (br. s., 2H), 3.51 (t,
J=5.6 Hz, 2H), 2.41 (d, J=1.5 Hz, 2H), 1.42 (s, 9H).
Step B. (.+-.)-rel-(3R,4R)-tert-Butyl
4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate
##STR00348##
[0685] To sodium borohydride (2.282 g, 60.3 mmol) in THF (81 ml) at
0.degree. C. was added boron trifluoride diethyl etherate (9.86 ml,
78 mmol) dropwise via addition funnel. The ice bath was removed and
the solution was allowed to warm to rt and stir for 1 h. The
reaction was chilled to 0.degree. C., then tert-butyl
4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate
(7.46 g, 19.5 mmol) in THF (8.11 ml) was added dropwise via
additional funnel. After complete addition, the reaction was
allowed to warm to rt and was stirred for 2 h. The reaction was
cooled to 0.degree. C. and quenched with water (16.2 ml) until the
effervescence subsided. To this mixture was sequentially added
aqueous 10% sodium hydroxide (14.2 ml, 38.9 mmol), aqueous 30%
hydrogen peroxide (13.91 ml, 136 mmol) and EtOH (16.2 ml). The
resulting mixture was stirred at rt for 16 h. The mixture was
diluted with ice water and extracted with dichloromethane. The
combined organic layers were dried with magnesium sulfate,
filtered, and concentrated in vacuo to afford
(.+-.)-rel-(3R,4R)-tert-butyl
4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate
(7.32 g, 94% yield) as a white solid: LC-MS [M+H]+=328.2; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.53-7.28 (m, 5H), 7.18-7.07
(m, 2H), 6.97 (d, J=8.2 Hz, 1H), 5.14 (s, 2H), 4.82 (d, J=5.6 Hz,
1H), 4.10 (br. s., 1H), 3.95 (br. s., 1H), 3.40 (tt, J=10.2, 5.2
Hz, 1H), 2.81-2.60 (m, 1H), 2.46-2.35 (m, 1H), 1.66 (dd, J=13.4,
3.1 Hz, 1H), 1.59-1.46 (m, 1H), 1.42 (s, 9H).
Step C. (3R,4R)-tert-Butyl
4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate
and (3S,4S)-tert-Butyl
4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate
##STR00349##
[0687] (.+-.)-rel-(3R,4R)-tert-Butyl
4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate
(17.1 g, from step B) was subjected to chiral SFC separation
(column=Chiralpak AD-H; isocratic solvent=30% methanol/70%
CO.sub.2; temp=40.degree. C.; flow rate=3 mL/min; .lamda.=220 nM;
Peak 1 (E-1)=3.8 min, Peak 2 (E-2)=7.7 min) to yield enantiomers
E-1 (7.2 g, 42% yield) and E-2 (7.5 g, 44% yield). Data for E-1:
LC-MS [M+H]+-t-Bu=346.1; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.52-7.26 (m, 5H), 7.18-7.06 (m, 2H), 6.97 (d, J=8.4 Hz,
1H), 5.14 (s, 2H), 4.81 (d, J=5.6 Hz, 1H), 4.09 (br. s., 1H), 3.95
(br. s., 1H), 3.39 (td, J=10.3, 5.3 Hz, 1H), 2.47-2.30 (m, 3H),
1.72-1.62 (m, 1H), 1.59-1.45 (m, 1H), 1.42 (s, 9H). Data for E-2:
LC-MS [M+H]+-t-Bu=346.1; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 7.52-7.27 (m, 5H), 7.19-7.06 (m, 2H), 6.97 (dd, J=8.4, 1.1
Hz, 1H), 5.14 (s, 2H), 4.81 (d, J=5.6 Hz, 1H), 4.10 (br. s., 1H),
3.95 (br. s., 1H), 3.49-3.35 (m, 1H), 2.46-2.33 (m, 3H), 1.72-1.63
(m, 1H), 1.59-1.46 (m, 1H), 1.46-1.32 (m, 9H).
Step D. (3S,4S)-tert-Butyl
4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate
##STR00350##
[0689] To (3S,4S)-tert-butyl
4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate
(4.0 g, 9.96 mmol, E-2 from step C) in degassed MeOH (100 mL) was
added 10% Pd/C (0.191 g, 1.79 mmol) and the reaction was repeated
evacuated and flushed with hydrogen gas. Then placed under 1 atm of
hydrogen for 4 h. The reaction solution was purged with nitrogen
and filtered through celite. The filtrated was concentrated to
afford (3S,4S)-tert-butyl
4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate
(2.99 g, 96% yield) as a grey oil. LC-MS [M+H].sup.+-tBu=256.05;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.03-6.95 (m, 1H),
6.89-6.78 (m, 2H), 4.78 (d, J=4.6 Hz, 1H), 4.09 (br. s., 2H), 3.94
(br. s., 1H), 3.36 (dd, J=9.5, 4.7 Hz, 1H), 3.17 (s, 1H), 2.80-2.58
(m, 1H), 2.42-2.27 (m, 1H), 1.65 (dd, J=13.4, 3.4 Hz, 1H),
1.56-1.33 (m, 10H).
Step E. (3S,4S)-tert-Butyl
3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate
##STR00351##
[0691] To (3S,4S)-tert-butyl
4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate
(2.99 g, 9.60 mmol) in DCM (75 mL) at 0.degree. C. was added DAST
(6.34 mL, 48.0 mmol) dropwise. The reaction was then allowed to
warm to room temperature and stir for 2 h. The reaction was slowly
quenched with ice water. The reaction was then extracted with
dichloromethane, washed with additional water, dried with magnesium
sulfate, filtered and concentrated in vacuo to afford
(3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.88
g, quantitative yield) as a yellow viscous oil: LC-MS [M-H]+312.2;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.22-7.10 (m, 1H),
7.00-6.76 (m, 3H), 5.76 (s, 2H), 4.60 (td, J=10.1, 5.2 Hz, 1H),
4.50 (td, J=10.1, 5.2 Hz, 1H), 4.27 (br. s., 1H), 4.07-3.78 (m,
2H), 3.66-3.50 (m, 1H), 3.00-2.65 (m, 4H), 1.81-1.69 (m, 1H),
1.63-1.50 (m, 1H), 1.46-1.30 (m, 14H), 1.20-1.01 (m, 2H).
Step E. (3S,4S)-tert-Butyl
3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate
##STR00352##
[0693] To (3S,4S)-tert-butyl
3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.01
g, 9.61 mmol) in dioxane (10 mL) was added HCl (4 M in Dioxane) (24
mL, 96 mmol) and the reaction was allowed to stir at room
temperature for 5 h. The reaction was concentrated to an oil. The
oil was taken up in saturated aqueous sodium bicarbonate and
extracted with EtOAc/5% MeOH. The combined organic layers were
concentrated in vacuo to afford
2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (2.15 g,
quantitative yield): LC-MS [M+H]+=214.1; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 6.93 (d, J=12.4 Hz, 1H), 6.85-6.72 (m, 2H),
4.49 (td, J=9.9, 4.9 Hz, 1H), 4.39 (td, J=10.0, 5.0 Hz, 1H),
3.27-3.19 (m, 3H), 2.85 (d, J=11.4 Hz, 2H), 2.62-2.54 (m, 2H),
2.46-2.37 (m, 4H), 1.76-1.64 (m, 2H), 1.57-1.37 (m, 3H).
Step F. (R)-3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)
piperidin-1-yl)-1-(4-methylbenzyl) pyrrolidin-2-one
##STR00353##
[0695] A solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl
methanesulfonate (0.106 g, 0.375 mmol, from example 112, step D) in
acetonitrile (1 mL) was added to a mixture of
2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.04 g, 0.188
mmol, from step E) and DIPEA (0.098 mL, 0.563 mmol) in acetonitrile
(2 mL) heated at 80.degree. C. The reaction mixture was then
stirred at 80.degree. C. for 16 h. The mixture was allowed to cool
to rt and then concentrated in vacuo. The residue was purified
using preparative LC/MS (Waters XBridge C18, 19.times.150 mm, 5
.mu.m; Guard Column: Waters XBridge C18, 19.times.10 mm, 5 .mu.m;
Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH.sub.4OAc;
Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH.sub.4OAc;
Gradient: 15-60% B over 25 min, followed by a 10 min hold at 60% B
and 5 min hold at 100% B; Flow: 15 mL/min). Fractions containing
the desired product were combined concentrated in vacuo using a
Genevac centrifugal evaporator to the titled compound of Example
115 (31 mg, 0.077 mmol, 41% yield) as pale yellow solid. LC-MS
(M+H).sup.+401; .sup.1H NMR: (400 MHz, DMSO-d.sub.6) d=7.19-7.06
(m, 5H), 6.95-6.84 (m, 2H), 4.70-4.48 (m, 1H), 4.41-4.24 (m, 2H),
3.55 (s, 1H), 3.48-3.29 (m, 3H), 2.76-2.63 (m, 2H), 2.62-2.52 (m,
1H), 2.28 (s, 4H), 2.16-2.03 (m, 1H), 1.89 (s, 3H), 1.79-1.54 (m,
2H).
Example 116
(R)-1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)pip-
eridin-1-yl)pyrrolidin-2-one
##STR00354##
[0696] Step A.
(S)-3-(tert-Butyldimethylsilyloxy)-1-(4-chlorobenzyl)pyrrolidin-2-one
##STR00355##
[0698] A 60% dispersion of sodium hydride in mineral oil (0.608 g,
13.9 mmol) was added to a stirred solution of
(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (2.0 g, 9.29
mmol, from example 114, step A) in THF (7 mL) at 0.degree. C. After
15 min, a solution of 1-(bromomethyl)-4-chlorobenzene (1.72 g, 8.37
mmol) in THF (7 mL) was added to the reaction mixture. The
resulting mixture was stirred at RT for 6 h. The reaction was
quenched with pellets of ice. The resulting mixture was extracted
with EtOAc. The combined organic layers were washed with water,
dried over sodium sulfate, filtered and concentrated in vacuo. The
crude reaction mixture was purified using silica gel column
chromatography (0-15% EtOAc/hexanes) to afford
(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one
(1.34 g, 42% yield): LCMS (M+H).sup.+340.2; .sup.1H NMR (500 MHz,
chloroform-d) .delta. .sup.1H NMR (500 MHz, chloroform-d) .delta.
7.36-7.29 (m, J=8.4 Hz, 2H), 7.23-7.16 (m, J=8.4 Hz, 2H), 4.51-4.33
(m, 3H), 3.31-3.22 (m, 1H), 3.11 (dt, J=9.7, 7.4 Hz, 1H), 2.37-2.25
(m, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H), 0.21 (s, 3H), 0.18 (s,
3H).
Step B. (S)-1-(4-Chlorobenzyl)-3-hydroxypyrrolidin-2-one
##STR00356##
[0700] A solution of 4 M HCl in dioxane (4.93 ml, 19.7 mmol) was
added to a stirred solution of
(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one
(1.34 g, 3.94 mmol) in dichloromethane (4 mL) at RT. The reaction
mixture was stirred for 2 h. The reaction mixture was concentrated
in vacuo to afford (S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one
(910 mg, 4.03 mmol, quantitative yield): LC-MS (M+H).sup.+226.1;
.sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.37-7.33 (m, J=8.5
Hz, 2H), 7.27-7.23 (m, J=8.5 Hz, 2H), 4.52-4.37 (m, 2H), 4.34 (t,
J=8.2 Hz, 1H), 3.30-3.18 (m, 2H), 1.84 (dq, J=12.8, 8.5 Hz,
1H).
Step C. (S)-1-(4-Chlorobenzyl)-2-oxopyrrolidin-3-yl
methanesulfonate
##STR00357##
[0702] Triethylamine (0.825 mL, 5.92 mmol) and methansulfonyl
chloride (0.338 mL, 4.34 mmol) was added to a stirred solution of
(S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (890 mg, 3.94
mmol) in dichloromethane (20 mL) at 0.degree. C.
[0703] The reaction mixture was stirred at 0.degree. C. for 1 h.
The resulting mixture was diluted with water and the aqueous
mixture was extracted with dichloromethane. The combined organic
layers were washed with 10% sodium bicarbonate solution, dried over
sodium sulfate, filtered, and concentrated in vacuo. The crude
material was purified using silica gel column chromatography
(0-100% EtOAc). The pure fractions were combined and concentrated
in vacuo to afford (S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl
methanesulfonate (1.1 g, 3.62 mmol, 92% yield) as a white solid:
LC-MS (M+H)+304.1; .sup.1H NMR (500 MHz, chloroform-d) .delta.
7.38-7.33 (m, 2H), 7.22-7.17 (m, 2H), 5.25 (dd, J=8.2, 7.6 Hz, 1H),
4.52-4.41 (m, 2H), 3.40-3.31 (m, 4H), 3.25 (dt, J=10.0, 7.3 Hz,
1H), 2.58 (dddd, J=13.7, 8.4, 7.5, 3.3 Hz, 1H), 2.33-2.20 (m,
1H).
Step D. (S)-1-(4-Chlorobenzyl)-2-oxopyrrolidin-3-yl
methanesulfonate
##STR00358##
[0705] To a solution of
2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (1.0 g, 4.7 mmol,
from example 114, step E) in acetonitrile (25 mL) was added
diisopropylethylamine (2.5 mL, 14 mmol) and it was heated to
60.degree. C. for 30 min. To this preheated mixture was then added
(S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.710
g, 5.63 mmol, from step C) in acetonitrile (15 mL). The reaction
mixture was heated at 90.degree. C. for 16 h. The reaction was
diluted with sat. aqueous sodium bicarbonate and extracted with
EtOAc. The organic layers were combined and concentrated to a black
oil. The oil was purified using silica gel column chromatography
(20-100% EtOAc/hexanes then 0-20% MeOH/dichloromethane) to afford
1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperi-
din-1-yl)pyrrolidin-2-one (752 mg, 38% yield). Chiral HPLC analysis
revealed that the final product was a (3:1) mixture of
diastereoisomers, due to partial epimerization. The diastereomeric
mixture (750 mg) was separated by preparative chiral SFC
(column=Lux Cellulose-2 (21.times.250 mm, 5 .mu.m); isocratic
solvent=35% methanol in CO.sub.2, 150 bar; temp=35.degree. C.; flow
rate=40 mL/min; injection volume=0.75 mL (.about.42 mg/mL in MeOH)
stacked intervals; .lamda.=220 nM; Peak 1=5.5 min, Peak 2=7.9 min)
to afford the titled compound (482 mg) of Example 116 (the second
peak to elute). Data for Example 116: LC-MS m/z 421 (M+H.sup.+);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.63 (s, 1H), 7.42 (d,
J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.17-7.03 (m, 1H), 6.88 (s,
2H), 4.78-4.46 (m, 1H), 4.38 (d, J=11.5 Hz, 2H), 3.70-3.48 (m, 1H),
3.45-3.37 (m, 1H), 3.28-3.03 (m, 2H), 2.82-2.63 (m, 2H), 2.61-2.53
(m, 1H), 2.40-2.21 (m, 1H), 2.18-2.02 (m, 1H), 1.98-1.84 (m, 1H),
1.82-1.50 (m, 2H).
Example 117 (Peak-1)
(S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxy-
phenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00359##
[0706] and
Example 117 (Peak-2)
(R)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxy-
phenyl)piperidin-1-yl)pyrrolidin-2-one
##STR00360##
[0708] A stirred mixture of
3-bromo-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (100 mg, 0.328
mmol, intermediate 2a),
2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (70 mg, 0.328
mmol, from example 114, step E), and triethylamine (0.137 mL, 0.985
mmol) in acetonitrile (2 mL) was heated at 120.degree. C. in a CEM
microwave for one hour. The reaction mixture was diluted with water
and extracted with ethyl acetate (100 mL). The organic layer was
washed with brine solution, dried over sodium sulfate, and
evaporated under reduced pressure to give a crude residue. The
crude residue was purified via preparative LC/MS (column: Waters
Xbridge C18, 19.times.150 mm, 5 .mu.m; guard column: Waters XBridge
C18, 19.times.10 mm, 5 .mu.m; mobile phase A: 5:95 methanol:water
with 10 mM NH.sub.4OAc; mobile Phase B: 95:5 methanol:water with 10
mM NH4OAc; Gradient: 15-50% B over 25 min, followed by a 10 min
hold at 50% B and 5 min hold at 100% B; flow: 15 ml/min) to afford
1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphe-
nyl)piperidin-1-yl)pyrrolidin-2-one (68 mg, 46%). The
diastereomeric mixture was separated by preparative chiral SFC
(column=Chiralpak AD-H (250 mm.times.21 mm, 5 .mu.m); isocratic
solvent=40% methanol (w/0.25% DEA) in CO.sub.2, 100 bar;
temp=25.degree. C.; flow rate=75 g/min; injection volume=1.1 mL (6
mg/mL in MeOH); .lamda.=220 nM; Peak 1=3.2 min, Peak 2=5.0 min) to
afford the titled compounds of example 117 (18 mg of peak-1, and 20
mg of peak-2). Data for example 117, P-1: LC-MS m/z 437 (M+H)+;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.55 (d, J=8.03
Hz, 2H) 7.42 (s, 2H) 6.97-7.04 (m, 1H) 6.62-6.95 (m, 3H) 4.48-4.68
(m, 3H) 3.76 (t, J=8.78 Hz, 1H) 3.50 (dt, J=3.31, 1.64 Hz, 0H)
3.25-3.31 (m, 0H) 3.11-3.18 (m, 0H) 2.99-3.05 (m, 0H) 2.41-2.71 (m,
3H) 2.16-2.26 (m, 1H) 2.08 (dq, J=12.91, 8.79 Hz, 1H) 1.78-1.91 (m,
2H). Data for example 117, P-2: LC-MS m/z 437 (M+H)+; .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. ppm 7.55 (d, J=8.03 Hz, 2H)
7.41 (d, J=8.28 Hz, 2H) 7.00 (dd, J=12.39, 1.91 Hz, 1H) 6.62-6.93
(m, 3H) 4.47-4.70 (m, 3H) 3.69-3.77 (m, 1H) 3.38-3.55 (m, 1H)
3.24-3.30 (m, 1H) 3.15 (dt, J=3.31, 1.64 Hz, 1H) 2.74-2.83 (m, 2H)
2.52-2.72 (m, 2H) 2.44 (td, J=10.02, 4.80 Hz, 1H) 2.03-2.27 (m, 2H)
1.76-1.90 (m, 2H).
Biological Methods
[0709] Radioligand Binding Assay.
[0710] Binding experiments to determine binding to NR2B-subtype
NMDA receptors were performed on forebrains of 8-10 weeks old male
Sprague Dawley rats (Harlan, Netherlands) using .sup.3H Ro 25-6981
(Mutel V; Buchy D; Klingelschmidt A; Messer J; Bleuel Z; Kemp J A;
Richards J G. Journal of Neurochemistry, 1998, 70(5):2147-2155.
Rats were decapitated without anesthesia using a Guillotine
(approved by animal ethics committee) and the harvested brains were
snap-frozen and stored at -80.degree. C. for 3-6 months for
membrane preparation.
[0711] For membrane preparation, rat forebrains were thawed on ice
for 20 minutes in homogenization buffer composed of 50 mM
KH.sub.2PO.sub.4 (pH adjusted to 7.4 with KOH), 1 mM EDTA, 0.005%
Triton X 100 and protease inhibitor cocktail (Sigma Aldrich).
Thawed brains were homogenized using a Dounce homogenizer and
centrifuged at 48000.times.g for 20 min. The pellet was resuspended
in cold buffer and homogenized again using a Dounce homogenizer.
Subsequently, the homogenate was aliquoted, snap-frozen and stored
at -80.degree. C. for not more than 3-4 months.
[0712] To perform the competition binding assay, thawed membrane
homogenate was added to each well of a 96-well plate (20
.mu.g/well). The experimental compounds were serially diluted in
100% DMSO and added to each row of the assay plate to achieve
desired compound concentrations, keeping the DMSO concentration in
the assay plate at 1.33% of the final reaction volume. Next,
.sup.3H Ro 25-6981 (4 nM) was added to the assay plate. After
incubation for 1 hr at room temperature, the membrane bound
radioligand was harvested on to GF/B filter plates (treated with
0.5% PEI for 1 hr at room temperature). The filter plates were
dried at 50.degree. C. for 20 mins, incubated with microscint 20
for 10 minutes and finally, the counts were read on TopCount
(Perkin Elmer). Non-specific binding was determined using MK-0657
(the preparation of this compound is described as example 1 in WO
2004 108705 (40 .mu.M). CPM values were converted to % inhibition
and the concentration response curves were plotted using custom
made software. Each experiment was repeated at least twice to
obtain the final binding K.sub.1 values for experimental compounds.
Using this assay, the compound of example 1 shows a binding Ki of 4
nM.
TABLE-US-00003 NR2B Binding Example Structure Ki, nM 1 ##STR00361##
3 2a ##STR00362## 740 2b ##STR00363## 1.4 3 ##STR00364## 1320 4
##STR00365## 5000 5 ##STR00366## 4.4 6a ##STR00367## 850 6b
##STR00368## 4.7 7 ##STR00369## 37 8 ##STR00370## 420 9a
##STR00371## 180 9b ##STR00372## 1400 9c ##STR00373## 5000 9d
##STR00374## 160 10 ##STR00375## 1020 11 ##STR00376## 510 12
##STR00377## 4 13a ##STR00378## 41 13b ##STR00379## 1.6 14
##STR00380## 15 ##STR00381## 12 16 ##STR00382## 560 17 ##STR00383##
1.6 18a ##STR00384## 170 18b ##STR00385## 1.5 19 ##STR00386## 3.9
20 ##STR00387## 43 21a ##STR00388## 37 21b ##STR00389## 410 22
##STR00390## 2.9 23a ##STR00391## 11 23b ##STR00392## 1.4 24
##STR00393## 4.7 25a ##STR00394## 1200 25b ##STR00395## 5.3 26
##STR00396## 31 27 ##STR00397## 20 28a ##STR00398## 420 28b
##STR00399## 10 29 ##STR00400## 78 30 ##STR00401## 4.7 31
##STR00402## 800 32 ##STR00403## 100 33a ##STR00404## 5000 33b
##STR00405## 44 34 ##STR00406## 670 35 ##STR00407## 17 36
##STR00408## 34 37 ##STR00409## 21 38 ##STR00410## 150 39
##STR00411## 300 40 ##STR00412## 480 41a ##STR00413## 990 41b
##STR00414## 200 42 ##STR00415## 720 43 ##STR00416## 150 44, E-1
##STR00417## 650 44, E-2 ##STR00418## 5.7 45, P-1 ##STR00419## 260
45, P-2 ##STR00420## 3.1 45, P-3 ##STR00421## 380 45, P-4
##STR00422## 2.5 46, P-1 ##STR00423## 430 46, P-2 ##STR00424## 4.3
46, P-3 ##STR00425## 340 46, P-4 ##STR00426## 4.0 47, P-1
##STR00427## 470 47, P-2 ##STR00428## 470 47, P-3 ##STR00429## 3.8
47, P-4 ##STR00430## 3.4 48, P-1 ##STR00431## 760 48, P-2
##STR00432## 1700 48, P-3 ##STR00433## 11 48, P-4 ##STR00434## 13
49, P-1 ##STR00435## 420 49, P-2 ##STR00436## 73 50, P-1
##STR00437## 5000 50, P-2 ##STR00438## 890 50, P-3 ##STR00439##
5000 50, P-4 ##STR00440## 1300 51, P-1 ##STR00441## 660 51, P-2
##STR00442## 7.6 51, P-3 ##STR00443## 30 51, P-4 ##STR00444## 11
52, P-1 ##STR00445## 690 52, P-2 ##STR00446## 6.2 52, P-3
##STR00447## 89 52, P-4 ##STR00448## 6.7 53, P-1 ##STR00449## 1100
53, P-2 ##STR00450## 5.8 54, P-1 ##STR00451## 530 54, P-2
##STR00452## 8.5 54, P-3 ##STR00453## 110 54, P-4 ##STR00454## 26
55, P-1 ##STR00455## 280 55, P-2 ##STR00456## 32 55, P-3
##STR00457## 130 55, P-4 ##STR00458## 430 56, P-1 ##STR00459## 5000
56, P-2 ##STR00460## 1400 56, P-3 ##STR00461## 5000 56, P-4
##STR00462## 660 57 ##STR00463## 490 58 ##STR00464## 8.7 59
##STR00465## 81 60 ##STR00466## 110 61 ##STR00467## 46 62
##STR00468## 6.7 63 ##STR00469## 10 64 ##STR00470## 490 65
##STR00471## 3.6 66 ##STR00472## 1500 67 ##STR00473## 6.5 68
##STR00474## 710 69 ##STR00475## 34 70 ##STR00476## 180 71
##STR00477## 560 72 ##STR00478## 6.0 73 ##STR00479## 330 74
##STR00480## 680 75 ##STR00481## 8.0 76 ##STR00482## 33
77 ##STR00483## 27 78 ##STR00484## 190 79 ##STR00485## 40 80
##STR00486## 560 81 ##STR00487## 3.8 82 ##STR00488## 860 83
##STR00489## 5.0 84 ##STR00490## 950 85 ##STR00491## 23 86
##STR00492## 78 87 ##STR00493## 540 88 ##STR00494## 5.3 89
##STR00495## 200 90 ##STR00496## 77 91, P-1 ##STR00497## 76 91, P-2
##STR00498## 14 92 ##STR00499## 59 93 ##STR00500## 67 94
##STR00501## 390 95, P-1 ##STR00502## 54 95, P-2 ##STR00503## 12
96, P-1 ##STR00504## 490 96, P-2 ##STR00505## 18 97 ##STR00506## 45
98 ##STR00507## 230 99, P-1 ##STR00508## 380 99, P-2 ##STR00509##
22 100 ##STR00510## 570 101, P-1 ##STR00511## 13 101, P-2
##STR00512## 11 102, P-1 ##STR00513## 740 102, P-2 ##STR00514## 30
103 ##STR00515## 81 104 ##STR00516## 130 105 ##STR00517## 180 106,
P-1 ##STR00518## 990 106, P-2 ##STR00519## 4.6 107, P-1
##STR00520## 1200 107, P-2 ##STR00521## 7.7 108, P-1 ##STR00522##
1200 108, P-2 ##STR00523## 15 109 ##STR00524## 290 110 ##STR00525##
36 111 ##STR00526## 590 112, P-1 ##STR00527## 4.4 112, P-2
##STR00528## 8.4 113 ##STR00529## 33 114, P-1 ##STR00530## 3.5 114,
P-2 ##STR00531## 180 115 ##STR00532## 2.7 116 ##STR00533## 2.0 117,
P-1 ##STR00534## 79 117, P-2 ##STR00535## 2.9
[0713] Ex Vivo Occupancy Assay.
[0714] This assay demonstrates that the compound of example 1
occupies brain-resident NR2B-subtype receptors in animals after
dosing. 7-9 weeks old male CD-1 mice were dosed intravenously in a
vehicle consisting of 10% dimethylacetamide, 40% PEG-400, 30%
hydroxypropyl betacyclodextrin, and 30% water with experimental
compounds and the forebrains were harvested 15 minutes post-dosing
by decapitation. The brain samples were immediately snap-frozen and
stored at -80.degree. C. On the following day, the dosed brain
samples were thawed on ice for 15-20 minutes followed by
homogenization using Polytron for 10 seconds in cold homogenization
buffer composed of 50 mM KH.sub.2PO.sub.4 (pH adjusted to 7.4 with
KOH), 1 mM EDTA, 0.005% Triton X 100 and protease inhibitor
cocktail (Sigma Aldrich). The crude homogenates were further
homogenized using a Dounce homogenizer and the homogenized membrane
aliquots from all animals were flash-frozen and stored at
-80.degree. C. until further use. The whole homogenization process
was performed on ice.
[0715] For determining occupancy, the membrane homogenates were
first thawed on ice and then needle-homogenized using a 25 gauge
needle. The homogenized membrane (6.4 mg/ml) was added to a 96-well
plate followed by addition of .sup.3H Ro 25-6981 (6 nM). The
reaction mixture was incubated for 5 minutes on a shaker at
4.degree. C. and then harvested onto GF/B filter plates (treated
with 0.5% PEI for 1 hr at room temperature). The filter plates were
dried at 50.degree. C. for 20 mins, incubated with microscint 20
for 10 minutes and read on TopCount (Perkin Elmer). Each dose or
compound group consisted of 4-5 animals. The control group of
animals was dosed with vehicle alone. Membrane from each animal was
added in triplicates to the assay plate. Non-specific binding was
determined using 10 .mu.M Ro 25-6981 added to the wells containing
membrane homogenates from vehicle-dosed animals. Specific
counts/minute was converted to % occupancy at each dose of a
compound for each animal using the following equation:
% Occupancy ( animal A ) = 100 - ( specific CPM of animal A Average
CPM from control group .times. 100 ) ##EQU00001##
Using this procedure, the compound of example 46, P-4 shows 95%
NR2B receptor occupancy after a 3 mg/Kg i.v. dose. Drug levels were
determined by mass spectroscopy in the usual manner. Drug levels in
the blood plasma were 1106 nM in at this dose, and drug levels in
the homogonized brain tissue were 1984 nM. The compound of example
114, P-1 showed 97% NR2B receptor occupancy after a 3 mg/Kg i.v.
dose. Drug levels in the blood plasma were 1800 nM in at this dose,
and drug levels in the homogonized brain tissue were 2200 nM.
[0716] hERG Electrophysiology Assay.
[0717] The experimental compounds were assessed for hERG activity
on HEK 293 cells stably expressing hERG channels using patch clamp
technique. Coverslips plated with hERG expressing cells were placed
in the experimental chamber and were perfused with a solution
composed of (in mM): 140 NaCl, 4 KCl, 1.8 CaCl.sub.2, 1 MgCl.sub.2,
10 Glucose, 10 HEPES (pH 7.4, NaOH) at room temperature.
Borosilicate patch pipettes had tip resistances of 2-4 Mohms when
filled with an internal solution containing: 130 KCl, 1 MgCl.sub.2,
1 CaCl.sub.2, 10 EGTA, 10 HEPES, 5 ATP-K.sub.2 (pH 7.2, KOH). The
cells were clamped at -80 mV in whole cell configuration using an
Axopatch 200B (Axon instruments, Union City, Calif.) patch clamp
amplifier controlled by pClamp (Axon instruments) software. Upon
formation of a gigaseal, the following voltage protocol was
repeatedly (0.05 Hz) applied to record tail currents:
depolarization step from -80 mV to +20 mV for 2 seconds followed by
a hyperpolarization step to -65 mV (3 seconds) to elicit tail
currents and then, back to the holding potential. Compounds were
applied after stabilization of tail current. First, tail currents
were recorded in presence of extracellular solution alone (control)
and subsequently, in extracellular solution containing increasing
compound concentrations. Each compound concentration was applied
for 2-5 minutes. The percentage inhibition at each concentration
was calculated as reduction in peak tail current with respect to
the peak tail current recorded in the presence of control solution.
Data analysis was performed in custom made software. The percent
inhibitions at different concentrations were plotted to obtain a
concentration response curve, which was subsequently fitted with a
four parameter equation to calculate the hERG IC.sub.50 value.
Using this procedure, the compound of example 46, P-4 is a poor
inhibitor of the hERG channel, with an IC.sub.50=28 .mu.M. The
compound of example 114, P-1 is a poor inhibitor of the hERG
channel, with an IC.sub.50=13.5 .mu.M.
[0718] Mouse Forced Swim Test (mFST).
[0719] Forced Swim Test (FST) is an animal model used to assess
antidepressant compounds in preclinical studies. The FST was
performed similar to the method of Porsolt et al. with
modifications (Porsolt R D, Bertin A, Jalfre M. Behavioral despair
in mice: a primary screening test for antidepressants. Arch Int
Pharmacodyn Ther 1977; 229:327-36). In this paradigm, mice are
forced to swim in an inescapable cylinder filled with water. Under
these conditions, mice will initially try to escape and eventually
develop immobility behavior; this behavior is interpreted as a
passive stress-coping strategy or depression-like behavior. Swim
tanks were positioned inside a box made of plastic. Each tank was
separated from each other by opaque plastic sheets to the height of
cylinders. Three mice were subjected to test at a time. Swim
sessions were conducted for 6 min by placing mice in individual
glass cylinders (46 cm height X 20 cm diameter) containing water
(20-cm deep, maintained at 24-25.degree. C.). At this water level,
the mouse tail does not touch the bottom of the container. The
mouse was judged to be immobile whenever it remained floating
passively without struggling in the water and only making those
movements necessary to keep its nose/head above the water and to
keep it afloat. The duration of immobility was evaluated during the
total 6 min of the test and expressed as duration (sec) of
immobility. Each mouse was tested only once. At the end of each
session, mice were dried with a dry cloth and returned to their
home cage placed on a thermal blanket to prevent hypothermia. Water
was replaced after each trial. All testing sessions were recorded
with a video camera (Sony Handicam, Model: DCR-HC38E; PAL) and
scoring was done using the Forced Swim Scan, Version 2.0 software
(Clever Systems Inc., Reston, Va., USA; see Hayashi E, Shimamura M,
Kuratani K, Kinoshita M, Hara H. Automated experimental system
capturing three behavioral components during murine forced swim
test. Life Sci. 2011 Feb. 28; 88(9-10):411-7 and Yuan P, Tragon T,
Xia M, Leclair C A, Skoumbourdis A P, Zheng W, Thomas C J, Huang R,
Austin C P, Chen G, Guitart X. Phosphodiesterase 4 inhibitors
enhance sexual pleasure-seeking activity in rodents. Pharmacol
Biochem Behav. 2011; 98(3):349-55). For NCE testing: Test compound
was administered in mice 15 min before swim session by i.v. route
and immobility time was recorded for next 6 min. At the end of FST,
the mouse were euthanized by rapid decapitation method and plasma
and brain samples were collected and stored under -80.degree. C.
till further analysis. In the mouse forced swim assay, the compound
of example 1 was dosed intravenously in a vehicle of 30%
hydroxypropyl betacyclodextrin/70% citrate buffer pH 4 at a 5 mL/Kg
dosing volume. The compound of example 46, P-4 demonstrated a
statistically significant decrease in immobility time at 1 mg/Kg
under these conditions. Drug levels were 268+/-128 nM in the plasma
and 749+/-215 nM in the brain at this dose. The NR2B receptor
occupancy was determined as reported above and was determined to be
73%. The compound of example 224, P-2 demonstrated a statistically
significant decrease in immobility time at 1 mg/Kg under these same
conditions. Drug levels were 360 nM in the plasma. The NR2B
receptor occupancy was determined to be 79%.
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