U.S. patent application number 10/272877 was filed with the patent office on 2008-06-19 for process for the preparation of oxazolidinones and method of use thereof.
This patent application is currently assigned to Board of Trustees of Michigan State University. Invention is credited to Zongmin Dai, Rawle I. Hollingsworth, Jianmin Mao, Raghavakaimal Padmakumar, Kanakamma Puthuparampil, Guijun Wang, Huiping Zhang.
Application Number | 20080146458 10/272877 |
Document ID | / |
Family ID | 29739345 |
Filed Date | 2008-06-19 |
United States Patent
Application |
20080146458 |
Kind Code |
A1 |
Hollingsworth; Rawle I. ; et
al. |
June 19, 2008 |
PROCESS FOR THE PREPARATION OF OXAZOLIDINONES AND METHOD OF USE
THEREOF
Abstract
Substituted oxazolidinone of the formula: ##STR00001## wherein
R.sub.2 is alkyl selected from the group consisting of methyl,
ethyl, and isopropyl moieties, are described. The compounds are
antibacterial.
Inventors: |
Hollingsworth; Rawle I.;
(Haslett, MI) ; Wang; Guijun; (New Orleans,
LA) ; Padmakumar; Raghavakaimal; (Dayton, NJ)
; Mao; Jianmin; (North Brunswick, NJ) ; Zhang;
Huiping; (Bellemead, NJ) ; Dai; Zongmin;
(Chicago, IL) ; Puthuparampil; Kanakamma;
(Plainsboro, NJ) |
Correspondence
Address: |
MCLEOD & MOYNE, P.C.
2190 COMMONS PARKWAY
OKEMOS
MI
48864
US
|
Assignee: |
Board of Trustees of Michigan State
University
East Lansing
MI
Synthon Chiragenics Corporation
Monmouth Junction
NJ
|
Family ID: |
29739345 |
Appl. No.: |
10/272877 |
Filed: |
October 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60330266 |
Oct 18, 2001 |
|
|
|
60330268 |
Oct 18, 2001 |
|
|
|
Current U.S.
Class: |
506/15 ; 514/376;
548/229 |
Current CPC
Class: |
C07D 417/12 20130101;
C07D 263/20 20130101; A61P 31/04 20180101; C40B 50/08 20130101;
G01N 2333/31 20130101; C07D 263/24 20130101; C40B 30/04 20130101;
C12Q 1/18 20130101; C07D 413/12 20130101; C40B 40/04 20130101; A61P
31/00 20180101 |
Class at
Publication: |
506/15 ; 514/376;
548/229 |
International
Class: |
C40B 40/04 20060101
C40B040/04; A61K 31/421 20060101 A61K031/421 |
Claims
1-76. (canceled)
77-84. (canceled)
85. A compound having the formula ##STR00307## wherein R.sub.2 is
alkyl selected from the group consisting of methyl, ethyl and
isopropyl moieties.
86. A compound having the formula ##STR00308##
87. The compound of claim 85 wherein the alkyl is ethyl.
88. The compound of claim 85 wherein the alkyl is isopropyl.
89. The compound of claim 85 wherein the alkyl is methyl.
90. (canceled)
91. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application No. 60/330,266 filed Oct. 18, 2001, and U.S.
Provisional Application No. 60/330,268 filed Oct. 18, 2001.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
REFERENCE TO A "COMPUTER LISTING APPENDIX SUBMITTED ON A COMPACT
DISC"
[0003] Not Applicable.
BACKGROUND OF THE INVENTION
[0004] (1) Field of the Invention
[0005] The present invention relates to a process for preparing
N-(substituted)-C-(substituted methyl)-oxazolidinones,
C-(substituted methyl)-oxazolidinones, and
N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably
chiral, from optically active C-(protected
oxymethyl)-oxazolidinones. The process can be used to produce
combinatorial libraries of the above substituted oxazolidinones in
a two or three step reaction comprising a plurality of reagents
differing in numbers of carbons or particular substituted
oxazolidinones. A number of substituted oxazolidinones produced
using the above process have been discovered to have antimicrobial
activity.
[0006] (2) Description of Related Art
[0007] Oxazolidinones, particularly substituted oxazolidinones such
as 3-(substituted)-5-alkylaminomethyl- and
3-(substituted)-5-acylaminomethyl-2-oxazolidinones, are an
important class of drug substances which are used for a wide
variety of drug applications. These applications include use as
antibacterial agents and in therapies for treating behavior
disorders (Bowersock et al., Antimicrob. Agents Chemotherp. 44:
1367-1369 (2000); Skold, Acta Vet. Scand. Suppl. 93: 23-36 (2000);
Diekema and Jones, Drugs 59: 7-16 (2000); Genin et al., J. Med.
Chem. 43: 953-970 (2000); Johnson et al., J. Antimicrob. Chemother.
45: 225-230 (2000); Schulin et al., Antimicrob. Agents Chemotherp.
43: 2873-2876 (1999); Cynamon et al., Antimicrob. Agents
Chemotherp. 43: 1189-1191 (1999); Chen and Reamer, Organic Letts.
1: 293-294 (1999); Brenner et al., Clin Therapeut. 22: 411-419
(2000); Clemett and Markham, Drugs 59: 815-827 (2000); Brickner et
al., J. Med. Chem. 39: 673-679 (1996); Barry, Antimicrob. Agents
Chemotherp. 32: 150-152 (1988); Slee et al., Antimicrob. Agents
Chemotherp. 31: 1791-1797 (1987); Manninen et al., Abs. Paps. Amer.
Chem. Soc. 212: 389-ORGN, Part 2, (Aug. 25, 1996)).
[0008] There are several methods for making the oxazolidinone
nucleus in 3-(substituted)-5-alkylaminomethyl- and
3-(substituted)-5-acylaminomethyl-2-oxazolidinones. The general
structure of 3-(substituted)-5-(substituted methyl)-2-oxazolidinone
is
##STR00002##
wherein R.sub.1 is alkyl, aryl, heteroalkyl, heteroaryl, or mixture
thereof, or hydrogen or hydroxy, and R.sub.2 is alkyl, aryl,
heteroalkyl, heteroaryl, or mixture thereof. The following disclose
processes for preparing oxazolidinones and substituted
oxazolidinones.
[0009] U.S. Pat. No. 6,288,238 B1 to Hollingsworth and Wang
disclose a process for preparing 5-hydroxymethyl-2-oxazolidinones
in one step from 3,4-boronic acid ester protected
3,4-dihydroxybutyramides.
[0010] U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang
discloses a process for preparing
5-trityloxymethyl-2-oxazolidinones and suggests a scheme for the
alkylation of N-lithio-N-substituted carbamates with oxiranes such
as glycidyl butyrate as shown in Scheme 1.
##STR00003##
Glycidyl equivalents such as epichlorohydrin can be used instead of
glycidyl butyrate.
[0011] Schaus and Jacobsen (Tetrahedron Letts. 37: 7937-7940
(1996)) teach using optically active N-oxiranylmethylacetamides to
prepare chiral 3-(substituted)-5-acetamidomethyl-2-oxazolidinones
in one step by the alkylation of N-lithio-N-aryl (or alkyl)
carbamates as shown in Scheme 2.
##STR00004##
[0012] However, the above processes do not allow for the rapid
synthesis of a plurality of substituted oxazolidinones at the same
time in the same reaction. Thus, producing a plurality of
substituted oxazolidinones for drug screening is slow and
cumbersome which affects the rate in which new and useful drugs can
be discovered. Therefore, there remains a need for a rapid and
simple process that can produce a plurality of substituted
oxazolidinones at the same time in the same reaction. Being able to
produce a plurality of drug candidates in a short period of time
would accelerate the rate at which new and useful drugs and other
compounds are discovered. The present invention provides a simple
and rapid process for synthesizing substituted oxazolidinones.
[0013] Strains of Gram positive bacteria resistant to the present
repertoire of antibiotics have been increasing in prevalence over
the past several decades (Skold, Acta Vet. Scand. Suppl. 93: 23-36
(2000)). Resistant Gram positive that have been commonly
encountered include among others those in the staphylococci,
streptococci, pneumococci, and enterococci families. Because of the
increasing prevalence of these antibiotic resistant bacterial
strains, there is a clear need for new antimicrobial agents.
[0014] Several species of substituted oxazolidinones have been
discovered to be effective antimicrobial agents against particular
antibiotic resistant strains of Gram positive bacteria. Linezolid
(Clemett and Markham, Drugs 59: 815-827 (2000); Johnson et al., J.
Antimicrob. Chemother. 45: 225-230 (2000)) is a substituted
oxazolidinone which has been approved for the treatment of
microbial infections. The structure of linezolid is shown
below.
##STR00005##
[0015] A number of other substituted oxazolidinones with varying
degrees of antibacterial activity against Gram positive and in some
cases Gram negative bacteria are also known (Barry, Antimicrob.
Agents Chemotherp. 32: 150-152 (1988); Brickner et al., J. Med.
Chem. 39: 673-679 (1996); Genin et al., J. Med. Chem. 43: 953-970
(2000); Slee et al., Antimicrob. Agents Chemotherp. 31: 1791-1797
(1987)).
[0016] Most, if not all, of the known substituted oxazolidinones
which have been found to have antibacterial activity have the
structure shown below wherein the R.sub.3 substituent is aryl and
the relative stereochemistries of the groups on the chiral center
(C-5) is as indicated.
##STR00006##
[0017] A comparison of the structures for all of the known
substituted oxazolidinones which have antimicrobial activity, the
general consensus has arisen that there are at least three elements
of these substituted oxazolidinones which are critical for
biological activity. The first element is that when the
oxazolidinone ring is oriented as shown below such that all the
ring atoms are in one plane, the carbonyl oxygen points up, the
ring nitrogen is to the left, and the 5-substituent is to the
right, then of the two possible orientations for the 5-substituent
(distal or proximal), the proximal substituent is required for
biological activity.
##STR00007##
The second element is that the 3-substituent is an aryl. The third
element is that the 5-substituent is an alkylamino methyl or an
acetamidomethyl group. No substituted oxazolidinone which has
antibacterial activity has been found which does not have all three
of the above elements.
[0018] Because microorganisms will eventually develop resistance to
antibiotics, there is a continual need for new antibiotics. The
present invention provides families of novel substituted
oxazolidinones which have antimicrobial activity but which have
structures which do not conform to the consensus structure thought
to be necessary for antimicrobial activity.
SUMMARY OF THE INVENTION
[0019] The present invention provides a process for preparing
N-(substituted)-C-(substituted methyl)-oxazolidinones,
C-(substituted methyl)-oxazolidinones, and
N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably
chiral, from optically active C-(protected
oxymethyl)-oxazolidinones. The process can be used to produce
combinatorial libraries of the above substituted oxazolidinones in
a two or three step reaction comprising a plurality of reagents
differing in numbers of carbons or particular substituted
oxazolidinones.
[0020] Therefore, the present invention provides a process for
producing a library of substituted oxazolidinones which comprises
(a) reacting a C-(protected oxymethyl)-oxazolidinone in an
anhydrous organic solvent containing a first reagent including a
plurality of compounds having different numbers of carbons which
are reactive with N in the C-(protected oxymethyl)-oxazolidinone
under alkylation or Buchwald conditions in an inert atmosphere to
produce a mixture of N-(substituted)-C-(protected
oxymethyl)-oxazolidinones (I); and (b) reacting the mixture of (I)
produced in step (a) in an aqueous organic solvent with a second
reagent which removes the protecting group and replaces it with
another group from the second reagent to produce the library of
substituted oxazolidinones.
[0021] In a further embodiment of the above process, the second
reagent is a reducing agent which removes the protecting group of
the N-(substituted)-C-(protected oxymethyl)-oxazolidinone to
provide a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones
(II) as the library of substituted oxazolidinones.
[0022] In a further embodiment of the above process, the mixture of
(II) is further reacted with a third reagent containing a plurality
of compounds reactive with the hydroxymethyl in an anhydrous
organic solvent to produce a mixture of
N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the
library of substituted oxazolidinones. Preferably, the anhydrous
organic solvent further includes pyridine. In particular
embodiments, the third reagent produces a mixture of
3-(substituted)-5-(substituted methyl)-2-oxazolidinones or a
mixture of 3-(substituted)-4-(substituted
methyl)-2-oxazolidinones.
[0023] The present invention further provides a process for
producing a library of substituted oxazolidinones which comprises
(a) reacting a C-(protected oxymethyl)-oxazolidinone in an
anhydrous organic solvent containing a first reagent including a
plurality of compounds having different numbers of carbons which
are reactive with N in the C-(protected oxymethyl)-oxazolidinone
under alkylation or Buchwald conditions in an inert atmosphere to
produce a mixture of N-(substituted)-C-(protected
oxymethyl)-oxazolidinones (I); (b) reacting the mixture of (I)
produced in step (a) in an aqueous organic solvent with a second
reagent which removes the protecting group of the
N-(substituted)-C-(protected oxymethyl)-oxazolidinones to produce a
mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II); and
(c) reacting the mixture of (II) produced in step (b) in an
anhydrous organic solvent with a third reagent containing a
plurality of compounds reactive with the hydroxymethyl of the
mixture of (II) to produce a mixture of
N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the
library of substituted oxazolidinones. Preferably, the anhydrous
organic solvent in step (c) further includes pyridine. In
particular embodiments, the third reagent produces a mixture of
3-(substituted)-5-(substituted methyl)-2-oxazolidinones or a
mixture of 3-(substituted)-4-(substituted
methyl)-2-oxazolidinones.
[0024] In a further embodiment of the above processes, substituted
is selected from the group consisting of acyl, alkyl, aryl, aryl
sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and
mixtures thereof.
[0025] In a further embodiment of the above processes, the
substituted oxazolidinones in the library are separated
chromatographically.
[0026] In a preferred embodiment of the above process, the
protecting group is a trityl group.
[0027] In a further embodiment of the above processes, under the
alkylation conditions in step (a) the anhydrous organic solvent
further includes an alkali without substantial reducing activity,
preferably, the alkali is an ionic hydride, most preferably, the
ionic hydride is sodium hydride, and under the Buchwald conditions
in step (a) the anhydrous organic solvent further includes a
palladium catalyst, preferably, the palladium catalyst is
Pd(OAc).sub.2.
[0028] In a further embodiment of the above processes, the mixture
of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I)
produced in step (a) are purified by extracting the reaction
mixture with the organic solvent, drying over a drying agent, and
then removing the solvent.
[0029] In a still further embodiment of the above processes, the
N-(substituted)-C-hydroxymethyl-oxazolidinones (II) produced in
step (b) are purified by removing the solvent.
[0030] In a still further embodiment of the above processes, the
N-(substituted)-C-(substituted methyl)-oxazolidinones (III)
produced in step (c) are purified by extracting the reaction
mixture with the organic solvent, drying over a drying agent, and
then removing the solvent.
[0031] In a further embodiment of the above processes, the present
invention provides a process for preparing a library of substituted
oxazolidinones which comprises reacting a
C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent
including pyridine with a reagent containing a plurality of
compounds reactive with the hydroxy group to produce a mixture of
substituted oxazolidinones as the library of substituted
oxazolidinones.
[0032] In a further embodiment of the above processes, the reaction
produces a mixture of 5-(substituted methyl)-2-oxazolidinones, a
mixture of 4-(substituted methyl)-2-oxazolidinones, a mixture of
N-(substituted)-C-(hydroxymethyl)-2-oxazolidinones, or a mixture of
N-(substituted)-C-(substituted methyl)-2-oxazolidinones.
[0033] In a further embodiment of the above processes, substituted
is selected from the group consisting of acyl, alkyl, aryl, aryl
sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and
mixtures thereof.
[0034] In a further embodiment of the above processes, the
substituted oxazolidinones in the library are separated
chromatographically.
[0035] The present invention further provides a library of
substituted oxazolidinones selected from the group consisting of
N-(substituted)-C-(substituted methyl)-oxazolidinones,
N-(substituted)-C-hydroxymethyl-oxazolidinones, and C-(substituted
methyl)-oxazolidinones.
[0036] In a further embodiment of the library, substituted in
N-(substituted) includes at least 10 different individual
groups.
[0037] In a further embodiment of the library, substituted in
C-(substituted) includes at least 10 different individual
groups.
[0038] In a further embodiment of the library, the library is a
mixture of N-(substituted)-C-hydroxymethyl-2-oxazolidinones or a
mixture selected from the group consisting of
3-(substituted)-5-(substituted methyl)-2-oxazolidinones and
3-(substituted)-4-(substituted methyl)-2-oxazolidinones.
[0039] In a further embodiment of the library, substituted is
selected from the group consisting of acyl, alkyl, aryl, aryl
sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and
mixtures thereof.
[0040] The present invention further provides a method of screening
substituted oxazolidinones for biological activity which comprises
(a) providing a library of the substituted oxazolidinones wherein
the substituted oxazolidinones are selected from the group
consisting of N-(substituted)-C-(substituted
methyl)-oxazolidinones,
N-(substituted)-C-hydroxymethyl-oxazolidinones, and C-(substituted
methyl)-oxazolidinones; (b) chromatographically separating the
substituted oxazolidinones in the library; and (c) testing the
separated substituted oxazolidinones for the biological
activity.
[0041] In a further embodiment of the above method, substituted in
N-(substituted) includes at least 10 different individual
groups.
[0042] In a further embodiment of the above method, substituted in
C-(substituted methyl) includes at least 10 different individual
groups.
[0043] In a further embodiment of the above method, the substituted
oxazolidinones is a mixture of
N-(substituted)-C-hydroxymethyl-2-oxazolidinones or a mixture
selected from the group consisting of
3-(substituted)-5-(substituted methyl)-2-oxazolidinones,
3-(substituted)-4-(substituted methyl)-2-oxazolidinones,
5-(substituted methyl)-2-oxazolidinones, and 4-(substituted
methyl)-2-oxazolidinones.
[0044] In a further embodiment of the above method, substituted is
selected from the group consisting of acyl, alkyl, aryl, aryl
sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and
mixtures thereof.
[0045] The present invention further provides a substituted
oxazolidinone with biological activity obtained by the above
method.
[0046] The present invention further provides a process for
producing a substituted oxazolidinone which comprises (a) reacting
a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic
solvent containing a first reagent including a compound which is
reactive with N in the C-(protected oxymethyl)-oxazolidinone under
alkylation or Buchwald conditions in an inert atmosphere to produce
an N-(substituted)-C-(protected oxymethyl)-oxazolidinone; (b)
reacting the N-(substituted)-C-(protected oxymethyl)-oxazolidinone
in an aqueous organic solvent with a second reagent with a second
reagent which replaces the protecting group of the
N-(substituted)-C-(protected oxymethyl)-oxazolidinone with a
hydrogen to produce an
N-(substituted)-C-hydroxymethyl-oxazolidinone; and (c) reacting the
N-(substituted)-C-hydroxymethyl-oxazolidinone in an anhydrous
organic solvent with a third reagent containing a compound reactive
with the hydroxy group to produce N-(substituted)-C-(substituted
methyl)-oxazolidinones as the substituted oxazolidinone.
[0047] In a further embodiment of the above process, the anhydrous
organic solvent in step (c) further includes pyridine.
[0048] In a further embodiment of the above process, substituted is
selected from the group consisting of acyl, alkyl, aryl, aryl
sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and
mixtures thereof.
[0049] In a further embodiment of the above process, the protecting
group is a trityl group.
[0050] In a further embodiment of the above process, the
substituted oxazolidinone has the formula
##STR00008##
wherein R.sub.1 is selected from the group consisting of hydrogen,
acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl,
aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R.sub.2 is
selected from the group consisting of acyl, alkyl, aryl,
heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl,
thio, and mixture thereof, or a hydrogen, wherein hetero is an atom
selected from the group consisting of O, N, P, and S; and y is a
heteroatom selected from the group consisting of O, N, and S.
[0051] In a further embodiment of the above process, the
substituted oxazolidinone has the formula
##STR00009##
wherein R.sub.1 is selected from the group consisting of alkyl
sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R.sub.2 is
selected from the group consisting of alkyl, acyl, aryl, and thio;
or, the substituted oxazolidinone has the formula
##STR00010##
wherein R.sub.1 is selected from the group consisting of alkyl
sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R.sub.2 is
selected from the group consisting of alkyl, acyl, aryl, and thio;
or, the substituted oxazolidinone has the formula
##STR00011##
wherein R.sub.1 is selected from the group consisting of alkyl,
acyl, thio, and aryl, R.sub.2 is selected from the group consisting
of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral
centers, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, the substituted oxazolidinone
has the formula
##STR00012##
wherein R.sub.1 is selected from the group consisting of alkyl,
acyl, thio, and aryl, R.sub.2 is selected from the group consisting
of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral
centers, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, the substituted oxazolidinone
has the formula
##STR00013##
wherein R.sub.1 is selected from the group consisting of C-3, C-4,
and C-5 chiral synthons with 1, 2, or 3 chiral centers, R2 is
selected from the group consisting of alkyl, aryl, acyl, thio, and
heterocycle, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, the substituted oxazolidinone
has the formula
##STR00014##
wherein R.sub.1 is selected from the group consisting of alkyl,
aryl, acyl, thio, or heterocycle, R.sub.2 is selected from the
group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or
3 chiral centers, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, the substituted oxazolidinone
has the formula
##STR00015##
wherein R.sub.1 is selected from the group consisting of alkyl,
aryl, acyl, thio, and heterocycle and R.sub.2 is selected from the
group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or
3 chiral centers; or, the substituted oxazolidinone has the
formula
##STR00016##
wherein R.sub.1 is selected from the group consisting of alkyl,
aryl, acyl, thio, and heterocycle and R.sub.2 is selected from the
group consisting of C-3, C-4, with C-5 chiral synthons with 1, 2,
or 3 chiral centers.
[0052] In a further embodiment of the above process, under the
alkylation conditions in step (a) the anhydrous organic solvent
further includes an alkali without substantial reducing activity,
preferably, the alkali is an ionic hydride, most preferably, the
ionic hydride is sodium hydride.
[0053] In a further embodiment of the above process, under the
Buchwald conditions in step (a) the anhydrous organic solvent
further includes a palladium catalyst, preferably, the palladium
catalyst is Pd(OAc).sub.2.
[0054] In a further embodiment of the above process, the mixture of
N-(substituted)-C-(protected oxymethyl)-oxazolidinone produced in
step (a) is purified by extracting the reaction mixture with the
organic solvent, drying over a drying agent, and then removing the
solvent.
[0055] In a further embodiment of the above process, the
N-(substituted)-C-hydroxymethyl-oxazolidinone produced in step (b)
is purified by removing the solvent.
[0056] In a further embodiment of the above process, the
N-(substituted)-C-(substituted methyl)-oxazolidinone produced in
step (c) is purified by extracting the reaction mixture with the
organic solvent, drying over a drying agent, and then removing the
solvent.
[0057] The present invention further provides a substituted
oxazolidinone which has the formula
##STR00017##
wherein R.sub.1 is selected from the group consisting of hydrogen,
acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl,
aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R.sub.2 is
selected from the group consisting of acyl, alkyl, aryl,
heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl,
thio, and mixture thereof, or a hydrogen, wherein hetero is an atom
selected from the group consisting of O, N, P, and S; and y is a
heteroatom selected from the group consisting of O, N, and S.
[0058] The present invention further provides a substituted
oxazolidinone which has the formula
##STR00018##
wherein R.sub.1 is selected from the group consisting of alkyl
sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R.sub.2 is
selected from the group consisting of alkyl, acyl, aryl, and thio;
or, a substituted oxazolidinone which has the formula
##STR00019##
wherein R.sub.1 is selected from the group consisting of alkyl
sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R.sub.2 is
selected from the group consisting of alkyl, acyl, aryl, and thio;
or, a substituted oxazolidinone which has the formula
##STR00020##
wherein R.sub.1 is selected from the group consisting of alkyl,
acyl, thio, and aryl, R.sub.2 is selected from the group consisting
of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral
centers, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, a substituted oxazolidinone
which has the formula
##STR00021##
wherein R.sub.1 is selected from the group consisting of alkyl,
acyl, thio, and aryl, R.sub.2 is selected from the group consisting
of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral
centers, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, a substituted oxazolidinone
which has the formula
##STR00022##
wherein R.sub.1 is selected from the group consisting of C-3, C-4,
and C-5 chiral synthons with 1, 2, or 3 chiral centers, R2 is
selected from the group consisting of alkyl, aryl, acyl, thio, and
heterocycle, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, a substituted oxazolidinone
which has the formula
##STR00023##
wherein R.sub.1 is selected from the group consisting of alkyl,
aryl, acyl, thio, or heterocycle, R.sub.2 is selected from the
group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or
3 chiral centers, and X is selected from the group consisting of F,
NO.sub.2, Cl, alkyl, and aryl; or, a substituted oxazolidinone
which has the formula
##STR00024##
wherein R.sub.1 is selected from the group consisting of alkyl,
aryl, acyl, thio, and heterocycle and R.sub.2 is selected from the
group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or
3 chiral centers; or, a substituted oxazolidinone which has the
formula
##STR00025##
wherein R.sub.1 is selected from the group consisting of alkyl,
aryl, acyl, thio, or heterocycle and R.sub.2 is selected from the
group consisting of C-3, C-4, with C-5 chiral synthons with 1, 2,
or 3 chiral centers.
[0059] The present invention further provides an antimicrobial
composition comprising a carrier and one or more substituted
oxazolidinones of the formula
##STR00026##
wherein R.sub.1 is selected from the group consisting of hydrogen,
acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl,
aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R.sub.2 is
selected from the group consisting of acyl, alkyl, aryl,
heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl,
thio, and mixture thereof, or a hydrogen, wherein hetero is an atom
selected from the group consisting of O, N, P, and S; and y is a
heteroatom selected from the group consisting of O, N, and S.
OBJECTS
[0060] Therefore, it is the object of the present invention to
provide a process for producing substituted oxazolidinones which
are substituted at the N-position or the C-position, or both.
[0061] It is a further object of the present invention to provide a
process for producing a library of substituted oxazolidinones
comprising a plurality of oxazolidinones substituted at the
N-position, a plurality of oxazolidinones substituted at the
C-position, or a plurality of oxazolidinones substituted at both
the N-position and the C-position.
[0062] These and other objects of the present invention will become
increasingly apparent with reference to the following drawings and
preferred embodiments.
DESCRIPTION OF THE DRAWINGS
[0063] FIG. 1A shows the conversion of
5-trityloxymethyl-2-oxazolidinone to
3-(2,5-dimethoxyphenacyl)-5-trityloxymethyl-2-oxazolidinone.
[0064] FIG. 1B shows the conversion of
3-(2,5-dimethoxyphenacyl)-5-trityloxymethyl-2-oxazolidinone to
3-(2,5-dimethoxyphenacyl)-5-hydroxymethyl-2-oxazolidinone.
[0065] FIG. 1C shows the conversion of
3-(2,5-dimethoxyphenacyl)-5-hydroxymethyl-2-oxazolidinone to a
library of ten 3-(2,5-dimethoxyphenacyl)-5-(substituted
methyl)-2-oxazolidinones.
[0066] FIG. 2 shows the ten chlorides used in the
O-functionalization.
[0067] FIG. 3 shows an HPLC profile of the library of ten
3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones
prepared as shown in FIGS. 1A to 1C.
[0068] FIG. 4 shows the structure of the ten
3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones
identified in FIG. 3.
DETAILED DESCRIPTION OF THE INVENTION
[0069] All patents, patent applications, government publications,
government regulations, and literature references cited in this
specification are hereby incorporated herein by reference in their
entirety. In case of conflict, the present description, including
definitions, will control.
[0070] The present invention provides a novel process for preparing
collections or combinatorial libraries of substituted
oxazolidinones. In particular, the present invention provides a
process for preparing libraries of optically active or chiral
N-(substituted)-C-(substituted methyl)-oxazolidinones,
N-(substituted)-C-(methyl)-oxazolidinones, and C-(substituted
methyl)-oxazolidinones bearing alkyl or aryl substituents in the
N-substituted position (3-position) and a methyl group substituted
with a heteroatom such as O, N, or S in the C-substituted position
(4- or 5-position) and wherein the heteroatom is further
substituted with hydrogen or acyl, alkyl, aryl, heteroalkyl,
heteroaryl, heterocycle, phenacyl, aryl sulfonyl, or mixture
thereof.
[0071] In a preferred embodiment, the substituted oxazolidinones
comprising the library are optically active or chiral
N-(substituted)-C-(substituted methyl)-2-oxazolidinones,
N-(substituted)-C-- (methyl)-2-oxazolidinones, and
C-(substituted)-2-oxazolidinones bearing alkyl or aryl substituents
in the N-substituted position (3-position) and a methyl group
substituted with a heteroatom in the C-substituted position (4- or
5-position) and wherein the heteroatom is further substituted with
hydrogen or acyl, alkyl, aryl, heteroalkyl, heteroaryl,
heterocycle, phenacyl, aryl sulfonyl, or mixture thereof.
[0072] As used herein, the term "substituted" refers to groups
other than hydrogen substituted at the N-position or the methyl at
the C-position. Preferably, the substituting group is an organic
group. Therefore, when the N-position is substituted, it is
substituted with a group such as acyl, alkyl, aryl, heteroalkyl,
heteroaryl, heterocycle, aryl sulfonyl, phenacyl, or mixture
thereof. When N is not referred to as being "substituted", the N
has a hydrogen at the N-position. When the C-position methyl is
substituted, it is referred to as "substituted methyl" wherein
"substituted" is a group such as acyl, alkyl, aryl, heteroalkyl,
heteroaryl, heterocycle, phenacyl, aryl sulfonyl, or mixture
thereof.
[0073] The general structure of these substituted oxazolidinones is
shown below
##STR00027##
wherein R.sub.1 is an acyl, alkyl, aryl, heteroalkyl, heteroaryl,
heterocycle, phenacyl, aryl sulfonyl, thio, or mixture thereof, or
a hydrogen, R.sub.2 is an acyl, alkyl, aryl, heteroalkyl,
heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, or mixture
thereof, or a hydrogen (when N is not substituted by an organic
group), and y is a heteroatom selected from the group consisting of
O, N, and S. The heteroatom comprising R.sub.1 or R.sub.2 can
include one or more atoms selected from the group consisting of O,
P, S, N, Al, and Si.
[0074] The above genus comprises at least eight families of
substituted oxazolidinones. The first family (Family I) comprises
substituted oxazolidinones with the following general structure
##STR00028##
wherein R.sub.1 is alkyl sulfonyl, aryl sulfonyl, alkyl, acyl,
aryl, or thio and R.sub.2 is alkyl, acyl, aryl, or thio.
[0075] The second family (Family II) comprises substituted
oxazolidinones with the following general structure
##STR00029##
wherein R.sub.1 is alkyl sulfonyl, aryl sulfonyl, alkyl, acyl,
aryl, or thio and R.sub.2 is alkyl, acyl, aryl, or thio.
[0076] The third family (Family III) comprises substituted
oxazolidinones with the following general structure
##STR00030##
wherein R.sub.1 is alkyl, acyl, thio, or aryl, R.sub.2 is a C-3,
C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers, and X is
F, NO.sub.2, Cl, Alkyl, or aryl.
[0077] The fourth family (Family IV) comprises substituted
oxazolidinones with the general structure
##STR00031##
wherein R.sub.1 is alkyl, acyl, thio, or aryl, R.sub.2 is a C-3,
C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers, and X is
F, NO.sub.2, Cl, Alkyl, or aryl.
[0078] The fifth family (Family V) comprises substituted
oxazolidinones with the general structure
##STR00032##
wherein R.sub.1 is a C-3, C-4, or C-5 chiral synthon with 1, 2, or
3 chiral centers, R.sub.2 is alkyl, aryl, acyl, thio, or
heterocycle, and X is F, NO.sub.2, Cl, Alkyl, or aryl.
[0079] The sixth family (Family VI) comprises substituted
oxazolidinones with the general structure
##STR00033##
wherein R.sub.1 is alkyl, aryl, acyl, thio, or heterocycle, R.sub.2
is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral
centers, and X is F, NO.sub.2, Cl, Alkyl, or aryl.
[0080] The seventh family (Family VII) comprises substituted
oxazolidinones with the general structure
##STR00034##
wherein R.sub.1 is alkyl, aryl, acyl, thio, or heterocycle and
R.sub.2 is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral
centers.
[0081] The eighth family (Family VIII) comprises substituted
oxazolidinones with the general structure
##STR00035##
wherein R.sub.1 is alkyl, aryl, acyl, thio, or heterocycle and
R.sub.2 is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral
centers.
[0082] Examples of the C-3, C-4, and C-5 chiral synthons with 1, 2,
or 3 chiral centers include, but are not limited to,
(R)-3-acetoxy-4-bromobutyric acid, (S)-3-acetoxy-4-bromobutyric
acid, (R)-3-Acetoxy-4-bromobutiryl chloride,
(S)-3-Acetoxy-4-bromobutiryl chloride,
(R)-2-Acetoxy-1,4-dibromobutane, (S)-2-Acetoxy-1,4-dibromobutane,
(R)-3-Acetoxy-gamma-butyrolactone,
(S)-3-Acetoxy-gamma-butyrolactone,
(R)-4-Acetoxy-2-thioxopyrrolidine,
(S)-4-Acetoxy-2-thioxopyrrolidine,
(R)-4-Acetylthio-2-pyrrolidinone, (S)-4-Acetylthio-2-pyrrolidinone,
(R)-4-Amino-1,3-butanediol, (S)-4-Amino-1,3-butanediol,
(R)-3-Amino-1,2-dihydroxypropane, hydrochloride,
(S)-3-Amino-1,2-dihydroxypropane, hydrochloride,
(R)-4-Amino-3-hydroxy-1-trityloxy-butane,
(S)-4-Amino-3-hydroxy-1-trityloxy-butane,
(R)-4-Amino-3-hydroxybutanoic acid, (S)-4-Amino-3-hydroxybutanoic
acid, (S)-4-Aminomethyl-2,2-dimethyl-1,3-dioxolane,
(R)-3-Amino-1,2-propanediol, (S)-3-Amino-1,2-propanediol,
(S)--N-Benzyl-3,4-dihydroxybutyramide,
(R)-1-Benzyl-4-hydroxy-2-pyrrolidinone,
(S)-1-Benzyl-4-hydroxy-2-pyrrolidinone, (R)-1-Benzyl-3-mesyloxy
pyrrolidine, (S)-1-Benzyl-3-mesyloxy pyrrolidine,
(R)-1-Benzyl-3-pyrrolidinol, (S)-1-Benzyl-3-pyrrolidinol,
(R)-3-Bromo-1-(bromomethyl)propyl-methoxymethyl,
(S)-3-Bromo-1-(bromomethyl)propyl-methoxymethyl ether,
(R)-4-Bromo-1,3-butanediol, (S)-4-Bromo-1,3-butanediol,
(R)-4-Bromo-1,3-diacetoxy-butane, (S)-4-Bromo-1,3-diacetoxy-butane,
(R)-3-Bromo-1,2-dihydroxypropane, (S)-3-Bromo-1,2-dihydroxypropane,
(R)-4-Bromo-1,2-epoxybutane, (S)-4-Bromo-1,2-epoxybutane,
(R)-5-Bromo-4-(methoxymethoxy)-pentanenitrile,
(S)-5-Bromo-4-(methoxymethoxy)-pentanenitrile,
(4R)-4-Bromomethyl-2-phenyl-1,3-dioxane,
(4S)-4-Bromomethyl-2-phenyl-1,3-dioxane, (R)-1,3-Butanediol,
(S)-1,3-Butanediol, (R)-1,2,4-Butanetriol, (S)-1,2,4-Butanetriol,
(R)-1,2,4-Butanetriol trimesylate, (S)-1,2,4-Butanetriol
trimesylate, (R)-4-Cyano-1,2-epoxybutane,
(S)-4-Cyano-1,2-epoxybutane, 1,3-Dehydro-2-deoxy-N-acetylneuraminic
acid, (R)-1,4-Dibromo-2-butanol, (S)-1,4-Dibromo-2-butanol,
(R)-3,4-Dihydroxybutyramide, (S)-3,4-Dihydroxybutyramide,
(R)-2,2-Dimethyl-4-aminomethyl-1,3-dioxane,
(S)-2,2-Dimethyl-4-aminomethyl-1,3-dioxane,
(R)-2,2-Dimethyl-1,3-dioxolane-4-acetamide,
(S)-2,2-Dimethyl-1,3-dioxolane-4-acetamide,
(R)-2,2-Dimethyl-1,3-dioxolane-4-acetic acid, methyl ester,
(S)-2,2-Dimethyl-1,3-dioxolane-4-acetic acid, methyl ester,
(R)-2,2-Dimethyl-1,3-dioxolane-4-acetonitrile,
(S)-2,2-Dimethyl-1,3-dioxolane-4-acetonitrile,
(R)-2,2-Dimethyl-1,3-dioxolane-4-propanol,
(S)-2,2-Dimethyl-1,3-dioxolane-4-propanol,
(3R)-1,3-Dioxane-2-methyl-4-carboxylic acid,
(3S)-1,3-Dioxane-2-methyl-4-carboxylic acid,
(R)-1,4-Ditosyloxy-2-butanol, (S)-1,4-Ditosyloxy-2-butanol,
(3R)-3-(1-Ethoxyethoxy)-gamma-butyrolactone,
(S)-3-(1-Ethoxyethoxy)-gamma-butyrolactone,
(2R)-2-(1-Ethoxyethoxy)-1,4-butanediol,
(2S)-2-(1-Ethoxyethoxy)-1,4-butanediol, Ethyl
(R)-4-bromo-3-hydroxybutanoate, Ethyl
(S)-4-bromo-3-hydroxybutanoate, Ethyl
(R)-4-chloro-3-hydroxybutanoate, Ethyl
(S)-4-chloro-3-hydroxybutanoate, (R)-4-cyano-3-hydroxybutanamide,
(S)-4-cyano-3-hydroxybutanamide, Ethyl
(R)-4-cyano-3-hydroxybutanoate, Ethyl
(S)-4-cyano-3-hydroxybutanoate, Ethyl (R)-3,4-epoxybutanoate, Ethyl
(S)-3,4-epoxybutanoate, Ethyl (R)-3-hydroxy-decanoate, Ethyl
(S)-3-hydroxy-decanoate, Ethyl (R)-3-hydroxy-tetradecanoate, Ethyl
(S)-3-hydroxy-tetradecanoate, Ethyl (R)-4-iodo-3-hydroxybutanoate,
Ethyl (S)-4-iodo-3-hydroxybutanoate, (R)-4-(4-Fluorophenoxy)methyl
butyrolactone, (S)-4-(4-Fluorophenoxy)methyl butyrolactone,
(1S,3R)-3-Hydroxy-cyclopentanecarboxylic acid,
(1S,3S)-3-Hydroxy-cyclopentanecarboxylic acid,
(R)-4-Hydroxy-1-cyclopentene-1-carboxylic acid,
(S)-4-Hydroxy-1-cyclopentene-1-carboxylic acid,
(R)-4-Hydroxy-2-pyrrolidinone, (S)-4-Hydroxy-2-pyrrolidinone,
(4R)-4-(2-Hydroxyethyl)-2-phenyl-1,3-dioxolane,
(4S)-4-(2-Hydroxyethyl)-2-phenyl-1,3-dioxolane,
(R)-2-Hydroxy-gamma-butyrolactone,
(S)-2-Hydroxy-gamma-butyrolactone,
(R)-3-Hydroxy-gamma-butyrolactone,
(S)-3-Hydroxy-gamma-butyrolactone, (R)-4-Hydroxymethyl
butyrolactone, (S)-4-Hydroxymethyl butyrolactone,
(R)-4-Hydroxy-2-pyrrolidinethione,
(S)-4-Hydroxy-2-pyrrolidinethione, (R)-3-Hydroxytetrahydrofuran,
(S)-3-Hydroxytetrahydrofuran, (R)-4-Mercapto-2-pyrrolidinone,
(S)-4-Mercapto-2-pyrrolidinone,
(R)-2-(Methoxy-1-methylethoxy)-butanediol,
(S)-2-(1-Methoxy-1-methylethoxy)-butanediol, Methyl
(R)-4,5-dihydroxyisopropylidenepentanoate, Methyl
(S)-4,5-dihydroxyisopropylidenepentanoate, Methyl
(R)-2-phenyl-1,3-dioxolane-4-acetate, Methyl
(S)-2-phenyl-1,3-dioxolane-4-acetate, Methyl
(R)-3-hydroxy-4-trityloxy-butanoate, Methyl
(S)-3-hydroxy-4-trityloxy-butanoate, (R)-3-Pyrrolidinol,
(S)-3-Pyrrolidinol, (R)-3-Chloro-1,2-propanediol,
(S)-3-Chloro-1,2-propanediol, (2S)-(+)-glycidal tosylate, Benzyl
(R)-glycidyl ether, (R)-3-chlorolactic acid, Ethyl
(S)-4-chloro-3-hydroxybutanoate, (S)-3-Hydroxybutyrolactone,
(R)-2-hydroxybutyrolactone, (S)-2-Hydroxybutyrolactone,
(R)-2-Chlrobutyric acid, (R)-2-bromobutyric acid,
(S)-1-iso-propylaminopropanediol, (S)-1-tert-Butylaminopropanediol,
(R)-1-cyclohexyl-ethyl-amine, (R)-Ethyl-nipecotate,
(S)-Ethyl-nipecotate, (R)-Glycerol-3-phosphate,
alpha-Glycerophosphatidylcholine,
alpha-glycerophosphatidylethanolamine, (R)-0-Isopropylidene
glycerol, (S)-0-Isopropylidene glycerol, (R)-0-Isopropylidene
glycerol mesylate, (S)-0-Isopropylidene glycerol mesylate,
(R)-0-Isopropylidene glycerol tosylate, (S)-0-Isopropylidene
glycerol tosylate, (R)-0-methyl-0-isopropylidene glycerate,
(R)-2-tetrahydrofuroic acid, (R)-1-Tosyl-glycerol, and
(S)-1-Tosyl-glycerol.
[0083] The process for synthesis of the substituted oxazolidinones
preferably uses an optically active C-protected oxazolidinone as
the starting material, preferably a 5-(protected
hydroxymethyl)-oxazolidinone such as
5-trityloxymethyl-oxazolidinone wherein the trityl is
triphenylmethyl. Most preferably, the protected oxazolidinone is a
5-(protected hydroxymethyl)-2-oxazolidinone which in a further
preferred embodiment is a 5-trityloxymethyl-2-oxazolidinone. The
synthesis of 5-trityloxymethyl-2-oxazolidinone and its use are
disclosed in U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang.
The structure of 5-trityloxymethyl-2-oxazolidinone is shown
below.
##STR00036##
[0084] The general process for producing a library of substituted
oxazolidinones comprises the following steps. First, a C-(protected
oxymethyl)-oxazolidinone is N-arylated with a mixture of compounds
comprising a plurality of different aryl acyl, alkyl, aryl,
heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, or phenacyl
bromides under Buchwald conditions (Yin and Buchwald, Org. Letts 2:
1101-1104 (2000)) or by simple alkylation under nitrogen. This
produces a plurality of N-(substituted)-C-(protected
oxymethyl)-oxazolidinones (I).
[0085] For example, under simple alkylation conditions, a
C-(protected oxymethyl)-oxazolidinone is dissolved in an organic
solvent such as tetrahydrofuran (THF) containing a strong base
(alkali) which preferably does not have substantial reducing
activity or which has reducing activity which is suppressed at low
temperatures. Hydrides are strong bases which are suitable for the
reaction. Preferably, the strong base is an ionic hydride such as
an alkali hydride. Most preferred is sodium hydride which is a
powerful base without substantial reducing activity. Other strong
bases which may be used include lithium hydride, potassium hydride,
rubidium hydride, cesium hydride, sodium alcoholates, sodium amide,
and metallic sodium. In general, about 1 equiv. of the strong base
(alkali), preferably sodium hydride, is added to the solvent
containing the C-(protected oxymethyl)-oxazolidinone. In the case
of sodium hydride, which is insoluble in organic solvents, the
sodium hydride is provided as a suspension in an organic solvent
such as hexane. After allowing the mixture containing the protected
oxazolidinone and strong base to incubate at about 0.degree. C. for
about 10 minutes with stirring under an inert atmosphere such as
nitrogen, the mixture is warmed to room temperature and stirred for
about two hours and a mixture of n different arylating reagents,
preferably in a molar ratio of about 1 to 1 to 1 to 2 (C-(protected
oxymethyl)-oxazolidinone to mixture), is added. The reaction is
incubated at room temperature with stirring for a time (about eight
hours) sufficient to arylate the N at the 3-position with the n
different arylating reagents to produce n
N-(substituted)-C--(protected oxymethyl)-oxazolidinones. The
reaction is then quenched by adding an aqueous solution containing
an acid such as NH.sub.4Cl and the N-(substituted)-C-protected
oxymethyl)-oxazolidinones are recovered by extracting the quenched
reaction with the organic solvent, drying the extract over a drying
agent such as anhydrous Na.sub.2SO.sub.4, and concentrating the
extract under reduced pressure (in vacuo). The
N-(substituted)-C-(protected oxymethyl)-oxazolidinones are
preferably purified by chromatography.
[0086] Under Buchwald conditions, the C-(protected
oxymethyl)-oxazolidinone and about 1 to 2 equiv. of a mixture of n
different arylating reagents are incubated with a Pd(OAc).sub.2
catalyst in an organic solvent such as tetrahydrofuran (THF) under
an inert atmosphere such as argon at a temperature between about
45.degree. to 110.degree. C. for a time sufficient to arylate the N
at the 3-position with the n different arylating reagents to
produce n N-(substituted)-C-(protected oxymethyl)-oxazolidinones
(in general, about eight hours as determined by gas
chromatography). The reaction is then cooled to room temperature,
diluted with an organic solvent such as dichloromethane, filtered,
and concentrated under reduced pressure (in vacuo). The
N-(substituted)-C-(protected oxymethyl)-oxazolidinones are
preferably purified by chromatography.
[0087] Next, the N-arylated oxazolidinones (N-substituted) are
deprotected in the usual fashion by hydrogenolysis using H.sub.2
and a palladium catalyst or an acid such as to produce a library of
n N-(substituted)-C-hydroxymethyl-oxazolidinones (II). For example,
the N-arylated oxazolidinones, preferably purified by
chromatography or the like, are incubated in an aqueous solvent
such as wet dichloromethane (CH.sub.2Cl.sub.2) (about 8:1
CH.sub.2Cl.sub.2:H.sub.20) further containing an acid such as
trifluoroacetic acid (CF.sub.3CO.sub.2H) at room temperature for a
time sufficient (about four hours) to deprotect the
C-hydroxymethyl. Preferably, the C-protecting group in the above
reaction is a triphenylmethyl group. The reaction is quenched by
adding triethylamine or other quenching agent and the deprotected
oxazolidinone concentrated under reduced pressure (in vacuo). The
concentrated deprotected oxazolidinone is preferably further
purified by chromatography.
[0088] In a further step, the n
N-(substituted)-C-hydroxymethyl-oxazolidinones (II) are
O-functionalized with a mixture of n different alkylation,
acylation, sulfonylation, halogenation, or other such species. For
example, a mixture containing a plurality of different acyl, alkyl,
aryl, heteroalkyl, heteroacyl, heteroaryl, heterocycle, phenacyl,
aryl sulfonyl, amides thereof, thiols thereof, or other such
species, or the O of the hydroxymethyl is replaced by N-aryl,
N-sulfonyl, N-sulfide, or other N-species, or the O of the
hydroxymethyl is replaced by a thioalkyl, thioaryl, or other
thio-species. Methods for converting the hydroxyl group to a
nitrogen containing function can be done by any of the methods
which are known. These include mesylation or tosylation followed by
displacement with ammonia, azide, benzylamine, or other nitrogen
nucleophiles as taught for example in U.S. Pat. No. 6,288,239 B1 to
Hollingsworth and Wang or U.S. Pat. No. 5,837,870 to Pearlman et
al. For example, n substituted oxazolidinones (II), preferably
purified by chromatography or the like, are then incubated in an
organic solvent such as dry dichloromethane containing about 1
equiv. pyridine and about 1 equiv. of a mixture of n different
acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl,
aryl sulfonyl, thios and amides thereof, or other such species
halides at room temperature for time sufficient (about 12 to 16
hours) to functionalize the C-hydroxymethyl at the 4- or
5-position. Afterwards, the reaction is quenched by addition of
ammonium chloride, extracting the organic layer with
dichloromethane, drying the organic layer extract over a drying
agent such as anhydrous Na.sub.2SO.sub.4, and concentrating under
reduced pressure (in vacuo). The above process generates a library
of n.sup.2 N-(substituted)-C-(substituted methyl)-oxazolidinones
(III). For example, if ten different aryl bromides reagents are
used in the first step and ten different halide reagents in the
second step, 100 N-(substituted)-C-(substituted)-oxazolidinones
(III) are obtained.
[0089] Each of the products (I, II, or III) produced above can be
separated chromatographically and each separately evaluated as drug
or antimicrobial candidates.
[0090] The process takes advantage of the ease of reaction of the
nitrogen atom at the 3-position in C-(protected
oxymethyl)-oxazolidinones which enables both arylation and
alkylation sequences for substituting the N to be used. A further
advantage is that in one or two steps, the protecting group can be
removed and the hydroxyl group functionalized. In the same scheme,
the oxygen substituent at the C-position methyl can be replaced
with halo, thio, phenoxy, azido, or substituted nitrogen groups
under standard Mitsunobu conditions (Mitsunobu, Synthesis 1
(1981)). Alternatively, the hydroxyl group can be first converted
to a sulfonate, halo, or other such activating group.
[0091] Thus, the process involves essentially two steps, the first
step is generating a first library of n
N-(substituted)-C-hydroxymethyl-oxazolidinones from a C-protected
oxazolidinone and the second step is O-functionalizing acylating
the C-hydroxymethyl to generate a library of n.sup.2
N-(substituted)-C-(substituted methyl)-oxazolidinones.
[0092] In a preferred embodiment, the first library comprises at
least 10 different N-(substituted)-C-hydroxymethyl-oxazolidinones
prepared by reacting C-(protected oxymethyl)-oxazolidinones with at
least 10 different N-arylating reagents and the second library
comprises at least 100 different
N-(substituted)-C-(substituted)-oxazolidinones prepared by reacting
the ten N-(substituted)-C-hydroxymethyl-oxazolidinones with at
least ten different O-functionalizing acylating reagents. In other
embodiments of the library, the substituted oxazolidinones comprise
a plurality of molecules with N-position substitutions and a single
substitution group at the C-position of the molecules or a
plurality of molecules with C-position substitutions and a single
substitution group at the N-position of the molecules. A further
embodiment of the library can comprise substituted oxazolidinones
with either N-position substitutions only
(N-(substituted)-C-(methyl)-oxazolidinones) or C-position
substitutions only (C-(substituted methyl)-oxazolidinones. The
particular library embodiment chosen depends on the particular
objectives of the drug or antimicrobial screening program.
[0093] In a preferred embodiment, the oxazolidinone is
2-oxazolidinone. In a further preferred embodiment as shown in
Scheme 3 below, the C-(protected hydroxymethyl)-2-oxazolidinone is
C-trityloxymethyl-2-oxazolidinone. The
C-trityloxymethyl-2-oxazolidinone is N-arylated (N at position 3)
with a mixture of n different aryl acyl, alkyl, aryl, heteroalkyl,
heteroaryl, heterocycle, aryl sulfonyl, or phenacyl bromides, or
other such bromides under Buchwald conditions (Yin and Buchwald,
Org. Letts. 2: 1101-1104 (2000)) or simple alkylation under
nitrogen to produce
N-(substituted)-C-trityloxymethyl-2-oxazolidinones. The trityl (Tr)
group is then removed by hydrogenation to produce a library of n
N-(substituted)-C-hydroxymethyl-2-oxazolidinones.
##STR00037##
[0094] In a further step, the
N-(substituted)-C-hydroxymethyl-2-oxazolidinones are
O-functionalized acylated with a mixture of n different acyl,
alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl
sulfonyl, amides thereof, or other such species halides, or the O
of the hydroxymethyl is replaced by N-aryl, N-sulfonyl, N-sulfide,
or other N-species, or the O is replaced by a thioalkyl, thioaryl,
or other thio-species. This generates a library of n.sup.2
N-(substituted)-C-(substituted methyl)-2-oxazolidinones. For
example, if ten aryl bromides reagents are used in the first step
and ten halide species reagents in the second step, a total of 100
N-(substituted)-C-(substituted methyl)-2-oxazolidinones are made.
In one embodiment, the starting oxazolidinone is 4-(protected
oxymethyl)-2-oxazolidinone, preferably
4-trityloxymethyl-oxazolidinone, and the n library comprises
3-(substituted)-4-hydroxymethyl-2-oxazolidinone and the n.sup.2
library comprises 3-(substituted)-4-(substituted
methyl)-2-oxazolidinone. In a preferred embodiment, the starting
oxazolidinone is 5-(protected oxymethyl)-2-oxazolidinone,
preferably 5-trityloxymethyl-oxazolidinone, and the n library
comprises 3-(substituted)-5-hydroxymethyl-2-oxazolidinone and the
n.sup.2 library comprises 3-(substituted)-5-(substituted
methyl)-2-oxazolidinone.
[0095] The novel process allows for the rapid synthesis of a
plurality of substituted oxazolidinones including but not limited
to 3-(substituted)-5-(substituted methyl)-oxazolidinones,
3-(substituted)-4-(substituted methyl)-oxazolidinones,
3-(substituted)-5-(substituted methyl)-2-oxazolidinones,
3-(substituted)-4-(substituted methyl)-2-oxazolidinones,
3-(substituted)-5-hydroxymethyl-oxazolidinones,
3-(substituted)-4-hydroxymethyl-oxazolidinones,
3-(substituted)-5-hydroxymethyl-2-oxazolidinones, and
3-(substituted)-4-hydroxymethyl-2-oxazolidinones. The number of
substituted oxazolidinones synthesized by the novel process depends
on the number of substituting reagents included in the process.
Therefore, the use of substituting reagents such as sulfur,
nitrogen, and oxygen nucleophiles on the primary hydroxyl group and
the amine group of the oxazolidinones affords access to a plurality
of families of optically active compounds in a single process which
is fast and simple.
[0096] The substituted oxazolidinones produced by the above process
can be separated using standard chromatography methods and the
separated substituted oxazolidinones screened for biological
activity including antimicrobial activity or for usefulness as a
drug or an intermediate for synthesizing a drug. Technologies and
methods for screening compounds in combinatorial libraries are well
known in the art.
[0097] For any particular substituted oxazolidinone which has
useful characteristics, biological activities, or which is a useful
intermediate for the synthesis of other compounds, the above
process for making the combinatorial library is modified to a
process for making the particular substituted oxazolidinone. The
modified process differs from the process for preparing the library
in that the plurality of reagents shown in Scheme 3 and described
above is replaced with the particular reagents which will result in
the synthesis of the particular substituted oxazolidinone. Thus,
the general method involves the following steps: (1) substituting
the N-group of optically active C-protected oxazolidinone,
preferably trityloxy-2-oxazolidione, by simple alkylation under
nitrogen or N-arylating under Buchwald conditions to produce an
N-substituted oxazolidinone, (2) removing the C-protecting group,
and (3) substituting the hydrogen of the C-4 or C-5 hydroxymethyl
with an alkylation, acylation, arylation, sulfonylation, or other
such species halide, or substituting the hydroxy group with a
thioalkyl, thioaryl, or other thio-group species to replace the 0
of the hydroxymethyl with S, or substituting the hydroxy group
under conditions with an N-acyl, N-sulfonyl, N-sulfide, or other
N-group species to replace the 0 of the hydroxymethyl with N. The
above process enables particular substituted oxazolidinones of any
one of the eight families (Families I to VIII) to be prepared.
[0098] When libraries comprising substituted oxazolidinones
prepared according to the process of the present invention were
tested for antimicrobial activity, many of the substituted
oxazolidinones in the libraries with the genus structure were
discovered to have antimicrobial activity against gram positive and
Gram negative bacteria. In particular, many of the substituted
oxazolidinones were found to be active against Gram positive
bacteria such as those of the genera Staphlococcus and Enterococcus
and Gram negative bacteria such as those of the genera Escherichia
with 90 to 100% Minimum Inhibitory Concentrations (MIC.sub.90-100)
of less than 10 .mu.g/mL. The discovery that many of the novel
substituted oxazolidinones had antibacterial activity was
surprising since the novel substituted oxazolidinones do not
contain all three elements considered necessary for antibacterial
activity. Thus, the novel substituted oxazolidinones represent an
new class of antimicrobial agents which are active against a
variety of bacteria, in particular, Gram positive bacteria such as
Staphylococcus aureus, Pseudomonas aeriginose, pneumococci
(Streptococcus pneumoniae), enterococci (Enterococcus faecium,
Enterococcus faecalis, Enterococcus gallinarum), Groups A, B, C,
and G streptococci, Streptococcus oralis, and Streptococcus sanguis
and Gram negative bacteria such as Escherichia coli.
[0099] Preferably, the substituted oxazolidinones with
antimicrobial activity are embraced by the species of Families I to
VIII. Tables 2 and 3 show examples of substituted oxazolidinones
produced as disclosed herein which have been shown to have
antimicrobial activity. Tables 1 and 2 show the results of analyses
of the antimicrobial activity for several of the substituted
oxazolidinones. The substituted oxazolidinones which are
particularly useful antimicrobials have an MIC.sub.90-100 against
at least one gram positive bacteria of about 300 .mu.g/mL or less,
preferably, of about 100 .mu.g/mL or less, most preferably, of
about 10 .mu.g/mL or less. Because particular strains of these
bacteria species have developed antibiotic resistance, the novel
substituted oxazolidinones are particularly useful for use against
the antibiotic resistant strains of bacteria such as those shown in
Table 1.
[0100] To inhibit or prevent a bacterial infection from developing
in a human or animal or to treat a bacterial infection in a human
or animal patient, compositions comprising a carrier and one or
more of the novel substituted oxazolidinones disclosed herein can
be administered to the human or animal intravenously; by injection;
orally by tablet, capsule, or liquid suspension; or topically.
[0101] For intravenous administration, one or more of the novel
substituted oxazolidinones is dissolved in dimethyl sulfoxide or
other pharmaceutically acceptable organic solvent, which is then
diluted to about 5% (v/v) in a carrier which is a sterile isotonic
solution. A suitable isotonic solution includes sodium citrate,
citric acid, and dextrose wherein the Na.sup.+ content is about
0.38 mg/mL (1.7 mEq/100 mL). Linezolid in the above isotonic
solution has been approved for human use by the U.S. Food and Drug
Administration. The intravenous solution can be applied as 15- to
20-minute infusions or by continuous infusion over an extended time
period through a catheter surgically implanted through the
patient's vein. In particular embodiments, the one or more novel
substituted oxazolidinones is combined with one or more antibiotics
or other antibacterial agents.
[0102] For injection, one or one or more of the novel substituted
oxazolidinones is dissolved in dimethyl sulfoxide or other
pharmaceutically acceptable organic solvent, which is then diluted
to about 5% (v/v) in a carrier which is a sterile isotonic solution
or sterile distilled water. The solution can be administered
subcutaneously, intramuscularly, or peritoneally. In particular
embodiments, one or more the substituted oxazolidinones is combined
with one or more antibiotics or other antibacterial agents.
[0103] For oral administration, one or more of the novel
substituted oxazolidinones is mixed with a pharmaceutically
acceptable carrier and the mixture compressed into a tablet, which
can be film coated, or encapsulated within a pharmaceutically
acceptable capsule. For example, one or more of the novel
oxazolidinones are admixed with a carrier which includes as the
inactive ingredients: corn starch, microcrystalline cellulose,
hydroxy propylcellulose, sodium starch glycolate, magnesium
stearate, hydroxypropyl methylcellulose, polyethylene glycol,
titanium dioxide, and carnauba wax. The admixture is formed into
tablets or encapsulated in capsules. Each tablet or capsule
contains about 0.1 mEq Na.sup.+. Linezolid in a carrier which
includes the above inactive ingredients has been approved for human
use by the U.S. Food and Drug Administration. In particular
embodiments, one or more of the substituted oxazolidinones is
combined with one or more antibiotics or other antibacterial
agents.
[0104] Alternatively, the novel substituted oxazolidinones are
administered orally as a suspension. In this embodiment, one or
more of the novel substituted oxazolidinones is provided in a
pharmaceutically acceptable flavored granule or powder carrier for
constitution into a suspension for oral administration. For
example, one or more of the novel substituted oxazolidinones are
admixed with a granule or powder which includes as the inactive
ingredients: sucrose, citric acid, sodium citrate, microcrystalline
cellulose, carboxy methyl cellulose sodium, aspartame, xanthan gum,
mannitol, sodium benzoate, colloidal silicon dioxide, sodium
chloride, and flavors. Linezolid in a granule or powder containing
the above inactive ingredients has been approved for human use by
the U.S. Food and Drug Administration. In particular embodiments,
one or more of the substituted oxazolidinones is combined with one
or more antibiotics or other antibacterial agents.
[0105] For topical administration, one or more of the substituted
oxazolidinones can be provided in an ointment, a lotion, a cream,
or a gel. In particular embodiments, one or more of the substituted
oxazolidinones is combined with one or more steroids, one or more
antibiotics or other antibacterial agents, or both.
[0106] The following examples are intended to promote a further
understanding of the present invention.
EXAMPLE 1
[0107] This example illustrates the preparation of
(S)-5-trityloxymethyl-2-oxazolidinone using the process disclosed
in U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang.
[0108] In a flask, (S)-3,4-dihydroxybutyramide (11.9 g, 0.10 moles)
was dissolved in 50 mL of tetrahydrofuran (THF) to which 50 mL of
dimethylformamide and 10 mL pyridine was added followed by 30.6 g
(0.11 moles) of trityl chloride. A drying tube filled with calcium
chloride was used to exclude moisture. The reaction mixture was
stirred for 36 hours at room temperature. Afterwards, the reaction
mixture was filtered to remove the solids.
[0109] The liquid was concentrated under reduced pressure to remove
most of the solvent. The concentrate was poured into ice water,
stirred for about half an hour, and then the water layer was
removed from the organic layer containing the 3-Hydroxy-4-trityloxy
butyramide. The product was a semi-crystalline liquid which was
dried in vacuo. Afterwards, the excess trityl chloride was washed
away by tituration with hexane.
[0110] The 3-hydroxy-4-trityloxy butyramide (3.61 g, 0.01 moles)
was dissolved in 30 mL THF. Fifteen mL of a 13% sodium hypochlorite
solution was added and the mixture was stirred vigorously. Next,
1.6 g of sodium hydroxide dissolved in 10 mL of water was added.
The reaction was stirred at 55-60.degree. C. for eight hours after
which time the conversion to 5-trityloxymethyl-2-oxazolidinone was
completed as indicated by TLC and .sup.1H-NMR spectroscopy. The
organic layer was separated from the aqueous layer and saved. The
aqueous layer was extracted three times with THF. The saved organic
layer and the THF extracts were combined and then concentrated to
remove the solvent. The residue was taken up in dichloromethane and
the solution dried over sodium sulfate. Afterwards, the solution
was concentrated to remove the solvent and the oxazolidinone was
obtained as a white crystalline product (3.4 g, yield 95%).
Normally, this crude product did not need further purification.
EXAMPLE 2
[0111] This comparative example illustrates the N-arylation of
5-trityloxymethyl-2-oxazolidinone to produce
(S)-3-(2-nitro)phenyl-5-trityloxymethy)-2-oxazolidinone using the
procedure disclosed in Shakespeare, Tetrahedron Lett. 40: 2035-2038
(1999).
[0112] To 36 mg of 5-trityloxymethyl-2-oxazolidinone, 30 mg (1.5
equivs) 1-bromo-2-nitrobenzene, 2.4 mg (0.1 equivs) palladium (II)
acetate, 5.5 mg (0.1 equivs) 1,1'-bis(diphenylphosphino)-ferrocene,
16 mg (0.15 equivs) potassium t-butoxide, and 1 mL toluene were
added under a nitrogen atmosphere. The mixture was heated at
110.degree. C. for 14 hours after which time the mixture was
resolved by thin-layer chromatography (TLC) comprising silica with
dichloromethane as the eluant.
[0113] The TLC indicated complete conversion to a single product:
(S)-3-(2-nitro)phenyl-5-trityloxymethyl-2-oxazolidinone. The
mixture was cooled and diluted with dichloromethane. The dark brown
organic solution was washed with 5% sodium carbonate, concentrated,
and chromatographed on silica gel using dichloromethane as the
eluant. The product (47 mg, 98%) was obtained as a pale yellow
solid which crystallized from chloroform:methanol as off-white
crystals with a melting point of 236-237.degree. C. The product was
analyzed by .sup.1H-NMR, .sup.13C NMR, IR, MS, and HRMS.
[0114] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.03 (dd, 1H,
J=8.0, 2.1 Hz), 7.65 (td, 1H, J=8.0, 2.1 Hz), 7.46-7.53 (m, 6H),
7.44 (td, 1H, J=8.0, 2.1 Hz), 7.20-7.36 (m, 10H), 4.83 (m, 1H),
4.07 (t, 1H, J=8.5 Hz), 3.89 (t, 1H, J=8 Hz), 3.58 (dd, 1H, J=11.8,
4.5 Hz), 3.36 (dd, 1H, J=11.8, 4.5 Hz). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 176.4, 143.5, 134.1, 131.7, 127.6, 87.5, 73.4,
64.0, 49.4. IR cm.sup.-1 3057, 2924, 1760, 1607, 1532, 1489, 1449,
1411, 1355. MS (electron impact) m/z 57, 71, 91, 105, 131, 165,
243, 259, 403, 463, 480 (M.sup.+). HRMS (electron impact) analyzed
for C.sub.29H.sub.24N.sub.2O.sub.5:theoretical MW 480.1685,
observed MW 480.1683.
EXAMPLE 3
[0115] This example illustrates the preparation of a library of
substituted 2-oxazolidinones, which are members of Family II,
according to the process of the present invention. In this example,
(S)-5-trityloxymethyl-2-oxazolidinone is N-acylated with
2,5-dimethoxyphenacyl bromide, detritylated, and then acylated with
ten different acyl halides or anhydrides to produce a library of
n=10 3-(2,5-dimethoxyphenacyl)-5-(substituted
methyl)-2-oxazolidinones.
[0116] In the first step (FIG. 1A),
(S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone was
produced in a reaction comprising
(S)-5-trityloxymethyl-2-oxazolidinone and the aryl bromide:
2,5-dimethoxyphenacyl bromide. To a solution of 3.59 g (10 mmoles)
of(S)-5-trityloxymethyl-2-oxazolidinone (MW 359.2) in 40 mL THF at
4.degree. C., 400 mg (10 mmoles) NaH (MW 24) as a 60% suspension in
hexane was added. The reaction mixture was stirred for about 10
minutes under nitrogen at 0.degree. C. and then warmed up to room
temperature and stirred for an additional two hours. Then, 2.59 g
(10 mmoles) of 2-bromo-4'dimethoxyacetophenone (MW 259.1) was added
and the reaction mixture stirred at room temperature for about
eight hours. Afterwards, the reaction was quenched by adding 20 mL
20% NH.sub.4Cl. The organic layer was removed and saved. The
aqueous layer was extracted two times with 40 mL aliquots of THF.
The THF extracts were combined with the saved organic layer and the
mixture dried with 2.5 g anhydrous Na.sub.2SO.sub.4. The mixture
was then concentrated in vacuo to provide a crude product. The
crude product was purified by flash column chromatography using 40%
EtOAc:Hexane followed by 60% EtOAc:Hexane. This produced 2.73 g
(51% yield) of the
(S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone
(product) (MW 537.6). The product was compared to the starting
material by TLC using 40% EtOAC/Hexane as the solvent. The Rf of
the starting material was 0.2 and the Rf of the product was
0.4.
[0117] In the second step (FIG. 1B), the trityl group was removed
from the
(S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone. To
1.07 g (2.0 mmoles) of
(S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone in
wet CH.sub.2Cl.sub.2 (8 mL CH.sub.2Cl.sub.2, 1 mL H.sub.2O), 0.14
mL CF.sub.3CO.sub.2H (210 mg, 1.8 mmoles) (MW 114.02) was added and
the reaction mixture stirred for about four hours.
[0118] Afterwards, the reaction was quenched by adding 0.2 mL
triethylamine and the reaction mixture concentrated in vacuo. The
residue was purified by flash chromatography to produce 472 mg (80%
yield) of
(S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone
(product) (MW 295.29). The product was compared to the starting
material by TLC using 80% EtOAC:Hexane as the solvent. The Rf of
the starting material was 0.7 and the Rf of the product was
0.1.
[0119] In the third step (FIG. 1C), the library of ten substituted
2-oxazolidinones was produced in a reaction comprising the
(S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone and
the ten different acetyl chlorides shown in FIG. 2. To about 295 mg
(1.0 mmoles) of
(S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone in
dry CH.sub.2Cl.sub.2 (8 mL CH.sub.2Cl.sub.2), 1.0 equiv. (1.1
mmoles) of pyridine was added and the reaction mixture stirred at
room temperature. To this reaction mixture was added 1.0 equiv. of
a mixture of ten different acetyl chlorides. The reaction was
stirred overnight at room temperature. Afterwards, TLC of an
aliquot indicated that complete conversion of the
(S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone to
(S)-3-(2,5-dimethocyphenacyl)-5-(substituted
methyl)-2-oxazolidinone had occurred. Therefore, about 3 mL of 20%
NH.sub.4Cl was added to the reaction mixture and the organic layer
removed and saved. The aqueous layer was extracted two times with
40 mL aliquots of CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extracts
were combined with the saved organic layer and the mixture dried
with 2.5 g anhydrous Na.sub.2SO.sub.4. The mixture was then
concentrated in vacuo to provide a crude product. The crude product
was analyzed by .sup.1H-NMR, .sup.13C NMR, HPLC, and TLC using a
EtOAc:hexane (2:1) solvent system.
[0120] An HPLC profile of the
(S)-3-(2,5-dimethocyphenacyl)-5-(substituted
methyl)-2-oxazolidinone products made is shown in FIG. 3. The
products represented by the peaks in the HPLC are shown in FIG. 4.
This example illustrates the principle of the present invention. As
shown by this example, providing n=10 acetyl halides in a single
reaction produces 10 (S)-3-(2,5-dimethocyphenacyl)-5-(substituted
methyl)-2-oxazolidinone products. If n=10 aryl bromides had been
used as well to arylate the N at the 3-position, the process would
have generated 100 (S)-3-(substituted)-5-(substituted
methyl)-2-oxazolidinone products.
EXAMPLE 4
[0121] The substituted oxazolidinone
(S)-3-(3,3-dimethyl-2-butone)-5-(4-nitro-benzenesulfonyloxymethyl)-2-oxaz-
olidinone
##STR00038##
is prepared as follows.
[0122] In the first step,
(S)-3-(3,3-dimethyl-2-butone)-5-trityloxymethyl-2-oxazolidinone is
produced in a reaction comprising
(S)-5-trityloxymethyl-2-oxazolidinone and
BrCH.sub.2COC(CH.sub.3).sub.3. To a solution of about 10 mmoles of
(S)-5-trityloxymethyl-2-oxazolidinone in 40 mL tetrahydrofuran
(THF) at 4.degree. C., 10 mmoles NaH as a 60% suspension in hexane
is added. The reaction mixture is stirred for about 10 minutes
under nitrogen at 0.degree. C. and then warmed up to room
temperature and stirred for an additional two hours.
[0123] Then, about 10 mmoles of BrCH.sub.2COC(CH.sub.3).sub.3 is
added and the reaction mixture stirred at room temperature for
about eight hours. Afterwards, the reaction is quenched by adding
20 mL 20% NH.sub.4Cl. The organic layer is removed and saved. The
aqueous layer is extracted two times with 40 mL aliquots of THF.
The THF extracts are combined with the saved organic layer and the
mixture dried with 2.5 g anhydrous Na.sub.2SO.sub.4. The mixture is
then concentrated in vacuo to provide
(S)-3-(3,3-dimethyl-2-butone)-5-trityloxymethyl-2-oxazolidinone as
a crude product. The crude product is purified by flash column
chromatography using 40% EtOAc:Hexane followed by 60% EtOAc:Hexane.
The product is compared to the starting material by TLC using 40%
EtOAC/Hexane as the solvent.
[0124] In the second step, the trityl group is removed from the
(S)-3-(3,3-dimethyl-2-butone)-5-trityloxymethyl-2-oxazolidinone. To
about 2.0 mmoles of the crude product in wet CH.sub.2Cl.sub.2 (8 mL
CH.sub.2Cl.sub.2, 1 mL H.sub.2O), 0.14 mL CF.sub.3CO.sub.2H (1.8
mmoles) is added and the reaction mixture stirred for about four
hours. Afterwards, the reaction is quenched by adding 0.2 mL
triethylamine and the reaction mixture concentrated in vacuo. The
residue is purified by flash chromatography to produce
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone.
The product can be compared to the starting material by TLC using
80% EtOAC:Hexane as the solvent to determine the yield.
[0125] In the third step, the
(S)-3-(3,3-dimethyl-2-butone)-5-(4-nitro-benzenesulfonyloxymethyl)-2-oxaz-
olidinone is produced in a reaction comprising the
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone and
nitrobenzenesulfonyl chloride. To about 1.0 mmoles of the
((S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone in
dry CH.sub.2Cl.sub.2 (8 mL CH.sub.2Cl.sub.2), 1.0 equiv. (1.1
mmoles) of pyridine is added and the reaction mixture stirred at
room temperature. To this reaction mixture is added 1.0 equiv. of
compound nitrobenzenesulfonyl chloride. The reaction is stirred
overnight at room temperature. Afterwards, an aliquot of the
reaction is analyzed by TLC to determine whether complete
conversion of the
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone to
the substituted oxazolidinone has occurred. Thereafter, about 3 mL
of 20% NH.sub.4Cl is added to the reaction mixture and the organic
layer is removed and saved. The aqueous layer is extracted two
times with 40 mL aliquots of CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2
extracts are combined with the saved organic layer and the mixture
is dried with 2.5 g anhydrous Na.sub.2SO.sub.4. The mixture is then
concentrated in vacuo to provide a crude product of the substituted
oxazolidinone. The crude product is analyzed by .sup.1H-NMR,
.sup.13C NMR, HPLC, and TLC using a EtOAc:hexane (2:1) solvent
system and is further purified by standard chromatography
methods.
EXAMPLE 5
[0126] The substituted oxazolidinone
(S)-3-(3,3-dimethyl-2-butone)-5-(4-isocyanobenzenesulfonyloxymethyl)-2-ox-
azolidinone
##STR00039##
is prepared as follows.
[0127]
(S)-3-(3,3-dimethyl-2-butone)-5-hydroxymethyl-2-oxazolidinone is
prepared as in Example 4. Then the
(S)-3-(3,3-dimethyl-2-butone)-5-(4-isocyanobenzenesulfonyloxymethyl)-2-ox-
azolidinone is produced in a reaction comprising the
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone and
isocyanobenzenesulfonyl chloride as follows.
[0128] To about 1.0 mmoles of the
((S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone in
dry CH.sub.2Cl.sub.2 (8 mL CH.sub.2Cl.sub.2), 1.0 equiv. (1.1
mmoles) of pyridine is added and the reaction mixture stirred at
room temperature. To this reaction mixture is added 1.0 equiv. of
isocyanobenzenesulfonyl chloride. The reaction is stirred overnight
at room temperature. Afterwards, an aliquot of the reaction is
analyzed by TLC to determine whether complete conversion of the
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone to
the substituted oxazolidinone has occurred. Thereafter, about 3 mL
of 20% NH.sub.4Cl is added to the reaction mixture and the organic
layer is removed and saved. The aqueous layer is extracted two
times with 40 mL aliquots of CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2
extracts are combined with the saved organic layer and the mixture
is dried with 2.5 g anhydrous Na.sub.2SO.sub.4. The mixture is then
concentrated in vacuo to provide a crude product of the substituted
oxazolidinone. The crude product is analyzed by .sup.1H-NMR,
.sup.13C NMR, HPLC, and TLC using a EtOAc:hexane (2:1) solvent
system and is further purified by standard chromatography
methods.
EXAMPLE 6
[0129] The substituted oxazolidinone
(S)-3-(3,3-dimethyl-2-butone)-5-(7-chloro-2,1,3-benzoxadiazole-4-sulfonyl-
oxymethyl)-2-oxazolidinone (34)
##STR00040##
is prepared as follows.
[0130]
(S)-3-(3,3-dimethyl-2-butone)-5-hydroxymethyl-2-oxazolidinone is
prepared as in Example 4. The substituted oxazolidinone 34 is then
produced in a reaction comprising the
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone and
7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride as follows.
[0131] To about 1.0 mmoles of the
((S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone in
dry CH.sub.2Cl.sub.2 (8 mL CH.sub.2Cl.sub.2), 1.0 equiv. (1.1
mmoles) of pyridine is added and the reaction mixture stirred at
room temperature. To this reaction mixture is added 1.0 equiv. of
compound 7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride. The
reaction is stirred overnight at room temperature. Afterwards, an
aliquot of the reaction is analyzed by TLC to determine whether
complete conversion of the
(S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone to
the substituted oxazolidinone 34 has occurred. Thereafter, about 3
mL of 20% NH.sub.4Cl is added to the reaction mixture and the
organic layer is removed and saved. The aqueous layer is extracted
two times with 40 mL aliquots of CH.sub.2Cl.sub.2. The
CH.sub.2Cl.sub.2 extracts are combined with the saved organic layer
and the mixture is dried with 2.5 g anhydrous Na.sub.2SO.sub.4. The
mixture is then concentrated in vacuo to provide a crude product of
the substituted oxazolidinone 34. The crude product is analyzed by
.sup.1H-NMR, .sup.13C NMR, HPLC, and TLC using a EtOAc:hexane (2:1)
solvent system and is further purified by standard chromatography
methods.
EXAMPLE 7
[0132] The substituted oxazolidinone
(S)-3-(3-butene-2-one)-5-(7-chloro-2,1,3-benzoxadiazole-4-sulfonyloxymeth-
yl)-2-oxazolidinone
##STR00041##
is prepared as follows.
[0133] In the first step,
(S)-3-(3-butene-2-one)-5-trityloxymethyl-2-oxazolidinone is
produced in a reaction comprising
(S)-5-trityloxymethyl-2-oxazolidinone and BrCHCHCOCH.sub.3. To a
solution of about 10 mmoles of
(S)-5-trityloxymethyl-2-oxazolidinone in 40 mL tetrahydrofuran
(THF) at 4.degree. C., 10 mmoles NaH as a 60% suspension in hexane
is added. The reaction mixture was stirred for about 10 minutes
under nitrogen at 0.degree. C. and then warmed up to room
temperature and stirred for an additional two hours. Then, about 10
mmoles of BrCHCHCOCH.sub.3 is added and the reaction mixture
stirred at room temperature for about eight hours. Afterwards, the
reaction is quenched by adding 20 mL 20% NH.sub.4Cl. The organic
layer is removed and saved. The aqueous layer is extracted two
times with 40 mL aliquots of THF. The THF extracts are combined
with the saved organic layer and the mixture dried with 2.5 g
anhydrous Na.sub.2SO.sub.4. The mixture is then concentrated in
vacuo to provide
(S)-3-(3-butene-2-one)-5-trityloxymethyl-2-oxazolidinone as a crude
product. The crude product is purified by flash column
chromatography using 40% EtOAc:Hexane followed by 60% EtOAc:Hexane.
The product is compared to the starting material by TLC using 40%
EtOAC/Hexane as the solvent.
[0134] In the second step, the trityl group is removed from the
(S)-3-(3-butene-2-one)-5-trityloxymethyl-2-oxazolidinone as in
Example 4 to produce
(S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone.
[0135] In the third step, the substituted oxazolidinone is produced
in a reaction comprising the
(S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone and
7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride. To about 1.0
mmoles of the
((S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone in dry
CH.sub.2Cl.sub.2 (8 mL CH.sub.2Cl.sub.2), 1.0 equiv. (1.1 mmoles)
of pyridine is added and the reaction mixture stirred at room
temperature. To this reaction mixture is added 1.0 equiv. of
7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride. The reaction is
stirred overnight at room temperature. Afterwards, an aliquot of
the reaction is analyzed by TLC to determine whether complete
conversion of the
(S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone to the
substituted oxazolidinone has occurred. Thereafter, about 3 mL of
20% NH.sub.4Cl is added to the reaction mixture and the organic
layer is removed and saved. The aqueous layer is extracted two
times with 40 mL aliquots of CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2
extracts are combined with the saved organic layer and the mixture
is dried with 2.5 g anhydrous Na.sub.2SO.sub.4. The mixture is then
concentrated in vacuo to provide a crude product of the substituted
oxazolidinone. The crude product is analyzed by .sup.1H-NMR,
.sup.13C NMR, HPLC, and TLC using an EtOAc:hexane (2:1) solvent
system and is further purified by standard chromatography
methods.
EXAMPLE 8
[0136] The substituted oxazolidinones were tested for antimicrobial
activity as follows.
[0137] The following American Type Culture Collection (ATCC, 10801
University Boulevard, Manassas, Va.) quality control strains were
selected for the initial screening of the antimicrobial properties
of the substituted oxazolidinones as suggested by the NCCLS:
Enterococcus faecalis 29212, Escherichia coli 25922, Pseudomonas
aeruginosa 27853, and Staphylococcus aureus 29213. See, NCCLS
document M7-A5. Methods for Dilution Antimicrobial Susceptibility
Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth
Edition. Volume 20, Number 2. January 2000, (ISBN 1-56238-394-9)
and Lorian V. Antibiotics. Laboratory Medicine. 4th ed. Baltimore:
Williams and Wilkins, pp. 52-111 (1996). For subsequent testing,
the following strains have been used: Staphylococcus aureus NRS4
(992; HIP5836; New Jersey) (Smith et al., New Engl. J. Med. 340:
493-501 (1999); Tenover et al., J. Clin. Microbiol. 36: 1020-1027
(1998)), Staphylococcus aureus NRS3 (963 sm; HIP5827; Michigan)
(Smith et al., ibid.; Tenover et al., ibid.), Staphylococcus aureus
NRS103 (Becker) (Karakawa and Vann, Sem. Infect. Dis. 4: 285
(1982), Staphylococcus aureus NRS102 (Reynolds) Karakawa and Vann,
ibid; McMurray et al., JID 162: 759-762 (1990)), Staphylococcus
epidermidis NRS101 (ATCC 35984), Streptococcus pneumoniae (ATCC
49619), Enterococcus faecalis (ATCC 51299), and Staphylococcus
aureus (ATCC 43300.
[0138] Stock cultures of these strains were obtained by seeding
colonies from overnight streak plates (Tryptic Soy Agar II (TSAII)
and 5% sheep's blood (SB) agar plates: Becton Dickinson,
CA#2211261) into sterile Mueller-Hinton Broth (MHB)(Becton
Dickinson, CA#211443) and growing the suspensions to mid-late log
phase in 13 mL screw-cap tubes. Glycerol (Sigma, CA#G-6279) was
sterilized by autoclaving for 15 minutes at 121.degree. C. in 6 mL
volumes, and then stored at 2-8.degree. C. This was diluted to 20%
in dH.sub.2O, and then added 1:1 (250 .mu.L:250 .mu.L, 10% final
glycerol concentration) to the logarithmically growing bacterial
suspension of each strain. Tubes were frozen and stored at
-70.degree. C. Purity of the stock cultures was tested by thawing
one tube of each strain in a water bath at 37.degree. C. and
plating them on TSAII with 5% SB. Plates were incubated overnight
at 37.degree. C. and colonies were examined for morphology. Growth
curves and approximate CFU/mL were also obtained.
[0139] DMSO susceptibility determinations were performed as
follows. DMSO (Alfa Aesar, CA#22914) was diluted to 2.times. the
final starting concentration of 20% in MHB, pH 7.36 (this was the
consistent pH value of MHB) (should be between 7.2-7.4 according to
NCCLS). Two-fold serial dilutions were performed in 15 mL conical
tubes and poured into sterile reservoirs. Using an 8-channel
micropipetman, 50 .mu.L from each reservoir was transferred to
every well in the corresponding column (1-11) of a sterile 96-well,
U-bottom microplate (Nalge Nunc, Intl., CA#262162). As a positive
growth control, 50 .mu.L of MHB alone was added to each well of
Column 12. Bacteria were grown overnight on TSAII+5% SB, and 3-4
colonies were seeded into 6 mL of sterile MHB in 13 mL screw cap
tubes. Tubes were grown at 35.degree. C. to mid-log phase, and were
diluted to an optical density of 0.12 at 625 nm (or approx.
1.times.10.sup.8 CFU/mL), using 0.9% sterile saline. This solution
was further diluted 1:100 with 0.9% sterile saline
(1.times.10.sup.6 CFU/mL), and 50 .mu.L was added to each well for
a final inoculum of 1.times.10.sup.5 CFU/mL. As a negative growth
control, well H12 was inoculated only with 0.9% sterile saline. The
plate was tightly fitted with sealing tape (Corning Costar,
CA#3095) and was incubated for a period of 18 hours at 35.degree.
C., after which growth was observed. 2.5% DMSO was determined to be
the smallest concentration of DMSO to exhibit no visual effects on
bacterial growth as compared with the positive controls for all
strains tested. This was confirmed by performing colony counts to
assess cell viability in the presence of DMSO. For each strain, 10
.mu.L was removed from one of the inoculated wells containing 2.5%,
0.15%, and 0% DMSO (after mixing). This was diluted 1:100000 in
sterile 0.9% DMSO, plated on TSAII+5% SB, and grown overnight at
35.degree. C. Plates were then observed for differences in the
number of viable colonies (theoretically, each colony arises from a
single cell) based on the varying concentrations of DMSO. No
differences were observed.
[0140] High purity substituted oxazolidinones prepared according to
the method of the present invention and a ZYVOX standard (ZYVOX is
a trade name for linezolid available from Pharmacia Corporation)
were provided by Synthon Corporation, Monmouth Junction, NJ.
Compounds were dissolved at 10 mg/mL in DMSO, as after a dilution
of approx. 39.0 to reach the desired final starting concentration
of 256 .mu.g/ml, the concentration of DMSO is approximately 2.5%.
Compounds were then stored at room temperature (25.degree. C.) in
the dark.
[0141] Antimicrobial susceptibility screening was as follows. All
compounds were initially screened for activity in duplicate at 256
.mu.g/mL (2.5% DMSO), including ZYVOX, the positive control for
antimicrobial activity. A single well of bacterially inoculated
2.5% DMSO served as a positive control for bacterial growth, while
a well of DMSO inoculated with of 50 .mu.L of sterile 0.9% saline
served as a negative growth control. Controls were prepared on
every microplate, so that 46 was the maximum number of compounds
that were screened per plate. Broth was pipetted into sterile
microcentrifuge tubes, to which the compounds were then added
(1:19.53 dilution or 2.times. final concentration). Each tube was
vortexed, and 50 .mu.L was immediately transferred to the
microplate wells for each strain. Solubility was assessed by visual
observation. MB (medium broth solubility) was recorded if the
solution appeared only slightly cloudy. LB (low broth solubility)
was recorded if the solution was extremely cloudy, and especially
if larger, clumpy precipitates formed. Bacteria were grown as
described above, although absorbance was measured at 650 nm and
bacteria were diluted to an initial OD of 0.12-0.15. Bacteria were
then further diluted 1:100 with 0.9% sterile saline. Within 15
minutes of this final dilution, 50 .mu.L of this suspension was
added to each well for a final volume of 0.1 L, and a final
bacterial concentration of 1.times.10.sup.5 CFU/mL (except for the
negative control well). Plates were grown as above and all
observations were recorded.
[0142] Compounds exhibiting activity at this concentration were
then screened for their MICs (minimum inhibitory concentration) in
duplicate, at concentrations ranging from 256-0.25 .mu.g/mL
(columns 1-11) using the broth microdilution method. Two-fold
dilutions were obtained using an 8-channel micropipetman and tips
were changed between each column transfer, after mixing 10 times
and expelling the maximum amount of fluid. The MIC was defined as
the lowest concentration of test compound that inhibited visible
growth after a period of 18 hours incubation at 35.degree. C.
Bacteria were prepared, and the microwell plates were incubated as
described above. In addition, bacteria were routinely sampled
before addition to the wells. From the pre-well concentration,
samples were diluted 1:200 with 0.9% sterile saline. At this
concentration, 100 .mu.L was plated and the remaining sample was
diluted 1:10. 100 .mu.L of this was then also spread-plated onto
TSAII+5% SB and grown overnight at 35.degree. C. Colonies were
counted and multiplied by the dilution factor to obtain starting
CFU/mL. As a positive MIC control, ZYVOX was tested in parallel for
each strain, and the dilution of 5% (2.times. final concentration)
DMSO served as a positive growth control. To control for variation
between the volume transferred by each tip of the 8-channel
micropipetman, 5% (2.times. final concentration) DMSO was added to
column 12 using the micropipetman. All wells, but that of the
negative control (H12), were inoculated with the same bacterial
suspension resulting in a final starting concentration of
1.times.10.sup.5 CFU/mL. The negative control was inoculated with
0.9% sterile saline.
[0143] At this time, a total of 1625 substituted oxazolidinones
have been successfully screened for activity at 256 .mu.g/mL
(Compounds 1422, 1474, 147$, 1595 were absent). Of these, 71 were
tested against Staphylococcus aureus (Gram positive), 60 were
tested against Enterococcus faecalis (Gram positive), and one
compound tested against Escherichia coli (Gram negative) have
proven effective with MICs at or below 256 .mu.g/mL.
[0144] Tables 1 and 2 show the antimicrobial activity for several
of the substituted oxazolidinones. Table 1 further shows that
several were also able to inhibit the growth of myeloid, erythroid,
and megakaryocytic cells. Table 3 shows several substituted
oxazolidinones which have been found to be particularly
antimicrobial. In general, many of the substituted oxazolidinones
were as effective as ZYVOX. Thus, the results show that many of the
substituted oxazolidinones prepared according to the process herein
have antimicrobial applications, in particular, as antimicrobial
agents against drug resistant strains of gram positive
bacteria.
TABLE-US-00001 TABLE 1 In Vitro Antimicrobial Test Results for
Several Substituted Oxazolidinones MIC.sub.90-100 (.mu.g/mL) Bone
Marrow Cell Growth Inhibition Pen. R (IC.sub.50 .mu.g/mL) SA EF MR
SA MR SA VS EF MR SA SA Ref SA Myeloid Erythroid Megakaryocytic
Strain ATCC ATCC New Michigan ATCC ATCC Reynolds Becker 29212 29213
Jersey 51299 43300 Compound 1687 2 2 2 2 3 3 20 0.01 6 1705 2 4 3 2
8 4 32 4 5 0.5 0.08 1715 2 4 3 3 8 4 32 8 5 0.7 0.08 1808 4-8 2 4 3
2 8 16 16 1809 4-8 4 3 3 2 4 8 4 2278 4 2 4 4 8 8 2405 2 2 4 2 8 4
2428 4 4 4-8 4-8 32 16 1021 16-32 250 256 256 >256 100 20 20 0.9
1192 4-8 250 256 256 >256 128 5 0.05 0.6 126 8-16 250 256 256
256 256 5 0.02 9.0 207 64-125 250 0.8 0.2 3.0 253 8-16 250 256 256
>256 >256 30 7 10.0 971 4-8 250 256 256 >256 100 40
>0.01 30.0 ZYVOX 2 2 2 2 0.5 1 1 1 20 0.08 4 VR is vancomycin
resistant, VS is vancomycin sensitive, MR is methicillin resistant,
MS is methicillin sensitive, SA is Staphylococcus aureus, and EF is
Entercoccus faecalis.
TABLE-US-00002 TABLE 2 MIC.sub.(90-100)(ug/mL)
MIC.sub.(90-100)(ug/mL) COMPOUND COMPOUND # SA-ATCC29213
EF-ATCC29212 ##STR00042## 34 250 ##STR00043## 108 62.5 ##STR00044##
110 31.3 ##STR00045## 126 15.6 ##STR00046## 235 62.5 ##STR00047##
236 31.3 ##STR00048## 250 250 ##STR00049## 253 15.6 ##STR00050##
254 125 ##STR00051## 255 62.5 250 ##STR00052## 260 250 ##STR00053##
266 15.6 ##STR00054## 272 250 ##STR00055## 276 125 250 ##STR00056##
285 62.5 250 ##STR00057## 291 250 ##STR00058## 294 31.3 250
##STR00059## 323 250 125 ##STR00060## 324 62.5 250 ##STR00061## 334
62.5 ##STR00062## 369 250 31.3 ##STR00063## 388 125 ##STR00064##
401 250 62.5 ##STR00065## 533 125 ##STR00066## 589 125 ##STR00067##
669 62.5 ##STR00068## 674 250 125 ##STR00069## 695 62.5
##STR00070## 771 15.6 ##STR00071## 860 64 ##STR00072## 870 16
##STR00073## 905 256 ##STR00074## 921 256 ##STR00075## 924 256
##STR00076## 929 64 ##STR00077## 942 32 ##STR00078## 952 32
##STR00079## 971 8 ##STR00080## 1001 64 125 ##STR00081## 1021 32
##STR00082## 1026 256 ##STR00083## 1058 256 ##STR00084## 1063 16
##STR00085## 1066 256 ##STR00086## 1081 256 ##STR00087## 1097 32
##STR00088## 1160 128 ##STR00089## 1192 8 ##STR00090## 1196 256 128
##STR00091## 1210 256 ##STR00092## 1411 64 128 ##STR00093## 1629
256 64 ##STR00094## 1631 16 16 ##STR00095## 1632 16 64 ##STR00096##
1808 8 2 ##STR00097## 1809 8 4 ##STR00098## 1960 32 8 ##STR00099##
1965 32 8 ##STR00100## 1985 8 124 ##STR00101## 1998 16 64
##STR00102## 2017 16 8 ##STR00103## 2019 16 32 ##STR00104## 2020 64
124 ##STR00105## 2023 64 32 ##STR00106## 2025 64 32
TABLE-US-00003 TABLE 3 External ID internal ID Structure SCC 001
126 ##STR00107## SCC 002 207 ##STR00108## SCC 003 253 ##STR00109##
SCC 004 971 ##STR00110## SCC 005 1021 ##STR00111## SCC 006 1192
##STR00112## SCC 007 1687 ##STR00113## SCC 008 1705 ##STR00114##
SCC 009 1715 ##STR00115## SCC 010 1808 ##STR00116## SCC 011 1809
##STR00117## SCC 012 2278 ##STR00118## SCC 013 2405 ##STR00119##
SCC 014 2428 ##STR00120## SCC 015 2570 ##STR00121## Standard Zyvox
##STR00122##
EXAMPLE 9
[0145] This example shows the synthesis of various examples of the
substituted oxazolidinones.
A. Sulphonates and Esters
1. Synthesis of Precursors
N-Ethyl 5-hydroxymethyl-2-oxazolidinone
##STR00123##
[0147] To a solution containing the oxazolidinone (5.0 g, 13.9
mmol) in dry THF (50 mL) was added potassium-t-butoxide (2.03 g,
18.1 mmol, 1.3 equiv) at RT and stirred under N.sub.2 atm for 0.5
h. To this solution was added ethyl iodide (3.25 g, 20.8 mmol, 1.5
equiv) and stirred for 2 h after which TLC (1:1 hex-EtOAc) showed
completion of reaction. The reaction was quenched by adding satd.
NH.sub.4Cl solution. THF was removed on rotovap and residue diluted
with CH.sub.2Cl.sub.2 (100 mL). Organic layer washed with brine and
dried (MgSO.sub.4). Removal of solvent gave a light yellow oil.
This crude product was taken in CH.sub.2Cl.sub.2 (50 mL). Added
trifluoroacetic acid (4.75 g, 41.7 mmol, 3.0 equiv)-water (1.0 g,
55.5 mmol, 4 equiv) dropwise and stirred for 2 h. The solvent was
removed on rotovap and residue purified by flash column
chromatography (silica gel, EtOAc) to get the product as a
colorless oil (1.3 g, 66% in two steps).
[0148] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 4.6 (m, 1H), 4.1
(s, 1H), 3.88 (dd, 1H) 3.6 (m, 5H), 1.2 (t, 3H). .sup.13C NMR
(CDCl.sub.3, 50 MHz): .delta. 157.86, 73.45, 62.69, 45.01, 38.59,
12.22.
[0149] A similar procedure was followed for the alkylation of the
oxazolidinone with B12 (R&S), B38(R&S), B39, E11(R&S),
E16(R&S), E81(R&S), G3(R&S), G4-oxa-C4, W14, W15, W17,
W19 and W23.
##STR00124## ##STR00125##
N-isopropyl-5-trityloxymethyl-2-oxazolidinone
##STR00126##
[0151] To a solution containing the oxazolidinone (15.0 g, 41.7
mmol) in dry THF (150 mL) was added potassium-t-butoxide (8.4 g,
75.0 mmol, 1.8 equiv) at RT and stirred under N.sub.2 atm for 0.5
h. To this solution was added isopropyl iodide (7.8 g, 45.9 mmol,
1.1 equiv) and stirred at 70.degree. C. for 15 h. The reaction was
quenched by adding satd. NH.sub.4Cl solution. THF was removed on
rotovap and residue diluted with CH.sub.2Cl.sub.2 (200 mL). Organic
layer washed with brine and dried (MgSO.sub.4). Removal of solvent
gave a light yellow oil. The residue was purified by flash column
chromatography (silica gel, hexane-EtOAc, 4:1) to get the product
as a colorless solid (15.0 g, 90%).
[0152] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.3 (m, 15H),
4.56 (m, 1H), 4.1 (m, 1H), 3.3 (m, 4H), 1.1 (m, 6H). .sup.13C NMR
(CDCl.sub.3, 50 MHz): .delta. 157.0, 143.4, 128.6, 127.9, 127.2,
86.8, 71.9, 64.0, 44.6, 41.6, 19.8, 19.6.
Synthesis of ethyl (2-bromo)-t-butyl ketone (Class G4)
##STR00127##
[0154] To a suspension of SnBr.sub.2 (242 mg, 5 mol %) in
CH.sub.2Cl.sub.2 (5.0 mL) was added pinacolone trimethylsilyl enol
ether (3.0 g, 17.4 mmol) in CH.sub.2Cl.sub.2 (2.0 mL) followed by
bromomethyl methylether (3.26 g, 26.1 mmol, 2.1 mL, 1.5 equiv) in
CH.sub.2Cl.sub.2 (2.0 mL). Stirred at RT for 3.5 h after which TLC
showed complete conversion. The solvent was removed on rotovap to
get an orange yellow liquid. The crude product was passed through a
short pad of silica packed in hexane and the product was eluted
with 5% EtOAc-hexanes as a pale yellow liquid (2.65 g, 79%).
[0155] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 3.54 (t, 2H),
3.06 (t, 2H), 1.12 (s, 9H). .sup.13C NMR (CDCl.sub.3, 50 MHz):
.delta. 212.4, 43.9, 39.6, 26.0.
[0156] Homologation of t-butylacetyl chloride
##STR00128##
[0157] t-Butylacetyl chloride (4.0 g, 29.7 mmol) was added dropwise
to a solution of trimethylsilyldiazomethane (37.1 mL, 74.3 mmol) in
CH.sub.3CN-THF (100 mL, 1:1) at 0.degree. C. added the
t-butylacetyl chloride (4.0 g, 29.7 mmol) dropwise and then
refrigerated for 40 h. Solvent was removed on rotovap and residue
diluted with CH.sub.2Cl.sub.2(100 mL). Washed with satd.
NaHCO.sub.3(50 mL) solution followed by brine, dried (MgSO.sub.4)
and concentrated to an yellow liquid (4.5 g). This product was
taken in THF (25 mL) and cooled to 0.degree. C. and added HBr (48%)
(8.4 g, 104.0 mmol, 3.5 equiv) dropwise. After the addition,
reaction mixture stirred at that temp for 30 min. Diluted with
CH.sub.2Cl.sub.2 (75 mL) and washed with satd. NaHCO.sub.3(50 mL)
followed by brine, dried (MgSO.sub.4) and concentrated to an yellow
liquid. Purified by column chromatography (silica gel) and the
product was eluted with 2-4% EtOAc-hexane. Pale yellow liquid (3.3
g, 82.5%).
[0158] .sub.1H NMR (CDCl.sub.3, 200 MHz): .delta. 3.84 (s, 2H),
2.48 (s, 2H), 0.98 (s, 9H). .sup.13C NMR (CDCl.sub.3, 50 MHz):
.delta. 200.8, 51.7, 36.2, 31.1, 29.4.
[0159] Following a similar procedure W14, W15, W19, W23 were
prepared from corresponding acid chlorides.
##STR00129##
Synthesis of C4-Oxazolidinone
4,4-dibenzylamino-1,3-(S)butanediol
##STR00130##
[0161] R.B charged with LiBr (14.8 g, 170.8 mmol, 4.0 equiv),
NaBH.sub.4 (6.37 g, 170.8 mmol, 4.0 equiv) and THF (125 mL) and
stirred at 50.degree. C. for 2 h. Added the ester (14.0 g, 42.7
mmol, 1.0 equiv) in THF (25 mL) slowly and stirring continued for 2
h (TLC no SM). Reaction mixture cooled to RT and added satd.
NH.sub.4Cl dropwise (cool in ice-bath) till no gas evolution. Most
of the THF was removed on rotovap and residue diluted with EtOAc
(250 mL). Washed with brine, dried (MgSO.sub.4) and concentrated to
a colorless oil and purified by column chromatography (70%
EA-hexane).
[0162] Product obtained as a colorless syrup (yield: 9.2 g,
77%).
[0163] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.2 (m, 10H), 3.8
(m, 6H), 3.4 (d, 2H), 2.4 (m, 2H), 1.6 (m, 2H). .sup.13C NMR
(CDCl.sub.3, 50 MHz): .delta. 138.3, 128.9, 128.3, 127.2, 66.8,
60.7, 59.5, 58.4, 36.3.
4-Amino-1,3-(S)butanediol
##STR00131##
[0165] THF-MeOH (30+40 mL) suspension containing the diol (9.0 g,
31.5 mmol) and wet Pd(OH).sub.2 (10%, 3.5 g) was hydrogenated under
40 psi (2.81 kgf/cm.sup.2) for 20 h. The solution warmed and the
hot solution filtered through a short pad of celite. Washed several
times with methanol (towards the end few drops of TEA added).
Removal of solvent gave a colorless oil (3.3 g, quantitative).
4-(Benzyloxycarbonyl)-amino-1,3-(S)butanediol
##STR00132##
[0167] R. B. charged with the amine (3.3 g, 31.3 mmol, 1.0 equiv)
and THF--H.sub.2O (20+40 mL). Added Na.sub.2CO.sub.3 (4.0 g, 37.8
mmol, 1.2 equiv) and cooled to 5.degree. C. Added CbzCl (6.45 g,
37.8 mmol, 5.4 mL, 1.2 equiv) dropwise keeping temp. below
5.degree. C. and stirred at that temp. for 3 h. Diluted with water
(100 mL) and extracted into EtOAc (3.times.100 mL). Washed with
brine, dried (MgSO.sub.4) and concentrated to a colorless oil which
solidified on keeping (9.0 g).
[0168] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.2 (s, 5H), 5.6
(s, 1H), 5.0 (s, 2H), 3.5 (m, 7H), 1.6 (m, 2H). .sup.13C NMR
(CDCl.sub.3, 50 MHz): .delta. 157.1, 136.2, 128.4, 128.0, 127.9,
70.2, 66.8, 60.4, 46.9, 35.7.
4-(Benzyloxycarbonyl)-amino-1(O-trityl)-3-(S)butanediol
##STR00133##
[0170] Reaction mix. containing the crude diol (.about.9.0 g, 31.5
mmol, 1.0 equiv), TrCl (10.5 g, 37.6 mmol, 1.2 equiv) and TEA (7.96
g, 78.6 mmol, 2.5 equiv) in CH.sub.2Cl.sub.2 (100 mL) stirred at RT
for 21 h. The reaction mixture washed with water, brine and dried
(MgSO.sub.4) and concentrated to a pale yellow oil (20.0 g).
5-trityloxyethyl-2-oxazolidinone
##STR00134##
[0172] The above crude product (20 g, .about.31.5 mmol based on
purity) taken in anhydrous THF (150 mL) and treated with KtBuO
(7.84 g, 70 mmol, 2.2 equiv) and stirred at RT for 7 h. Diluted
with water (100 mL), bulk of the THF removed on rotovap. Residue
extracted with EtOAc (3.times.100 mL), washed with brine, dried
(MgSO.sub.4) and concentrated to a light brown oil. Purified by
column chromatography (40% EtOAc-hexane) to get a pale yellow foamy
oil which solidifies (10.7 g, 91% in three steps).
[0173] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.25 (m, 15H),
5.75 (s, 1H), 4.8 (m, 1H), 3.6 (t, 1H), 3.2 (t, 3H), 2.0 (m, 2H).
.sup.13C NMR (CDCl.sub.3, 50 MHz): .delta. 159.6, 143.8, 128.5,
127.8, 127.0, 86.9, 75.0, 59.3, 46.0, 35.2.
N-(4-nitrophenyl)-5-trityloxymethyl-2-oxazolidinone
##STR00135##
[0175] The reaction mixture containing the oxazolidinone (5.0 g,
13.9 mmol), 4-bromonitrobenzene (4.2 g, 20.8 mmol, 1.5 equiv), 1,1'
bis(diphenylphosphinoferrocene) (0.77 g, 1.39 mmol, 0.1 equiv),
Pd(OAc).sub.2 (0.31 g, 1.39 mmol, 0.1 equiv) and sodium-t-butoxide
(2.0 g, 20.8 mmol, 1.5 equiv) in dry toluene (130 mL) was stirred
under N.sub.2 atm at 110.degree. C. for 8 h. The solvent was
removed on rotovap and the dark residue was chromatographed on
silica gel using 30% EtOAc-hexane to get the product as a dark
yellow foamy solid (2.7 g, 41%).
[0176] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 8.2 (d, 2H), 7.6
(d, 2H), 7.2 (m, 15H), 4.8 (m, 1H), 4.2 (t, 1H), 3.9 (m, 1H), 3.8
(dd, 1H), 3.4 (dd, 1H). .sup.13C NMR (CDCl.sub.3, 50 MHz): .delta.
155, 145, 144, 129.5, 129.3, 129, 126, 118, 87, 72, 64, 47.
2. Synthesis of Library-Sulphonates and Esters
##STR00136##
[0178] 0.1 mM solution of the oxazolidinone in CH.sub.2Cl.sub.2 (25
mL) was prepared. From the above std. soln. syringed out 1.0 mL
each (0.10 mmol) into 3 mL capped vials. Added triethylamine, 28
.mu.L/vial (0.2 mmol, 2.0 equiv). Added 1.0 mL (0.10 mmol) of the
stock solution (0.10 mM) of acid/sulphonyl chlorides into
respective vials. The vial capped, the solution mixed well and kept
aside at RT (20 h). All compounds purified by prep. TLC.
(EtOAc-hexane). Silica gel band containing the product was taken in
CH.sub.3CN (15.0 mL). Filtered and washed with more CH.sub.3CN (3
mL), and solvent removed on rotovap. The product obtained was
transferred to small vials using CH.sub.2Cl.sub.2, all samples air
dried and finally dried in vacuo. All samples were analyzed by
LCMS.
[0179] Oxazolidinones and sulphonyl/acid chlorides used:
B12: K2, K4, K5, K8, K9, K10, K11, E112
B12 (R): K2, K10, K21, K22, K23, K83, E112
B38: K00, K0, K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, E0, E1,
E4, E7, E8, E9, E10, E11, E15, E16, E112
B38(R): K10, E112, E117, E120, E124, E136, E154,
B39: K00, K0, K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, E0, E1,
E4, E7, E8, E9, E10, E11, E15, E16, E112
E11: K2, K4, K5, K8, K9, K10, K11, E112
E11(R): K2, K10, K21, K22, K23, K83, E112
E16: K00, K0, K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, E14,
E0, E1, E4, E7, E8, E9, E10, E11, E15, E16, E112
E16(R): K2, K10, K21, K22, K23, K83, E8, E112
E81: K4, K5, K8, K9, K10, K11, E112
E81(R): K2, K10, K21, K22, K23, K83, E112
[0180] G4: K2, K4, K5, K8, K10, K11, K21, K22, K23, K27, K30, K52,
K54, K55, K56, K59, K60, K66, K83, K90, K91, K92, K93, K94, K95,
K96, K97, E4, E11, E81, E82, E90, E107, E112, E113, E117, E159,
E164, E168
G4(R): K10, K21, K22, K23, K83,
[0181] G5: K00, K0, K1, K2, K3, K4, K5, K8, K9, K10, K11, K12, K21,
K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83, K90,
K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102,
K117, E8, E11, E81, E82, E90, E107, E112, E113, E117, E120, E124,
E136, E154, E159, E164, E168, E183, E184
G5(R): K10, K11, K12, K21, K22, K23, K83
G9(R): K2, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100,
K101, K102, K117,
[0182] G12: K00, K0, K1, K2, K3, K4, K5, K8, K9, K10, K11, K12,
K21, K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83,
K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102,
K104, K105, K106, K107, K109, K110, K112, K113, K114, K115,
K117,
G12(R): K2, K101, K102, K117, E112, E183, E184
[0183] G13(R): K00, K0, K1, K2, K3, K4, K5, K8, K9, K10, K11, K12,
K21, K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83,
K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102,
K104, K105, K106, K107, K109, K100, K112, K113, K114, K115, E112,
E183
W14: K101, K102, K104, K105, K106, K107, K109, K110, K112, K113,
K114, K115, E112, E183
W15: K10, K21, K22, K23, K83, E8, E11, E81, E82, E90, E107, E112,
E113, E117, E120, E124, E136, E154, E159, E164, E168
[0184] W17: K2, K4, K9, K10, K11, K12, K21, K27, K29, K30, K31,
K52, K53, K54, K55, K56, K59, K60, K61, K66, K70 E8, E11, E81, E82,
E90, E107, E112, E113, E159, E164, E168
W19: K10, K11, K12, K21, K22, K23, K83 E8, E11, E81, E82, E90,
E107, E112, E113, E117, E120, E124, E136, E154, E157, E159, E164,
E168
[0185] W23: K2, K4, K9, K10, K11, K21, K22, K23, K27, K29, K30,
K31, K52, K53, K54, K55, K56, K59, K60, K61, K66, K70, K83, E8,
E11, E81, E82, E90, E107, E112, E113, E117, E120, E124, E136, E154,
E157, E159, E164, E168 G12-oxa-C4: K2, K10, K11, K93, K95, K96,
K97, K100, K101, K102, K104, K105, K106, K107, K109, K110, K112,
K115, K117, E183, E184
[0186] G3-oxa-C4: K2, K10, K11, K93, K95, K96, K97, K100, K101,
K102, K104, K105, K106, K107, K109, K110, K112, K115, K117, E183,
E184
Amines
A. Amides and Sulphonamides
1. Synthesis of Precursors
(5R)-methanesulphonyloxymethyl-3-[(1R)-phenylethyl-oxazolidine-2-one)
##STR00137##
[0188] To an ice-cooled solution of the oxazolidinone (5.0 g, 22.6
mmol, 1.0 equiv) in CH.sub.2Cl.sub.2 (50 mL) was added TEA (4.57 g,
45.1 mmol, 2.0 equiv) followed by MsCl (3.36 g, 29.3 mmol, 1.3
equiv) dropwise and then stirred for 2 h. Diluted with
CH.sub.2Cl.sub.2 (50 mL), washed with water (25 mL), brine, dried
(MgSO.sub.4) and concentrated to get an oil which solidified on
keeping (6.5 g, 97%).
[0189] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.4 (s, 5H), 5.25
(m, 1H), 4.7 (m, 1H), 4.4 (m, 2H), 3.4 (m, 2H), 3.15 (s, 3H), 1.65
(d, 3H). .sup.13C NMR (CDCl.sub.3, 50 MHz): .delta. 156.1, 138.9,
128.5, 127.8, 126.7, 69.8, 68.8, 51.5, 41.3, 37.4, 16.0.
(5R)-Azidomethyl-3-[(1R)-phenylethyl-oxazolidine-2-one)
##STR00138##
[0190] Reaction mixture containing the mesylate (6.5 g, 21.7 mmol)
and NaN3 (2.12 g, 32.6 mmol, 1.5 equiv) in DMSO (60 mL) was stirred
at 80.degree. C. for 3 h under N.sub.2 atm. Then cooled to RT,
diluted with water (100 mL) and CH.sub.2Cl.sub.2 (150 mL). Organic
layer washed with brine, dried (MgSO.sub.4) and concentrated to a
pale yellow liquid. Crude product filtered through a short pad of
silica using 40% EtOAc-hexane. Colorless oil which crystallized on
keeping (5.0 g, 94%).
[0191] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.4 (s, 5H), 5.3
(m, 1H), 4.6 (m, 1H), 3.4 (m, 4H), 1.66 (d, 3H). .sup.13C NMR
(CDCl.sub.3, 50 MHz): .delta. 156.4, 139.0, 128.6, 127.8, 126.8,
71.1, 53.1, 51.4, 42.3, 16.0
(5R)-Aminomethyl-3-[(1R)-phenylethyl-oxazolidine-2-one)
##STR00139##
[0193] R.B charged with Pd--C (10%, 500 mg) and ethanol (10 mL).
Added oxazolidinone (2.0 g) in ethanol (10 mL). Flushed with
H.sub.2 three times and stirred under H.sub.2 overnight (17 h).
Filtered through a short celite pad and washed with methanol.
Solvent removed on rotovap to a light orange oil. Purified by
silica gel column (20-50% MeOH in EtOAc) to get a light orange oil
which solidifies on keeping (1.1 g, 62%).
[0194] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.4 (s, 5H), 5.3
(m, 1H), 4.6 (m, 1H), 3.4 (m, 2H), 3.1 (t, 2H), 2.8 (s, 2H), 1.66
(d, 3H). .sup.13C NMR (CDCl.sub.3, 50 MHz): .delta. 157.1, 139.4,
128.6, 127.8, 126.9, 73.7, 58.0, 51.4, 42.6, 16.2.
[0195] Amines belonging to classes G3, G5, G9, G12, B38 (both
isomers), G3-oxa-C4, G12-oxa-C4 were prepared in a similar
manner.
##STR00140##
2. Library-Synthesis
##STR00141##
[0197] 0.1 mM Solution of the oxazolidinone in CH.sub.2Cl.sub.2 (25
mL) was prepared. From the above std. soln. syringed out 1.0 mL
each (0.10 mmol) into 3 mL capped vials. Added triethylamine, 28
.mu.L/vial (0.2 mmol, 2.0 equiv). Added 1.0 mL (0.10 mmol) of the
stock solution (0.10 mM) of acid/sulphonyl chlorides into
respective vials. The vial capped, the solution mixed well and kept
aside at RT (20 h). All compounds purified by prep. TLC.
(EtOAc-hexane). Silica gel band containing the product was taken in
CH.sub.3CN (15.0 mL). Filtered and washed with more CH.sub.3CN (3
mL), and solvent removed on rotovap. The product obtained was
transferred to small vials using CH.sub.2Cl.sub.2, all samples air
dried and finally dried in vacuo. All samples were analyzed by
LCMS.
[0198] Other Amines used for the library:
G3(R), G5(R), G5(S), G12(R), G9(R), G9(S), G13(S).
##STR00142##
[0200] Sulphonyl/acid chlorides used:
B38: K1, K9, K10, K11, K21, K22, K23, K83, E112
[0201] G12-oxa-C4: K2, K93, K95, K96, K97, K99, K100, K101, K102,
K117, E183, E184
G12: K2, K93, K95, K96, K97, K99, K100, K101, K102, K117, E183,
E184
G9(R): E183, E184
G9(S): E183, E184
[0202] G5: K00, K0, K1, K2, K3, K4, K5, K8, K10, K11, K12, K21,
K22, K23, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99,
K100, K101, K102, K117, E183, E112, E184
G5(R): K2, K93, K95, K96, K97, K99, K100, K101, K102, K117, E183,
E184
G3(R): K2, K93, K95, K96, K97, K100, K101, K102, K117, E183,
E184
G13(R): K00, K0, K1, K2, K5, K9, K10, K11, K12, K21, K22, K23, K52,
K60, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100,
K101, K102, E183,
[0203] B. Urea Type Compounds
##STR00143##
[0204] Oxazolidinone (0.1 mmol, 14 mg) in CH.sub.2Cl.sub.2 (1.0 mL)
treated with the respective isocyante (0.1 mmol). In cases where
the solution was not homogeneous 0.5 mL THF was also added.
Reaction mixture kept at RT for 16 h and purified by prep. TLC
(hexane-EtOAc). All products were analyzed by LCMS.
[0205] Other amines used for the library: G12(R), G12(S), G5(S),
G9(R), G9(S),
##STR00144##
[0206] Isocyanates used for the library:
G12(R): DD2, DD3, DD4, DD5, DD6, DD7
G12: DD2, DD3, DD4, DD5, DD6, DD7
G5: DD2, DD3, DD4, DD5, DD6, DD7
G5(R): DD2, DD3, DD4, DD5, DD6, DD7
[0207] G12-oxa-C4: DD2, DD3, DD4, DD5, DD6, DD7
G9(R): DD2, DD3, DD4, DD5, DD6, DD7
G9(S): DD2, DD3, DD4, DD5, DD6, DD7
G3: DD2, DD3, DD4, DD5, DD6, DD7
[0208] C. Sulphenyl Compounds
[0209] 0.1 mM solution of the oxazolidinone in CH.sub.2Cl.sub.2 (5
mL) was prepared. From the above std. soln. syringed out 1.0 mL
each (0.10 mmol) into 3 mL capped vials. Added triethylamine, 28
.mu.L/vial (0.2 mmol, 2.0 equiv). Added 1.0 mL (0.10 mmol) of the
stock solution (0.10 mM) of sulphenyl chlorides into respective
vials. The vial capped, the solution mixed well and kept aside at
RT (20 h). All compounds purified by prep. TLC. (EtOAc-hexane).
Silica gel band containing the product was taken in CH.sub.3CN(15.0
mL). Filtered and washed with more CH.sub.3CN (3 mL), and solvent
removed on rotovap. The product obtained was transferred to small
vials using CH.sub.2Cl.sub.2, all samples air dried and finally
dried in vacuo. All samples were analyzed by LCMS.
[0210] Amines used for the library: G5, G12, G9, G9(R),
G12-oxa-C4
##STR00145##
[0211] Oxazolidinones and sulphenyl chlorides used:
G5: BB3, BB5, BB7, BB9
G5(R): BB3, BB5, BB7, BB9
G12: BB3, BB5, BB7, BB9
G12(R): BB3, BB5, BB7, BB9
G9: BB3, BB5, BB7, BB9
G9(R): BB3, BB5, BB7, BB9
[0212] G12-oxa-C4: BB3, BB5, BB7, BB9
[0213] D. Substituted Aryl Amines-Buchwald Coupling
##STR00146##
[0214] The reaction mixture containing the aminooxazolidinone (50
mg, 0.35 mmol), CuI (3.3 mg, 5 mol %), K.sub.3PO.sub.4 (148.6 mg,
0.70 mmol, 2 equiv), ethyleneglycol (43.4 mg, 0.70 mmol) and the
aryl iodide (0.52 mmol, 1.5 equiv) in isopropanol (1.5 mL) was
stirred at 70.degree. C. for 24 h. Reaction mixture was cooled and
filtered. Filtrate purified by prep. TLC. Products were analyzed by
LCMS.
[0215] Other amines used for library: G5(R), G9(R), G9(S),
G12(R)
##STR00147##
Oxazolidinones and aryl iodides used:
G9(S): AA6, AA7, AA9, AA11, AA12 AA16, AA17, AA18, AA26, AA35
G9(R): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA35
G12(R): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA27, AA35
G12(S): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA35
G5(R): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA35
Ether Derivatives
5-Tosyloxymethyl-N-isopropyl-2-oxazolidinone
##STR00148##
[0217] CH.sub.2Cl.sub.2 (25 mL) solution containing the
oxazolidinone (2.3 g, 14.4 mmol, 1.0 equiv) was cooled in ice-bath.
Added TEA (3.65 g, 36.1 mmol, 2.5 equiv) followed by TsCl (4.1 g,
21.5 mmol, 1.5 equiv) in small portions. Stirring continued at
0.degree. C.-RT (7 h). Diluted with more CH.sub.2Cl.sub.2 (50 mL),
washed with 1N HCl (50 mL), water, brine, dried (MgSO.sub.4) and
concentrated to a brown liquid. Crude product passed through a
silica gel column (60% EtOAc-hexane) to get the product as a
colorless solid (4.3 g, 96%).
[0218] .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 7.5 (ABq, 4H),
4.6 (m, 1H), 4.0 (m, 3H), 3.5 (t, 1H), 3.3 (dd, 1H), 2.39 (s, 3H),
1.2 (m, 6H). .sup.13C NMR (CDCl.sub.3, 50 MHz): .delta. 155.8,
145.2, 131.9, 129.9, 127.7, 69.5, 68.7, 44.7, 40.9, 21.4, 19.4,
19.3.
Library Synthesis
Method 1
##STR00149##
[0220] 3.0 mL vial charged with 1-naphthol (12.7 mg, 0.09 mmol, 1.1
equiv) and THF (1.0 mL). Added KtBuO (13.4 mg, 0.12 mmol, 1.5
equiv). Stirred for 30 min. at RT. Added the tosylate (25 mg, 0.08
mmol, 1.0 equiv) in THF (1 mL). Stirred at RT for 2.0 h. Purified
by prep. TLC (EtOAc-hexane) to get the pure product. Analyzed by
LCMS.
[0221] Other libraries synthesized
##STR00150##
Method 2
##STR00151##
[0223] To a solution containing the oxazolidinone (14.4 mg, 0.1
mmol), PPh.sub.3-polystyrene (120 mg, 1.2 equiv, loading 1.0
mmol/g), phenol (0.1 mmol, 1.0 equiv) and CH.sub.2Cl.sub.2 (1.0
mL). Added DIAD/DEAD (1.2 equiv) in THF (1.0 mL) slowly. Stirred
gently for 24 h. The crude product was purified by prep. TLC
(hexane-EtOAc).
[0224] Other libraries synthesized: G9, G5
##STR00152##
[0225] Alcohols/phenols used:
B38: M1, M2, M3, M4, M5, M6, M14, M37, M38,
B39: M3, MS, M35, M38
G5: M39, M42, M43, M44, M45, M46, M47
G12(S): M1, M2, M3, M4, M5, M6, M11, M13, M14, M24, M30, M34, M35,
M37, M38, M39, M40, M41, M42, M43, M44, M45, M46, M47
G12(R): M40, M41
G9(R): M1, M2, M3, M4, M5, M6, M11, M13, M14, M24, M30, M34, M35,
M37, M38, M39, M40, M41,
Sulphonylchlorides (K):
##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157##
##STR00158## ##STR00159##
[0226] Acid chlorides (E):
##STR00160## ##STR00161## ##STR00162## ##STR00163##
Phenols (M):
##STR00164## ##STR00165## ##STR00166##
[0227] Aryl iodides (AA):
##STR00167## ##STR00168##
Sulphenyl chlorides (BB), Isocyantes (DD)
##STR00169##
##STR00170##
Experimental
[0228] 1. Preparation of the Precursors of Libraries.
[0229] General Methods. Column chromatography was performed on
silica gel. TLC was performed on silica gel GF254. NMR spectra were
recorded with an Varian VXR-200 NMR spectrometer .sup.1H NMR and
.sup.13C NMR spectra were recorded at either 200 MHz or 50 MHz.
LC-MS was carried out at PE-Sciex AP150EX single quadrapole
instrument.
[0230] Typical Reactions for preparation of the alcohols (3):
Method A:
[0231] A solution of t-BuOK (50 mL, 50 mmol, 1 M) in THF was
dropped into a solution of starting material 1 (18 g, 50 mmol) in
dry THF (120 mL) under nitrogen at rt in 5 min. The mixture was
stirred for 10 min at rt. Methyl bromoacetate (7.65 g, 50 mmol) was
dropped into the flask in 5 min. The mixture was stirred for 1 h at
rt. 10% NH.sub.4Cl (20 mL) and hexanes (40 mL) were added,
respectively. The organic phase is separated. The solvents were
evaporated to give a crude product, without purification for next
step. The crude product was dissolve into DCM (100 mL). Water (1.8
mL, 100 mmol) and TFA (8.55 g, 75 mmol) were added to the flask.
The mixture was stirred for 2 h at rt. Removal of volatile
materials gave a residue, which was co-evaporated with CH3CN
(2.times.60 mL) to remove the trace water. Column
chromatography:purification (1:1 ethyl acetate/hexanes, then ethyl
acetate) afforded a pure product (3a) (5.2 g, 55%). NMR:
.quadrature..sub.H 3.4-4.1 (7H, m), 3.66 (3H, s), 4.5-4.7 (1H, m)
ppm, .quadrature..sub.C:44.98, 46.10, 52.17, 62.61, 74.08, 158.20
(C.dbd.O), 168.92 (C.dbd.O, ester) ppm.
[0232] 3b: yield: 36%, NMR: .delta..sub.H 2.9 (1H, br,s), 3.46-3.86
(4H, m), 4.02 (2H, s,), 4.54-4.70 (1H, m), 5.14 (2H, s), 7.2-7.3
(5H, m) ppm.
[0233] 3e: yield: 8.1%. .delta..sub.H 2.5 (1H, br), 3.51-3.94 (4H,
m), 3.79 (3H, s), 4.67 (2H, s), 4.5-4.7 (1H, m), 7.1-7.5 (4H, m)
ppm.
Method B:
[0234] NaH (0.4 g, 10 mmol, 60%) was added in portions into a
solution of starting material 1 (3.59 g, 10 mmol) in dry THF (40
mL) under nitrogen at rt in 10 min. The mixture was stirred for 1 h
at rt. Bromopinacolone (1.79 g, 10 mL) was dropped into the flask
in 10 min. The mixture was stirred overnight at rt. 10% NH4Cl (10
mL) and hexanes (20 mL) were added, respectively. The organic phase
is separated. The solvents were evaporated to give a crude product,
without purification for next step. The crude product was dissolve
into DCM (30 mL). Water (0.36 mL, 20 mmol) and TFA (1.71 g, 15
mmol) were added to the flask. The mixture was stirred for 1 h at
rt. Removal of volatile materials gave a residue, which was
co-evaporated with CH.sub.3CN (2.times.30 mL) to remove the trace
water. Column chromatography purification (3:1 ethyl
acetate/hexanes, then ethyl acetate) afforded a pure product (3c)
(1.68 g, 78%). NMR: .delta..sub.H 1.14 (9H, s), 3.36-3.9 (6H, m),
4.18 (2H, s), 4.54-4.7 (1H, m) ppm, .delta..sub.C:26.08, 43.10,
46.30, 48.21, 63.11, 74.05, 158.45 (C.dbd.O), 209.60 (C.dbd.O,
ketone) ppm.
[0235] 3d: yield: 8.1%. .delta..sub.H 2.5 (1H, br), 3.56-3.9 (4H,
m), 4.66 (2H, s), 4.5-4.7 (1H, m) 7.43, 7.47, 7.84, 7.88 (4H, AB)
ppm.
[0236] Method C:
[0237] A solution of t-BuOK (10 mL, 10 mmol, 1 M) in THF was
dropped into a solution of starting material 1 (3.59 g, 10 mmol) in
dry THF (40 mL) under nitrogen at rt in 5 min. The mixture was
stirred for 1 h at rt. A solution of methyl bromoacetamide (1.52 g,
10 mL) in THF was dropped into the flask in 10 min. The mixture was
stirred overnight at rt. Con. NH.sub.4Cl (5 mL) and brine (5 mL)
were added, respectively. The organic phase is separated. The
solvents were evaporated to give a crude product. Flash column
chromatography (hexanes/ethyl acetate 1:1) gave a pure product. To
a solution of the pure material in DCM (30 mL) was added TFA (1.71
g, 15 mmol) and water (0.36 g). The mixture was stirred for 1 h at
rt. Removal of volatile materials gave a residue, which was
partitioned in water (50 mL) and t-BuOMe (20 mL). The separated
aqueous layer was washed with t-BuOMe (20 mL). Water was evaporated
to give a residue, which was co-evaporated with CH.sub.3CN
(2.times.30 mL) to remove the trace water. A product (3f) (0.91 g,
48%) obtained, without further purification for next step.
[0238] 3g: yield: 99%. .delta..sub.H 2.91, 2.96 (6H, 2 s), 3.5-3.9
(4H, m), 3.92-4.16 (2H, AB), 4.41 (1H, br), 4.5-4.7 (1H, m)
ppm.
[0239] 3h: yield: 74%. .delta..sub.H 3.25-3.61 (13H, m), 4.04 (2H,
s), 4.5-4.7 (1H, m) ppm.
[0240] 3i: yield: 99%.
[0241] 3j: yield: 81%.
2. Preparation of Libraries:
A. Parallel Synthesis:
[0242] Typical reaction procedures (Reaction scales might be
various accordingly):
[0243] Library 4-esters: To a solution of an acyl chloride (E) (0.1
mmol) in dry DCM (1 mL) were add a solution of 3 (0.1 mmol, 0.1 M)
in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was
standing overnight at rt. The reaction was completed. The product
was purified with preparative TLC.
[0244] Library 4-sulfonates: To a solution of a sulfonyl chloride
(K) (0.1 mmol) in dry DCM (1 mL) were add a solution of 3 (0.1
mmol, 0.1 M) in DCM and triethyl amine (20.2 mg, 0.2 mmol). The
mixture was standing overnight at rt. The reaction was
completed.
[0245] The product was purified with preparative TLC.
[0246] Library 4-ethers: To a mixture of 3 (0.1 mmol), a phenol (M)
(0.1 mmol) and Ph3P-polystyrene (0.1 g, 0.1 mmol Ph.sub.3P) in dry
DCM (1 mL) was add a solution of DEAD (1 mL, 0.1 M). The mixture
was standing at rt for three days. The reaction was completed. The
product was purified with preparative TLC.
Libraries:
[0247] (1) 4a-esters:
TABLE-US-00004 Entry MW mMol E0 140.57 0.1 E1 182.65 0.1 E2 252.62
0.1 E3 252.62 0.1 E4 186.66 0.1 E5 212.53 0.1 E6 194.54 0.1 E7
198.60 0.1 E8 212.63 0.1 E9 256.08 0.1 E12 178.02 0.1 E13 178.02
0.1 E14 211.98 0.1 E15 131.52 0.1 E16 130.53 0.1 E17 130.53 0.1 E37
274.08 0.1 E40 154.60 0.1 E49 190.63 0.1 E55 175.03 0.1 E90 181.04
0.1 E92 215.48 0.1 E99 216.73 0.1 E113 229.06 0.1 E117 223.68 0.1
E120 207.61 0.1 E124 176.00 0.1 E136 200.67 0.1 E154 309.07 0.1
E157 226.66 0.1 E159 293.67 0.1 E164 319.76 0.1 E168 192.60 0.1
[0248] (2) 4a-sulfonates:
TABLE-US-00005 Entry MW mMol K0 190.65 0.1 K00 190.65 0.1 K1 211.07
0.1 K2 221.62 0.1 K3 206.65 0.1 K5 182.65 0.1 K6 254.71 0.1 K8
290.65 0.1 K9 195.62 0.1 K10 253.06 0.1 K11 327.71 0.1 K12 227.67
0.1 K16 438.33 0.1 K17 180.62 0.1 K21 218.62 0.1 K23 234.69 0.1 K29
238.65 0.1 K30 252.67 0.1 K31 363.21 0.1 K52 279.79 0.1 K53 249.70
0.1 K54 317.69 0.1 K55 249.70 0.1 K56 330.74 0.1 K59 301.12 0.1 K60
259.74 0.1 K61 306.82 0.1 K66 237.66 0.1 K70 256.71 0.1 K76 262.72
0.1 K83 234.69 0.1 K90 194.61 0.1 K91 255.52 0.1 K92 232.73 0.1 K93
244.62 0.1 K94 245.51 0.1 K96 256.06 0.1 K97 289.62 0.1 K98 302.86
0.1 K100 235.65 0.1 K101 217.63 0.1 K102 201.63 0.1 K104 229.06 0.1
K105 279.07 0.1 K106 245.51 0.1 K107 212.60 0.1 K109 312.62 0.1
K110 240.71 0.1 K111 330.74 0.1 K112 230.59 0.1 K113 242.69 0.1
K114 262.72 0.1 K115 243.67 0.1
[0249] (3) 4a-ethers:
TABLE-US-00006 Materials MW mMol M1 173 0.1 M2 128.55 0.1 M3 112.10
0.1 M5 162.11 0.1 M6 137.18 0.1 M11 95.1 0.1 M14 148.16 0.1 M24
161.16 0.1 M25 349.23 0.1 M30 160.17 0.1 M34 213.15 0.1 M35 146.14
0.1 M37 211.21 0.1 M38 189.25 0.1
[0250] (4) 4b-sulfonates:
TABLE-US-00007 Entry MW mMol K0 190.65 0.1 K00 190.65 0.1 K1 211.07
0.1 K2 221.62 0.1 K3 206.65 0.1 K5 182.65 0.1 K6 254.71 0.1 K8
290.65 0.1 K10 253.06 0.1 K11 327.71 0.1 K12 227.67 0.1 K21 218.62
0.1 K23 234.69 0.1 K56 330.74 0.1 K70 256.71 0.1 K76 262.72 0.1 K83
234.69 0.1 K90 194.61 0.1 K91 255.52 0.1 K92 232.73 0.1 K93 244.62
0.1 K94 245.51 0.1 K96 256.06 0.1 K97 289.62 0.1 K98 302.86 0.1
K100 235.65 0.1 K101 221.62 0.1 K102 201.63 0.1 K104 229.06 0.1
K105 279.07 0.1 K106 245.51 0.1 K107 212.60 0.1 K109 312.62 0.1
K110 240.71 0.1 K111 330.74 0.1 K112 230.59 0.1 K113 242.69 0.1
K114 262.72 0.1 K115 243.67 0.1
[0251] (5) 4c-esters:
TABLE-US-00008 Entry MW mMol E0 140.57 0.25 E00 120.58 0.25 E1
182.65 0.25 E2 252.62 0.20 E4 186.66 0.25 E5 212.53 0.25 E6 194.54
0.25 E7 198.60 0.25 E8 212.63 0.25 E10 108.52 0.25 E11 104.53 0.25
E12 178.02 0.25 E13 178.02 0.25 E14 211.98 0.25 E15 131.52 0.25 E16
130.53 0.25
[0252] (6) 4c-sulfonates:
TABLE-US-00009 Entry MW mMol K0 190.65 0.15 K00 190.65 0.15 K1
211.07 0.15 K2 221.62 0.15 K3 206.65 0.15 K4 217.63 0.15 K5 182.65
0.15 K6 254.72 0.15 K8 290.65 0.15 K9 195.62 0.15 K10 253.06 0.15
K11 327.71 0.15 K12 227.67 0.15
[0253] (7) 4d-esters:
TABLE-US-00010 Entry MW mMol E7 198.60 0.09 E10 108.52 0.09 E11
104.53 0.09 E15 131.52 0.09
[0254] (8) 4d-sulfonates:
TABLE-US-00011 Entry MW mMol K5 182.65 0.09 K8 290.65 0.09 K10
253.06 0.09 K11 327.71 0.09
[0255] (9) 4e-esters:
TABLE-US-00012 Entry MW mMol E0 140.57 0.075 E1 182.65 0.075 E4
186.66 0.075 E8 212.63 0.075 E7 198.60 0.075 E10 108.52 0.075 E11
104.53 0.075 E15 131.52 0.075 E16 130.53 0.075
[0256] (10) 4e-sulfonates:
TABLE-US-00013 Entry MW mMol K0 190.65 0.075 K00 190.65 0.075 K1
211.07 0.075 K2 221.62 0.075 K3 206.65 0.075 K4 217.63 0.075 K5
182.65 0.075 K6 254.72 0.075 K8 290.65 0.075 K9 195.62 0.075 K10
253.06 0.075 K11 327.71 0.075 K12 227.67 0.075
[0257] (11) 4f-esters:
TABLE-US-00014 Entry MW Wt/V mMol E183 185.56 0.1 E184 230.56
0.1
[0258] (12) 4f-sulfonates:
TABLE-US-00015 Entry MW Wt/V mMol K2 221.62 0.1 K96 256.06 0.1 K101
221.62 0.1 K106 245.51 0.1 K117 221.62 0.1
[0259] (13) 4g-sulfonates:
TABLE-US-00016 Entry MW Wt/V mMol K0 190.65 0.1 K00 190.65 0.1 K1
211.07 0.1 K2 221.62 0.1 K4 217.63 0.1 K5 182.65 0.1 K6 254.71 0.1
K8 290.65 0.1 K10 253.06 0.1 K11 327.71 0.1 K12 227.67 0.1 K19
229.09 0.1 K21 218.62 0.1 K22 253.07 0.1 K23 234.69 0.1 K30 252.67
0.1 K52 279.79 0.1 K54 317.69 0.1 K55 249.70 0.1 K56 330.74 0.1 K59
301.12 0.1 K60 259.74 0.1 K66 237.66 0.1 K69 181.60 0.1 K70 256.71
0.1 K76 262.72 0.1 K83 234.69 0.1 K90 194.61 0.1 K91 255.52 0.1 K92
232.73 0.1 K93 244.62 0.1 K94 245.51 0.1 K95 266.62 0.1 K96 256.06
0.1 K97 289.62 0.1 K98 302.86 0.1 K99 266.57 0.1 K100 235.65 0.1
K101 217.63 0.1 K104 229.06 0.1 K105 279.07 0.1 K106 245.51 0.1
K107 212.60 0.1 K109 312.62 0.1 K110 240.71 0.1 K111 330.74 0.1
K112 230.59 0.1 K113 242.69 0.1 K115 243.67 0.1
[0260] (14) 4h-esters:
TABLE-US-00017 Entry MW mMol E0 140.57 0.1 E1 182.65 0.1 E2 252.62
0.1 E3 252.62 0.1 E4 186.66 0.1 E5 212.53 0.1 E6 194.54 0.1 E7
198.60 0.1 E8 212.63 0.1 E9 256.08 0.1 E12 178.02 0.1 E13 178.02
0.1 E14 211.98 0.1 E15 131.52 0.1 E16 130.53 0.1 E17 130.53 0.1 E37
274.08 0.1 E40 154.60 0.1 E49 190.63 0.1 E55 175.03 0.1 E90 181.04
0.1 E92 215.48 0.1 E99 216.73 0.1 E113 229.06 0.1 E117 223.68 0.1
E120 207.61 0.1 E124 176.00 0.1 E136 200.67 0.1 E154 309.07 0.1
E157 226.66 0.1 E159 293.67 0.1 E164 319.76 0.1 E168 192.60 0.1
[0261] (15) 4h-sulfonates:
TABLE-US-00018 Entry MW Wt/V mMol K0 190.65 0.1 K00 190.65 0.1 K1
211.07 0.1 K2 221.62 0.1 K3 206.65 0.1 K4 217.63 0.1 K5 182.65 0.1
K6 254.71 0.1 K8 290.65 0.1 K9 195.62 0.1 K10 253.06 0.1 K11 327.71
0.1 K12 227.67 0.1 K19 229.09 0.1 K21 218.62 0.1 K23 234.69 0.1 K27
247.95 0.1 K30 252.67 0.1 K52 279.79 0.1 K53 249.70 0.1 K54 317.69
0.1 K55 249.70 0.1 K56 330.74 0.1 K59 301.12 0.1 K60 259.74 0.1 K61
306.82 0.1 K66 237.66 0.1 K69 181.60 0.1 K70 256.71 0.1 K76 262.72
0.1 K83 234.69 0.1
[0262] (16) 4h-ethers:
TABLE-US-00019 Materials MW Wt/V mMol M1 173 0.1 M2 128.55 0.1 M3
112.10 0.1 M5 162.11 0.1 M6 137.18 0.1 M14 148.16 0.1 M24 161.16
0.1 M34 213.15 0.1 M35 146.14 0.1
(17) 41-sulfonates:
TABLE-US-00020 Entry MW Wt/V mMol K0 190.65 0.1 K00 190.65 0.1 K1
211.07 0.1 K2 221.62 0.1 K3 206.65 0.1 K5 182.65 0.1 K6 254.71 0.1
K8 290.65 0.1 K10 253.06 0.1 K11 327.71 0.1 K12 227.67 0.1 K16
438.33 0.1 K19 229.09 0.1 K21 218.62 0.1 K22 253.07 0.1 K23 234.69
0.1 K52 279.79 0.1 K60 259.74 0.1 K70 256.71 0.1 K76 262.72 0.1 K83
234.69 0.1 K90 194.61 0.1 K91 255.52 0.1 K92 232.73 0.1 K93 244.62
0.1 K94 245.51 0.1 K96 256.06 0.1 K97 289.62 0.1 K98 302.86 0.1
K100 235.65 0.1 K101 221.62 0.1 K102 201.63 0.1 K104 229.06 0.1
K105 279.07 0.1 K106 245.51 0.1 K107 212.60 0.1 K109 312.62 0.1
K110 240.71 0.1 K111 330.74 0.1 K112 230.59 0.1 K113 242.69 0.1
K115 243.67 0.1
(18) 4j-sulfonates:
TABLE-US-00021 Entry MW Wt/V mMol K0 190.65 0.1 K1 211.07 0.1 K2
221.62 0.1 K3 206.65 0.1 K8 290.65 0.1 K21 218.62 0.1 K60 259.74
0.1 K70 256.71 0.1 K83 234.69 0.1 K90 194.61 0.1 K91 255.52 0.1 K93
244.62 0.1 K94 245.51 0.1 K97 289.62 0.1 K98 302.86 0.1 K100 235.65
0.1 K101 221.62 0.1 K102 201.63 0.1
B. Combinatorial synthesis.
[0263] Procedure: To a solution of 3c (4.0 mmol), DMAP (9.8 mg,
0.08 mmol), pyridine (576.8 mg. 8.0 mmol) in CH.sub.2Cl.sub.2 (15
mL) was drop a solution of the acyl chlorides in CH.sub.2Cl.sub.2
(5 mL) into the flask in 5 min. The mixture was stirred at rt. for
24 h, washed with 1 N NaHCO.sub.3 and dried over Na.sub.2SO.sub.4.
Removal of the solvents gave a crude product (1.35 g). The products
were separated with HPLC (4.6.times.25 cm, C-18 Column; flow rate:
1.0 mL/min; 0 min: H.sub.2O(70), CH.sub.3CN(12), CH.sub.3OH (18);
20 min: H.sub.2O(50), CH.sub.3CN(20), CH.sub.3OH (30); 22 min:
H.sub.2O(50), CH.sub.3CN(0), CH.sub.3OH (50); 55 min: H.sub.2O(17),
CH.sub.3CN(O), CH.sub.3OH (83); post run; 10 min).
[0264] (19) 4c-esters:
TABLE-US-00022 Entry MW mMol E0 140.57 0.25 mmol E00 120.58 0.25
mmol E1 182.65 0.25 mmol E2 252.62 0.25 mmol E4 186.66 0.25 mmol E5
212.53 0.25 mmol E6 194.54 0.25 mmol E7 198.60 0.25 mmol E8 212.63
0.25 mmol E10 108.52 0.25 mmol E11 104.53 0.25 mmol E12 178.02 0.25
mmol E13 178.02 0.25 mmol E14 211.98 0.25 mmol E15 131.52 0.25 mmol
E16 130.53 0.25 mmol
##STR00171##
1. Preparation of Precursors of Libraries:
[0265] Azide 5: To a solution of 3c (0.52 g, 2.4 mmol) and
Ph.sub.3P (0.79 g, 3.0 mmol) in THF was dropped DEAD (0.56 g, 3.2
mmol) and DPPA (0.83 g, 3.0 mmol) at 0.degree. C., respectively.
The mixture was allowed to warm to rt. The mixture was stirred at
rt for 2 h. Removal of volatile materials gave a residue, which was
purified by column chromatography to afford a pure product (5) (0.5
g, 87%).
[0266] Amine 6: To a solution of 5 (0.48 g, 2.0 mmol) in THF was
added Ph.sub.3P (0.63 g, 2.4 mmol) at rt. The mixture was stirred
at rt overnight. Removal of volatile materials gave a residue. 90%
MeOH (20 mL) was added to the flask. The solution was stirred at rt
for 2 h. Removal of the solvents gave a residue, which was purified
by column chromatography to afford a pure product (6) (0.2 g, 47%).
.delta..sub.H 1.17 (9H, s), 1.41 (2H, br), 2.8-3.2 (2H, m), 3.2-3.6
(2H, m), 4.07, 4.16, 4.22, 4.31 (2H, AB), 4.48-4.64 (1H, m)
ppm.
2. Preparation of Libraries (Parallel Synthesis):
[0267] Procedure: To a solution of a sulfonyl chloride (K) (0.1
mmol) in dry DCM (1 mL) were add a solution of 6 (0.1 mmol, 0.1 M)
in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was
standing at rt for 6 h. The reaction was completed. The product was
purified with preparative TLC.
(20) Library 7-sulfonamides:
TABLE-US-00023 Entry Materials MW Wt/V mMol K2 221.62 mg 0.1 K4
217.63 mg 0.1 K5 182.65 mg 0.1 K8 290.65 mg 0.1 K9 195.62 mg 0.1
K10 253.06 mg 0.1 K11 327.71 mg 0.1 K12 227.67 mg 0.1 K21 218.62 mg
0.1 K22 253.06 mg 0.1 K23 234.68 mg 0.1 K83 234.68 mg 0.1
##STR00172##
1. Preparation of Precursors of Libraries:
[0268] Alcohol 9: A solution of t-BuOK (10 mL, 10 mmol, 1 M) in THF
was dropped into a solution of starting material 1 (3.59 g, 10
mmol) in dry THF (40 mL) under nitrogen at rt in 5 min. The mixture
was stirred for 10 min at rt. Bromoacetonitrile (1.2 g, 10 mmol)
was dropped into the flask in 5 min. The mixture was stirred for 1
h at rt. 10% NH.sub.4Cl (20 mL) and hexanes (40 mL) were added,
respectively. The organic phase is separated. The solvents were
evaporated to give a crude product, without purification for next
step. The crude product was dissolve into DCM (30 mL). Water (0.36
mL, 20 mmol) and TFA (1.71 g, 15 mmol) were added to the flask. The
mixture was stirred for 2 h at rt. Removal of volatile materials
gave a residue, which was co-evaporated with CH.sub.3CN (2.times.30
mL) to remove the trace water. Column chromatography purification
(1:1 ethyl acetate/hexanes, then ethyl acetate) afforded a pure
product (9) (0.59 g, 38%). .delta..sub.H 2.49 (1H, br), 3.35-3.66
(4H, m), 4.36 (1H, s), 4.5-4.7 (1H, m) ppm.
2. Preparation of Libraries (Parallel Synthesis):
[0269] Procedure: (1) Esters: To a solution of an acyl chloride (E)
(0.1 mmol) in dry DCM (1 mL) were add a solution of 9 (0.1 mmol,
0.1 M) in N-methylmorpholine and triethyl amine (20.2 mg, 0.2
mmol). The mixture was standing overnight at rt. The reaction was
completed. The product was purified with preparative TLC.
(21) Library 10-esters:
TABLE-US-00024 Entry MW Wt/V mMol E183 185.56 0.1 E184 230.56
0.1
(2) Sulfonates: To a solution of a sulfonyl chloride (K) (0.1 mmol)
in dry DCM (1 mL) were add a solution of 9 (0.1 mmol, 0.1 M) in
N-methylmorpholine and triethyl amine (20.2 mg, 0.2 mmol). The
mixture was standing at rt for 6 h. The reaction was completed. The
product was purified with preparative TLC. (22) Library
10-sulfonates:
TABLE-US-00025 Entry MW Wt/V mMol K2 221.62 0.1 K96 256.06 0.1 K101
221.62 0.1 K106 245.51 0.1 K117 221.62 0.1
##STR00173##
1. Preparation of Precursors of Libraries:
[0270] Compound 11: NaH (0.44 g, 11 mmol, 60%) was added in
portions into a solution of starting material 1 (3.59 g, 10 mmol)
in dry HMPA (30 mL) under nitrogen at rt in 10 min. The mixture was
stirred for 1 h at rt. (MeO).sub.2CCH.sub.3CH.sub.2Br (1.83 g, 10
mL) was dropped into the flask in 10 min. The mixture was stirred
overnight at rt, then heated to 80.degree. C. for two days. The
reaction was cooled down to rt. Con. NH.sub.4Cl (10 mL) and brine
(10 mL) were added. The mixture was extracted by t-BuOMe
(2.times.30 mL). The organic phase was dried over Na.sub.2SO.sub.4.
was separated. Removal of volatile materials gave a residue, which
was purified by column chromatography (4:1 ethyl acetate/hexanes)
to afford a pure product (11) (2.0 g, 45%). .delta..sub.H 1.25 (3H,
s), 3.1-3.7 (6H, m), 3.18 (6H, s), 4.5-4.7 (1H, m) ppm.
[0271] Compound 12: To a solution 11 (1.8 g, 3.9 mmol) in DCM (20
mL) was added TFA (1.71 g, 15 mmol) and water (0.36 g). The mixture
was stirred for 1 h at rt. Removal of volatile materials gave a
residue, which was partitioned in water (30 mL) and t-BuOMe (20
mL). The separated aqueous layer was washed with t-BuOMe (20 mL).
Water was evaporated to give a residue, which was co-evaporated
with CH.sub.3CN (2.times.30 mL) to remove the trace water. A
product (12) (0.43 g, 64%) obtained, without further purification
for next step. .delta..sub.H 2.15 (3H, s), 3.47-3.90 (5H, m), 4.06
(1H, s), 4.59-4.72 (1H, m) ppm.
2. Preparation of Libraries (Parallel Synthesis):
[0272] Sulfonates: To a solution of a sulfonyl chloride (K) (0.1
mmol) in dry DCM (1 mL) were add a solution of 12 (0.1 mmol, 0.1 M)
in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was
standing overnight at rt. The reaction was completed. The product
was purified with preparative TLC.
(23) Library 13-sulfonates:
TABLE-US-00026 Entry MW Wt/V mMol K2 221.62 0.1 K5 182.65 0.1 K6
254.71 0.1 K10 253.06 0.1 K11 327.71 0.1 K12 227.67 0.1 K19 229.09
0.1 K21 218.62 0.1 K22 253.07 0.1 K23 234.69 0.1 K54 317.69 0.1 K60
259.74 0.1 K83 234.69 0.1 K90 194.61 0.1 K91 255.52 0.1 K92 232.73
0.1 K93 244.62 0.1 K94 245.51 0.1 K96 256.06 0.1 K97 289.62 0.1 K98
302.86 0.1 K99 266.57 0.1 K100 235.65 0.1 K101 217.63 0.1 K102
201.63 0.1
Reaction Procedure:
Amine Compound Synthesis:
Method 1:
a). Alkylation:
TABLE-US-00027 ##STR00174## [0273] ##STR00175## Materials d MW Wt/V
mMol SM 359.42 14.8 g 41 60% NaH 24 2.0 g 50 G3 2.28 141.94 3.6 mL
61.5 THF 140 mL
Procedure:
[0274] 1. To a solution of oxazolidinone and THF, sodium hydride
power was added under N2 protection, and ice bath. [0275] 2. The
mixture was stirred for half hour at 0.degree. C., then let it warm
up to room temperature. [0276] 3. G3 was added into the solution
slowly, and the reaction was stirred for overnight. [0277] 4. The
reaction was quenched with water and extracted with Ethyl
acetate/hexane mixture. The combined organic layer was washed with
NH.sub.4Cl, brine and dried over Na.sub.2SO.sub.4. [0278] 5. The
organic solvents were removed by water Rota-vap and the crude
residue was carried on next step without purification.
b). Deprotection:
TABLE-US-00028 ##STR00176## ##STR00177## [0279] Materials d MW Wt/V
mMol equiv SM 373.17 crude 41 TFA 1.48 114.02 4.7 mL 62 1.5 water
18 1.5 mL 82 2.0 CH.sub.2Cl.sub.2 10 ml
Procedure:
[0280] 1. The mixture was stirred for 3 h at room temperature. 2.
The reaction was quenched by three drops of triethyl amine and
dried over Na.sub.2SO.sub.4. 3. The solvents were removed by
Rota-vap and the residue was purified by column chromatography. The
elute solvents: 2/1=hexane/EtOAc to 1/2=hexane/EtOAc, then use pure
EtOAc. c). Tosylation and azidelation:
TABLE-US-00029 ##STR00178## Materials d MW Wt/V mMol Equiv SM
131.13 3.93 30 1 MsCl 1.48 114.55 3.01 39 1.3 Et.sub.3N 101 5.8 mL
42 1.4 CH.sub.2Cl.sub.2 THF DMSO NaN.sub.3 65 3.1 g 48 1.6
Procedure:
[0281] 1). Starting material was treated with methanesulfonyl
chloride in the presence of triethylamine in methylene chloride. 2)
The reaction mixture was stirred at ice bath for 3 hours. 3). The
reaction was washed with water and the organic layer was dried over
Na.sub.2SO.sub.4 4). The organic solvent was removed to give the
residue, which was treated with sodium azide in DMSO, 5) The result
solution was heated up to 80.degree. C. for two hours, then diluted
with water and extracted with methylene chloride. 6). The organic
layer was dried over Na.sub.2SO.sub.4 7). The solvent was removed
and the crude was purified by flash column chromatography to afford
azide compound.
d). Hydrogenation
##STR00179##
[0282] Oxazolidinone: 3.4 g
Pd--C (10%): 800 mg
EtOH: 30 mL
[0283] 1. Hydrogenation bottle was charged with azide compound and
EtOH. [0284] 2. Flushed with N.sub.2 [0285] 3. Pd--C was
deactivated with two drops of water then added into the reaction
mixture. [0286] 4. Reaction was run for overnight under
hydrogenater with 30 Psi (2 atmosphere) [0287] 5. TLC showed
complete conversion and the reaction mixture was filtered under
water pump. [0288] 6. The residue (2.46 g) was obtained and used to
carry on next step without purification.
Library Design:
[0289] Oxazolidinones: RC2, SP40 (0.08 nM) in CH.sub.2Cl.sub.2
[0290] Acid chlorides: E0, E2, E8, E92, E124, E154, E157, E159,
E117, E120, E164, E136
Parallel synthesis procedure: 1). Oxazolidinones (0.16 nM) were
made and transferred into small vials. 2). To those vials Et.sub.3N
(1.5 equiv) was added. 3). After 20 mins, acid chlorides or
sulfonyl chlorides were added into the reaction vials. 4). The
compounds were isolated by CombiFlash, sq 16.times. open access
purification system.
Library:
[0291] Oxazolidinones: RC2, SP40 (0.08 nM) in CH.sub.2Cl.sub.2
[0292] Sulfonyl chlorides: K2, K3, K4, K10, K21, K22, K23, K83,
K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100
Parallel synthesis procedure: 1). Oxazolidinones (0.16 nM) were
made and transferred into small vials. 2). To those vials Et.sub.3N
(1.5 equiv) was added. 3). After 20 mins, acid chlorides or
sulfonyl chlorides were added into the reaction vials. 4). The
compounds were isolated by para-TLC (2/1=EtOAC/Hexane).
[0293] Nitrogen linkage library compound synthesis
##STR00180##
Library Design:
[0294] Oxazolidinone: amine
[0295] Acid Chloride: E0, E2, E8, E92, E124, E154, E157, E159,
E117, E120, E164, E136
[0296] Sulfonyl chlorides: K2, K3, K4, K10, K21, K22, K23, K83,
K90, K91, K92, K93, K94, K95, K96, K97, K98, K100
Parallel Synthesis Procedure:
[0297] 1). Oxazolidinones (0.01 nM) were made and transferred into
small vials. 2). To those vials Et.sub.3N (1.5 equiv) was added.
3). After 20 mins, acid chlorides or sulfonyl chlorides were added
into the reaction vials. 4). The compounds were isolated by
para-TLC (2/1 EtOAC/Hexane).
Library:
##STR00181##
[0299] Oxazolidinones: SG3, SC3, and SC5 (0.08 nM) in
CH.sub.2Cl.sub.2
[0300] Acid chlorides: E0, E2, E8, E92, E124, E154, E157, E159,
E117, E120, E164, E136
Parallel Synthesis Procedure:
[0301] 1). Oxazolidinones (0.16 nM) were made and transferred into
small vials. 2). To those vials Et3N (1.5 equiv) was added. 3).
After 20 mins, acid chlorides or sulfonyl chlorides were added into
the reaction vials. 4). The compounds were isolated by para-TLC
(2/1 EtOAC/Hexane). Ether type of Linkages:
##STR00182##
Library Design:
[0302] Oxazolidinones: SG3, SC5
[0303] M compounds: M1, M2, M3, M4, M5, M6, M6, M11, M14, M14, M24,
M30 M34, M35, M37, M38 DEAD=0.10 nM in THF (MW 174
Ph.sub.3P-polystyrene 1 mmol/g 100 mg for each compound 0.1
mMol
THF 1 mL
Procedure:
[0304] 1. The vials were charged with starting material, THF,
CH.sub.2Cl.sub.2 and Ph.sub.3P-polystrene. [0305] 2. A solution of
DEAD was added into the reaction mixture. [0306] 3. The reactions
were stand for overnight. [0307] 4. Separated by pre-TLC. N-Aryl
linkage:
Using Buchwald Reaction:
TABLE-US-00030 ##STR00183## [0308] ##STR00184## Materials d MW Wt/V
mMol equiv SM 359.42 1.0 g 2.7 1 Bromo compound 202.01 0.76 g 3.7
1.3 Palladium(II) acetate 224.49 82 mg 0.36 0.13 sodium t-butoxide
96.11 0.4 g 4.16 1.5 Ferrocene 554.40 155 mg 0.27 0.1 Toluene 140
mL
Procedure:
[0309] 1. A 100 mL flask loaded with oxazolidinone, bromo compound,
palladium(II) acetate, 1,1'-bis(diphenylphosphino)-ferrocene and
sodium t-butoxide and flashed by N2 protection for 10 mins. [0310]
2. Toluene was added and heated up to 110.degree. C. for overnight
and then diluted with dichloromethane after it cooled down to room
temperature.
Buchwald Reaction:
TABLE-US-00031 ##STR00185## [0311] ##STR00186## Materials d MW Wt/V
mMol equiv SM 359.42 6.0 g 16.7 1 Bromo compound 182.12 3.65 g 20
1.2 Palladium(II) acetate 224.49 487 mg 2.2 0.13 sodium t-butoxide
96.11 2.4 g 25 1.5 Ferrocene 554.40 926 mg 1.67 0.1 Toluene 140
mL
Procedure:
[0312] 1. A 100 mL Round flask was loaded with oxazolidinone, bromo
compound, palladium(II) acetate,
1,1'-bis(diphenylphosphino)-ferrocene and sodium t-butoxide and
flashed by N.sub.2 protection for 10 mins. [0313] 2. Toluene was
added and heated up to 110.degree. C. for overnight and then cool
down to room temperature, diluted with dichloromethane. [0314] 3.
filtered by celite. [0315] 4. Separated by column. EtOAc/Hexane=4
elute solvent.
Synthesis of 3-trityloxy-2-hydroxy-propylamine
##STR00187##
[0316] Procedure:
[0317] 1. To a 500 mL Round flask was charged with 18 g SM and 90
mL of isopropyl alcohol 10 mL of MeOH then 50 mL of LiOH saturated
solution. [0318] 2. The mixture was heated under reflux overnight
at .about.70.degree. C. [0319] 3. Cool down to room temperature and
solvents were removed on Rota-vap. [0320] 4. Extract with EtOAc
(1.times.50 mL, and 1.times.50 mL). [0321] 5. The combined EtOAc
layers was washed with saturated NaCl, and dried with anhydrous
Na.sub.2SO.sub.4. [0322] 6. The solid was filtered and solution was
divided into three parts and concentrated them separately. Total
18.05 g, 100% yield was obtained. Amine Oxazolidinone
formation:
Method 2:
[0323] a). Hydrazine formation:
TABLE-US-00032 ##STR00188## ##STR00189## Materials d MW Wt/V mMol
Equiv SM 327.18 5.7 g 17.42 1 EtOH 10 mL hydrazine 32 3 mL 26
1.5
[0324] 1. To a round flask was Loaded hydrazine, EtOH and ester.
[0325] 2. The reaction was heated up to reflux for overnight.
[0326] 3. The solvents were removed by water rota-vap. [0327] 4.
NMR showed there is no ester.
b). Curtius Rearrangement:
TABLE-US-00033 ##STR00190## [0328] ##STR00191## Materials d MW Wt/V
mMol Equiv SM 329.44 17.4 1 H.sub.2SO.sub.4 98 2.04 g 20.8 1.2
NaNO.sub.2 69 2.4 34.8 2 water 17 mL
Procedure:
[0329] 1). The hydrazide compound was dissolved in water (17 mL).
2). To the reaction mixture, concentrated sulfuric acid (2.04 g)
diluted in water (10 mL) was added into the stirred solution. 3).
The mixture was cooled in the ice bath and then NaNO2 was added.
4). The reaction mixture was stirred at 50.degree. C. for 2
hrs.
Buchwald Reaction:
[0330] Org. Lett., Vol. 2, No. 8, 2000
Pd-Catalyzed Amination of Activated Aryl Halides:
TABLE-US-00034 ##STR00192## [0331] ##STR00193## Materials d MW Wt/V
mMol equiv SM 359.42 454 mg 1.26 1 Bromo compound 202 305 mg 1.5
1.2 Pd(OAC)2 224.49 2.9 mg 0.013 0.01 Cesium carbonate 325.82 575
mg 1.8 1.4 Xantphos 578.63 10 mg 0.018 0.015 1,4-dioxane 3 mL
Procedure:
[0332] 1. A 10 mL Round flask was loaded with oxazolidinone, bromo
compound, palladium(II) acetate, Xantphos and Cesium carbonate.
[0333] 2. The flask was back-filled N.sub.2 for 10 mins. [0334] 3.
1,4-dioxane was added and heated up to 100.degree. C. for overnight
and then cool down to room temperature, diluted with
dichloromethane. [0335] 4. filtered by silicon gel. [0336] 5.
TABLE-US-00035 [0336] Oxazolidinone MW SC2 169.18 SC3 184 SG2 173
B11 295.26 SG3 131.13 K2 221.62 K10 253.06 K6 254.72
Desired Products:
SC2K2, SC3K2, SC5K2, SC5K10, SG2K10, BllK6, SG3K2
[0337] 0.2 nmol of starting material were used in the presence of 3
equivalent of triethylamine as base in 1 mL of dichloromethane. The
reactions were stirred for overnight.
[0338] Remake some of the library compounds for testing according
to the result on Mar. 14, 2002.
TABLE-US-00036 Oxazolidinone MW SC3 184 SG2 173 SG3 131.13 K2
221.62 K10 253.06 K3 206.65 K23 234.68 K22 254.12 SG3-N 130.07 E8
212.63
Desired Products:
SC3E8, SG3E8, SG3-N-E8, SG3-N-K2, SG3-N-K3,
Procedure:
[0339] 0.1 nmol of starting material were used in the presence of
1.5 equivalent of triethylamine as base in 1 mL of dichloromethane.
The reactions were stirred for overnight.
E112-Oxazolidione Library Compound Synthesis:
O-linkage and N-linkage:
TABLE-US-00037 [0340] Oxazolidinone MW SC2 169.18 SC3 184 SG2 173
B11 295.26 B10 264 SG3 131.1 SG3-NH-- 130.07 SC5 157 SC1 157
Desired products:
SC3E112, SG3-N-E112, SG3-E112, SClE112, BllEll2.
##STR00194##
[0341] 300 mg of ZD3-75-2
500 mg of Pd(OH)2
5 mL of THF
5 mL of MeOH
[0342] The reaction was stirred at room temperature 10 mins (see
new spot and starting material on TLC, new spot is more polar) and
40 mins (see one new spot, which is less polar than starting
material, and only one spot shown on TLC).
##STR00195##
Variety of E112-Oxazolidione library compound synthesis:
TABLE-US-00038 Oxazolidinone MW RC2 169.18 B10 264 SG3 131.1 SC5
157 RC5 157 RC1 157
##STR00196##
[0343] Desired products:
RC2 E112 SB10E112 SG3 E112 SC5 E112 RC5E112 RC1E112 ZD3-87-E112
(387.36 or 567.49), ZD3-88-1 (206.24), ZD3-88-2 (206.24), ZD3-88-3
(206.24)
Exploring New Linkages:
1). Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
TABLE-US-00039 ##STR00197## [0344] ##STR00198## Materials d MW Wt/V
mMol equiv SM 130.15 100 mg 1 Iodo compound 204.0 170 mg 1.1 CuI
190.44 7.6 mg 0.05 K.sub.3PO.sub.4 212.5 322 mg 2
HO(CH.sub.2).sub.2OH 1.13 62.07 0.1 mL 2 Isopropanol 1 mL
Procedure:
[0345] To a schlenk tube, CuI and K.sub.3PO.sub.4 were added then
the tube was back-filled with nitrogen for 10 mins, and then rest
of starting material were added, the reaction mixture was heated up
to 80.degree. C.
Results and Discussion:
[0346] Desired product was obtained by para-TLC.
(2/1=EtOAc/Hexane).
TABLE-US-00040 ##STR00199## ##STR00200## Materials d MW Wt/V mMol
equiv SM 359.42 0.5 g 2.78 1 Pyrrolidine 0.2 mL 37% HCHO 0.2 mL
Ethanol 6 mL
Procedure:
[0347] A solution of SM, pyrrolidine and formaldehyde in ethanol (6
mL) was refluxed for 2 h. The solvent was evaporated.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
[0348] Organic Lett. 2002 Vol. 4, No. 4. page 581-584
TABLE-US-00041 ##STR00201## ##STR00202## Materials d MW Wt/V mMol
equiv SM 130.15 100 mg 1 Iodo compound 204.0 170 mg 1.1 CuI 190.44
7.6 mg 0.05 K.sub.3PO.sub.4 212.5 322 mg 2 HO(CH.sub.2).sub.2OH
1.13 62.07 0.1 mL 2 Isopropanol 1 mL
Procedure:
[0349] To a schlenk tube, CuI and K.sub.3PO.sub.4 were added then
the tube was back-filled with Nitrogen for 10 mins, and then rest
of starting material were added, the reaction mixture was heated up
to 80.degree. C.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
[0350] Organic Lett. 2002 Vol. 4, No. 4. page 581-584
TABLE-US-00042 ##STR00203## ##STR00204## Materials d MW Wt/V mMol
equiv SM 130.15 100 mg 0.76 1 Iodo compound 234.0 211 mg 0.84 1.1
CuI 190.44 7.6 mg 0.05 K.sub.3PO.sub.4 212.5 322 mg 2 HO(CH2)2OH
1.13 62.07 0.1 mL 2 Isopropanol 1 mL
Procedure:
[0351] To a schlenk tube, CuI and K.sub.3PO.sub.4 were added then
the tube was back-filled with Nitrogen for 10 mins, and then rest
of starting material were added, the reaction mixture was heated up
to 90.degree. C.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
[0352] Organic Lett. 2002 Vol. 4, No. 4. page 581-584
TABLE-US-00043 ##STR00205## ##STR00206## Materials d MW Wt/V mMol
equiv SM 130.15 40 mg 1 Iodo compound 218.0 72 mg 1.1 CuI 190.44 3
mg 0.05 K.sub.3PO.sub.4 212.5 128 mg 2 HO(CH.sub.2).sub.2OH 1.13
62.07 0.1 mL 2 Isopropanol 1 mL
Procedure:
[0353] To a schlenk tube, CuI and K.sub.3PO.sub.4 were added then
the tube was back-filled with Nitrogen for 10 mins, and then rest
of starting material were added, the reaction mixture was heated up
to 90.degree. C.
CAN. J. CHEM. Vol. 61, 411 (1983)
TABLE-US-00044 ##STR00207## [0354] ##STR00208## Materials d MW Wt/V
mMol equiv SM 359.42 0.68 g 2.78 1 Morpholine 87.12 0.4 mL 37% HCHO
0.4 mL Ethanol 8 mL
Procedure:
[0355] A solution of SM, morpholine and formaldehyde in 8 mL in
ethanol was refluxed for 4 h. The solvent was evaporated.
TABLE-US-00045 ##STR00209## ##STR00210## Materials d MW Wt/V mMol
equiv SM 117 0.47 g Pyrrolidine 0.2 mL 37% HCHO 0.4 mL Ethanol 3
mL
Procedure:
[0356] A solution of SM, morpholine and formaldehyde in 3 mL in
ethanol was refluxed for 2 h. The solvent was evaporated.
Deprotection:
TABLE-US-00046 ##STR00211## [0357] ##STR00212## Materials d MW Wt/V
mMol equiv SM 442.55 24 mg 0.05 1 TFA one drop H.sub.2O one drop
CH.sub.2Cl.sub.2 1 mL
Stir for overnight.
##STR00213##
amine compound: 18 mg
D-glucose: 140 mg
MeOH: 3 mL
Procedure:
[0358] To a schlenk tube was added Amine compound, D-glucose and
MeOH. The reaction was heated up to 60.degree. C. for
overnight.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
[0359] Organic Lett. 2002 Vol. 4, No. 4. page 581-584
TABLE-US-00047 ##STR00214## ##STR00215## Materials d MW Wt/V mMol
equiv SM 130.15 40 mg 1 Iodo compound 218.0 72 mg 1.1 CuI 190.44 3
mg 0.05 K.sub.3PO.sub.4 212.5 128 mg 2 HO(CH.sub.2).sub.2OH 1.13
62.07 0.1 mL 2 Isopropanol 1 mL
Procedure:
[0360] To a schlenk tube, CuI and K.sub.3PO.sub.4 were added then
the tube was back-filled with Nitrogen for 10 mins, and then rest
of starting material were added, the reaction mixture was heated up
to 95.degree. C. for overnight.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
[0361] Organic Lett. 2002 Vol. 4, No. 4. page 581-584
TABLE-US-00048 ##STR00216## ##STR00217## Materials d MW Wt/V mMol
equiv SM 130.15 40 mg 1 Iodo compound 248.0 72 mg 1.0 CuI 190.44 3
mg 0.05 K.sub.3PO.sub.4 212.5 128 mg 2 HO(CH2)2OH 1.13 62.07 0.1 mL
2 Isopropanol 1 mL
Procedure:
[0362] To a schlenk tube, CuI and K.sub.3PO.sub.4 were added then
the tube was back-filled with Nitrogen for 10 mins, and then rest
of starting material were added, the reaction mixture was heated up
to 95.degree. C. for overnight.
##STR00218##
[0363] The solution of 4 equiv of Hunig's base and 1 equiv of amine
starting material in CH.sub.3CN was stirred at 50.degree. C. for
overnight.
Reduction of Nitro Group
TABLE-US-00049 ##STR00219## [0364] ##STR00220## Materials d MW Wt/V
mMol equiv SM 417.46 70 mg 0.24 1 HCOONH.sub.4 63 56 0.88 3.6 Pd/C
(Wt) 10 THF 0.4 mL MeOH 0.4 mL
[0365] 1. To a solution of oxazolidinone and THF-MeOH(1:1) was
Ammonium formate and Pd--C. [0366] 2. The reaction was stirred at
room temperature for 2 h. [0367] 3. Diluted with THF. [0368] 4.
Filtered and washed several times with THF. [0369] 5. Filtrate
concentrated to a dark yellow solid.
Reduction of Nitro Group
TABLE-US-00050 ##STR00221## [0370] ##STR00222## Materials d MW Wt/V
mMol equiv SM 269.23 120 0.45 1 Pd(OH).sub.2 10% THF 1 mL MeOH 1
mL
[0371] The reaction was stirred at room temperature under H.sub.2
for 2 hrs.
Deprotection:
TABLE-US-00051 ##STR00223## [0372] ##STR00224## Materials d MW Wt/V
mMol equiv SM 458.55 800 mg 0.57 1 TFA 0.3 mL H.sub.2O 0.1 mL
CH.sub.2Cl.sub.2 3 mL
TABLE-US-00052 ##STR00225## ##STR00226## ##STR00227## Materials d
MW Wt/V mMol equiv SM 130.15 40 mg 0.31 1 CuI 190.44 3 mg 0.05
K.sub.3PO.sub.4 212.5 128 mg 2 HO(CH.sub.2).sub.2OH 1.13 62.07 0.1
mL 2 Isopropanol 1 mL AA Group: 0.31 mmol AA6 77 mg AA7 77 mg AA9
91 mg AA12 65 mg
Procedure:
[0373] To a test tube, CuI and K.sub.3PO.sub.4 were added then the
tube was back-filled with Nitrogen for 10 mins, and then rest of
starting material were added, the reaction mixture was heated up to
80.degree. C. for overnight.
TABLE-US-00053 ##STR00228## ##STR00229## Materials d MW Wt/V mMol
equiv SM 130.15 200 mg CuI 190.44 15 mg K.sub.3PO.sub.4 212.5 640
mg HO(CH.sub.2).sub.2OH 1.13 62.07 0.5 mL Isopropanol 2 mL AA8 249
385 mg
Procedure:
[0374] To a test tube, CuI and K.sub.3PO.sub.4 were added then the
tube was back-filled with Nitrogen for 10 mins, and then rest of
starting material were added, the reaction mixture was heated up to
90.degree. C. for overnight.
TABLE-US-00054 ##STR00230## ##STR00231## ##STR00232## Materials d
MW Wt/V mMol equiv SM 130.15 40 mg 0.31 1 CuI 190.44 3 mg 0.05
K.sub.3PO.sub.4 212.5 128 mg 2 HO(CH2)2OH 1.13 62.07 0.1 mL 2
Isopropanol 1 mL AA Group: 0.31 mmol AA13, AA14, AA15 77 mg; AA16,
AA18 84 mg; AA17 68 mg; AA19 77 mg
Procedure:
[0375] To a small vial, CuI and K.sub.3PO.sub.4 were added then the
tube was back-filled with Nitrogen for 10 mins, and then rest of
starting material were added, the reaction mixture was heated up to
80.degree. C. for overnight.
CAN.J. CHEM.Vol. 61, 411 (1983)
TABLE-US-00055 ##STR00233## [0376] ##STR00234## Materials d MW Wt/V
mMol equiv SM 296 0.1 g 0.4 1 Morpholine 87.12 0.1 mL 37% HCHO 0.1
mL Ethanol 1.5 mL
Procedure:
[0377] A solution of SM, morpholine and formaldehyde in 1.5 mL in
ethanol was refluxed for 2 h. The solvent was evaporated.
TABLE-US-00056 ##STR00235## ##STR00236## Materials d MW Wt/V mMol
equiv SM 296.36 0.1 g Pyrrolidine 0.1 mL 37% HCHO 0.1 mL Ethanol
1.5 mL
Procedure:
[0378] A solution of SM, morpholine and formaldehyde in 1.5 mL in
ethanol was refluxed for 2 h. The solvent was evaporated.
Ether Type of Linkages:
##STR00237##
[0379] Library Design:
[0380] Oxazolidinones: SG3, 130 mg in 5 mL of CHCl2. 0.5 mL was
took for each reaction. M compounds: M1, M4, MS, M11, M14, M24,
M30, M35, M37, M38 DIAD=0.10 nM in THF (MW 202), 202 mg in 10 mL
THF. 1 mL was for each reaction. Ph3P-polystyrene 1 mmol/g 100 mg
for each compound 0.1 mMol
Procedure:
[0381] 1. The vials were charged with SM and Ph.sub.3P-polystrene.
[0382] 2. A solution of DIAD in THF was added into the reaction
mixture. [0383] 3. The reactions were stirred for overnight.
Ether Type of Linkages:
##STR00238##
[0384] Library Design:
[0385] Oxazolidinones: SG3, 130 mg in 5 mL of CHCl2. 0.5 mL was
took for each reaction. M compounds: M9, M13, M20, M21, M22, M23,
M23, M29, M32, M33 DIAD=0.10 nM in THF (MW 202), 202 mg in 10 mL
THF and 1.5 mL of DMPU as co-solvent. 1.2 mL was took for each
reaction.
[0386] Ph.sub.3P-polystyrene 1 mmol/g 100 mg for each compound 0.1
mMol
Procedure:
[0387] 1. The vials were charged with SM and Ph.sub.3P-polystrene.
[0388] 2. A solution of DIAD in THF was added into the reaction
mixture. [0389] 3. The reactions were stirred for overnight. Acid
Hydrazide from Ester
TABLE-US-00057 ##STR00239## [0389] ##STR00240## Materials d MW Wt/V
mMol Equiv SM 217.26 2 g 9.2 1 EtOH 5 mL hydrazine 32 588 mg 18.4
2
[0390] 1. Loaded hydrazine and EtOH with a round flask and ester
was added slowly. [0391] 2. The reaction was heated up to reflux
for overnight. [0392] 3. The solvents were removed by water
rota-vap. [0393] 4. NMR showed there is no ester.
Curtius Rearrangement:
TABLE-US-00058 ##STR00241## [0394] ##STR00242## Materials d MW Wt/V
mMol Equiv SM 203 9.2 1 H.sub.2SO.sub.4 98 1.0 g 11 1.2 NaNO.sub.2
69 1.27 18.4 2 water 15 mL
Procedure:
[0395] 1). The hydrazide compound was dissolved in water (7 mL),
and concentrated sulfuric acid (1.0 g) diluted in water (3 mL) and
added into the stirred solution. The mixture was cooled in the ice
bath and then NaNO.sub.2 (in 5 mL water) was added slowly.
[0396] 2). The reaction mixture was stirred at 50.degree. C. for
overnight.
Library:
TABLE-US-00059 [0397] SG3-N- MW 130.15 SG3 MW 131.13
For SG3: K107, K96, K100, K114, K115, K76
For SG3-N: K76, K96, K100, K101, K112, K114, K115. K2
Procedure:
0.10 mol of S
[0398] 0.15 mmol of Et.sub.3N 0.08 mmol of K compounds Acid
Hydrazide from Ester
TABLE-US-00060 ##STR00243## ##STR00244## Materials d MW Wt/V mMol
Equiv SM 343.46 16 g 46.6 1 EtOH 30 mL hydrazine 32 2.2 g 70
1.5
[0399] 1. Loaded hydrazine and EtOH with a schlenk tube and ester.
[0400] 2. The reaction was heated up to 80.degree. C. for
overnight. [0401] 3. The solvents were removed by water
rota-vap.
Ether Type of Linkages:
##STR00245##
[0402] Library Design:
[0403] Oxazolidinones: SG3, 104 mg in 4 mL of CH.sub.2Cl.sub.2. 0.5
mL was took for each reaction. M compounds: M2, M3, M6, M34, M38,
M39, M40, M41, DIAD=0.10 nM in THF (MW 202), 160 mg in 8 mL THF. 1
mL was for each reaction.
[0404] Ph.sub.3P-polystyrene 1 mmol/g 100 mg for each compound 0.1
mMol
Procedure:
[0405] 1. The vials were charged with SM and Ph.sub.3P-polystrene.
[0406] 2. A solution of DIAD in THF was added into the reaction
mixture. [0407] 3. The reactions were stirred for overnight. Nitro
compounds with special linkages,
##STR00246##
TABLE-US-00061 [0407] SG3-N- MW 130.15 SG3 MW 131.13
[0408] For SG3 and SG3-N: K117, BB3, BB5, E183
Procedure:
[0409] 0.1 mmol of Starting material 0.15 mmol of Et.sub.3N 0.08
mmol of K and B compounds Exploration of different linkages
Alkylation:
TABLE-US-00062 ##STR00247## [0410] ##STR00248## ##STR00249##
##STR00250## Materials MW Wt/V mMol Equiv For G16, SM 359.42 1 g
2.78 1 G16 143.42 0.6 mL t-BuOK 3 mL THF 8 mL For G14 SM 359.42 1 g
2.78 1 G14 (d 2.1) 209.94 0.4 mL 4.17 1.5 t-BuOK 3 mL THF 8 mL
Alkylation: (By NaH)
TABLE-US-00063 ##STR00251## [0411] ##STR00252## ##STR00253##
##STR00254## Materials MW Wt/V mMol Equiv For G16, SM 359.42 1 g
2.78 1 G16 143.42 0.6 mL NaH (60%) 24 166 mg 4.17 1.5 THF 8 mL For
G14 SM 359.42 1 g 2.78 1 G14 (d 2.1) 209.94 0.4 mL 4.17 1.5 NaH
(60%) 24 166 mg 4.17 1.5 THF 8 mL
Alkylation: (By NaH)
TABLE-US-00064 ##STR00255## [0412] ##STR00256## Materials MW Wt/V
mMol Equiv For G16, SM 359.42 6.5 g 18.1 1 G15 (d 1.74) 170 2.5 mL
NaH (60%) 24 941.2 mg THF 50 mL
Deprotection: (G15)
TABLE-US-00065 ##STR00257## [0413] ##STR00258## TFA 2 mL H.sub.2O
0.5 mL CH2Cl2 5 mL
Deprotection: (combine 1 g of the reaction of G16 with BUOK and
with NaH)
TABLE-US-00066 ##STR00259## ##STR00260## TFA 1 mL H.sub.2O 0.3 mL
CH.sub.2Cl.sub.2 3 mL
Glycosylation:
##STR00261##
[0414] 5 mg of starting material 10 mg of sugar
1 mL of MeOH
Glycosylation
##STR00262##
[0415] 10 mg of starting material 18 mg of sugar
1 mL of MeOH
Deprotection:
TABLE-US-00067 ##STR00263## [0416] ##STR00264## SM 700 mg TFA 1.2
mL H.sub.2O 0.3 mL CH.sub.2Cl.sub.2 3 mL
[0417] The mixture was stirred for two hours. The TLC showed no
starting material left.
Library:
TABLE-US-00068 [0418] SG3-N- MW 130.15 SG3 MW 131.13 SC3 MW
183.20
K100 (235.65), K101(221.62), K102(201.63), K103(339.51), K104
(229.06), K105 (279.06), K106 (245.51), K107 (212.60), K108
(372.67), K109 (312.62) K110 (240.71), K111 (330.74)
Procedure:
0.11 mol of S
[0419] 0.15 mmol of Et.sub.3N 0.08 mmol of K compounds
New Library Linkage:
##STR00265##
[0420] Copper-Catalyzed Coupling of Alkylamines and Aryl
Iodides
[0421] Organic Lett. 2002 Vol. 4, No. 4. page 581-584
TABLE-US-00069 ##STR00266## ##STR00267## Materials d MW Wt/V mMol
equiv SM 131 100 mg 1 Iodo compound 272.01 500 mg 1.8 CuI 190.44 19
mg 0.1 K.sub.3PO.sub.4 212.5 322 mg 2 HO(CH.sub.2).sub.2OH 1.13
62.07 0.15 mL 2 Isopropanol 1 mL
Procedure:
[0422] To a small vial, CuI and K.sub.3PO.sub.4 were added then the
tube was back-filled with Nitrogen for 10 mins, and then rest of
starting material were added, the reaction mixture was heated up to
60.degree. C. for overnight, and Isolated by parp-TLC.
CAN. J. CHEM.Vol. 61, 411 (1983)
TABLE-US-00070 ##STR00268## [0423] ##STR00269## Materials d MW Wt/V
mMol equiv SM 359.42 0.1 g 2.78 1 Morpholine 87.12 0.1 mL 37% HCHO
0.05 mL Ethanol 1.5 mL
Procedure:
[0424] A solution of SM, morpholine and formaldehyde in 1.5 mL in
ethanol was heated it up to 60.degree. C. for overnight.
CAN.J. CHEM.Vol. 61, 411 (1983)
TABLE-US-00071 ##STR00270## [0425] ##STR00271## Materials d Mw Wt/V
mMol equiv SM 117.10 456 mg 3.9 1 Morpholine 87.12 1 mL 37% HCHO
0.4 mL Ethanol 3 mL
Procedure:
[0426] A solution of SM, morpholine and formaldehyde in 3 mL in
ethanol was heated it up to 60.degree. C. for overnight.
TABLE-US-00072 ##STR00272## ##STR00273## Materials d MW Wt/V mMol
equiv SM 117 443 mg 3.78 1 pyrrolidine 1 mL 37% HCHO 0.4 mL Ethanol
3 mL
Procedure:
[0427] A solution of SM, morpholine and formaldehyde in 3 mL in
ethanol was heated it up to 60.degree. C. for overnight.
TABLE-US-00073 ##STR00274## ##STR00275## Materials d MW Wt/V mMol
equiv SM 130.15 40 mg 0.31 1 CuI 190.44 3 mg 0.05 K.sub.3PO.sub.4
212.5 128 mg 2 HO(CH.sub.2).sub.2OH 1.13 62.07 0.1 mL 2 Isopropanol
1 mL
AA Group: 0.31 mmol
AA20, AA21, AA22, AA23, AA24, AA25, AA26, AA27, AA28
Procedure:
[0428] To a test tube, CuI and K.sub.3PO.sub.4 were added then the
tube was back-filled with Nitrogen for 10 mins, and then rest of
starting material were added, the reaction mixture was heated up to
65.degree. C. for overnight.
Library Linkage:
##STR00276##
[0429] Starting material: 22 mg for each reaction K2, K90, K91,
K92, K95, K96, K97, K100, K101, K102, K114, K117, E183, E184, BB3,
BB5
Procedure:
[0430] 0.1 mmol of starting material 0.15 mmol of Et.sub.3N 0.1
mmol of K and BB or E compounds. The reactions were stirred for
overnight.
Buchwald Reaction:
[0431] Org. Lett., Vol. 2, No. 8,2000
Pd-Catalyzed Amination of Activated Ary Halides:
TABLE-US-00074 ##STR00277## [0432] ##STR00278## Materials d MW Wt/V
mMol equiv SM 296.36 454 mg 1.6 1 Iodo compound 272 500 mg 1.8 1.2
Pd(OAC).sub.2 224.49 10 mg 0.016 0.01 Cesium carbonate 325.82 730
mg 2.24 1.4 Xantphos 578.63 14 mg 0.024 0.015 1,4-dioxane 3 mL
Procedure:
[0433] 1. A 10 mL Round flask was loaded with oxazolidinone, bromo
compound, palladium(II) acetate, Xantphos and Cesium carbonate and
flashed by N2 protection for 10 mins.
[0434] 2. 1,4-dioxane was added and heated up to 70.degree. C. for
overnight and then cool down to room temperature, diluted with
dichloromethane.
Library Linkage:
##STR00279##
[0435] Starting material: 22 mg for each reaction K2, K90, K91,
K92, K95, K96, K97, K100, K101, K102, K117, E183, BB3
Procedure:
[0436] 0.2 mmol of starting material 0.15 mmol of Et.sub.3N 0.2
mmol of K and BB or E compounds. The reactions were stirred for
overnight.
Alkylation: (By NaH)
TABLE-US-00075 ##STR00280## [0437] ##STR00281## For G16, Materials
MW Wt/V mMol Equiv SM 359.42 50 g 139 1 G3 (d 2.28) 141.9 17 mL 278
2 NaH (60%) 24 10.3 g 257 1.8 THF 400 mL
[0438] NaH was added into the pre-cooled (by dry ice and acetone)
the THF and SM solution, then stirred for two hours. G3 were added
after re-cooled the reaction mixture.
Deprotection: (G3)
TABLE-US-00076 ##STR00282## [0439] ##STR00283## TFA 14 mL H.sub.2O
4 mL CH.sub.2Cl.sub.2 50 mL
Ether Type of Linkages:
##STR00284##
[0440] Library Design:
[0441] Oxazolidinones: 25 mg (1.17 equiv) for each reaction. M
compounds: M1, M2, M3, M4, M5, M6, M11, M14, M24, M30, M34, M35,
M37, M38, M39, M40, M41(1 equiv) DIAD=0.10 nM in THF (MW 202), 400
mg in 17 mL THF. 1 mL was taken for each reaction.
Ph.sub.3P-polystyrene 1 mmol/g 100 mg for each compound 0.1
mMol
Procedure:
[0442] 4. The vials were charged with SM and Ph.sub.3P-polystrene.
[0443] 5. A solution of DIAD in THF was added into the reaction
mixture. [0444] 6. The reactions were stirred for overnight.
CAN. J. CHEM.Vol. 61, 411 (1983)
TABLE-US-00077 ##STR00285## [0445] ##STR00286## Materials d MW Wt/V
mMol equiv SM 117.10 500 mg Nitro compound 207.23 884 mg 37% HCHO
0.6 mL Ethanol 6 mL
Procedure:
[0446] A solution of SM, nitro compound and formaldehyde in 3 mL in
ethanol was heated it up to 65.degree. C. for overnight.
TABLE-US-00078 ##STR00287## ##STR00288## Materials d MW Wt/V mMol
equiv SM 117 500 mg pyrrolidine 1 mL 37% HCHO 0.6 mL Ethanol 3
mL
Procedure:
[0447] A solution of SM, morpholine, and formaldehyde in 3 mL in
ethanol was heated it up to 60.degree. C. for overnight.
Alkylation: (By NaH)
TABLE-US-00079 ##STR00289## [0448] ##STR00290## For C18, Materials
MW Wt/V mMol Equiv SM 359.42 0.5 g 1.39 1 C18 (d1.5) 120 0.2 mL
2.78 2 NaH (60%) 24 100 mg 2.57 1.8 THF 4 mL
[0449] NaH was added into the pre-cooled (by dry ice and acetone)
the THF and SM solution, then stirred for two hours. G3 were added
after re-cooled the reaction mixture.
alkylation: (By NaH)
TABLE-US-00080 ##STR00291## ##STR00292## For C18, Materials MW Wt/V
mMol Equiv SM 359.42 0.5 g 1.39 1 C19 149 414 mg 2.78 2 NaH (60%)
24 100 mg 2.57 1.8 THF 4 mL
[0450] NaH was added into the pre-cooled (by dry ice and acetone)
the THF and SM solution, then stirred for two hours. C19 were added
after re-cooled the reaction mixture.
Curtius Rearrangement:
TABLE-US-00081 ##STR00293## [0451] ##STR00294## Materials d MW Wt/V
mMol Equiv SM 329.44 26 79 1 H.sub.2SO.sub.4 98 9.2 mL 95 1.2
NaNO.sub.2 69 8.2 g 118 1.5 water 100 mL
Procedure:
[0452] 1). The hydrazide compound was dissolved in water (75 mL),
and concentrated sulfuric acid (9.2 mL) diluted in water (25 mL)
and added into the stirred solution. The mixture was cooled in the
ice bath and then NaNO.sub.2 in water (20 mL) was added
dropwise.
[0453] 2). The reaction mixture was stirred at room temperature for
overnight. Then was put on the water rota-vap without vacuum to
shake for 6 hours at 50.degree. C.
[0454] 3). The reaction was neutralized by sodium carbonate and
extracted with EtOAc three times, brine and dried over
Na.sub.2SO.sub.4.
[0455] 4). The solvents were removed by water rota-vap to afford
residues.
[0456] 5). Column chromatograph to isolate the desired
compound.
TABLE-US-00082 ##STR00295## ##STR00296## Materials d MW Wt/V mMol
Equiv SM 329.44 4.5 g 1 H.sub.2SO.sub.4 98 1.6 mL 1.2 NaNO.sub.2 69
1.4 g 1.5 water 30 mL
Procedure:
[0457] 1). The hydrazide compound was dissolved in water (25 mL),
and concentrated sulfuric acid (1.6 mL) diluted in water (5 mL) and
added into the stirred solution. The mixture was cooled in the ice
bath and then NaNO.sub.2 powder was added directly.
[0458] 2). The reaction mixture was stirred at room temperature for
overnight. Then was put on the water rota-vap without vacuum to
shake for 6 hours at 50.degree. C.
[0459] 3). The reaction was neutralized by sodium carbonate and
extracted with EtOAc three times, brine and dried over
Na.sub.2SO.sub.4.
[0460] 4). The solvents were removed by water rota-vap to afford
residues.
[0461] 5). Column chromatographed to isolate the desired
compound.
##STR00297##
300 mg of ZD3-75-2
500 mg of Pd(OH).sub.2
5 mL of THF
5 mL of MeOH
[0462] The reaction was stirred at room temperature 10 mins (see
new spot and starting material on TLC, new spot is more polar) and
40 mins (see one new spot, which is less polar than starting
material, and only one spot shown on TLC).
##STR00298##
300 mg of ZD3-75-2
500 mg of Pd(OH).sub.2
5 mL of THF
5 mL of MeOH
[0463] The reaction was stirred at room temperature 10 mins (see
new spot and starting material on TLC, new spot is more polar) and
40 mins (see one new spot, which is less polar than starting
material, and only one spot shown on TLC).
##STR00299##
[0464] To a solution of starting material in THF, Et3N was added
then BB3 was added. The reaction was stirred for overnight.
Isolated by parp-TLC (3/1=EtOAc/Hexane)
Library:
[0465] Oxazolidinone derivatives: SC1, H, SG3-N, RG3, RC3 (0.1 nmol
CH.sub.2Cl.sub.2 solution except H in THF) Nitrobenzene
derivatives: BB3, BB7, BB8, BB9 ((0.1 nmol CH.sub.2Cl.sub.2
solution except BB7 in THF) Base: triethylamine (0.15 nmol) The
reactions were set up in the usual way and kept for overnight.
Isolated by parp-TLC (3/1=EtOAc/Hexane).
Library
[0466] New M compounds: Oxazolidinone derivatives: RG3, RC5, RC3
(0.1 nmol CH.sub.2Cl.sub.2 solution) Nitrobenzene derivatives: M42,
M43, M44, M45, M46, M47 (0.1 nmol) DIAD=0.10 nM in THF (MW 202), 1
equiv. Ph.sub.3P-polystyrene 1 mmol/g 100 mg for each compound 0.1
mMol
Procedure:
[0467] 7. The vials were charged with SM and Ph.sub.3P-polystrene.
[0468] 8. A solution of DIAD in THF was added into the reaction
mixture. The reactions were stirred for overnight. The reactions
were set up in the usual way and kept for overnight. Isolated by
parp-TLC (3/1=EtOAc/Hexane). Alkylation: (By t-BuOK)
TABLE-US-00083 [0468] Alkylation: (By t-BuOK) ##STR00300## For C18,
Materials MW Wt/V mMol Equiv SM 359.42 0.5 g 1.39 1 C18 (d1.5) 120
0.2 mL 2.78 2 t-BuOK 3 mL 2.57 1.8 THF 5 mL
[0469] To a solution of SM and THF was added t-BuOK, then C19 was
added. The reaction mixture was heated up to 60.degree. C. in
sealed tube.
Alkylation: (By t-BuOK)
TABLE-US-00084 ##STR00301## ##STR00302## For C19, Materials MW Wt/V
mMol Equiv SM 359.42 0.5 g 1.39 1 C19 149 414 mg 2.78 2 t-BuOK 3 mL
2.57 1.8 THF 5 mL
[0470] To a solution of SM and THF was added t-BuOK, then C19 was
added. The reaction mixture was heated up to 60.degree. C. in
sealed tube.
Alkylation: (By t-BuOK)
TABLE-US-00085 ##STR00303## ##STR00304## For C18, Materials MW Wt/V
mMol Equiv SM 359.42 0.5 g 1.39 1 C18 (d1.5) 120 0.2 mL 2.78 2
t-BuOK 3 mL 2.57 1.8 THF 5 mL
[0471] To a solution of SM and THF was added t-BuOK, then C19 was
added. The reaction mixture was heated up to 60.degree. C. in
sealed tube.
Library Linkage:
##STR00305##
[0472] ZD4-55-1
[0473] Starting material: 22 mg for each reaction K2, K91, K92,
K95, K96, K97, K100, K101, K117, E183, E184, BB3, BB7, BB9, BB5,
K93, K98, K94, K106, AC2, AC3, AC5, AC7.
Procedure:
[0474] 0.08 mol of starting material 0.15 mmol of Et.sub.3N 0.09
mmol of K and BB, AC or E compounds. The reactions were stirred for
weekend.
[0475] Library Linkage:
##STR00306##
ZD4-55-1
[0476] Starting material: 14 mg for each reaction.
AC1, AC4, AC8, AC9, AC10, AC11, AC12, MsCl
Procedure:
[0477] 0.04 mmol of starting material 0.15 mmol of Et.sub.3N 0.06
mmol of AC compounds. The reactions were stirred for overnight.
[0478] While the present invention is described herein with
reference to illustrated embodiments, it should be understood that
the invention is not limited hereto. Those having ordinary skill in
the art and access to the teachings herein will recognize
additional modifications and embodiments within the scope thereof.
Therefore, the present invention is limited only by the claims
attached herein.
* * * * *