U.S. patent application number 11/461203 was filed with the patent office on 2007-03-01 for methods for preparing n-arylated oxazolidinones via a copper catalyzed cross coupling.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Stephane Caron, Arun Ghosh, Janice E. Sieser.
Application Number | 20070049759 11/461203 |
Document ID | / |
Family ID | 32233544 |
Filed Date | 2007-03-01 |
United States Patent
Application |
20070049759 |
Kind Code |
A1 |
Ghosh; Arun ; et
al. |
March 1, 2007 |
Methods for Preparing N-Arylated Oxazolidinones Via A Copper
Catalyzed Cross Coupling
Abstract
Methods for the preparation of N-arylated oxazolidinone
compounds via a copper catalyzed cross coupling reaction are
disclosed.
Inventors: |
Ghosh; Arun; (Madison,
CT) ; Caron; Stephane; (Stonington, CT) ;
Sieser; Janice E.; (Ivoryton, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
32233544 |
Appl. No.: |
11/461203 |
Filed: |
July 31, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10645779 |
Aug 21, 2003 |
|
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11461203 |
Jul 31, 2006 |
|
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60423328 |
Nov 1, 2002 |
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Current U.S.
Class: |
548/229 |
Current CPC
Class: |
A61P 3/06 20180101; C07D
263/22 20130101; C07D 291/04 20130101; A61P 9/10 20180101; C07D
207/12 20130101 |
Class at
Publication: |
548/229 |
International
Class: |
C07D 263/00 20060101
C07D263/00 |
Claims
1-4. (canceled)
5. A compound
(R)-4-ethyl-3-(4-trifluoromethyl-phenyl)-oxazolidin-2-one of
formula V ##STR19##
6. A compound (R)-4-ethyl-3-(4-trifluoromethyl-phenyl)-[1 , 2,
3]oxathiazolidine-2-oxide of formula VI ##STR20##
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/423,328 filed Nov. 1, 2002.
FIELD OF THE INVENTION
[0002] This invention relates to intermediates useful in the
preparation of CETP inhibitors and methods of preparation
thereof.
BACKGROUND OF THE INVENTION
[0003] Atherosclerosis and its associated coronary artery disease
(CAD) is the leading cause of mortality in the industrialized
world. Despite attempts to modify secondary risk factors (smoking,
obesity, lack of exercise) and treatment of dyslipidemia with
dietary modification and drug therapy, coronary heart disease (CHD)
remains the most common cause of death in the U.S.
[0004] Risk for development of this condition has been shown to be
strongly correlated with certain plasma lipid levels. While
elevated LDL-C may be the most recognized form of dyslipidemia, it
is by no means the only significant lipid associated contributor to
CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D. J.,
et al.: "High-density Lipoprotein Cholesterol and Cardiovascular
Disease", Circulation, (1989), 79: 8-15).
[0005] High LDL-cholesterol and triglyceride levels are positively
correlated, while high levels of HDL-cholesterol are negatively
correlated with the risk for developing cardiovascular diseases.
Thus, dyslipidernia is not a unitary risk profile for CHD but may
be comprised of one or more lipid aberrations.
[0006] Among the many factors controlling plasma levels of these
disease dependent principles, cholesteryl ester transfer protein
(CETP) activity affects all three. The role of this 70,000 dalton
plasma glycoprotein found in a number of animal species, including
humans, is to transfer cholesteryl ester and triglyceride between
lipoprotein particles, including high-density lipoproteins (HDL),
low density lipoproteins (LDL), very low density lipoproteins
(VLDL), and chylomicrons. The net result of CETP activity is a
lowering of HDL cholesterol and an increase in LDL cholesterol.
This effect on lipoprotein profile is believed to be
pro-atherogenic, especially in subjects whose lipid profile
constitutes an increased risk for CHD.
[0007] No wholly satisfactory HDL-elevating therapies exist. Niacin
can significantly increase HDL, but has serious toleration issues
resulting in reduced compliance. Fibrates and the HMG-CoA reductase
inhibitors raise HDL-C only modestly. As a result, there is a
significant unmet medical need for a well-tolerated agent, which
can significantly elevate plasma HDL levels, thereby reversing or
slowing the progression of atherosclerosis.
[0008] PCT application publication number WO 00102887 discloses the
use of catalysts comprising certain novel ligands for transition
metals in transition metal-catalyzed carbon-heteroatom and
carbon-carbon bond formation.
[0009] Commonly assigned U.S. Pat. No. 6,140,343, the disclosure of
which is incorporated herein by reference, discloses, inter alia,
the CETP inhibitor,
cis4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluorom-
ethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester,
and processes for the preparation thereof.
[0010] Commonly assigned U.S. Pat. No. 6,197,786, the disclosure of
which is incorporated herein by reference, discloses, inter alia,
the CETP inhibitor,
cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6--
trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl
ester, and processes for the preparation thereof.
SUMMARY
[0011] According to one aspect of the present invention there is
provided a method for preparing a compound of formula I ##STR1##
wherein
[0012] R.sup.1 is a partially saturated, fully saturated or fully
unsaturated (C.sub.1-C.sub.4) straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo or hydroxy,
said sulfur is optionally mono- or di-substituted with oxo, said
nitrogen is optionally mono- or di-substituted with oxo; or said
R.sup.1 is a partially saturated, fully saturated or fully
unsaturated three to five membered ring optionally having one
heteroatom selected independently from oxygen, sulfur and nitrogen;
wherein said R.sup.1 ring is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkoxy,
nitro, (C.sub.1-C.sub.4)alkyloxycarbonyl;
[0013] R.sup.2 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl;
[0014] phenyl optionally substituted with C.sub.1-C6 alkoxy or OY
wherein Y is a hydroxy protecting group, halogen, C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl, trifluoromethyl, nitro, carbo-C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkoxy-carbonyl, carbonyl, or cyano;
[0015] or benzyl with the phenyl moiety of the benzyl optionally
substituted with C.sub.1-C.sub.6 alkoxy or OY wherein Y is a
hydroxy protecting group, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl, trifluoromethyl, amido, nirto,
carbo-C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-carbonyl,
carbonyl or cyano;
[0016] Ar is aromatic moiety as described below comprising reacting
a compound of formula II ##STR2## wherein
[0017] R.sup.4 is a partially saturated, fully saturated or fully
unsaturated (C.sub.1-C.sub.4) straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo or hydroxy,
said sulfur is optionally mono- or di-substituted with oxo, said
nitrogen is optionally mono- or di-substituted with oxo; or said
R.sup.1 is a partially saturated, fully saturated or fully
unsaturated three to five membered ring optionally having one
heteroatom selected independently from oxygen, sulfur and nitrogen;
wherein said R.sup.1 ring is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkoxy,
nitro, (C.sub.1-C.sub.4)alkyloxycarbonyl;
[0018] R.sup.5 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl;
[0019] phenyl optionally substituted with C.sub.1-C.sub.6 alkoxy or
OY wherein Y is a hydroxy protecting group, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl, trifluoromethyl, nitro,
carbo-C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-carbonyl,
carbonyl, or cyano;
[0020] or benzyl with the phenyl moiety of the benzyl optionally
substituted with C.sub.1-C.sub.6 alkoxy or OY wherein Y is a
hydroxy protecting group, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl, trifluoromethyl, amido, nirto,
carbo-C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-carbonyl,
carbonyl or cyano;
with an aryl halide of formula III Ar--L (III) wherein Ar is Ar is
an aromatic hydrocarbon or heteroaromatic moiety selected from the
group consisting of phenyl, naphthyl, pyridyl, thiophenyl, furanyl,
pyrrolyl and pyrimidyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,
pyrazolyl, pyrazinyl, pyridazinyl each of which may be optionally
substituted by one or more, preferably one to two, substituents
independently selected from the group consisting of halogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl, trifluoromethyl (CF.sub.3), nirto,
carbo-C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-carbonyl,
carbonyls (ketones and aldehydes), cyano;
[0021] L is an activated leaving group, such as a halide,
preferably iodide or bromide; or alkyl- or aryl-sulfonate, such as
mesylate, triflate, tosylate in the presence of a bidentate ligand
of formula IV ##STR3## wherein
[0022] R.sup.6, R.sup.7, R.sup.8, R.sup.9 are independently
selected from hydrogen, cyclic or acyclic C.sub.1-C.sub.6 alkyl,
alkenyl, aryl,
[0023] X and Y are independently selected from nitrogen and oxygen;
where nitrogen is incorporated as an amine or imine or as a part of
nitrogen heterocylce; where oxygen is incorporated as a hydroxy ,
alkoxy, or oxo substituent,
[0024] and in the presence of a copper catalyst.
[0025] According to another aspect of the present invention there
is provided a method for preparing the compound of formula I as
described above wherein the activated leaving group is an iodide or
bromide.
[0026] According to another aspect of the present invention there
is provided a method for preparing the compound of formula I as
described above wherein the ligand is N,N-dimethyl
ethylenediamine.
[0027] According to another aspect of the present invention there
is provided a method for preparing the compound of formula I as
described above wherein the ligand is 1,2-diaminocyclohexane.
[0028] Still another aspect of the present invention provides a
compound (R)4-ethyl-3-(4-trifluoromethyl-phenyl)-oxazolidin-2-one
of formula V ##STR4##
[0029] Another aspect of the present invention provides a compound
(R)4-ethyl-3-(4-trifluoromethyl-phenyl)-[1,2,3]oxathiazolidine
2-oxide of formula V ##STR5##
[0030] Ligands Used in the N-Arylation Sequence: ##STR6##
TABLE-US-00001 TABLE Conditions for N-arylation R.sub.1 (%) R.sub.2
X.sub.1 X.sub.2 BASE HR LIGAND YIELD Ph C(O)NHC.sub.3H.sub.7 Br I
K.sub.2CO.sub.3 18 A 93 Ph CN Br I K.sub.2CO.sub.3 23 A 95 Ph H Br
I K.sub.2CO.sub.3 23 A 95 Ph H I I K.sub.2CO.sub.3 20 A 66 Ph H I I
K.sub.3PO.sub.4 18 E 93 Ph.sup.1 H I I K.sub.3PO.sub.4 18 E 38 Ph
CF.sub.3 I I K.sub.3PO.sub.4 18 E 98 Ph F I I K.sub.3PO.sub.4 18 E
85 Ph.sup.1 F I I K.sub.3PO.sub.4 18 E 45 Ph CF.sub.3 Br --
K.sub.2CO.sub.3 16 C' 70 Ph CF.sub.3 Br -- K.sub.2CO.sub.3 22 C' 80
Ph CF.sub.3 Br I(3%) K.sub.2CO.sub.3 16 C' 41 Ph CF.sub.3 Br
Br.sub.2 K.sub.2CO.sub.3 16 C 41 Ph CF.sub.3 Br Br.sub.2.sup.2
K.sub.2CO.sub.3 16 C 55 Ph CF.sub.3 Br Br.sub.2.sup.2
K.sub.2CO.sub.3 16 A 90 Ph CF.sub.3 Br Br.sub.2.sup.2
K.sub.2CO.sub.3 17 F 6 Ph CF.sub.3 Br Br.sub.2.sup.2
K.sub.2CO.sub.3 17 D 33 Ph CF.sub.3 Br Br.sub.2.sup.2
K.sub.2CO.sub.3 22 B 12 Ph CF.sub.3 Br Br.sub.2.sup.2
K.sub.2CO.sub.3 22 E 95 Et CF.sub.3 Br I K.sub.2CO.sub.3 19 A 85 Et
CF.sub.3 Br Br.sub.2.sup.2 K.sub.2CO.sub.3 16 A 95 Et CF.sub.3 Br
Br.sub.2.sup.2 K.sub.2CO.sub.3 16 E 66 Et CF.sub.3 Br
Br.sub.2.sup.2 K.sub.2CO.sub.3 16 H 25 Et CF.sub.3 Br
Br.sub.2.sup.2 K.sub.2CO.sub.3 16 I 12 Typical Conditions: (mMol)
oxazolidinone:aryl halide:Cu:Ligand:Base:dioxane 1:1:0.1:0.1:2:1 ml
.sup.1Toluene substituted for dioxane .sup.2Oxazolidinone,
CuBr.sub.2 and ligand premixed in dioxane
[0031] In this specification and in the claims that follow,
reference will be made to a number of terms that shall be defined
to have the following meanings:
[0032] "Alkyl" refers to the radical of saturated aliphatic groups,
including straight-chain alkyl groups, branched-chain alkylgroups
cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups,
and cycloalkyl substituted alkyl groups. Moreover, the term "alkyl
is intended to include both "unsubstituted alkyls" and "substituted
alkyls", the latter of which refers to alkyl moieties having
substituent replacing a hydrogen on one or more carbons of the
hydrocarbon backbone. Such substituent can include, for example, a
halogen, a hydroxyl, a carbonyl (such as carboxyl, an ester, a
formyl, or a ketone), a thiocarbonyl (such as a thioester, a
thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a
phosphonate, a phosphinate, an amino, an amido, an amidine, an
imine, a cyano, a nitro, an azido, a sulthydryl, an alkylthio, a
sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a
heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
It will be understood by those skilled in the art that the moieies
substituted on the hydrocarbon chain can themselves be substituted,
if appropriate.
[0033] The terms "alkenyl" and "alkynyl" refer to unsaturated
aliphatic groups analogous in length and possible substitution to
the alkyls described above, but that contain at least one double or
triple bond respectively.
[0034] The term "aryl" as used herein includes 5-, 6- and
7-membered single-ring aromatic groups that may include from zero
to four heteroatoms, for example, benzene, pyrrole, furan,
thiophene, imidazole, oxazole, thiazole, triazole, pyrazole,
pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those
aryl groups having heteroatoms in the ring structure may also be
referred to as "aryl heterocycles" or "heteroaromatics." The
aromatic ring can be substituted at one or more ring positions with
such substituent as described above, for example, halogen, azide,
alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino,
nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,
ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic
moieties, --CF.sub.3, --CN, or the like. The term "aryl" also
includes polycyclic ring systems having two or more cyclic rings in
which two or more carbons are common to two adjoining rings (the
rings are "fused rings") wherein at least one of the rings is
aromatic, e.g. the other cyclic rings can be cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
[0035] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
nitrogen, oxygen, sulfur and phosphorous.
[0036] The terms "amine" and "amino" are art recognized and refer
to both unsubstituted and substituted amines.
[0037] The terms "alkoxyl" or "alkoxy" refer to an alkyl group, as
defined above, having an oxygen radical attached thereto.
[0038] The terms "imine" or "imido" refer to a nitrogen-containing
organic substance having a carbon to nitrogen double bond.
[0039] The term "halide" refers to fluoride, chloride, bromide and
iodide.
[0040] The term "halogen" refers to fluorine, chlorine, bromine,
iodine and astatine.
[0041] The term "hydroxyl" indicates the OH group in an organic
compound.
[0042] Chemical structures herein are represented by planar
chemical structure diagrams that are viewed from a perspective
above the plane of the structure. A wedge line (?)appearing in such
chemical structures represents a bond that projects up from the
plane of the structure.
DETAILED DESCRIPTION OF THE INVENTION
[0043] In general, the oxazolidinone, aryl halide, copper catalyst,
and base are charged in a flask under nitrogen atmosphere. The
flask is evacuated and backfilled with N.sub.2 before adding the
solvent (preferably ethereal) and a bidentate, chelating-ligand.
The reaction mixture is then heated to the desired temperature
until the starting materials are consumed, as judged by LCMS. The
reaction mixture is then cooled, diluted, and filtered. The
combined filtrates are concentrated and dried to produce the
desired oxazolidinones.
[0044] The general nature of this copper-catalyzed N-arylation of
oxazolidinones was established using copper having a formal
oxidation state of (O), (I) or (II) or a combination thereof as a
catalyst, and is sometimes referred herein as "copper catalyst".
Inorganic salts of copper that may be used include the iodide,
bromide, and chloride with copper (I) iodide being preferred. In
addition to the prescribed solvent in the typical procedure,
several other polar solvents, e.g., DMF, NMP, toluene, DME, and
bases, including carbonates, phosphates, hydroxide, or alkoxide,
preferably carbonates, are useful for this transformation.
[0045] The aryl halide and the oxazolidinone substrates may be used
in an ideal molar ratio of about 1:1, or to completely consume one
of the components, e.g., aryl halide or oxazolidinone, either
reagent may be used in excess. A suitable molar ratio of aryl
halide or oxazolidinone to base is in the range of from about 1:1
to 1:5. A more preferred molar ratio of aryl halide or
oxazolidinone to base is in the range of from about 1:1 to 1:3.
[0046] Normally, the molar ratio of the copper catalyst to
substrate aryl halide or oxazolidinone is in the range of from
about 0.15:1 to about 0.05:1; a preferred molar ratio of the copper
catalyst to substrate aryl halide or oxazolidinone is about 0.1:1.
The molar ratio copper catalyst to the ligand is in the range of
from about 1:0.5 to about 1:5; preferably in the range of from 1:1
to about 1:2.
[0047] The order of addition of the various components to the
reaction vessel does not affect the outcome of the reaction. Thus,
solid components may be conveniently added to the vessel together,
prior to the addition of the liquid components as a solution in
appropriate solvent. Once all the components are present in the
same reaction vessel, the mixture may be heated to the desired
reaction temperature.
[0048] Reaction Scheme A illustrates the preferred process for
preparing the chiral isomer of formula I via a copper catalyzed
coupling of 1-bromo4-trifluoromethyl-benzene and
(R)4-ethyl-oxazolidin-2-one. ##STR7## General Procedure
[0049] All commercially available reagents were used as received
without further purification. Solvents were purged with nitrogen
prior to use. Flash chromatography was performed on silica gel 60
(230-400 mesh). All reactions were monitored by TLC, and/or, LC-MS.
.sup.1H and .sup.13C nuclear magnetic resonance (NMR) spectra were
recorded on a 400 MHz NMR spectrometer (Varian, Incorporated) at
ambient temperature in CDCl.sub.3 (Cambridge Isotope Laboratories,
Incorporated) unless otherwise stated.
[0050] According to Scheme A, the formula II compound
(R)-3-(4-trifluoromethyl-phenylamino)-pentanenitrile was prepared
as follows: ##STR8## (R)-4-ethyl-oxazolidin-2-one.
(R)-2-amino-1-butanol (42 mUO.44 mol), diethylcarbonate (107
mL/0.89 mol) and potassium carbonate (6.12 g/0.044 mol) were heated
in an oil bath set between 135.degree.-140.degree.. A distillate
was collected at approximately 90.degree. (79 mL). Heating was
continued until distillation ceased.
[0051] After cooling to room temperature, the reaction mixture was
diluted with 40 mL CH.sub.2Cl.sub.2 and washed with water (3x), and
brine. Drying (over MgSO.sub.4), concentration and vacuum drying
gave the oxazolidinone as a pale yellow oil (39.75 g) in 78%
yield.
[0052] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.9 (t, J=7.5 Hz,
3 H) 1.6 (m, 2 H), 3.8 (m,1 H), 4.0 (dd, J=8.5, 6.0 Hz, 1 H), 4.5
(t, J=8.5 Hz,1 H), 6.8 (s, 1 H). ##STR9##
(R)-4-ethyl-3-(4-trifluoromethyl-phenyl)-oxazolidin-2-one
[0053] K.sub.2CO.sub.3 (12.0 G/87 mMol) and Cul (0.83 g/4.4 mMol)
were charged to a flask under N.sub.2. 4-ethyl-oxazolidin-2-one
(5.0 g.43.5 mMol) and 1-bromo-4-trifluouomethyl-benzene (6.0
mL/42.8 mMol) each diluted in 20 mL dioxane added to the flask
followed by 1,2-diaminocyclohexane (0.52 mL/4,4 mMol). The bright
blue mixture was heated to 110.degree. and held for 22 hours.
[0054] The cooled mixture was diluted with CH.sub.2Cl.sub.2 and
filtered through celite. The filtrate was concentrated to an amber
oil and purified by silica chromatography to give the product in
86% yield.
Mass Spec 260.2 (m+1).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (t, J=7.5, 3H),
1.63-1.82 (m, 2H), 4.17-4.21 (m,1 H), 4.44-4.45 (m,1 H), 4.534.58
(m,1 H), 7.59-7-65 (m,4H).
[0055] .sup.13C NMR (CDCl.sub.3) .delta. 7.89, 24.44, 56.67, 66.56,
120.7, 126.52, 140.25, 155.60. ##STR10##
(R)-2-(4-trifluoromethyl-phenylamino)-butan-1-ol
[0056] NaOH (9.25 mL of 12.5 N/115 mMol) diluted in 10 mL water was
added to a solution of
4-ethyl-3-(4-trifluoromethyl-phenyl)-oxazolidin-2-one (5.99 g/23.11
mMol) in 10 mL EtOH. The mixture was heated to 50.degree. and held
for 30 minutes. HPLC/MS indicated the reaction was complete. The
cooled mixture was concentrated and diluted with MTBE. The pH was
adjusted to 6 with dilute HCl and the layers separated. The aqueous
layer was extracted twice more with MTBE and the combined extracts
washed with brine, dried, (Na.sub.2SO.sub.4), and concentrated to
give 5.2 g of the aminol as an amber oil (yield 97%). .sup.1H NMR
(400 MHz, CDCl.sub.3) ? 1.0 (t, J=7.5 Hz, 3 H), 1.6 (dd, J=14.5,
7.1 Hz, 1 H), 1.6 (m, 1 H), 3.4 (m,1 H), 3.6 (m, 1 H), 3.7 (dd,
J=10.8, 4.1 Hz, 1 H), 6.6 (d, J=8.3 Hz, 2 H), 7.4 (d, J=8.7 Hz, 2
H). ##STR11##
(R)-4-ethyl-3-(4-trifluoromethyl-phenyl)-[1,2,3]oxathiazolidine
2-oxide
[0057] SOCl.sub.2 (0.66 mL/9 mMol) and pyridine (3.5 mL/43 mMol)
were stirred together in 13.5 mL ice cold anhydrous THF under
N.sub.2. 2-(4-trifluoromethyl-phenylamino)-butan-1-ol (1.0 g/4.3
mMol) dissolved in 45 mL anhydrous THF added dropwise over 40
minutes to the rapidly stirred mixture. HPLC indicated no starting
material remained after the addition. Water (20 mL) was slowly
added to the cold mixture and the mixture extracted twice with
MTBE. The combined extracts were washed with water (3x) and brine,
dried (MgSO.sub.4) and concentrated to a yellow oil. After vacuum
drying the oxathiozolidine was recovered as a waxy solid in 81%
yield (0.974 g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.0 (t,
J=7.5 Hz, 3 H), 1.6 (m, 1 H), 1.7 (m, 1 H), 4.5 (dd, J=8.7, 2.5 Hz,
1 H), 4.9 (m, 1 H), 5.1 (dd, J=8.9, 6.0 Hz, 1 H), 7.1 (d, J=8.3 Hz,
2 H), 7.6 (m, 2 H). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 9.7,
23.9, 58.2, 74.0, 117.1, 118.4, 127.2, 142.4. ##STR12##
(R)-3-(4-trifluoromethyl-phenylamino)-pentanenitrile
[0058] NaCN (0.38 g/7.8 mMol) was added to room temperature
solution of
4-ethyl-3-(4-trifluoromethyl-phenyl)-[1,2,3]oxathiazolidine 2-oxide
(0.85 g/3.1 mMol) in 10 mL anhydrous DMF. The mixture was heated to
50.degree. for 12 hours. MTBE and water were added to the cooled
mixture and the layers separated. The aqueous layer was extracted
twice more with MTBE and the combined extracts washed with 1 N HCl
and brine. The desired nitrile was isolated as a yellow oil in 81 %
yield (0.6 g) after drying over MgSO.sub.4 and concentration. Both
chiral HPLC and H.sup.1 NMR of the product were identical to a
known standard of CP-696,775, cyclopropanemethanol,
methanesulfonate.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.1 (t, J=7.5 Hz 3 H),
1.8 (m, 2 H), 2.6 (d, J=4.1 Hz, 1 H), 2.7 (m, 1 H), 3.7 (m, 1 H),
6.6 (d, J=8.3 Hz 2 H), 7.4 (d, J=8.7 Hz, 2 H).
[0059] The following Examples illustrate the preparation of N-aryl
oxazolidinones of the present invention. The Examples are not
intended to be limiting to the scope of the invention in any
respect, and should not be so construed.
EXAMPLES 1-6
Example 1
[0060] ##STR13##
(S)-4-(4-Isopropyl-2-oxo-oxazolidin-3-yl)-N-propyl-benzamide
K.sub.2CO.sub.3 (0.272 g/2 mMol) and Cul (0.019 g/0.1 mMol) were
charged to a flask under N.sub.2. (S)-4-isopropyl-oxazolidin-2-one
(0.155 g/1.2 mMol) and 1-bromo-4-N-propyl-benzamide(0.242 g/1 mMol)
each diluted in 1 mL dioxane added to the flask followed by
1,2-diaminocyclohexane (0.012 mL/0.1 mMol). The bright blue mixture
was heated to 110.degree. and held for 22 hours. The cooled mixture
was diluted with CH.sub.2Cl.sub.2 and filtered through celite. The
filtrate was concentrated to an amber oil and purified by silica
chromatography to give the product in 75% yield. Mass spec: 291.4
(m+1). .sup.1H NMR (CDCl.sub.3) .delta. 0.77 (d, J=6.8, 3H), 0.88
(d, J=7.0, 3H), 0.91-0.95 (m, 3H), 1.57-1.63 (m, 2H), 2.07-2.15 (m,
1 H), 3.33-3.38 (m, 2H), 4.20-4.24 (m,1 H), 4.37-4.41 (m,1 H),
4.434.46 (m,1 H), 6.72-6.75 (m,1H), 7.48 (d, J=8.7, 2H), 7.77 (d,
J=8.7, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 11.86, 14.34, 17.81,
23.05, 27.67, 42.02, 60.25, 62.78, 121.18, 128.28, 131.34, 139.55,
155.95, 167.07.
Example 2
[0061] ##STR14## (R)-3,4-Diphenyl-oxazolidin-2-one The procedure
described in example 1 was used with the appropriate substitution
of reagents as follows: K.sub.2CO.sub.3 (0.275 g/2 mMol), Cul
(0.019 g/0.1 mMol), (R)-4-phenyl-oxazolidin-2-one (0.163 g/1 mMol),
Bromobenzene (0.1 ml/1 mMol), 1,2-diaminocyclohexane (0.012 mL/0.1
mMol) and 1 mL dioxane. The product was recovered in 99% yield.
Mass Spec 240.3 (m+1). .sup.1H NMR (CDCl.sub.3) .delta. 4.21 (dd,
J=5.81, 6.22,1 H), 4.78 (t, J=8.71, 1 H), 5.40 (dd, J=6.22, 6.22, 1
H), 7.06 (t, J=7.47, 1 H), 7.24-7.40 (m, 9H). .sup.13C NMR
(CDCl.sub.3) .delta. 60.90, 70.07, 121.06, 124.91, 126.48, 129.14,
129.60, 137.23, 138.46, 156.19.
Example 3
[0062] ##STR15##
(R)-4-(2-Oxo-4-phenyl-oxazolidin-3-yl)-benzonitrile The procedure
described in example 1 was used with the appropriate substitution
of reagents as follows: K.sub.2CO.sub.3 (0.276 g/2 mMol), Cul
(0.019 g/0.1 mMol), (R)4-phenyl-oxazolidin-2-one (0.195 g/1.2
mMol), 4-Bromobenzonitrile (0.182 g/1 mMol), 1,2-diaminocyclohexane
(0.012 mL/0.1 mMol) and 1 mL dioxane. The product was recovered in
82% yield. Mass Spec 265.2 (m+1). .sup.1H NMR (CDCl.sub.3) .delta.
4.17 (dd, J=5.6, 8.7, 1H), 4.78 (t, J=8.7, 1H), 5.46 (dd, J=5.6,
8.7, 1H), 7.24-7.37 (m, 5H), 7.44 (d, J=8.9, 2H), 7.55 (d, J=8.7,
2H) .sup.13C NMR (CDCl.sub.3) .delta. 60.19, 70.20, 107.31, 118.89,
120.18, 126.2, 129.42, 129.90, 133.17, 137.64, 141.40,155.48.
Example 4
[0063] ##STR16## (S)-3,4-Diphenyl-oxazolidin-2-one The procedure
described in example 1 was used with the appropriate substitution
of reagents as follows: K.sub.2CO.sub.3 (0.553 g/4 mMol), Cul
(0.039 g/0.2 mMol), (S)4-phenyl-oxazolidin-2-one (0.325 g/2 mMol),
lodobenzene (0.22 ml/2 mMol), 1,2-diaminocyclohexane (0.024 mL/0.2
mMol) and 2 mL dioxane. The product was recovered in 66% yield.
Example 5
[0064] ##STR17##
(S)-3-(4-Acetyl-phenyl)-5-trityloxymethyl-oxazolidin-2-one The
procedure described in example 1 was used with the appropriate
substitution of reagents as follows: K.sub.2CO.sub.3 (0.276 g/2
mMol), Cul (0.019 g/0.1 mMol),
(S)-5-trityloxymethyl-oxazolidin-2-one (0.359 g/1 mMol),
4'-Bromoacetophenone (0.201 g/1 mMol), N,N'-Dimethylethylenediamine
(0.01 mL/0.1 mMol) and 1 mL dioxane. The product was recovered in
92% yield. Mass Spec 478.2 (m+1). 1H NMR (400 MHz, CHLOROFORM-D)
.delta. ppm) 2.60 (s, 3 H) 3.26 (dd, J=10.4, 3.7 Hz, 1 H) 3.55-3.59
(m, 1 H) 3.8 (dd, J=8.7, 5.4 Hz, 1 H) 4.05-4.10 (m, 1 H) 4.72-4.78
(m, 1 H) 7.21-7.29 (m, 9 H) 7.38-7.45 (m, 6 H) 7.66-7.68 (m, 2
H)7.99-8.01 (m, 2 H).
Example 6
[0065] ##STR18## 3-(4-Bromo-phenyl)-4-phenyl-oxazolidin-2-one The
procedure described in example 1 was used with the appropriate
substitution of reagents as follows: K.sub.2CO.sub.3 (0.276 g/2
mMol), Cul (0.022 g/0.11 mMol), oxazol (0.161 g/0.99 mMol),
4'-Bromobromobenzene (0.236 g/1.0 mMol), 1,2-diaminocyclohexane
(0.1 ml/0.1 mMol). The product was recovered in 45% yield after
chromatography. Mass spec 318.1 (m+1). .sup.1H NMR (CDCl.sub.3)
.delta. 4.19 (dd, J=6.01, 6.01, 1 H), 4.78 (t, J=8.8, 1 H), 5.36
(dd, J=6.01, 6.01, 1H), 7.26-7.38 (m, 9H). .sup.13C NMR
(CDCl.sub.3) .delta. 60.70, 70.04, 117.84, 122.40, 126.42, 129.27,
129.75, 132.13, 136.36, 137.94, 155.90.
* * * * *