U.S. patent application number 10/470575 was filed with the patent office on 2005-03-10 for phenyloxazolidinones having a c-c bond to 4-8 membered heterocyclic rings.
Invention is credited to Anderson, David J., Barbachyn, Michael R., Brickner, Steven J., Ennis, Michael D., Hoffman, Robert L., Hutchinson, Douglas K., Poel, Toni-Jo, Thomas, Richard C..
Application Number | 20050054683 10/470575 |
Document ID | / |
Family ID | 21704418 |
Filed Date | 2005-03-10 |
United States Patent
Application |
20050054683 |
Kind Code |
A1 |
Hutchinson, Douglas K. ; et
al. |
March 10, 2005 |
Phenyloxazolidinones having a C-C bond to 4-8 membered heterocyclic
rings
Abstract
A process for preparing a compound of the formula I: 1 or
pharmaceutical acceptable salts thereof wherein X is --NR.sub.1--,
--S(O).sub.g--, or --O--; R.sub.1 is --H, C.sub.1-6 alkyl
optionally substituted with one or more --OH, --CN, or halo, or
R.sub.1 is --(CH.sub.2).sub.h-aryl, --COR.sub.1-1, --COOR.sub.1-2,
--CO--(CH.sub.2).sub.h--COR.sub.1-1, C.sub.1-6 alkyl sulfonyl,
--SO.sub.2--(CH.sub.2).sub.h-aryl, or --(CO).sub.i-Het; R.sub.2 is
--H, C.sub.1-6 alkyl, --(CH.sub.2).sub.h-aryl, or halo; R.sub.3 and
R.sub.4 are the same or different and are --H or halo; R.sub.5 is
--H, C.sub.1-12 alkyl optionally substituted with one or more halo,
C.sub.3-12 cycloalkyl, C.sub.1-6 alkoxy. The compounds are useful
antimicrobial agents.
Inventors: |
Hutchinson, Douglas K.;
(Antioch, IL) ; Ennis, Michael D.; (Portage,
MI) ; Hoffman, Robert L.; (Kalamazoo, MI) ;
Thomas, Richard C.; (Kalamazoo, MI) ; Poel,
Toni-Jo; (Wayland, MI) ; Barbachyn, Michael R.;
(Kalamazoo, MI) ; Brickner, Steven J.; (Ledyard,
CT) ; Anderson, David J.; (Kalamazoo, MI) |
Correspondence
Address: |
MARSHALL, GERSTEIN & BORUN LLP
6300 SEARS TOWER
233 S. WACKER DRIVE
CHICAGO
IL
60606
US
|
Family ID: |
21704418 |
Appl. No.: |
10/470575 |
Filed: |
March 22, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10470575 |
Mar 22, 2003 |
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09518701 |
Mar 3, 2000 |
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09518701 |
Mar 3, 2000 |
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09247347 |
Feb 10, 1999 |
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6258473 |
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09247347 |
Feb 10, 1999 |
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08696313 |
Aug 13, 1996 |
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5968962 |
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60003149 |
Sep 1, 1995 |
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Current U.S.
Class: |
514/340 ;
514/376; 546/271.4; 548/229 |
Current CPC
Class: |
C07D 413/10 20130101;
A61P 31/00 20180101; C07D 417/14 20130101; C07D 413/14 20130101;
A61P 31/04 20180101 |
Class at
Publication: |
514/340 ;
514/376; 546/271.4; 548/229 |
International
Class: |
A61K 031/4439; A61K
031/422; C07D 413/02 |
Claims
1-18. (canceled)
19. A compound of formula VI as an intermediate for preparing
oxazolidinones useful as antimicrobial agents 14wherein X.sub.2 is
--NH--, protected --NH--, --S(O).sub.g--, or --O--; R.sub.2 is H,
OH or C.sub.1alkyl; R.sub.3 and R.sub.4 are independently H or
halo; B is NH.sub.2, protected NH.sub.2, N.sub.3, or
--OSO.sub.2C.sub.1-4 alkyl; the dotted line in the ring system is a
single or a double bond; G is 0, 1, or 2; m is 0, 1, 2, 3, 4, or 5;
n is 0, 1, 2, 3, 4, or 5; and with the proviso that m and n taken
together are 1, 2, 3, 4 or 5.
20. A compound of formula VI of claim 19 which is an optically pure
enantiomer having the S-configuration at C5 of the oxazolidinone
ring as shown below: 15
21. A compound of formula VI of claim 20 wherein X.sub.2 is --NH--,
protected --NH--, --S(O).sub.g--, or --O--; R.sub.2 is H or OH;
R.sub.3 and R.sub.4 are independently H or F; B is, NH.sub.2,
N.sub.3, or --OSO.sub.2C.sub.1-4 alkyl.
22. A compound of formula VI as an intermediate for preparing
oxazolidinones useful as antimicrobial agents 16wherein X.sub.2 is
--NH--, protected --NH--, --S(O).sub.g--, or --O--; R.sub.2 is H,
OH or C.sub.1 alkyl; R.sub.3 and R.sub.4 are independently H or
halo; B is NH.sub.2, protected NH.sub.2, N.sub.3, or
--OSO.sub.2C.sub.1-4 alkyl; the dotted line in the ring system is a
single or a double bond; G is 0, 1, or 2; and m is 0 and n is 3; m
is 1 and n is 2; or m is 3 and n is 0.
23. A compound of formula VI of claim 22 which is an optically pure
enantiomer having the S-configuration at C5 of the oxazolidinone
ring as shown below: 17
24. A compound of formula VI of claim 22 wherein X.sub.2 is --NH--,
--S(O).sub.g--, or --O--; R.sub.2 is H or OH; R.sub.3 and R.sub.4
are independently H or F; B is NH.sub.2, N.sub.3, or
--OSO.sub.2C.sub.1-4 alkyl.
25. A compound of claim 19 wherein B is NH.sub.2, protected
NH.sub.2, N.sub.3, or --OSO.sub.2C.sub.1-4alkyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/518,701, filed Mar. 3, 2000 which is a
continuation of U.S. patent application Ser. No. 09/247,347, filed
Feb. 10, 1999, which is a divisional application of U.S. patent
application Ser. No. 08/696,313, filed Aug. 13, 1996, which in turn
claims the benefit of the following provisional application: U.S.
Ser. No. 60/003,149, filed Sep. 1, 1995, under 35 USC
119(e)(i).
BACKGROUND OF THE INVENTION
[0002] The present invention relates to new and useful
N-phenyloxazolidinone compounds and their preparations, and more
particularly to N-phenyloxazolidinone compounds in which the
phenyloxazolidinone moiety is linked to a variety of saturated, or
partially saturated, 4-8 membered heterocycles containing oxygen,
nitrogen, and sulfur through a carbon-carbon bond.
[0003] The compounds are useful antimicrobial agents, effective
against a number of human and veterinary pathogens, including
gram-positive aerobic bacteria such as multiply-resistant
staphylococci and streptococci, as well as anaerobic organisms such
as bacteroides and clostridia species, and acid-fast organisms such
as Mycobacterium tuberculosis and Mycobacterium avium. The
compounds are particularly useful because they are effective
against the latter organisms which are known to be responsible for
infection in persons with AIDS.
Information Disclosure
[0004] A series of Delalande patent applications (Derwent Abstracts
61219Y/35, 67436R-B, 84475A/47) disclose a saturated nitrogen
heterocycle linked through the nitrogen atom to a
phenyloxazolidinone moiety.
[0005] French Patent (FR2500450 A1 820827) discloses cyclohexenone
attached at the 3-position to a phenyloxazolidinone.
[0006] Other references disclose fully aromatic heterocycles
attached to a phenyloxazolidinone, including European Patent
Publication 0352 781 A2, U.S. Pat. No. 5,130,316, U.S. Pat. No.
5,254,577, U.S. Pat. No. 4,948,801, and WO 9309103-A1, whereas in
our present invention the heterocycle is saturated or partially
saturated.
SUMMARY OF THE INVENTION
[0007] The present invention provides new compounds of the Formula
(I) 2
[0008] or pharmaceutical acceptable salts thereof wherein:
[0009] X is
[0010] NR.sub.1, S(O).sub.g, or O;
[0011] R.sub.1 is
[0012] a) H,
[0013] b) C.sub.1-6 alkyl, optionally substituted with one or more
OH, CN, or halo,
[0014] c) --(CH.sub.2).sub.h-aryl,
[0015] d) --COR.sub.1-1,
[0016] e) --COOR.sub.1-2,
[0017] f) --CO--(CH.sub.2).sub.h--COR.sub.1-1,
[0018] g) --SO.sub.2--C.sub.1-6 alkyl,
[0019] h) --SO.sub.2--(CH.sub.2).sub.h-aryl, or
[0020] i) --(CO).sub.i-Het;
[0021] R.sub.1-1 is
[0022] a) H,
[0023] b) C.sub.1-6 alkyl, optionally substituted with one or more
OH, CN, or halo,
[0024] c) --(CH.sub.2).sub.h-aryl, or
[0025] d) --(CH.sub.2).sub.h--OR.sub.1-3;
[0026] R.sub.12 is
[0027] a) C.sub.1-6 alkyl, optionally substituted with one or more
OH, CN, or halo,
[0028] b) --(CH.sub.2).sub.h-aryl, or
[0029] c) --(CH.sub.2).sub.h--OR.sub.13;
[0030] R.sub.13 is
[0031] a) H,
[0032] b) C.sub.1-6 alkyl,
[0033] c) --(CH.sub.2).sub.h-aryl, or
[0034] d) --CO(C.sub.1-6alkyl);
[0035] R.sub.2 is
[0036] a) H,
[0037] b) C.sub.1-6 alkyl,
[0038] c) --(CH.sub.2).sub.h-aryl, or
[0039] d) halo;
[0040] R.sub.3 and R.sub.4 are the same or different and are
[0041] a) H, or
[0042] b) halo;
[0043] R.sub.5 is
[0044] a) H,
[0045] b) C.sub.1-12 alkyl, optionally substituted with one or more
halo,
[0046] c) C.sub.3-12 cycloalkyl,
[0047] d) C.sub.1-16 alkoxy;
[0048] g is 0, 1, or 2;
[0049] h is 1, 2, 3, or 4;
[0050] i is 0 or 1;
[0051] m is 0, 1, 2, 3, 4, or 5;
[0052] n is 0, 1, 2, 3, 4, or 5;
[0053] and with the provisio that m and n taken together are 1, 2,
3, 4, or 5.
[0054] More particularly, the present invention provides compounds
of formula (I) wherein R.sub.1 is H, fluoroethyl, cyanomethyl,
methyl sulfonyl; formyl, hydroxyacetyl, acetyl, methoxyacetyl,
benzyloxyacetyl, acetoxyacetyl, dichloroacetyl, methoxy carbonyl,
tert-butoxy carbonyl, benzyloxy carbonyl, 3-hydroxypropionyl,
3-methoxypropionyl, 4-oxopentanoyl, 2-indole carbonyl, 5-isoxazole
carbonyl, 5-nitro-2-thiazoyl, 4-oxo-2-thiazolinyl, or
5-methyl-1,3,4-thiadiazol-2-y- l.
[0055] R.sub.2 is H, F, or CH.sub.3;
[0056] R.sub.3 and R.sub.4 are the same or different and are H or
F; and
[0057] R.sub.5 is methyl or methyl substituted with one or more F
or Cl.
[0058] The present invention also provides a method for treating
microbial infections in patients by administering to a patient in
need thereof an effective amount of a compound of Formula (I). The
compound can be administered orally, parenterally or topically in a
pharmaceutical composition. Preferably, the compound is
administered in an amount of from about 0.1 to about 100 mg/kg of
body weight/day.
DETAILED DESCRIPTION OF THE INVENTION
[0059] For the purpose of the present invention, the term
"C.sub.1-6 alkyl" and the term "C.sub.1-12 alkyl" refer to any
straight or branched alkyl group having one to six or one to twelve
carbons respectively such as, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
isopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like.
[0060] The term "C.sub.1-6 alkyl sulfonyl" refers to any straight
or branched alkyl group having one to six carbons attached to
--SO.sub.2 forming such groups as, for example, methyl sulfonyl,
ethyl sulfonyl, isopropyl sulfonyl and the like.
[0061] The term "C.sub.3-12 cycloalkyl" refers to three to twelve
carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like.
[0062] The term "C.sub.1-4 alkoxy" and the term "C.sub.1-6 alkoxy"
refer to any straight or branched alkyl group having one to four or
one to six carbons, respectively, attached to an oxygen forming
such groups as, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy,
n-pentyloxy, isopentyloxy, n-hexyloxy, iso-hexyloxy and the
like.
[0063] The term halo refers to fluoro, chloro, bromo, or iodo.
[0064] The term "aryl" refers to a phenyl, pyridyl or napthyl
moiety which can be optionally-substituted with one or more F, Cl,
Br, I, CN, OH, SH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6
thioalkyl.
[0065] The term "Het" refers to 5 to 10 membered heterocyclic rings
containing one or more oxygen, nitrogen, and sulfur forming such
groups as, for example, pyridine, thiophene, furan, pyrazoline,
pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,
3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl,
1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl,
5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl,
4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole,
5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl,
2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl,
benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl,
3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl,
5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl,
1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl,
2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl,
1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl,
1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,
1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl,
1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or
5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione,
1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties
may be substituted as appropriate.
[0066] The term "pharmaceutically acceptable salts" refers to salts
useful for administering the compounds of this invention and
include hydrochloride, hydrobromide, hydroiodide, sulfate,
phosphate, acetate, propionate, lactate, mesylate, maleate, malate,
succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate
and the like. These salts may be in hydrated form.
[0067] In the structural representation of Formula (I) the dotted
line in the heterocyclic ring means that this bond can be either
single or double. In the case where the dotted line is a double
bond, the R.sub.2 group will not be present.
[0068] In a preferred embodiment of the N-phenyloxazolidinone
compounds of the present invention, the X group is preferably
NR.sub.1, SO.sub.2, or oxygen.
[0069] The R.sub.1 substituent on the nitrogen atom can be
introduced by synthetic methods known to those skilled in the art
from commercially available reagents.
[0070] The preferred R.sub.1 substituent is H; fluoroethyl,
cyanomethyl, methyl sulfonyl, formyl, hydroxyacetyl, acetyl,
methoxyacetyl, benzyloxyacetyl, acetoxyacetyl, dichloroacetyl,
methoxy carbonyl, tert-butoxy carbonyl, benzyloxy carbonyl,
3-hydroxypropionyl, 3-methoxypropionyl, 4-oxopentanoyl, 2-indole
carbonyl, 5-isoxazole carbonyl, 5-nitro-2-thiazolyl,
4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl. The most
preferred R.sub.1 substituent is formyl, methoxy carbonyl, or
hydroxyacetyl.
[0071] Where heterocyclic rings are the saturated derivatives, the
preferred R.sub.2 substituent is hydrogen, fluoro, or methyl.
[0072] The preferred R.sub.3 and R.sub.4 substituents are
independently hydrogen or fluoro.
[0073] The preferred R.sub.5 substituent is methyl.
[0074] The most preferred compounds in this series would be
prepared as the optically pure enantiomers having the
(S)-configuration according to the Cahn-Ingold-Prelog notation at
C5 of the oxazolidinone ring. Optically pure material could be
prepared by one of a number of asymmetric syntheses. For example,
treatment of intermediate compound 12 in CHART B with an
appropriate base, followed by addition of (R)-glycidyl butyrate
would afford the corresponding oxazolidinone in optically pure form
with the requisite (S)-configuration at the 5-position of the
oxazolidinone ring. Although the (S)-enantiomer of this series of
compounds is preferred since it is pharmacologically active as an
antibacterial agent, the racemic modification is also useful in the
same manner as the pure (S)-enantiomer; the difference being that
twice as much racemic material is required to elicit the same
antibacterial effect.
[0075] CHART A illustrates methods for preparing compounds of
Formula (I) having a heterocycle containing nitrogen. As shown in
CHART A, the key intermediate 1 can be used to make derivatives by
reactions known to those skilled in the art. For example, acylation
affords 2 and 3, the subsequent deprotection of 2 provides 2',
alkylation affords 5 (the substituents including hydroxy, nitro,
halo, aryl, and sulfonyl; structure 5 also encompasses products
having a heteroatomic nucleus), sulfonylation affords 6, and
alkoxyacylation affords 4.
[0076] A method for preparing compounds of intermediate 1 having a
4-membered heterocycle containing nitrogen in highly
enantiomerically enriched form is depicted in CHART B. The first
step involves treatment of structure 7 with ethyl cyanoacetate in
the presence of an appropriate base, such as sodium hydride or
potassium carbonate, at a temperature in the range of -10.degree.
C. to 100.degree. C. The subsequent alkylation using alkyl halides
or tosylates affords nitrile derivative 8. The nitrile derivative 8
is then reduced by catalytic hydrogenation in the presence of an
appropriate catalyst, such as palladium on carbon, W-2 Raney nickel
or platinum on sulfide carbon, in an appropriate solvent, such as
ethyl acetate, THF, methanol or combinations thereof, to give
amino-aniline 9, which upon treatment with an appropriate base,
preferably methyl or ethyl Grignard, affords the lactam 10.
Reduction of 10 by using an appropriate reducing agent, such as
LAH-or borane, gives the azetidine 11, which reacted with benzyl
chloroformate, at a temperature in the range of -10.degree. C. to
10.degree. C., affords the corresponding benzyl carbamate
derivatives 12. The treatment of 12 with n-butyllithium in an
appropriate solvent such as THF, at a temperature in the range of
-78.degree. C. to -40.degree. C., followed by addition of
commercially available (R)-glycidyl butyrate dropwise would afford
the corresponding oxazolidinone 13 in enantiomerically enriched
form at the 5-position of the oxazolidinone ring. As shown in CHART
B, compound 13 can be converted to the corresponding alkyl or aryl
sulfonate 14 by treatment with alkyl or aryl sulfonyl chloride in
the presence of triethylamine or pyridine (wherein R' is C.sub.1-4
alkyl or (un)substituted phenyl). The resultant sulfonate 14 is
then treated with an alkali metal azide such as sodium or potassium
azide, in an aprotic dipolar solvent such as DMF or
N-methylpyrrolidinone (NMP), with an optional catalyst such as
18-crown-6, at a temperature in the range of 50.degree. C. to
90.degree. C. to afford azide derivatives. The azide derivatives
can be reduced to the corresponding amine 15 by hydrogenation in
the presence of a palladium, platinum or nickel catalyst, in an
appropriate solvent such as ethyl acetate, THF, or methanol.
Alternatively, amine 15 can be prepared by treating 14 with an
appropriate solvent such as methanol and/or THF which is saturated
with ammonia and heating the mixture to 100.degree. C. in a sealed
tube. The reaction occurs over hours, e.g., 40-70 hours. Amine 15
is then acylated with an acid chloride or anhydride in the presence
of a base such as pyridine or triethylamine at temperatures ranging
from -40.degree. C. to 40.degree. C. to provide the N-acyl
oxazolidinone 16. Finally, catalytic hydrogenation of 16 in the
presence of a noble metal catalyst, such as palladium on carbon or
palladium hydroxide on carbon affords the azetidine 17. The
azetidine 17 can be used to prepare derivative compounds
demonstrated in CHART A.
[0077] The following compounds of Formula (I) having a 4-membered
heterocycle containing nitrogen, for example, are prepared directly
by the methods described in CHART A and CHART B:
[0078]
(S)-N-[[3-[3-Fluoro-4-[1-(carbobenzyloxy)-(3-methyl)-3-azetidinyl]--
phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0079]
(S)-N-[[3-[3-Fluoro-4-[3-methyl-3-azetidinyl]-phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]-acetamide;
[0080]
(S)-N-[[3-[3-Fluoro-4-[1-(carboxymethyl)-3-(3-methyl)-azetidinyl]-p-
henyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0081]
(S)-N-[[3-[3-Fluoro-4-[1-(methoxyacetyl)-3-(3-methyl)-azetidinyl]-p-
henyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0082]
(S)-N-[[3-[3-Fluoro-4-[1-(formyl)-3-(3-methyl)-azetidinyl]-phenyl]--
2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0083] (S)-N-[[3-[3-Fluoro-4-[1
(dichloroacetyl)-3-(3-methyl)-azetidinyl]--
phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0084]
(S)-N-[[3-[3-Fluoro-4-[1-(3-methoxypropionyl)-3-(3-methyl)-azetidin-
yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0085]
(S)-N-[[3-[3-Fluoro-4-[1-(3-hydroxypropionyl)-3-(3-methyl)-azetidin-
yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0086]
(S)-N-[[3-[3-Fluoro-4-[1-(4-oxopentanoyl)-3-(3-methyl)-azetidinyl]--
phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0087]
(S)-N-[[3-[3-Fluoro-4-[1-acetyl-3-(3-methyl)-azetidinyl]-phenyl]-2--
oxo-5-oxazolidinyl]methyl]-acetamide;
[0088]
(S)-N-[[3-[3-Fluoro-4-[1-(2-fluoroethyl)-3-(3-methyl)-azetidinyl]-p-
henyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0089]
(S)-N-[[3-[3-Fluoro-4-[1-(cyanomethyl)-3-(3-methyl)-azetidinyl]-phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0090]
(S)-N-[[3-[3-Fluoro-4-[1-(5-nitro-2-thiazolyl)-3-(3-methyl)-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0091]
(S)-N-[[3-[3-Fluoro-4-[1-(methanesulfonyl)-3-(3-methyl)-azetidinyl]-
-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0092]
(S)-N-[[3-[3-Fluoro-4-[1-(benzyloxyacetyl)-3-(3-methyl)-azetidinyl]-
-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide;
[0093]
(S)-N-[[3-[3-Fluoro-4-[1-(hydroxyacetyl)-3-(3-methyl)-azetidinyl]-p-
henyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
[0094] A second method for preparing compounds of intermediate 1
having a 4-membered heterocycle containing nitrogen, wherein
R.sub.2 is H, in highly enantiomerically enriched form is depicted
in CHART C. The first step involves reaction of structure 18 with a
protected aniline 19 in the presence of an appropriate base, such
as sec-butyllithium, in an appropriate solvent, such as THF, at a
temperature range of -40.degree. C. to -78.degree. C. to afford
compounds 20. Reaction of 20 with benzyl chloroformate at 0.degree.
C. to 25.degree. C. gives compound 21 which reacts further at
25.degree. C. to 100.degree. C. to give compound 22. Treatment of
22 with excess triethylsilane and trifluoroacetic acid in a
suitable solvent such as methylene chloride, at a temperature range
of 10.degree. C. to 40.degree. C. gives compound 23. The remaining
synthetic steps which lead to structure 17 are similar to the
procedures outlined in CHART B.
[0095] The following compounds of Formula (I) having a 4-membered
heterocycle containing nitrogen, for example, are prepared directly
by the methods described in CHART A and CHART C:
[0096]
(S)-N-[[3-[3-Fluoro-4-[1-(carbobenzyloxy)-3-azetidinyl]phenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide;
[0097]
(S)-N-[[3-[3-Fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]acetamide;
[0098]
(S)-N-[[3-[3-Fluoro-4-[1-(carboxymethyl)-3-azetidinyl]phenyl]-2-oxo-
-5-oxazolidinyl]methyl]acetamide;
[0099]
(S)-N-[[3-[3-Fluoro-4-[1-(formyl)-3-azetidinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]acetamide.
[0100] CHART D depicts a method for preparing compounds of
intermediate 1 having a 5-membered heterocycle containing nitrogen.
As shown in CHART D, the first step involves the coupling of
vinyltributyltin 24 (commercially available) and compound 25. The
compound 25 can be prepared according to the procedures described
in PCT/US92/08267 and PCT/US93/09589. The coupling occurs in the
presence of palladium catalyst to afford compound 26. The reaction
is carried out at a high temperature for several hours, e.g.,
reflux for 5-8 hours. The compound 26 is then treated with a
solution of N-benzyl-N-(methoxymethyl)trimethylsilyl-methylamine
(prepared according to the literature from commercially available
material) and trifluoroacetic acid in an appropriate solvent to
provide 27. The reaction occurs over several hours, e.g., 8-17
hours. The N-benzyl group of 27 is then removed by catalytic
hydrogenation in the presence of a noble metal catalyst, such as
palladium on carbon or palladium hydroxide on carbon to afford 28.
The compound 28 can bemused to prepare the derivative compounds
demonstrated in CHART A. Following a similar procedure and making
non-critical variations but substituting different vinyl
tributylstannyl derivatives for structure 24, a variety of other
heterocyclic derivatives of compound 26 can be obtained as
illustrated in EXAMPLE 80.
[0101] Alternatively, another method for preparing compounds of
intermediate 1 having a 5-membered heterocycle containing nitrogen
is depicted in CHART E. As shown in CHART E, nucleophilic aromatic
substitution of 7 with dimethylmalonate (commercial available)
affords the adduct 29. The reaction occurs in an appropriate
solvent such as THF, at a temperature in the range of -100.degree.
C. to 60.degree. C. The compound 29 is readily alkylated by a
reaction known to those skilled in the art to provide nitrile 30.
Catalytic reduction of 30 in the presence of a palladium, platinum
or nickel catalyst, in an appropriate solvent such as methanol
converts both nitro and nitrile to amines with concommittant
intramolecular cyclization to afford the lactam 31. The lactam 31
is then decarboxylated to provide 32, which upon reduction with an
appropriate reducing agent such as lithium aluminum hydride or
borane, in an appropriate solvent such as THF or ether, affords
compound 33. The remaining synthetic steps which lead to structure
34 are similar to the procedures outlined in CHART B.
[0102] The following compounds of Formula (I) having a 5-membered
heterocycle containing nitrogen, for example, are prepared directly
by the methods described in CHART A, CHART D and CHART E:
[0103]
(S)-N-[[3-[3-Fluoro-4-[1-(hydroxyacetyl)-3-pyrrolidinyl]phenyl]-2-o-
xo-5-oxazolidinyl]methyl]acetamide;
[0104]
(S)-N-[[3-[3-Fluoro-4-[1-(formyl)-3-pyrrolidinyl]phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide;
[0105] (S)-3-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2
fluorophenyl]-1-pyrrolidinecarboxylic acid methyl ester.
[0106] Following the general procedure depicted in CHART D for the
preparation of compound 26 and making non-critical variations but
substituting 6-(tributylstannyl)-3,4-dihydro-2H-dihydropyran for
structure 24, the following compound is prepared:
[0107]
(S)-N-[[3-[3-Fluoro-4-(3,4-dihydro-2H-pyran-6-yl)phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide.
[0108] A method for preparing compounds of formula (I) having a
5-membered heterocycle containing a sulfur atom, oxygen atom,
sulfone group or sulfoxide group in highly enantiomerically
enriched form wherein R.sub.3 or R.sub.4 is halo is depicted in
CHART F. As shown in CHART F, structure 35 (wherein X is O or S) is
reacted with a protected aniline 19 in the presence of an
appropriate base, such as sec-butyllithium, in an appropriate
solvent, such as THF, at a temperature range of -40.degree. C. to
-78.degree. C. to afford compounds 36. Reaction of 36 with benzyl
chloroformate at 0.degree. C. to 25.degree. C. gives compound 37.
The subsequent elimination reaction known to those skilled in the
art affords regiosiomers 38 and 39 as a mixture. Following the
general procedure outlined in CHART B provides compounds 40 and 41
as a mixture. In the case where X is S, the sulfur group can be
oxidized by an appropriate oxidizer such as N-methylmorpholine
N-oxide and osmium tetroxide in an appropriate solvent such as
mixtures of water and acetone, or by NaIO.sub.4 in an appropriate
solvent such as mixtures of water and methanol, to provide the
corresponding sulfones and sulfoxides, respectively. When it is
desirable, the double bond in the heterocycle ring may be reduced
by catalytic hydrogenation in the presence of an appropriate
catalyst and a suitable solvent. Furthermore, in the case where X
is O, SO, or SO.sub.2, the regioisomeric mixture of 40 and 41 can
be separated by chromatography as illustrated in EXAMPLEs 68 and
69.
[0109] The following compounds of Formula (I) having a 5-membered
heterocycle containing a sulfur atom, oxygen atom, sulfone group or
sulfoxide group, for example, are prepared directly by the method
of CHART F:
[0110]
(S)-(-)-N-[[3-[3-Fluoro-4-(dihydrothien-3-yl)-phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]acetamide;
[0111]
(5S)-N-[[3-[3-Fluoro-4-(2,5-dihydro-1-oxido-3-thienyl)-phenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide;
[0112]
(5S)-N-[[3-[3-Fluoro-4-(4,5-dihydro-1-oxido-3-thienyl)-phenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide;
[0113]
(S)-N-[[3-[3-Fluoro-4-(2,5-dihydro-1,1-dioxido-3-thienyl)-phenyl]-2-
-oxo-5-oxazolidinyl]methyl]acetamide;
[0114]
(S)-N-[[3-[3-Fluoro-4-(4,5-dihydro-1,1-dioxido-3-thienyl)-phenyl]-2-
-oxo-5-oxazolidinyl]methyl]acetamide.
[0115] A method for preparing compounds having a 6-membered
heterocycle containing a nitrogen atom, sulfur atom, oxygen atom,
sulfone group or sulfoxide group wherein R.sub.3 and R.sub.4 are
hydrogen is depicted in CHART G. As shown in CHART G, the first
step involves the condensation of structures 42 and 43-(wherein X
is O, S, or N) to afford compound 44. In the case where X is a
nitrogen atom, the amino group should be protected with an
appropriate protecting group such as carbobenzyloxy (CBz). The
protecting group is optionally removed after the synthesis to give
compounds 46 or 47 (wherein X is NH), which can be used to prepare
the derivative compounds demonstrated in CHART A. The reaction of
42 with 43 occurs in an appropriate solvent such as THF, at an
appropriate temperature such as -78.degree. C. to -40.degree. C.,
in the presence of a lithium base such as n-butyllithium. The
subsequent elimination reaction known to those skilled in the art
provides compound 45. The remaining synthetic steps which lead to
the compound 46 are similar to the procedures outlined in CHART B.
When it is desirable, the double bond in the heterocyclic ring may
be reduced to give 47 by catalytic hydrogenation; and when X is a
sulfur atom, the sulfur group can be oxidized to afford the
corresponding sulfones and sulfoxides as described above for CHART
F.
[0116] CHART H depicts a method for preparing compounds having a
6-membered heterocycle wherein substitutes R.sub.3 and/or R.sub.4
are halo. As shown in CHART H, structure 48 (X is O, S, or NR
wherein R is an appropriate protecting group) is reacted with a
protected aniline 19 in the presence of an appropriate base, such
as sec-butyllithium in an appropriate solvent such as THF at a
temperature in the range of -40.degree. C. to -78.degree. C.,
followed by the addition of zinc chloride and an appropriate
catalyst such as tetrakis(triphenylphosphine)- palladium with
further reaction at reflux to afford compound 49. Optionally, in
the case where X is nitrogen, structure 49 can be reduced to the
saturated derivatives at this point and carried on, or structure 49
can be acylated by the reaction known to those skilled in the art
to provide structure 50. The remaining synthetic steps which lead
to compound 51 are similar to the procedures outlined in CHART B.
In the case where X is a sulfur atom, the sulfur group of structure
51 can be oxidized to afford the corresponding sulfones and
sulfoxides as described above. In addition, where X is O, NR, or
SO.sub.2, structure 51 may be reduced to saturated derivatives by
catalytic hydrogenation in the presence of an appropriate catalyst
and a suitable solvent to provide the saturated derivative 52. As
stated above, in the case where X is a nitrogen atom, the amino
group is protected during the preparation with an appropriate
protecting group. In this case, the preferred protecting group is
1,1-dimethylethyl carbamate (BOC). The protecting group is removed
after the synthesis, and the resultant compound can used to prepare
the derivative compounds demonstrated in CHART A.
[0117] The following compounds of Formula (I) having a 6-membered
heterocycles containing a nitrogen atom, sulfur atom, oxygen atom,
sulfone group or sulfoxide group, for example, are prepared
directly by the methods of CHART A, CHART G, and CHART H:
[0118]
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]--
3,6-dihydro-1(2H)-pyridinecarboxylic acid phenylmethyl ester;
[0119]
(S)-(-)-N-[[2-Oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl-
]acetamide;
[0120]
(S)-(-)-N-[[3-[4-[1-[(Benzyloxy)acetyl]-4-piperidinyl]phenyl]-2-oxo-
-5-oxazolidinyl]methyl]acetamide;
[0121]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-4-piperidinyl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide;
[0122]
(S)-(-)-N-[[3-[4-[1-[(Benzyloxy)acetyl]-4-piperidinyl]-3-fluorophen-
yl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0123]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-4-piperidinyl]-3-fluorophenyl]--
2-oxo-5-oxazolidinyl]methyl]acetamide;
[0124]
(S)-(-)-N-[[3-[4-[1-[(Benzyloxy)acetyl]-4-piperidinyl]-3,5-difluoro-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0125]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-4-piperidinyl]-3,5-difluorophen-
yl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0126]
(S)-(-)-N-[[3-[4-[1-(Indole-2-carbonyl)-4-piperidinyl]-3-fluorophen-
yl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0127]
(S)-(-)-N-[[3-[4-[1-(Isoxazole-5-carbonyl)-4-piperidinyl]-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0128]
(S)-(-)-N-[[3-[4-[1-(Methylsulfonyl)-4-piperidinyl]-3-fluorophenyl]-
-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0129]
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluor-
ophenyl]-1-piperidinecarboxylic acid methyl ester;
[0130]
(S)-(-)-N-[[3-[4-[1-(Cyanomethyl)-4-piperidinyl]-3-fluorophenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide;
[0131] (S)-(-)-N-[[3-[4-[1-(2 Fluoroethyl)-4-piperidin
yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide-I
[0132]
(S)-(-)-N-[[3-[4-[1-(Formyl)-4-piperidinyl]-3-fluorophenyl]-2
oxo-5-oxazolidinyl]methyl]acetamide
[0133]
(S)-(-)-4-[4-[5-[[(2,2-Dichloroacetyl)amino]methyl]-2-oxo-3-oxazoli-
dinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid
1,1-dimethylethyl ester;
[0134] (S)-(-)-2,2-Dichloro-N-[[2,
oxo-3-[3-fluoro-4-(4-piperidinyl)phenyl-
]-5-oxazolidinyl]methyl]acetamide;
[0135]
(S)-(-)-2,2-Dichloro-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-4-
-piperidinyl]phenyl]-5-oxazolidinyl]methyl]acetamide,
[0136]
(S)-(-)-2,2-Dichloro-N-[[2-oxo-3-[3-fluoro-4-[1-(hydroxyacetyl)-4-p-
iperidinyl]phenyl]-5-oxazolidinyl]methyl]acetamide;
[0137]
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-4-piperidinyl]-
phenyl]-5-oxazolidinyl]methyl]acetamide;
[0138]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo--
5-oxazolidinyl]methyl]acetamide;
[0139]
(S)-(-)-N-[[3-[4-[Tetrahydro-2H-pyran-4-yl]-3-fluorophenyl]-2-oxo-5-
-oxazolidinyl]methyl]acetamide;
[0140]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide;
[0141]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide S,S-dioxide;
[0142]
(S)-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-o-
xo-5-oxazolidinyl]methyl]acetamide S,S-dioxide;
[0143]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-pyran-4-yl)phenyl]-2-oxo-5-oxazoli-
dinyl]methyl]acetamide;
[0144]
(S)-(-)-N-[[3-[4-[Tetrahydro-2H-pyran-4-yl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide;
[0145]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxa-
zolidinyl]methyl]acetamide;
[0146]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxa-
zolidinyl]methyl]acetamide S,S-dioxide;
[0147]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide S-oxide;
[0148]
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxa-
zolidinyl]methyl]acetamide S-oxide;
[0149]
(S)-(-)-N-[[3-[4-(Tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]acetamide S,S-dioxide;
[0150]
(S)-(-)-N-[[3-[4-[1-(4-Oxo-2-thiazolinyl)-4-piperidinyl]-3-fluoroph-
enyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0151]
(S)-(-)-N-[[3-[4-[1-(5-Methyl-1,3,4-thiadiazol-2-yl)-4-piperidinyl]-
-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
[0152] CHART I depicts a method for preparing compounds of
intermediate 1 which have a partially saturated 6-membered
heterocycle containing nitrogen in highly enantiomerically enriched
form. As shown in CHART I, the first step involves the coupling of
structure 53 and structure 54 to provide compounds 55 and 56. The
triflate group of structure 53 may be at either side of the double
bond, wherein both are readily prepared from the corresponding
commercially available ketones. The structure 54 may be prepared
according to the procedures described in PCT/US92/08267 and
PCT/US93/09589. The reaction occurs over a few days, e.g. 1-5 days
in the presence of an appropriate catalyst such as
tris(dibenzylideneacetone)dip- alladium(0). The amino protecting
group of 55 is removed by treatment with iodotimethylsilane and
that of 56 is removed by treatment with either trifluoroacetic acid
or iodotrimethylsilane to give the corresponding compounds 57 and
58. Compounds 57 and 58 can be used to prepare the derivative
compounds demonstrated in CHART A.
[0153] Following the general procedure as described above, and
making non-critical variations but substituting 7- or 8-membered
rings for the 6-membered ring of structure 53, compounds that have
a 7- or 8-membered heterocycle containing nitrogen in highly
enantiomerically enriched form can be prepared. Their preparations
are illustrated in further detail in EXAMPLEs 75 to 79.
[0154] The following compounds of Formula (I) for example, are
prepared directly by the methods of CHART A and CHART I:
[0155]
(S)-(-)-N-[[3-[4-[1-(4-Oxo-2-thiazolinyl)-3,6-dihydro-2H-pyridin-5--
yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0156]
(S)-(-)-N-[[3-[4-[1-(5-Methyl-1,3,4-thiadiazol-2-yl)-3,6-dihydro-2H-
-pyridin-4-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0157]
(S)-(-)-N-[[2-Oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)-3-fluorophenyl-
]-5-oxazolidinyl]methyl]acetamide;
[0158]
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,6-dihydro-2H-
-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide;
[0159]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-3,6-dihydro-2H-pyridin-4-yl]-3--
fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0160]
(S)-(-)-N-[[3-[4-[1-(Formyl)-3,6-dihydro-2H-pyridin-4-yl]-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0161]
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluor-
ophenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid methyl
ester;
[0162]
(S)-(-)-N-[[2-Oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-5-oxazo-
lidinyl]methyl]acetamide;
[0163]
(S)-(-)-N-[[2-Oxo-3-[4-[1-[(acetoxy)acetyl]-3,6-dihydro-2H-pyridin--
4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide;
[0164]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-3,6-dihydro-2H-pyridin-4-yl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0165]
(S)-(-)-N-[[3-[4-[1-(Formyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide;
[0166]
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]--
3,6-dihydro-1(2H)-pyridinecarboxylic acid methyl ester;
[0167]
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-dihydro-2H-pyr-
idin-3-yl]phenyl]-5-oxazolidinyl]methyl]acetamide;
[0168]
(S)-N-[[3-[4-[1-(Hydroxyacetyl)-5,6-dihydro-2H-pyridin-3-yl]-3-fluo-
rophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0169]
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-2,3,4,7-tetrahydro-
-1H-azepin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide;
[0170]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-2,3,4,7-tetrahydro-1H-azepin-5--
yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0171]
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-2,3,6,7-tetrah-
ydro-1H-azepin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide;
[0172]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-2,3,6,7-tetrahydro-1H-azepin-4--
yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0173]
(5S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)hexahydro-1H-azepin-4-yl]-3-flu-
orophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
[0174] A second method for preparing compounds of intermediate 1
which have a partially saturated 6-membered heterocycle containing
nitrogen in highly enantiomerically enriched form is depicted in
CHART J. As shown in CHART J, structure 59 is reacted with a
protected aniline 19 to afford structure 60. The subsequent
acylation reaction provides structure 61 which is treated with an
appropriate acid to give a mixture of 62 and 63. The regioisomers
can be separated by chromatography as described in EXAMPLEs 72 and
73 and carried on. The protecting groups then are removed by
treatement with iodotrimethylsilane to give the desired compounds
64 and 57, which can be used to prepare the derivative compounds
demonstrated in CHART A. Use of the 4-keto isomer of structure 59
provides an alternate route to the 4-isomer, structure 58.
Alternatively, the hydroxy group of structure 61 or its 4-isomer
may be replaced by a fluoro atom using an appropriate agent such as
diethylaminosulfur trifluoride in an appropriate solvent such as
methylene chloride. The elimination step shown for structure 61 is
not conducted in this situation. This replacement reaction is
further detailed in EXAMPLE 74.
[0175] The following compounds of Formula (I) for example, are
prepared directly by the methods of CHART A and CHART J.
[0176]
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-dihydro-2H-pyr-
idin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0177]
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-3,4-dihydro-2H-pyridin-5-yl]-3--
fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0178]
(S)-(-)-N-[[3-[4-[1-Formyl-4-fluoro-4-piperidinyl)-3-fluorophenyl]--
2-oxo-5-oxazolidinyl]methyl]acetamide.
[0179] These compounds are useful for treatment of microbial
infections in humans and other warm blooded animals, under both
parenteral and oral administration.
[0180] The pharmaceutical compositions of this invention may be
prepared by combining the compounds of Formula (I) of this
invention with a solid or liquid pharmaceutically acceptable
carrier and, optionally, with pharmaceutically acceptable adjuvants
and excipients employing standard and conventional techniques.
Solid form compositions include powders, tablets, dispersible
granules, capsules, cachets and suppositories. A solid carrier can
be at least one substance which may also function as a diluent,
flavoring agent, solubilizer, lubricant, suspending agent, binder,
tablet disintegrating agent, and encapsulating agent. Inert solid
carriers include magnesium carbonate, magnesium stearate, talc,
sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic
materials, low melting wax, cocoa butter, and the like. Liquid form
compositions include solutions, suspensions and emulsions. For
example, there may be provided solutions of the compounds of this
invention dissolved in water and water-propylene glycol and
water-polyethylene glycol systems, optionally containing suitable
conventional coloring agents, flavoring agents, stabilizers and
thickening agents.
[0181] Preferably, the pharmaceutical composition is provided
employing conventional techniques in unit dosage form containing
effective or appropriate amounts of the active component, that is,
the compound of Formula (I) according to this invention.
[0182] The quantity of active component, that is the compound of
Formula (I) according to this invention, in the pharmaceutical
composition and unit dosage form thereof may be varied or adjusted
widely depending upon the particular application, the potency of
the particular compound, the desired concentration. Generally, the
quantity of active component will range between 0.5% to 90% by
weight of the composition.
[0183] In therapeutic use for treating, or combatting, bacterial
infections in warm-blooded animals, the compounds or pharmaceutical
compositions thereof will be administered orally and/or
parenterally at a dosage to obtain and maintain a concentration,
that is, an amount, or blood-level of active component in the
animal undergoing treatment which will be antibacterially
effective. Generally, such antibacterially effective amount of
dosage of active component will be in the range of about 0.1 to
about 100, more preferably about 3.0 to about 50 mg/kg of body
weight/day. It is to be understood that the dosages may vary
depending upon the requirements of the patient, the severity of the
bacterial infection being treated, and the particular compound
being used. Also, it is to be understood that the initial dosage
administered may be increased beyond the above upper level in order
to rapidly achieve the desired blood-level or the initial dosage
may be smaller than the optimum and the daily dosage may be
progressively increased during the course of treatment depending on
the particular situation. If desired, the daily dose may also be
divided into multiple doses for administration, e.g., 2-4 four
times per day.
[0184] The compounds of Formula (I) according to this invention are
administered parenterally, i.e., by injection, for example, by
intravenous injection or by other parenteral routes of
administration. Pharmaceutical compositions for parenteral
administration will generally contain a pharmaceutically acceptable
amount of the compound according to Formula (I) or a soluble salt
(acid addition salt or base salt)<dissolved in a
pharmaceutically acceptable liquid carrier such as, for example,
water-for-injection and a buffer to provide a suitably buffered
isotonic solution, for example, having a pH of about 3.5-6.
Suitable buffering agents include, for example, trisodium
orthophosphate, sodium bicarbonate, sodium citrate,
N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few
representative buffering agents. The compound according to Formula
(I) generally will be dissolved in the carrier in an amount
sufficient to provide a pharmaceutically acceptable injectable
concentration in the range of about 1 mg/mL to about 400 mg/mL of
solution. The resulting liquid pharmaceutical composition will be
administered so as to obtain the above-mentioned antibacterially
effective amount of dosage. The compounds of Formula (I) according
to this invention are advantageously administered orally in solid
and liquid dosage forms.
[0185] Antimicrobial activity was tested in vivo using the Murine
Assay procedure. Groups of female mice (six mice of 18-20 grams
each) were injected intraperitoneally with bacteria which were
thawed just prior to use and suspended in brain heart infusion with
4% brewers yeast (Staphylococcus aureus) or brain heart infusion
(Streptococcus species). Antibiotic treatment at six dose levels
per drug was administered one hour and five hours after infection
by either oral intubation or subcutaneous routes. Survival was
observed daily for six days. ED.sub.50 values based on mortality
ratios were calculated using probit analysis. The subject compounds
are compared against well-known antimicrobials vancomycin and
U-100592 as controls. See "Upjohn Oxazolidinone Antibacterial
Agent", posters presented at the 35th Interscience Conference on
Antimicrobial Agents and Chemotherapy. The data are shown in Table
I and Table 2.
1TABLE 1 EXAMPLE No. ED.sub.50(mg/kg) Vancomycin ED.sub.50(mg/kg) 3
5.00 3.00 4 >20.00 3.10 5 3.60 1.30 6 >20.00 5.00 10 20.00
2.00 11 >20.00 2.90 12 20.00 2.00 13 >10.00 1.50 16 17.00
3.60 19 6.80 1.80 21 >20.00 1.80 22 2.30 2.40 23 >20.00 1.60
24 >20.00 1.90 28 15.30 1.90 29 5.00 1.90 33 10.60 1.60 34 6.30
1.60 37 8.70 1.80 39 3.00 1.80 40 1.00 1.80 44 5.00 0.90 47 7.10
1.90
[0186]
2 TABLE 2 EXAMPLE No. ED.sub.50(mg/kg) U-100592 ED.sub.50(mg/kg) 45
2.80 2.10 46 7.90 2.30 48 17.50 2.10 49 2.40 2.10 50 2.20 2.90 51
2.80 5.20 52 4.00 2.30 53 >20.00 2.30 54 6.60 2.90 55 2.30 2.50
56 4.40 2.70 57 6.20 2.70 59 4.2 4.40 61 6.10 2.70 62 12.0 2.40 63
4.90 4.60 64 4.60 2.90 67 13.3 6.0 68(a) 3.50 3.50 69(a) 10.0 7.80
71 13.4 4.40 74 10.3 4.40 76 >20 3.50 78 6.0 3.20 83 7.50 4.10
84 6.50 4.10
[0187] In order to more fully illustrate the nature of the
invention and the manner of practicing the same, the following
experimental examples are presented.
EXAMPLE 1
(S)-N-[[3-[3-Fluoro-4-[1-(carbobenzyloxy)-(3-methyl)-3-azetidinyl]-phenyl]-
-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0188] Step 1: Ethyl
1-cyano-1-(4-nitro-2-fluorophenyl)propionate
[0189] A flame-dried 3-neck 1-L round bottom flask equipped with a
magnetic spinbar and addition funnel was charged with 6.40 g sodium
hydride (0.160 mol, 60% oil dispersion) followed by washing with
pentane (3.times.40 mL) and drying under house vacuum. The hydride
was suspended in 100 mL tetrahydrofuran, cooled to 0.degree. C.,
and treated with a solution of ethyl cyanoacetate (8.6 mL, 0.080
mol) in 150 mL THF over 15 minutes with gas evolution. The
resulting milky solution of enolate was stirred five minutes then
treated with a solution of 3,4-difluoronitrobenzene (I) (8.8 mL,
0.080 mol) in 150 mL THF with immediate orange coloration. The
cooling bath was removed and the reaction mixture was warmed to
50.degree. C. for 18 hours. The now red suspension was cooled to
room temperature and successively treated with 100 g iodomethane
(0.72 mol), 33 g potassium carbonate (0.24 mol), and 100 mL
acetone. The visually unchanged solution was warmed to 60.degree.
C. for an additional 16 hours. The now tan suspension was cooled to
room temperature, filtered through a pad of CELITE, and the
filtrate was concentrated in vacuo. The resulting residue was
diluted with 500 mL water and extracted twice with ethyl acetate
(500 mL). The combined organics were washed once with brine (300
mL), dried over MgSO.sub.4, filtered, and concentrated to give
21.39 g of a brown oil. This crude material was purified by LC on
850 g (230-400) silica gel eluting with 20% ethyl acetate/hexanes
to afford 18.14 g (100%) of the title compound as a yellow oil that
spontaneously crystallized. mp 56.0-57.0 C; R.sub.f 0.34 (20% ethyl
acetate/hexanes); IR (neat) 1752, 1534, 1423, 1355, 1248, 1239,
1213, 1099, 811, 741 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.16 (m, 1H, aromatic), 8.03 (dd, 1H, J=2.3 Hz, J=10.4 Hz,
aromatic), 7.80 (dd, 1H, J=7.6 Hz, J=8.6 Hz, aromatic), 4.33 (m,
2H, O--CH.sub.2), 2.04 (s, 3H, CH.sub.3), 1.28 (t, 3H, J=7.2 Hz,
O--CH2-CH.sub.13). HRMS Calcd for
C.sub.12H.sub.11N.sub.2O.sub.4F.sub.1+H- .sub.1: 267.0781. Found:
267.0799.
[0190] Step 2: Ethyl
1-aminomethyl-1-(4-amino-2-fluorophenyl)propionate
[0191] A solution of ethyl
1-cyano-1-(4-nitro-2-fluorophenyl)propionate (17.9 g, 67.3 mmol) in
absolute ethanol (500 mL) was treated with Raney-Nickel (30.9 g of
a 50% slurry in water) and subjected to hydrogenation in a Parr
apparatus for 17 hours (25-30 psi H.sub.2, room temperature). The
reaction mixture was then filtered through Celite (repeated EtOH
washings) and concentrated in vacuo (heat gun, Hi-vac) to give the
title compound as a golden syrup (15.6 g, 97%). This material could
be purified by chromatography on silica gel using 15%
methanol/ethyl acetate but was typically carried on to the next
step without further purification: R.sub.f 0.32 (15% MeOH/EtOAc);
.sup.1H NMR (CDCl.sub.3) .delta. 7.00 (t, J=8.5, 1H, aromatic),
6.45 (dd, J=8.2, 2.3, 1H, aromatic), 6.36 (dd, J=13.1, 2.4,
aromatic), 4.18 (q, J=7.0, 3H, --CH.sub.2CH.sub.3), 3.76 (br s, 2H,
NH.sub.2), 3.06 (dd, J=18.2, 13.8, 2H, CH.sub.2N), 1.52 (s, 3H,
CCH.sub.3), 1.21 (t, J=7.1, 2H, --CH.sub.2CH.sub.3); IR (liquid)
1722, 1634, 1513, 1445, 1305, 1283, 1243, 1172, 1132, 845
cm.sup.-1; HRMS: Calcd (C.sub.12H.sub.17F.sub.1N.su- b.2O.sub.2)
240.1274; Found 240.1293.
[0192] Step 3: 3-Methyl-3-(4-amino-2-fluorophenyl)azetidinone
[0193] A solution of ethyl
1-aminomethyl-1-(4-amino-2-fluorophenyl)propion- ate (2.1 g, 8.7
mmol) in THF (50 mL) was added slowly via syringe to a cold
(0.degree. C.) solution of methyl magnesium bromide (15 mL of a 3 M
solution in ether, 45 mmol, diluted with 100 mL THF). When addition
was complete, the syringe was rinsed with additional THF
(2.times.12 mL). The cooling bath was removed and the beige
solution was allowed to stir at room temperature for three hours,
at which point it was poured into saturated ammonium chloride (aq,
ca. 500 mL) and volatiles were removed in vacuo. The resulting
aqueous phase was extracted three times with t-butyl methyl ether
and the combined organics were washed once with water, once with
brine, dried over MgSO.sub.4, filtered, and concentrated to give
1.4 g of a yellow syrup. Extraction of the aqueous phase with ethyl
acetate provided and additional 190 mg crude product. The crude
products thus obtained were combined and chromatographed on silica
gel using 50% ethyl acetate/hexane to give the title compound (1.0
g, 60%) as a pale yellow solid, mp 125-127.degree. C.: R.sub.f 0.21
(50% EtOAc/hexane); .sup.1H NMR (CDCl.sub.3) .delta. 7.46 (t,
J=8.3, 1H, aromatic), 6.43-6.35 (m, 2H, aromatics), 5.77 (br s, 1H,
NH), 3.75 (br s, 2H, NH.sub.2), 3.54 (dd, J=5.5, 2.4, 1H,
CH.sub.2), 3.45 (d, J=5.5, 1H, CH.sub.2), 1.64 (s, 3H, CH.sub.3);
IR (mull) 3439, 3342, 3236, 1738, 1635, 1516, 1441, 1210, 1146, 631
cm.sup.-1; Anal. calcd for C.sub.10H.sub.11F.sub.1N.sub.2O.sub.2;
C, 61.84, H, 5.71, N, 14.43. Found: C, 62.13, H, 5.81, N,
14.36.
[0194] Step 4: 3-(4-Amino-2-fluorophenyl)-3-methylazetidine
[0195] A flame-dried 3-neck 2-L round bottom flask equipped with
mechanical stirrer, reflux condenser, and addition funnel was
charged with 300 mL tetrahydrofuran and 350 mL 1M lithium
aluminumhydride (0.35 mol) followed by cooling to 0.degree. C. This
solution was treated with a solution of 9.85 g
3-Methyl-3-(4-amino-2-fluorophenyl)-2-azetidinone (0.051 mol) in
210 mL THF with gas evolution and a yellow coloration. The cooling
bath was removed and the reaction was heated to reflux with the
rapid formation of a white precipitate. After 20 hours, the
visually unchanged reaction mixture was cooled to room temperature
and quenched by the successive addition of 13 mL water, 12 mL 5M
sodium hydroxide, and 47 mL water. The resulting thick gelatinous
suspension was diluted with one L ethyl acetate, filtered through a
pad of CELITE, concentrated, and high vacuum dried to afford 9.82 g
of the title compound as a light orange syrup. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 6.78 (t, 1H, J=8.5 Hz, aromatic), 6.37 (m,
2H, aromatic), 4.06 (d, 2H, J=8.2 Hz, N--CH.sub.2As), 3.81 (bs, 3H,
NHs), 3.58 (d, 2H, J=8.2 Hz, N--CH.sub.2Bs), 1.65 (s, 3H,
CH.sub.3).
[0196] Step 5:
N-Carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-
-methylazetidine
[0197] A 500 mL round bottom flask equipped with a magnetic spinbar
and addition funnel was charged with 85 mL water, 38.4 g sodium
bicarbonate (0.46 mol) and a solution of 9.82 g
3-(4-amino-2-fluorophenyl)-3-methylaz- etidine (0.051 mol theory)
in 165 mL acetone. The resulting orange suspension was cooled to
0.degree. C. and treated with 43 mL benzylchloroformate (0.30 mol)
with gas evolution and the reaction turning a light yellow color.
The cooling bath was removed and the reaction mixture was stirred
at room temperature for 65 hours. TLC indicates incomplete
consumption of the starting aminoaniline and an additional 12.8 g
sodium bicarbonate (0.15 mol) and 14 mL benzylchloroformate (0.10
mol) was added with additional gas evolution. After two hours, the
reaction mixture was diluted with 350 mL saturated sodium
bicarbonate and extracted three times with ethyl acetate (300 mL).
The combined organics were washed once with water (200 mL), once
with brine (200 mL); dried over MgSO.sub.4, filtered, and
concentrated to give 29.86 g of a light yellow oil. This crude
material was purified by LC on 850 g (230-400) silica gel eluting
with 25% ethyl acetate/hexanes to afford 11.67 g (51%) of the title
compound as a light yellow solid. R.sub.f 0.18 (25% ethyl
acetate/hexanes); IR (neat) 1735, 1707, 1693, 1600, 1534, 1455,
1424, 1414, 1221, 1081 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.35 (m, 11H, aromatic), 6.96 (m, 3H, aromatic & NH),
5.19 (s, 2H, Ph--CH.sub.2), 5.09 (s, 2H, Ph--CH.sub.2), 4.30 (d,
2H, J=8.2 Hz, N--CH.sub.2As), 4.00 (d, 2H, J=8.4 Hz,
N--CH.sub.2Bs), 1.59 (s, 3H, CH.sub.3); .sup.13C NMR (75 MHz,
CDCl.sub.3) 160.4 (d, J.sub.CF=245 Hz), 156.6, 153.0, 138.1 (d,
J.sub.CF=11 Hz), 136.5, 135.7, 128.6, 128.4, 128.2, 127.9, 127.8,
127.5, 127.0, 126.9, 113.9, 106.6 (d, J.sub.CF=27 Hz), 67.1, 66.6,
60.8, 60.2, 36.1, 28.2; Anal. Calcd for
C.sub.26H.sub.25N.sub.2O.sub.4F.sub.1: C, 69.63; H, 5.62; N, 6.25.
Found: C, 69.37; H, 5.69; N, 5.87.
[0198] Step 6:
(R)-(-)-N-Carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-hydroxym-
ethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine
[0199] A 500 mL round bottom flask containing 11.48 g
N-carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl-3-methylazetidin-
e (25.6 mmol) was equipped with a magnetic spinbar, charged with
100 mL tetrahydrofuran (freshly distilled), and cooled to
-78.degree. C. This light yellow homogenous solution was treated
with 16.6 mL n-butyllithium (26.6 mmol) with a slight darkening in
color. The carbamate ion was stirred 30 minutes at this reduced
temperature followed by treatment with 3.8 mL R-glycidylbutyrate
(26.6 mmol) with no observable change. The cooling bath was removed
and the reaction was warned to room temperature for 16 hours. The
now orange opaque solution was diluted with 200 mL saturated
ammonium chloride and extracted twice with ethyl acetate (250 mL).
The combined organics were washed once with saturated sodium
bicarbonate (200 mL), once with brine (300 mL), dried over
MgSO.sub.4, filtered, and concentrated to give 15.72 g of the title
compound as an orange oil. This crude material was purified by LC
on 530 g (230-400) silica gel eluting with 80% ethyl
acetate/hexanes to afford 6.79 g (64%) of a light yellow amorphous
solid. R.sub.f 0.28 (80% ethyl acetate/hexanes); [.alpha.].sub.D
-35.degree.(c 0.8967, methanol); IR (neat) 1754, 1708, 1516, 1454,
1429, 1415, 1358, 1228, 1194, 1076 cm.sup.-1; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.44 (dd, 1H, J=2.2 Hz, J=13.0 Hz, aromatic),
7.33 (m, 5H, aromatic), 7.19 (dd, 1H, J=2.2 Hz, J=8.5 Hz,
aromatic), 7.03 (t, 1H, J=8.7 Hz, aromatic), 5.09 (s, 2H,
Ph--CH.sub.2), 4.73 (m, 1H, methine), 4.30 (d, 2H, J=8.2 Hz,
Ph--C--CH.sub.2a s), 3.97 (m, 5H, Ph--C--CH.sub.2bs,
Ph--N--CH.sub.2s, HO--CH.sub.2a), 3.73 (m, 1H, HO--CH.sub.2B), 2.80
(t, 1H, J=6.3 Hz, HO), 1.60 (s, 3H, CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 160.2 (d, J.sub.CF=246 Hz), 156.5, 154.2, 138.0
(d, J.sub.CF=11 Hz), 136.3, 128.2, 128.1, 127.8, 127.7, 126.9 (d,
J.sub.CF=7 Hz), 113.1 (d, J.sub.CF=3 Hz), 106.2 (J.sub.CF=27 Hz),
72.6, 66.5, 62.4, 60.1, 46.0, 35.9, 28.0; Melt solvate=3.8% ethyl
acetate; Anal. Calcd for C.sub.22H.sub.23N.sub.2O.sub.- 5F, plus
3.8% ethyl acetate: C, 63.41; H, 5.73; N, 6.50. Found: C, 63.15; H,
5.52; N, 6.58. HRMS Calcd for
C.sub.22H.sub.23N.sub.2O.sub.5F.sub.1: 415.1169. Found:
415.1674.
[0200] Step 7:
(R)-(-)-N-Carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-hydroxym-
ethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine methone sulfuride
ester
[0201] A 500 mL round bottom flask containing 6.55 g
(R)-(-)-N-carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-hydroxymethyl-2-oxo-3--
oxazolidinyl]phenyl]azetidine (15.3 mmol) was equipped with a
magnetic spinbar, charged with 150 mL dichloromethane, and cooled
to 0.degree. C. This light yellow homogenous solution was treated
successively with 3.2 mL triethylamine (23.0 mmol) and 1.4 mL
methanesulfonyl chloride (18.4 mmol) with no observable change. The
cooling bath was removed and the reaction mixture was warmed to
room temperature for one hour. The visually unchanged solution was
diluted with 100 mL 0.5 N hydrochloric acid, shaken, layers
separated and the acidic layer extracted once with dichloromethane
(100 mL). The combined organics were washed once with brine (75
mL), dried over MgSO.sub.4, filtered, and concentrated to give 7.68
g (100%) of the title compound as a light yellow amorphous solid.
R.sub.f 0.40 (80% ethyl acetate/hexanes); IR (mull) 1758, 1703,
1516, 1418, 1358, 1337, 1230, 1176, 1075, 965 cm.sup.-1; .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.44 (dd, 1H, J=2.2 Hz, J=12.8
Hz, aromatic), 7.33 (m, 5H, aromatic), 7.17 (dd, 1H, J=2.2 Hz,
J=8.5 Hz, aromatic), 7.06 (t, 1H, J=8.5 Hz, aromatic), 5.10 (s, 2H,
Ph--CH.sub.2), 4.92 (m, 1H, methine), 4.50 (dd, 1H, J=3.6 Hz, J=]
1.7 Hz, MsO--CH.sub.2A), 4.42 (dd, 1H, J=4.1 Hz, J=11.7 Hz,
MsO--CH.sub.2B), 4.31 (d, 2H, J=8.1 Hz, Ph--C--CH.sub.2As), 4.13
(t, 1H, J=9.2 Hz, Ph--N--CH.sub.2A), 4.00 (d, 1H, J=8.5 Hz,
Ph--C--CH.sub.2Bs), 3.94 (dd, 1H, J=6.2 Hz, J=9.2 Hz,
Ph--N--CH.sub.2B), 3.10 (s, 3H, S--CH.sub.3), 1.62 (s, 3H,
C--CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 160.3 (d,
J.sub.CF=247 Hz), 156.5, 153.3, 137.6 (d, J.sub.CF=11 Hz), 136.4,
129.0, 128.8, 128.3, 127.9, 127.8, 127.3, 127.2 (d, J.sub.CF=6 Hz),
113.3 (d, J.sub.CF=3 Hz), 106.5 (d, J.sub.CF=28 Hz), 69.4, 67.8,
66.6, 60.4, 46.2, 37.7, 36.1, 28.1; Anal. Calcd for
C.sub.23H.sub.5N.sub.2O.sub.7F.sub.1S.sub.1: C, 56.09; H, 5.12; N,
5.69. Found: C, 55.76; H, 5.17; N, 5.61.
[0202] Step 8:
(R)-(-)-N-Carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-aminomet-
hyl-2-oxo-3-oxazolidinyl]phenyl]azetidine
[0203] Two oven-dried 100 mL sealable tubes equipped with magnetic
spinbars were equally charged with a solution of 7.50 g
(R)-(-)-N-carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-hydroxymethyl-2-oxo-3--
oxazolidinyl]phenyl]azetidine methone sulfuride ester (15.2 mmol)
in 75 mL methanol and 75 mL tetrahydrofuran (freshly distilled).
These light yellow homogenous solutions were saturated with gaseous
ammonia over ten minutes becoming almost colorless, sealed with
teflon screwcaps, and heated to 100.degree. C. for 64 hours. The
reaction mixtures were combined and concentrated to afford the
title compound as a crude yellow foam.
[0204] Step 9:
(S)-N-[[3-[3-Fluoro-4-[1-(carbobenzyloxy)-(3-methyl)-3-azet-
idinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0205] The title compound was prepared as follows:
(R)-(-)-N-carbobenzoxy--
3-methyl-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidin-
e was diluted with 220 mL dichloromethane, cooled to 0.degree. C.,
and successively treated with 3.7 mL pyridine (46 mmol) and 1.8 mL
acetic anhydride (19 mmol) with no observable change. The cooling
bath was removed and the reaction mixture was warmed to room
temperature for 16 hours. The visually unchanged solution was
concentrated to a yellow foam, rediluted with 50 ml,
dichloromethane, and filtered to remove the remaining insoluble
precipitate. The filtrate was purified by LC on 340 g (230-400)
silica gel eluting with 2.5% methanol/ethyl acetate to afford 5.85
g (84%).sub.3 of
(S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-(3-methyl-
)-3-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide as a
colorless glass. R.sub.f 0.24 (2.5% methanol/ethyl acetate);
[.alpha.].sub.D -19.degree.(c 0.9971, methanol); IR (mull) 1754,
1706, 1676, 1516, 1430, 1415, 1357, 1227, 1194, 1075 cm.sup.-1;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.42 (dd, 1H, J=2.1 Hz,
J=12.9 Hz, aromatic), 7.33 (m, 5H, aromatic), 7.13 (dd, 1H, J=2.2
Hz, J=8.5 Hz, aromatic), 7.04 (t, 1H, J=8.5 Hz, aromatic), 6.56
(bt, 1H, J=6.2 Hz, NH), 5.10 (s, 2H, Ph--CH.sub.2), 4.79 (m, 1H,
methine), 4.30 (d, 2H, J=8.2 Hz, Ph--C--CH.sub.2As), 4.01 (m, 3H,
Ph--C--CH.sub.2Bs, Ph--N--CH.sub.2A), 3.78 (dd, 1H, J=6.7 Hz, J=9.1
Hz, Ph--N--CH.sub.2B), 3.64 (m, 2H, NH--CH.sub.2s), 2.02 (s, 3H,
O.dbd.C--CH.sub.3), 1.60, (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR
(75 MHz, CDCl.sub.3) 171.2, 160.3 (d, J.sub.CF=246 Hz), 156.6,
154.2, 137.9 (d, J.sub.CF=11 Hz), 136.5, 128.9 (d, J.sub.CF=14 Hz),
128.4, 127.9, 127.2 (d, J.sub.CF=7 Hz), 113.2 (d, J.sub.CF=2 Hz),
106.4 (d, J.sub.CF=28 Hz), 72.0; 66.6, 60.7, 60.3, 47.3, 41.7,
36.1, 28.1, 22.9; Anal. Calcd for
C.sub.24H.sub.26N.sub.3O.sub.5F.s- ub.1: C, 63.29; H, 5.75; N,
9.23. Found: C, 62.98; H, 5.96; N, 8.98.
EXAMPLE 2
(S)-N-[[3-[3-Fluoro-4-[3-methyl-3-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-acetamide
[0206] A 500 mL Parr flask was charged with a solution of 5.83 g
(S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-(3-methyl)-3-azetidinyl]-phenyl-
]-2-oxo-5-oxazolidinyl]methyl]-acetamide (12.8 mmol) in 100 mL
methanol and 1.17 g 10% palladium on carbon. The black suspension
was placed under 40 psi hydrogen with shaking for four hours with
the pressure remaining constant at 28 psi. The Parr was removed
from the hydrogenator, the reaction mixture was filtered through a
pad of CELITE, and concentrated to afford 4.05 g (99%) of an
off-white amorphous solid. A 1.00 g portion of this material was
purified by LC on 100 g (230-400) silica gel eluting with 2:17:83
NH.sub.4OH/methanol/dichloromethane to afford 776 mg of the title
compound as a colorless glass. R.sub.f 0.26 (2:17:83
NH.sub.4OH/methanol/dichloromethane); [.alpha.].sub.D -23.degree.(c
0.9015, methanol); IR (mull) 1752, 1662, 1630, 1554, 1515, 1483,
1435, 1412, 1227, 1194 cm.sup.-1; .sup.1HNMR (300 MHz, CDCl.sub.3)
.delta. 7.37 (dd, 1H, J=2.2 Hz, J=12.8 Hz, aromatic), 7.12 (dd, 1H,
J=2.2 Hz, J=8.5 Hz, aromatic), 6.99 (t, 1H, J=8.6 Hz, aromatic),
6.33 (bt, 1H, J=6 Hz, O.dbd.C--NH), 4.78 (m, 1H, methine), 4.04 (m,
3H, Ph--C--CH.sub.2As, Ph--N--CH.sub.2A), 3.78 (dd, 1H, J=6.8 Hz,
J=9.1 Hz, Ph--N--CH.sub.2B), 3.66 (m, 2H, NH--CH.sub.2s), 3.56 (d,
2H, J=7.8 Hz, Ph--C--CH.sub.2Bs), 2.40 (bs, 1H, NH), 2.02 (s, 3H,
O.dbd.C--CH.sub.3), 1.67 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 171.2, 160.0 (d, J.sub.CF=246 Hz), 154.2, 137.3
(d, J.sub.CF=11 Hz), 130.8 (d, J.sub.CF=15 Hz), 126.9 (d,
J.sub.CF=7 Hz), 113.2, 106.3 (d, J.sub.CF=27 Hz), 71.9, 58.0, 47.3,
41.7, 40.5, 27.3, 22.9; K.F. Water=0.89%; Anal. Calcd for
C.sub.16H.sub.20N.sub.3O.sub.3F.sub.1 with 0.89% water: C, 59.27;
H, 6.32; N, 12.96. Found: C, 59.07; H, 6.45; N, 12.89. HRMS Calcd
for C.sub.16H.sub.20N.sub.3O.sub.3+H.sub.1: 322.1567. Found:
322.1569.
EXAMPLE 3
(S)-N-[[3-[3-Fluoro-4-[1-(carboxymethyl)-3-(3-methyl)-azetidinyl]-phenyl]--
2-oxo-5-oxazolidinyl]methyl]-acetamide
[0207] An oven-dried 25 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 8
mL dichloromethane, and cooled to 0.degree. C. The colorless but
slightly opaque solution was treated with 0.16 mL triethylamine
(1.1 mmol) and 70 .mu.L methylchloroformate (0.90 mmol) with the
reaction mixture becoming clear. The cooling bath was removed and
the reaction mixture was warmed to room temperature over two hours.
The visually unchanged solution was diluted with 30 mL
dichloromethane, washed once with water (20 mL), once with brine
(15 mL), dried over MgSO.sub.4, filtered, and concentrated to give
267 mg of a white foam. This crude material was purified by LC on
18 g (230-400) silica gel eluting with 5% methanol/dichloromethane
to afford 219 mg (77%) of the title compound as a white foam.
R.sub.f 0.30 (5% methanol/dichloromethane); [.alpha.].sub.D
-21.degree.(c 1.0194, methanol); IR (mull) 1755, 1706, 1676, 1631,
1517, 1394, 1227, 1208, 1195, 1076 cm.sup.-1; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.43 (dd, 1H, J=2.2 Hz, J=12.9 Hz, aromatic),
7.14 (dd, 1H, J=2.2 Hz, J=8.5 Hz, aromatic), 7.05 (t, 1H, J=8.6 Hz,
aromatic), 6.35 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H, methine), 4.28
(d, 2H, J=8.2 Hz, CO.sub.2--N--CH.sub.2As), 4.04 (t, 1H, J=9.0 Hz,
Ph--N--CH.sub.2A), 3.97 (d, 2H, J=8.4 Hz, CO.sub.2--N--CH.sub.2Bs),
3.77 (dd, 1H, J=6.7 Hz, J=9.1 Hz, Ph--N--CH.sub.2B), 3.68 (m, 5H,
NH--CH.sub.2s, OCH.sub.3), 2.03 (s, 3H, O.dbd.C--CH.sub.3), 1.61
(s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 170.9,
160.2 (d, J.sub.CF=246 Hz), 157.1, 154.0, 137.8 (d, J.sub.CF=11
Hz), 128.5 (d, J.sub.CF=15 Hz), 127.0 (d, J.sub.CF=7 Hz), 113.1 (d,
J.sub.CF=3 Hz), 106.3 (d, J.sub.CF=27 Hz), 71.8, 60.4, 52.1, 47.2,
41.7, 35.9, 28.0, 22.9; K.F. Water 1.19%; Anal. Calcd for
C.sub.18H.sub.22N.sub.3O.sub.5F.sub.1 plus 1.19% water: C, 56.31;
H, 5.91; N, 10.94. Found: C, 56.27; H, 5.93; N, 10.93.
EXAMPLE 4
(S)-N-[[3-[3-Fluoro-4-[1-(methoxyacetyl)-3-(3-methyl)-azetidinyl]-phenyl]--
2-oxo-5-oxazolidinyl]methyl]-acetamide
[0208] An oven-dried 25 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 8
mL dichloromethane, and cooled to 0.degree. C. The colorless but
slightly opaque solution was treated with 0.16 mL triethylamine
(1.1 mmol) and 85 .mu.L methoxyacetylchloride (0.90 mmol) with a
smokey/haze developing. The cooling bath was removed and the
reaction mixture was warmed to room temperatue over two hours. The
now clear colorless solution was diluted with 25 mL
dichloromethane, washed once with water (15 mL), once with brine
(15 mL), dried over MgSO.sub.4, filtered, and concentrated to give
294 mg of a white foam. This crude material was purified by LC on
27 g (230-400) silica gel eluting with 7% methanol/dichloromethane
to afford 240 mg (81%) the title compound as a white amorphous
solid. R.sub.f 0.23 (7% methanol/dichloromethane); [.alpha.].sub.D
-20.degree.(c 0.9736, methanol); IR (mull) 1754, 1662, 1654, 1632,
1517, 1437, 1412, 1226, 1194, 1122 cm.sup.-1; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.45 (dd, 1H, J=2.1 Hz, J=13.0 Hz, aromatic),
7.15 (dd, 1H, J=2.1 Hz, J=8.5 Hz, aromatic), 7.07 (t, 1H, J=8.5 Hz,
aromatic), 6.47 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H, methine), 4.51
(d, 1H, J=9.0 Hz, Ph--C--CH.sub.2A), 4.35 (d, 1H, J=9.7 Hz,
Ph--C--CH.sub.2B), 4.25 (d, 1H, J=9.2 Hz, Ph--C--CH.sub.2A), 4.05
(m, 4H, O.dbd.C--CH.sub.2s, Ph--C--CH.sub.2B, Ph--N--CH.sub.2A),
3.66 (m, 1H, Ph--N--CH.sub.2B), 3.66 (m, 2H, NH--CH.sub.2s), 2.03
(s, 3H, O.dbd.C--CH.sub.3), 1.63 (s, 3H, Ph--C--CH.sub.3); .sup.13C
NMR (75 MHz, CDCl.sub.3) 171.2, 169.7, 160.4 (d, J.sub.CF=246 Hz),
154.2, 138.2 (d, J.sub.CF=11 Hz), 128.4 (d, J.sub.CF=14 Hz), 127.3
(d, J.sub.CF=6 Hz), 113.4, 106.6 (d, J.sub.CF=28 Hz), 72.1, 71.5,
62.4, 59.5, 59.2, 47.5, 41.9, 36.9, 28.3, 23.1; K.F. Water=2.03%;
Anal. Calcd for C.sub.19H.sub.24N.sub.3O.sub.5F, plus 2.03% water:
C, 56.83; H, 6.25; N, 10.47. Found: C, 56.99; H, 6.34; N, 10.49.
HRMS Calcd for C.sub.19H.sub.24N.sub.3O.sub.5F.sub.1: 394.1778.
Found: 394.1784.
EXAMPLE 5
(S)-N-[[3-[3-Fluoro-4-[1-(formyl)-3-(3-methyl)-azetidinyl]-phenyl]-2-oxo-5-
-oxazolidinyl]methyl]-acetamide
[0209] An oven-dried 25 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-Fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 8
mL dichloromethane, and cooled to 0.degree. C. The colorless but
slightly opaque solution was treated with 0.16 mL triethylamine
(1.1 mmol) and 73 .mu.L ethyl formate (0.90 mmol) with no
observable change. The cooling bath was removed and the reaction
mixture was warmed to room temperature for 16 hours. TLC analysis
of the now clear solution indicated incomplete consumption of
(S)-N-[[3-[3-Fluoro-4-[3-methyl-3-azetidinyl]-phenyl]-2-ox-
o-5-oxazolidinyl]methyl]-acetamide. The reaction mixture was
treated with an additional 0.14 mL ethyl formate (1.8 mmol) and 8.0
mL 1N sodium hydroxide with vigorous stirring for five minutes. The
reaction was diluted with 10 mL water and extracted twice with
dichloromethane (25 mL). The combined organics were washed once
with water (20 mL), once with brine (20 mL), dried over MgSO.sub.4,
filtered, and concentrated to give 253 mg of a white foam. This
crude material was purified by LC on 18 g (230-400) silica gel
eluting with 6% methanol/dichloromethane to afford 145 mg (55%) the
title compound as a white amorphous solid. R.sub.f 0.25 (7%
methanol/dichloromethane); [.alpha.].sub.D -20.degree.(c 0.9949,
methanol); IR (mull) 1754, 1666, 1631, 1548, 1516, 1478, 1433,
1414, 1227, 1195 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.06 (s, 1H, CHO), 7.47 (dd, 1H, J=2.0 Hz, J=13.0 Hz,
aromatic), 7.16 (dd, 1H, J=2.2 Hz, J=8.5 Hz, aromatic), 7.07 (t,
1H, J=8.6 Hz, aromatic), 6.33 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H,
methine), 4.42 (d, 1H, J=8.2 Hz, Ph--C--CH.sub.2A), 4.30 (d, 1H,
J=9.9 Hz, Ph--C--CH.sub.2B), 4.15 (d, 1H, J=8.3 Hz,
Ph--C--CH.sub.2A), 4.05 (m, 2H, Ph--C--CH.sub.2B,
Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.8 Hz, J=9.1 Hz,
Ph--N--CH.sub.2B), 3.67 (m, 2H, NH--CH.sub.2s), 2.03 (s, 3H,
O.dbd.C--CH.sub.3), 1.64 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 171.1, 162.3, 160.3 (d, J.sub.CF=246 Hz), 154.1,
138.2 (d, J.sub.CF=11 Hz), 127.9 (d, J.sub.CF=14 Hz), 127.1 (d,
J.sub.CF=6 Hz), 113.3, 106.4 (d, J.sub.CF=27 Hz), 71.9, 59.6, 58.2,
47.3, 41.7, 37.6, 28.0, 23.0; HRMS Calcd for
C.sub.17H.sub.20N.sub.3O.sub.4F.sub.1: 349.1438. Found:
349.1444.
EXAMPLE 6
(S)-N-[[3-[3-Fluoro-4-[1-(dichloroacetyl)-3-(3-methyl)-azetidinyl]-phenyl]-
-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0210] An oven-dried 25 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-Fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 8
mL dichloromethane, and cooled to 0.degree. C. The colorless but
slightly opaque solution was treated with 0.16 mL triethylamine
(1.1 mmol) and 87 .mu.L dichloroacetyl chloride (0.90 mmol) with a
smokey/haze developing. The cooling bath was removed and the
reaction mixture was warmed to room temperature over three hours.
The now clear colorless solution was diluted with 15 mL water and
extracted twice with dichloromethane (25 mL). The combined organics
were washed once with brine (15 mL), dried over MgSO.sub.4,
filtered, and concentrated to give 353 mg of a tan foam. This crude
material was purified by LC on 25 g (230-400) silica gel eluting
with 5% methanol/dichloromethane to afford 243 mg (75%) the title
compound as an off-white amorphous solid. R.sub.f 0.26 (5%
methanol/dichloromethane); [.alpha.].sub.D -18.degree.(c 0.9862,
methanol); IR (mull) 1752, 1666, 1631, 1545, 1517, 1440, 1412,
1288, 1227, 1193 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.48 (dd, 1H, J=2.1 Hz, J=13.0 Hz, aromatic), 7.18 (dd, 1H,
J=2.2 Hz, J=8.5 Hz, aromatic), 7.08 (t, 1H, J=8.6 Hz, aromatic),
6.52 (bt, 1H, J=6.1 Hz, NH), 4.81 (m, 1H, methine), 4.70 (d, 1H,
J=8.9 Hz, Ph--C--CH.sub.2A), 4.48 (d, 1H, J=9.1 Hz,
Ph--C--CH.sub.2B), 4.41 (d, 1H, J=10.1 Hz, Ph--C--CH.sub.2A), 4.13
(d, 1H, J=10.0 Hz, Ph--C--CH.sub.2B), 4.06 (t, 1H, J=9.0 Hz,
Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.7 Hz, J=9.1 Hz,
Ph--N--CH.sub.2B), 3.67 (m, 2H, NH--CH.sub.2s), 2.03 (s, 3H,
O.dbd.C--CH.sub.3), 1.67 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 171.3, 163.1, 160.3 (d, J.sub.CF=246 Hz), 154.2,
138.4 (d, J.sub.CF=11 Hz), 127.6 (d, J.sub.CF=15 Hz), 127.1 (d,
J.sub.CF=6 Hz), 113.4, 106.6 (d, J.sub.CF=27 Hz), 72.1, 64.6, 63.1,
60.3, 47.4, 41.8, 36.9, 28.2, 23.0; K.F. Water=1.3%. Anal. Calcd
for C.sub.18H.sub.20N.sub.3O.sub.4F.sub.1Cl.sub.2 plus 1.3% water:
C, 49.36; H, 4.75; N, 9.60. Found: C, 48.97; H, 4.80; N, 9.53. HRMS
Calcd for C.sub.18H.sub.20N.sub.3O.sub.4F.sub.1Cl.sub.2: 432.0893.
Found: 432.0900.
EXAMPLE 7
(S)-N-[[3-[3-Fluoro-4-1-(3-methoxypropionyl)-3-(3-methyl)-azetidinyl]-phen-
yl]-2-oxo-5-oxazolidinyl]meth 11-acetamide
[0211] An oven-dried 10 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 4
mL dichloromethane, 81 .mu.L 3-methoxypropionic acid (0.83 mmol),
0.13 mL of distilled diethylcyanophosphonate (0.83 mmol) and cooled
to 0.degree. C. The colorless solution was treated with 0.11 mL
triethylamine (0.78 mmol) becoming a pinkish color. The cooling
bath was removed and the reaction mixture was warmed to room
temperature over 66 hours. The now reddish brown solution was
diluted with 20 mL dichloromethane and washed once with water (15
mL), once with brine (15 mL), dried over MgSO.sub.4, filtered, and
concentrated to give 297 mg of a red foam. This crude material was
purified by LC on 18 g (230-400) silica gel eluting with 7%
methanol/dichloromethane to afford 216 mg of an off-white amorphous
solid. .sup.1H NMR indicates this material to be contaminated with
10%
(S)-N-[[3-[3-fluoro-4-[1-(formyl)-3-(3-methyl)-azetidinyl]-phenyl]-2-oxo--
5-oxazolidinyl]methyl]-acetamide which was removed by catalytic
hydrogenolysis with 22 mg 10% palladium on carbon in 30 mL
tetrahydrofuran containing 10 drops concentrated hydrochloric acid.
The resulting crude material was rechromatographed on 13 g
(230-400) silica gel eluting with 7% methanol/dichloromethane to
afford 135 mg (44% overall) the title compound as an off-white
amorphous solid. R.sub.f 0.23 (7% methanol/dichloromethane);
[.alpha.].sub.D -19.degree.(c 0.8324, methanol); IR (mull) 1755,
1644, 1630, 1548, 1516, 1440, 1410, 1226, 1192, 1115 cm.sup.-1;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45 (dd, 1H, J=2.0 Hz,
J=12.9 Hz, aromatic), 7.15 (dd, 1H, J=2.2 Hz, J=8.5 Hz, aromatic),
7.07 (t, 1H, J=8.5 Hz, aromatic), 6.29 (bt, 1H, J=6 Hz, NH), 4.80
(m, 1H, methine), 4.42 (d, 1H, J=8.0, Ph--C--CH.sub.2A), 4.30 (d,
1H, J=9.6 Hz, Ph--C--CH.sub.2B), 4.15 (d, 1H, J=8.2 Hz,
Ph--C--CH.sub.2A), 4.04 (m, 2H, Ph--C--CH.sub.2B,
Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.7 Hz, J=9.1 Hz,
Ph--N--CH.sub.2B), 3.67 (m, 4H, NH--CH.sub.2s, O--CH.sub.2s), 3.34
(s, 3H, OCH.sub.3), 2.36 (qrt, 2H, J=6.2 Hz,
O--(CH.sub.2)--CH.sub.2s), 2.03 (s, 3H, O.dbd.C--CH.sub.3), 1.61
(s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 171.5,
171.1, 162.5 (d, J.sub.CF=246 Hz), 154.2, 138.1 (d, J.sub.CF=11
Hz), 128.5 (d, J.sub.CF=15 Hz), 127.3 (d, J.sub.CF=6 Hz), 113.4,
106.5 (d, J.sub.CF=28 Hz), 72.0, 68.4, 61.6, 58.9, 47.5, 41.9,
35.6, 32.2, 28.6, 23.1; HRMS Calcd for
C.sub.20H.sub.26N.sub.3O.sub.5F.sub.1: 407.1856. Found:
407.1855.
EXAMPLE 8
(S)-N-[[3-[3-Fluoro-4-[1-(3-hydroxypropionyl)-3-(3-methyl)-azetidinyl]-phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0212] A 10 mL recovery flask equipped with magnetic stirrer was
charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidinyl]-phenyl]-2-oxo-5-
-oxazolidinyl]methyl]-acetamide (0.75 mmol) and 1.5 mL water then
cooled to 0.degree. C. The colorless but slightly opaque solution
was treated with 52 .mu.L R-propiolactone (0.75 mmol) with no
observable change. The cooling bath was removed and the reaction
mixture was warmed to room temperature for two hours. The visually
unchanged reaction mixture was diluted with 10 mL brine and
extracted twice with dichloromethane (20 mL). The combined organics
were dried over MgSO.sub.4, filtered, and concentrated to give 232
mg of an off-white foam. This crude material was purified by LC on
17 g (230-400) silica gel eluting with 7%, methanol/dichloromethane
to afford 178 mg (60%) the title coupound as a white amorphous
solid. R.sub.f 0.30 (10% methanol/dichloromethane); [.alpha.].sub.D
-19.degree.(c 0.9248, methanol); IR (mull) 3288, 1754, 1630, 1554,
1517, 1436, 1412, 1289, 1227, 1193 cm.sup.-1; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.46 (dd, 1H, J=2.1 Hz, J=13.0 Hz, aromatic),
7.14 (dd, 1H, J=2.2 Hz, J=8.5 Hz, aromatic), 7.07 (t, 1H, J=8.6 Hz,
aromatic), 6.55 (bt, 1H, J=6 Hz, NH), 4.81 (m, 1H, methine), 4.41
(d, 1H, J=8.3, Ph--C--CH.sub.2A), 4.32 (d, 1H, J=9.6 Hz,
Ph--C--CH.sub.2B), 4.12 (d, 1H, J=8.4 Hz, Ph--C--CH.sub.2A), 4.05
(m, 2H, Ph--C--CH.sub.2B, Ph--N--CH.sub.2A), 3.88 (bs, 2H;
HO--CH.sub.2s), 3.80 (dd, 1H, J=6.8 Hz, J=9.1 Hz,
Ph--N--CH.sub.2B), 3.67 (m, 2H, NH--CH.sub.2s), 3.46 (bs, 1H, HO),
2.37 (qrt, 2H, J=5.6 Hz, HO--(CH.sub.2)--CH.sub.2s), 2.03 (s, 3H,
O.dbd.C--CH.sub.3), 1.63 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 172.8, 171.2, 160.3 (d, J.sub.CF=246 Hz), 154.1,
138.1 (d, J.sub.CF=11 Hz), 128.0 (d, J.sub.CF=14 Hz), 127.1 (d,
J.sub.CF=6 Hz), 113.3, 106.5 (d, J.sub.CF=27 Hz), 72.0, 61.4, 58.8,
58.3, 47.3, 41.8, 35.7, 32.9, 28.2, 23.0; HRMS Calcd for
C.sub.19H.sub.24N.sub.3O.sub.5F.sub.1: 394.1778. Found:
394.1788.
EXAMPLE 9
(S)-N-[[3-[3-Fluoro-4-[1-(4-oxopentanoyl)-3-(3-methyl)-azetidinyl]-phenyl]-
-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0213] An oven-dried 10 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 4
mL dichloromethane, 100 .mu.L levulinic acid (0.98 mmol), 216 mg
EDC.HCL (1.13 mmol), 18 mg dimethylamino pyridine (0.15 mmol) and
cooled to 0.degree. C. The colorless solution was treated with 0.31
mL triethylamine (2.25 mmol) becoming a pale yellow color. The
cooling bath was removed and the reaction mixture was warmed to
room temperature over 16 hours. The visually unchanged solution was
diluted with 20 mL water and extracted twice with dichloromethane
(25 mL). The combined organics were washed once with saturated
sodium bicarbonate (20 mL), brine (15 mL), dried over MgSO.sub.4,
filtered, and concentrated to give 332 mg of a light yellow syrup.
This crude material was purified by LC on 20 g (230-400) silica gel
eluting with 5% methanol/dichloromethane to afford 256 mg of an
off-white amorphous solid. .sup.1H NMR indicates this material to
be contaminated with 8% (S)-N-[[3-[3-fluoro-4-[1-(formyl)-3-(-
3-methyl)-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
which was removed by catalytic hydrogenolysis with 26 mg 10%
palladium on carbon in 30 mL tetrahydrofuran containing ten drops
concentrated hydrochloric acid. The resulting crude material was
rechromatographed on 15 g (230-400) silica gel eluting with 5%
methanol/dichloromethane to afford 116 mg (37% overall) the title
compound as a white amorphous solid. R.sub.f 0.16 (5%
methanol/dichloromethane); [.alpha.].sub.D -19.degree.(c 0.9205,
methanol); IR (mull) 1754, 1716, 1631, 1548, 1517, 1440, 1411,
1227, 1193, 1166 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.46 (dd, 1H, J=2.1 Hz, J=13.0 Hz, aromatic), 7.15 (dd, 1H,
J=2.2 Hz, J=8.5 Hz, aromatic), 7.07 (t, 1H, J=8.5 Hz, aromatic),
6.32 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H, methine), 4.46 (d, 1H,
J=8.1, Ph--C--CH.sub.2A), 4.27 (d, 1H, J=9.4 Hz, Ph--C--CH.sub.2B),
4.19 (d, 1H, J=8.3 Hz, Ph--C--CH.sub.2A), 4.01 (m, 2H,
Ph--C--CH.sub.2B, Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.8 Hz, J=9.1
Hz, Ph--N--CH.sub.2B), 3.68 (m, 2H, NH--CH.sub.2s), 2.80 (t, 2H,
J=6.5 Hz, CH.sub.3CO--CH.sub.2s), 2.35 (m, 2H, N--CO--CH.sub.2),
2.19 (s, 3H, (CH.sub.2)--CO--CH.sub.3), 2.03 (s, 3H,
NCO--CH.sub.3), 1.63 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 207.3, 172.0, 170.9, 160.5 (d, J.sub.CF=246 Hz),
153.9, 137.8 (d, J.sub.CF=11 Hz), 128.2 (d, J.sub.CF=14 Hz), 127.0
(d, J.sub.CF=6 Hz), 113.1, 106.2 (d, J.sub.CF=28 Hz), 71.7, 61.3,
58.6, 47.1, 41.6, 37.6, 35.5, 29.7, 28.0, 24.6, 22.8; K.F.
Water=1.67%. Anal. Calcd for C.sub.21H.sub.26N.sub.3.degree. F.,
plus 1.67% water: C, 59.13; H, 6.33; N, 9.85. Found: C, 59.04; H,
6.38; N, 9.80. HRMS Calcd for
C.sub.21H.sub.26N.sub.3O.sub.5E.sub.1: 419.1856. Found:
419.1854.
EXAMPLE 10
(S)-N-[[3-[3-Fluoro-4-[1-acetyl-3-(3-methyl)-azetidinyl]-phenyl]-2-oxo-5-o-
xazolidinyl]methyl]-acetamide
[0214] An oven-dried 25 mL round bottom flask equipped with
magnetic spinbar was charged with 75 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidin-
yl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.23 mmol), 5
mL dichloromethane, and cooled to, 0.degree. C. The colorless but
slightly opaque solution was treated with 49 .mu.L triethylamine
(0.35 mmol) and 20 .mu.L acetyl chloride (0.28 mmol) becoming a
light yellow color. The cooling bath was removed and the reaction
mixture was warmed to room temperature over three hours. The now
clear yellow solution was diluted with 10 mL water and extracted
twice with dichloromethane (20 mL). The combined organics were
washed once with brine (15 mL), dried over MgSO.sub.4, filtered,
and concentrated to give 96 mg of an off-white foam. This crude
material was combined with 28900-RLH-017 and purified by LC on 10 g
(230-400) silica gel eluting with 7% methanol/dichloromethane to
afford 143 mg the title compound as a white amorphous solid.
R.sub.f 0.24 (7% methanol/dichloromethane); [.alpha.].sub.D
-21.degree.(c 0.9238, methanol); IR (mull) 1754, 1646, 1631, 1552,
1517, 1435, 1413, 1288, 1227, 1193 cm.sup.-1; .sup.1HNMR (300 MHz,
CDCl.sub.3) .delta. 7.46 (dd, 1H, J=2.1 Hz, J=13.1 Hz, aromatic),
7.14 (dd, 1H, J=2.2 Hz, J=8.6 Hz, aromatic), 7.07 (t, 1H, J=8.5 Hz,
aromatic), 6.40 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H, methine), 4.39
(d, 1H, J=7.9 Hz, Ph--C--CH.sub.2A), 4.30 (d, 1H, J=9.5 Hz,
Ph--C--CH.sub.2B), 4.11 (d, 1H, J=8.2 Hz, Ph--C--CH.sub.2A), 4.02
(m, 2H, Ph--C--CH.sub.2B, Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.8
Hz, J=9.1 Hz, Ph--N--CH.sub.2B), 3.66 (m, 2H, NH--CH.sub.2s), 2.03
(s, 3H, HNCO--CH.sub.3), 1.90 (s, 3H, NCO--CH.sub.3), 1.62 (s, 3H,
Ph--C--CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 171.0, 170.8,
160.3 (d, J.sub.CF=246 Hz), 154.0, 138.0 (d, J.sub.CF=11 Hz), 128.2
(d, J.sub.CF=14 Hz), 127.1 (d, J.sub.CF=6 Hz), 113.2, 106.3 (d,
J.sub.CF=27 Hz), 71.8, 61.7, 58.7, 47.3, 41.7, 35.2, 28.1, 22.9,
18.6; K.F. Water=1.83%. Anal. Calcd for
C.sub.18H.sub.22N.sub.3O.sub.4F, plus 1.83% water: C, 58.41; H,
6.20; N, 11.35. Found: C, 58.43; H, 6.45; N, 11.27. HRMS Calcd for
C.sub.18H.sub.22N.sub.3O.sub.4F.sub.1: 363.1594. Found:
363.1585.
EXAMPLE 11
(S)-N-[[3-[3-Fluoro-4-[1-(2-fluoroethyl)-3-(3-methyl)-azetidinyl]-phenyl]--
2-oxo-5-oxazolidinyl]methyl]-acetamide
[0215] An oven-dried 10 mL recovery flask equipped with magnetic
spinbar and reflux condenser was charged with 262 mg
2-fluoro-1-tosyl ethanol (1.2 mmol), 321' mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidinyl]-phenyl]-
-2-oxo-5-oxazolidinyl]methyl]-acetamide (1.0 mmol), 7.0 mL
acetonitrile, and 415 mg powdered potassium carbonate (3.0 mmol).
The resulting white suspension was heated to reflux for 16 hours.
The visually unchanged reaction mixture was cooled to room
temperature, volatiles removed in vacuo, resulting residue diluted
with 20 mL water, and extracted twice with dichloromethane (20 mL).
The combined organics were washed once with brine (20 mL), dried
over MgSO.sub.4, filtered, and concentrated to give 394 mg of a
light brown syrup. This crude material was purified by LC on 19 g
(230-400) silica gel eluting with 7% methanol/dichloromethane to
afford 260 mg (71%) the title compound as a light peach amorphous
solid. R.sub.f 0.30 (7% methanol/dichloromethane); [.alpha.].sub.D
-21.degree.(c 0.95445, methanol); IR (mull) 1753, 1660, 1630, 1550,
1515, 1481, 1435, 1411, 1225, 1195 cm.sup.-1; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.36 (dd, 1H, J=2.2 Hz, J=12.7 Hz, aromatic),
7.11 (dd, 1H, J=2.3 Hz, J=8.5 Hz, aromatic), 6.98 (t, 1H, J=8.6 Hz,
aromatic), 6.23 (bt. 1H, J=6 Hz, NH), 4.79 (m, 1H, methine), 4.47
(dt, 2H, J=4.8 Hz, J.sub.HF=47.4 Hz, F--CH.sub.2), 4.04 (t, 1H,
J=9.0 Hz, Ph--N--CH.sub.2A), 3.77 (dd, 1H, J=6.8 Hz, J=9.2 Hz,
Ph--N--CH.sub.2B), 3.66 (m, 4H, HN--CH.sub.2s, N--CH.sub.2As), 3.34
(d, 2H, J=7.2 Hz, N--CH.sub.2Bs), 2.75 (dt, 2H, J=4.9 Hz,
J.sub.HF=28.2 Hz, F--CH.sub.2--CH.sub.2), 2.03 (s, 3H,
O.dbd.C--CH.sub.3), 1.64 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 170.8, 159.9 (d, J.sub.CF=245 Hz), 153.9, 137.0
(d, J.sub.CF=11 Hz), 131.1 (d, J.sub.CF=16 Hz), 127.0 (d,
J.sub.CF=7 Hz), 113.2 (d, J.sub.CF=3 Hz), 106.2 (d, J.sub.CF=28
Hz), 82.6 (d, J.sub.CF=166 Hz), 71.7, 66.0, 58.5 (d, J.sub.CF=19
Hz), 47.2, 41.6, 36.8, 27.1, 22.8; K.F. Water=1.05%; Anal. Calcd
for C.sub.18H.sub.3N.sub.3O.sub- .3F.sub.2 plus 1.66% water: C,
57.87; H, 6.39; N, 11.25. Found: C, 57.67; H, 6.43; N, 11.18. HRMS
Calcd for C.sub.18H.sub.3N.sub.3O.sub.3F.sub.2: 368.1786. Found:
368.1789.
EXAMPLE 12
(S)-N-[[3-[3-Fluoro-4-[1-(cyanomethyl)-3-(3-methyl)-azetidinyl]-phenyl-2-o-
xo-5-oxazolidinyl]methyl]-acetamide
[0216] An oven-dried 10 mL recovery flask equipped with magnetic
spinbar and reflux condenser was charged with 321 mg
(S)-N-[[3-[3-fluoro-4-[3-met-
hyl-3-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
(1.0 mmol), 7.0 mL acetonitrile, 76 .mu.L chloroacetonitrile (1.2
mmol), and 415 mg powdered potassium carbonate (3.0 mmol). The
resulting white suspension was heated to reflux and quickly
darkened to a tan color. TLC after 20 minutes indicates almost
complete consumption of
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidinyl]-phenyl]-2-oxo-5-oxazolidiny-
l]methyl]-acetamide, and the reaction was stirred at room
temperature for 16 hours. The visually unchanged reaction mixture
was cooled to room temperature, volatiles removed in vacuo,
resulting residue diluted with 20 mL water, and extracted twice
with dichloromethane (20 mL). The combined organics were washed
once with brine (20 mL), dried over MgSO.sub.4, filtered, and
concentrated to give 340 mg of a yellow foam. This crude material
was purified by LC on 24 g (230-400) silica gel eluting with 5%
methanol/dichloromethane to afford 271 mg (75%) the title compound
as a white amorphous solid. R.sub.f 0.30 (5%
methanol/dichloromethane); [.alpha.].sub.D -22.degree.(c 0.9252,
methanol); IR (mull) 1752, 1661, 1631, 1546, 1516, 1480, 1434,
1412, 1227, 1195 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.39 (dd, 1H, J=2.3 Hz, J=12.8 Hz, aromatic), 7.13 (dd, 1H,
J=2.2 Hz, J=8.5 Hz, aromatic), 6.99 (t, 1H, J=8.6 Hz, aromatic),
6.30 (bt, 1H, J=6 Hz, NH), 4.79 (m, 1H, methine), 4.03 (t, 1H,
J=9.0 Hz, Ph--N--CH.sub.2A), 3.77 (dd, 1H, J=6.8 Hz, J=9.1 Hz,
Ph--N--CH.sub.2B), 3.66 (m, 2H, HN--CH.sub.2s), 3.55 (s, 4H,
N--CH.sub.2s), 3.49 (s, 2H, NC--CH.sub.2), 2.02 (s, 3H,
O.dbd.C--CH.sub.3), 1.64 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3); 171.1, 159.9 (d, J.sub.CF=246 Hz), 154.1, 137.4
(d, J.sub.CF=11 Hz), 129.7 (d, J.sub.CF=15 Hz), 126.9 (d,
J.sub.CF=7 Hz), 114.8, 113.3, 106.2 (d, J.sub.CF=28 Hz), 71.8,
63.3, 47.2, 43.9, 41.6, 36.5, 26.9, 22.8; K.F. Water=1.42%; Anal.
Calcd for C.sub.18H.sub.21N.sub.4O.sub.3F, plus 1.42% water: C,
59.14; H, 5.95; N, 15.33. Found: C, 58.96; H, 5.88; N, 15.33. HRMS
Calcd for C.sub.18H.sub.21N.sub.4O.sub.3FI: 360.1598. Found:
360.1610.
EXAMPLE 13
(S)-N-[[3-[3-Fluoro-4-1-(5-nitro-2-thiazoyl)-3-(3-methyl)-azetidinyl]-phen-
yl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0217] An oven-dried 10 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 4
mL dimethylsulfoxide, and 188 mg 2-bromo-5-nitrothiazole. This
golden homogenous solution was treated with 207 mg powdered
potassium carbonate (1.5 mmol) and stirred at room temperature for
16 hours. The now dark brown suspension was diluted with 40 mL
dichloromethane and washed with water (3.times.15 mL), once with
brine (15 mL), dried over MgSO.sub.4, filtered, and concentrated to
give 280 mg of an orange foam. This crude material was purified by
LC on 18 g (230-400) silica gel eluting with 5%
methanol/dichloromethane to afford 191 mg (56%) the title compound
as a yellow solid. This material was recrystallized from ethyl
acetate/hexane to afford 88 mg of a yellow solid. mp
182-185.degree. C. (dec.); R.sub.f 0.29 (5%
methanol/dichloromethane); [.alpha.].sub.D -20.degree.(c 0.4062,
DMSO); IR (mull) 1747, 1771, 1572, 1517, 1498, 1475, 1439, 1282,
1228, 1199, cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.50 (dd, 1H, J=2.1 Hz, J=13.1 Hz, aromatic), 7.20 (dd, 1H, J=2.2
Hz, J=8.5 Hz, aromatic), 7.12 (t, 1H, J=8.5 Hz, aromatic), 4.79 (m,
11H, methine), 4.51 (d, 2H, J=8.9, Ph--C--CH.sub.2s), 4.24 (d, 2H,
J=9.4 Hz, Ph--C--CH.sub.2s), 4.07 (t, 1H, J=9.0 Hz,
Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=7.0 Hz, J=9.5 Hz,
Ph--N--CH.sub.2B), 3.62 (m, 2H, NH--CH.sub.2s), 2.01 (s, 3H,
O.dbd.C--CH.sub.3), 1.75 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 201.0, 171.9, 171.8, 160.1 (d, J.sub.CF=247 Hz),
154.6, 145.5, 138.4 (d, J.sub.CF=11 Hz), 127.1, 126.9 (d,
J.sub.CF=6 Hz), 113.5, 106.5 (d, J.sub.CF=27 Hz), 72.2, 64.0, 47.4,
41.7, 38.1, 28.0, 22.4; K.F. Water=0.59%. Anal. Calcd for
C.sub.19H.sub.20N.sub.5O.sub.5F.s- ub.1S.sub.1 plus 0.59% water: C,
50.48; H, 4.53; N, 15.49. Found: C, 50.26, H, 4.69; N, 15.29.
EXAMPLE 14
(S)-N-[[3-[3-Fluoro-4-[1-(methanesulfonyl)-3-(3-methyl)-azetidinyl]-phenyl-
]-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0218] An oven-dried 15 mL round bottom flask equipped with
magnetic spinbar was charged with 241 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.75 mmol), 8
mL dichloromethane, and cooled to 0.degree. C. The colorless but
slightly opaque solution was treated with 0.16 mL triethylamine
(1.1 mmol) and 70 .mu.L methanesulfonyl chloride (0.90 mmol) with
no visible change. The cooling bath was removed and the reaction
mixture was warmed to room temperature over three hours. The now
clear solution was concentrated to a colorless syrup. This crude
material was purified by LC on 18 g (230-400) silica gel eluting
with 5% methanol/ethyl acetate to afford 234 mg (78%) the title
compound as a white foam. R.sub.f 0.30 (5% methanol/ethyl acetate);
[.alpha.].sub.D -9.degree.(c 0.9701, methanol; IR (mull) 1753,
1664, 1631, 1517, 1436, 1412, 1333, 1228, 1194, 1151 cm.sup.-1;
.sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 7.44 (dd, 1H, J=2.2 Hz,
J=13.0 Hz, aromatic), 7.16 (m, 1H, aromatic), 7.00 (t, 1H, J=8.6
Hz, aromatic), 6.30 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H, methine),
4.24 (d, 2H, J=7.4 Hz, Ms-N--CH.sub.2As), 4.05 (t, 1H, J=9.0 Hz,
Ph--N--CH.sub.2A), 3.88 (d, 2H, J=7.6 Hz, Ms-N--CH.sub.2Bs), 3.79
(m, 1H, Ph--N--CH2.sub.B), 3.66 (m, 2H, NH--CH.sub.2s), 2.87 (s,
3H, S--CH.sub.3), 2.03 (s, 3H, O.dbd.C--CH.sub.3), 1.68 (s, 3H,
Ph--C--CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 171.2, 160.2
(d, J.sub.CF=246 Hz), 154.2, 138.3 (d, J.sub.CF=11 Hz), 128.2 (d,
J.sub.CF=15 Hz), 126.9 (d, J.sub.CF=6 Hz), 113.5 (d, J.sub.CF=3
Hz), 106.5 (d, J.sub.CF=28 Hz), 72.0, 60.8, 47.4, 41.8, 36.2, 35.0,
27.4, 23.1; Melt solvate=0.3% ethyl acetate; K.F. Water=1.05%;
Anal. Calcd for C.sub.17H.sub.22N.sub.3O.sub.5F.sub.1S.sub.1 plus
0.3% ethyl acetate and 1.05% water: C, 50.59; H, 5.62; N, 10.38.
Found: C, 50.50; H, 5.81; N, 10.29. HRMS Calcd for
C.sub.17H.sub.22N.sub.3O.sub.5F.sub.1S.sub.1: 400.1342. Found:
400.1352.
EXAMPLE 15
(S)-N-[[3-[3-Fluoro-4-[1-(benzyloxyacetyl)-3-(3-methyl)-azetidinyl]-phenyl-
]-2-oxo-5-oxazolidinyl]methyl]-acetamide
[0219] An oven-dried 25 mL round bottom flask equipped with
magnetic spinbar was charged with 313 mg
(S)-N-[[3-[3-fluoro-4-[3-methyl-3-azetidi-
nyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.97 mmol), 10
mL dichloromethane, and cooled to 0.degree. C. The colorless but
slightly opaque solution was treated with 0.27 mL triethylamine
(2.0 mmol) and 0.23 mL benzyloxyacetyl chloride (1.5 mmol) with the
reaction mixture becoming clear and a pale yellow color. The
cooling bath was removed and the reaction mixture was warmed to
room temperature over 16 hours. The visually unchanged solution was
diluted with 15 mL saturated sodium bicarbonate and extracted twice
with dichloromethane (20 mL). The combined organics were washed
once with 15 mL brine, dried over MgSO.sub.4, filtered, and
concentrated to give 521 mg of a light yellow foam. This crude
material was purified by LC on 27 g (230-400) silica gel eluting
with 10% methanol/ethyl acetate to afford 370 mg (81%) the title
compound as a white foam. R.sub.f 0.29 (10% methanol/ethyl
acetate); [.alpha.].sub.D -17.degree.(c 0.9516, methanol); IR
(mull) 1754, 1654, 1631, 1548, 1516, 1438, 1411, 1226, 1193, 1122
cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45 (dd, 1H,
J=2.2 Hz, J=13.0 Hz, aromatic), 7.33 (m, 5H, aromatic), 7.15 (dd,
1H, J=2.2 Hz, J=8.5 Hz, aromatic), 7.04 (t, 1H, J=8.6 Hz,
aromatic), 6.42 (bt, 1H, J=6 Hz, NH), 4.79 (m, 1H, methine), 4.57
(s, 2H, Ph--CH.sub.2), 4.50 (d, 1H, J=9.0 Hz, Ph--C--CH.sub.2A),
4.33 (d, 1H, J=9.7 Hz, Ph--C--CH.sub.2B), 4.23 (d, 1H, J=9.2 Hz,
Ph--C--CH.sub.2B), 4.04 (m, 4H, Ph--C--CH.sub.2A, O--CH.sub.2,
Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.8 Hz, J=9.0 Hz,
Ph--N--CH.sub.2B), 3.66 (m, 2H, NH--CH.sub.2), 2.02 (s, 3H,
O.dbd.C--CH.sub.3), 1.61 (s, 3H, Ph--C--CH.sub.3); .sup.13C NMR (75
MHz, CDCl.sub.3) 171.1, 169.6, 160.3 (d, J.sub.CF=246 Hz), 154.1,
138.1 (d, J.sub.CF=11 Hz), 137.0, 128.4, 128.2, 128.0, 127.9, 127.2
(d, J.sub.CF=6 Hz), 113.3, 106.5 (d, J.sub.CF=26 Hz), 73.3, 71.9,
69.0, 62.4, 59.4, 47.4, 41.8, 36.7, 28.2, 23.0; HRMS Calcd for
C.sub.25H.sub.28N.sub.3O.sub.5F.sub.1: 470.2091. Found:
470.2101.
EXAMPLE 16
(S)-N-[[3-[3-Fluoro-4-[1-(hydroxyacetyl)-3-(3-methyl)-azetidinyl]-phenyl]--
2-oxo-5-oxazolidinyl]methyl]-acetamide
[0220] A 250 mL Parr flask was charged with a solution of 310 mg
(S)-N-[[3-[3-fluoro-4-[1-(benzyloxyacetyl)-3-(3-methyl)-azetidinyl]-pheny-
l]-2-oxo-5-oxazolidinyl]methyl]-acetamide (0.66 mmol) in 30 mL
methanol and 31 mg 10% palladium on carbon. The black suspension
was placed under 40 psi hydrogen with shaking for 16 hours with the
pressure remaining constant. The reaction was monitored by TLC
analysis with several additional equivalents of 10% palladium on
carbon (300 mg total amount) and prolonged time (five days) to
fully consume (S)-N-[[3-[3-fluoro-4-[1--
(benzyloxyacetyl)-3-(3-methyl)-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl]-m-
ethyl]-acetamide. The reaction mixture was filtered through a pad
of Celite and concentrated to afford 221 mg (88%) the title
compound as an off-white amorphous solid. R.sub.f 0.21 (15%
methanol/ethyl acetate); [.alpha.].sub.D -20.degree.(c 0.9432,
methanol); IR (mull) 1754, 1655, 1632, 1552, 1517, 1481, 1435,
1412, 1227, 1192 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.47 (d, 1H, J=2.1 Hz, J=13.0 Hz, aromatic), 7.15 (dd, 1H,
J=2.2 Hz, J=8.5 Hz, aromatic), 7.07 (t, 1H, J=8.6 Hz, aromatic),
6.37 (bt, 1H, J=6 Hz, NH), 4.80 (m, 1H, methine), 4.38 (m, 2H,
Ph--C--CH.sub.2A&B), 4.01 (m, 5H, Ph--C--CH.sub.2A&B,
HO--CH.sub.2, Ph--N--CH.sub.2A), 3.79 (dd, 1H, J=6.8 Hz, J=9.1 Hz,
Ph--N--CH.sub.2B), 3.68 (m, 2H, HN--CH.sub.2s), 2.03 (s, 3H,
O.dbd.C--CH.sub.3), 1.65 (s, 3H, Ph--C--CH) 171.3, 170.9, 160.1 (d,
J.sub.CF=246 Hz), 153.9, 138.1 (d, J.sub.CF=11 Hz), 127.6 (d,
J.sub.CF=14 Hz), 126.9 (d, J.sub.CF=6 Hz), 113.1, 106.3 (d,
J.sub.CF=28 Hz), 71.8, 60.1, 59.3, 58.5, 47.1, 41.6, 37.0, 28.0,
22.8; HRMS Calcd for C.sub.18H.sub.22N.sub.3O.sub.5F.sub.1:
379.1543. Found: 379.1542.
EXAMPLE 17
(S)-(-)-N-[[2-Oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetam-
ide
[0221] Step 1:
4-Hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-pi-
peridinecarboxylic acid phenylmethyl ester
[0222] To a solution of N-(carbobenzyloxy)-4-bromoaniline (5.00 g)
in dry tetrahydrofaran (80 mL) at -78.degree. C. under N.sub.2 is
added n-butyllithium (21.4 mL, 1.6M in hexanes) dropwise over five
minutes. The resulting yellow solution is stirred at -78.degree. C.
for 30 minutes and is then treated with a solution of
N-(carbobenzyloxy)-4-piperidone (3.99 g) in dry tetrahydrofuran (7
mL). The reaction mixture is stirred for three hours, during which
the reaction temperature is allowed to rise to 0.degree. C., and is
quenched with saturated aqueous ammonium chloride (30 mL). The
mixture is then diluted with water (100 mL), the layers are
separated, the aqueous phase is extracted with diethyl ether, and
the combined organic phase is washed with saline (50 mL), dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue is chromato-graphed on silica gel (230-400
mesh, 350 g), eluting with ethyl acetate/hexane (25/75), and those
fractions with an R.sub.f=0.38 by TLC (ethyl acetate/hexane, 50/50)
are pooled and con-centrated under reduced pressure to give the
title compound, mp 156.degree. C.-158.degree. C.
[0223] Step 2:
3,6-Dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(-
2H)-pyridinecarboxylic acid phenylmethyl ester
[0224] A solution of
4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl-
]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step
1, 2.50 g) in dry methylene chloride under N.sub.2 is treated with
trifluoroacetic acid (0.84 mL), stirred at ambient temperature for
three hours, diluted with saturated aqueous potassium carbonate (25
mL) to neutralize excess trifluoroacetic acid, and the layers are
separated. The organic phase is washed with water (20 mL) and
saline (20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure, and the residue is
chromatographed on silica gel (230-400 mesh, 300 g), eluting with a
gradient of ethyl acetate/hexane (20/80-50/50). Pooling of
fractions with an R.sub.f=0.69 by TLC (ethyl acetate/hexane, 50/50)
and removal of solvent under reduced pressure gives the title
compound, mp 146-148.degree. C.
[0225] Step 3:
(R)-(-)-3,6-Dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazoli-
dinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester
[0226] A solution of
3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phen-
yl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17,
Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at -78.degree. C.
under N.sub.2 is treated with n-butyllithium (0.73, mL, 1.6M in
hexanes) dropwise over five minutes. The resulting mixture is
stirred at -78.degree. C. for 45 minutes and is then treated with
(R)-(-)-glycidyl butyrate dropwise. The resulting solution is
allowed to warm to ambient temperature over approximately 45
minutes and is stirred for an additional 20 hours, after which the
reaction is quenched with saturated aqueous ammonium chloride (10
mL), diluted with water (20 mL) and extracted with ethyl acetate
(2.times.15 mL). The combined organic phase is washed with saline
(10 mL), dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the crude product which is
chromatographed on silica gel (230-400 mesh, 40 g), eluting with
methanol/methylene chloride (1/99). Pooling and concentration of
those fractions with an R.sub.f=0.37 by TLC (methanol/chloroform,
5/95) gives the title compound, mp 131.5-133.5.degree. C.
[0227] Step 4:
(R)-(-)-3,6-Dihydro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-
-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester
[0228] A solution of
(R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-o-
xazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl
ester (EXAMPLE 17, Step 3, 970 mg) and triethylamine (0.50 mL) in
dry methylene chloride (9.5 mL) at 0.degree. C. under N.sub.2 is
treated with methanesulfonyl chloride (0.20 mL) dropwise. The
resulting mixture is stirred at 0.degree. C. for one hour, diluted
with methylene chloride (40 mL), washed with water (10 mL),
saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL),
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give the title compound, mp 166-168.degree. C.
[0229] Step 5:
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-
phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid phenylmethyl
ester
[0230] A mixture of
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)oxy]meth-
yl]-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester (EXAMPLE 17, Step 4, 935 mg) and concentrated
aqueous ammonium hydroxide (4 mL) in isopropanol (4 mL) and
tetrahydrofuran (4 mL) is placed in a sealed tube and immersed in
an oil bath maintained at 95.degree. C. for 18 hours. The mixture
is then diluted with methylene chloride (40 mL), washed with saline
(20 mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the 5-aminomethyl-2-oxazolidinone
intermediate (R.sub.f=0.34 by TLC, methanol/chloroform, 10/90). A
solution of this intermediate (783 mg) and pyridine (1.55 mL) in
dry methylene chloride (9 mL) at 0.degree. C. under N.sub.2 is
treated with acetic anhydride (0.90 mL), and the resulting solution
is allowed to warm to ambient temperature with stirring over 1.5
hours. The mixture is then diluted with methylene chloride (20 mL),
washed with water (10 mL), saturated aqueous sodium bicarbonate
(2.times.10 mL) and saline (10 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the crude
product which is chromatographed on silica gel (230-400 mesh, 75
g), eluting with a gradient of methanol/methylene chloride
(1/99-2/98). Pooling and concentration of those fractions with an
R.sub.f=0.26 by TLC (methanol/chloroform, 5/95) gives the title
compound, mp 166-169.degree. C.
[0231] Step 6:
(S)-(-)-N-[[2-Oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidiny-
l]methyl]acetamide
[0232] A mixture of
(S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolid-
inyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid phenylmethyl
ester (EXAMPLE 17, Step 5, 625 mg) and 10% palladium-on-carbon (300
mg) in methanol (100 mL) is shaken on a Parr apparatus under a
hydrogen atmosphere at 40 psi for one hour and at 20 psi for 16
hours, the catalyst is removed by filtration through Celite and the
filtrate is concentrated under reduced pressure to give the title
compound, mp 169-171.degree. C.
EXAMPLE 18
(S)-(-)-N-[[3-[4-[1-[(Benzyloxy)acetyl]-4-piperidinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]acetamide
[0233] A mixture of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazol-
idinyl]methyl]acetamide (EXAMPLE 17, 300 mg) and triethylamine
(0.20 mL) in dry methylene chloride (19 mL) at 0.degree. C. under
N.sub.2 is treated with benzyloxyacetyl chloride (0.18 mL), and the
resulting solution is stirred at 0.degree. C. for one hour and at
ambient temperature for one hour. The reaction mixture is then
washed with water (2.times.10 mL), saturated aqueous sodium
bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the crude
product which is chromatographed on silica gel (230-400 mesh, 45
g), eluting with a gradient of methanol/methylene chloride
(1/99-2/98). Pooling and concentration of those fractions with an
R.sub.f=0.28 by TLC (methanol/chloroform, 5/95) gives the title
compound, NMR (CDCl.sub.3, 400 MHz) 7.45, 7.35, 7.18, 6.26, 4.75,
4.63, 4.22, 4.04, 3.78, 3.70, 3.60, 3.09, 2.70, 2.02, 1.85, 1.60
.delta..
EXAMPLE 19
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-4-piperidinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide
[0234] A mixture of
(S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 18, 207 mg)
and 10% palladium-on-carbon (100 mg) in methanol (9 mL) is shaken
on a Parr apparatus under a hydrogen atmosphere at 40 psi for 20
hours, the catalyst is removed by filtration through Celite and the
filtrate is concentrated under reduced pressure to give the crude
product which is chromatographed on silica gel (230-400 mesh, 20
g), eluting with a gradient of methanol/methylene chloride
(5/95-10/90). Pooling and concentration of those fractions with an
R.sub.f 0.26 by TLC (methanol/chloroform, 10/90) and
recrystallization from methylene chloride/diethyl ether gives the
title compound, mp 155-157.degree. C.
EXAMPLE 20
(S)-(-)-N-[[2-Oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]meth-
yl]acetamide
[0235] Step
1:1-(3-Fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclo-
pentane
[0236] A solution of freshly distilled diisopropylamine (22.9 mL)
in dry tetrahydrofuran (175 mL) at -78.degree. C. under N.sub.2 is
treated with n-butyllithium (1.6M in hexanes, 109 mL) dropwise over
15 minutes, and the resulting mixture is stirred at -78.degree. C.
for 45 minutes and is then added over ten minutes via cannula to a
solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166
mL) at -78.degree. C. under N.sub.2. The resulting reaction mixture
is stirred at -78.degree. C. for 50 minutes and is then treated
with a solution of 1,1,4,4-tetramethyl-1,4- -dichlorodisilethylene
(18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to
slowly warm to ambient temperature over four hours with stirring
and is then washed with water (2.times.200 mL) and saline (100 mL),
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give the title compound, NMR (CDCl.sub.3, 400 MHz)
7.12, 6.65, 6.58, 0.86, 0.24 .delta..
[0237] Step 2:
3,6-Dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridi-
necarboxylic acid 1,1-dimethylethyl ester
[0238] A solution of freshly distilled diisopropylamine (8.70 mL)
in dry tetrahydrofuran (133 mL) at -78.degree. C. under N.sub.2 is
treated with n-butyllithium (1.6M in hexanes, 41.5 mL) dropwise
over ten minutes, and the resulting mixture is stirred at
-78.degree. C. for one hour and is then treated with a solution of
1-(1,1-dimethylethoxycarbonyl)-4-piperido- ne (12.0 g) in dry
tetrahydrofuran (120 mL) dropwise over 10 minutes. The resulting
mixture is stirred at -78.degree. C. for 40 minutes and is then
treated with a solution of N-phenyltrifluoromethanesulfonimide
(22.0 g) in dry tetrahydrofuran (62 mL) over five minutes. The
reaction mixture is stirred at -78.degree. C. for 10 minutes and at
0.degree. C. for four hours and is then quenched with water (200
mL). The layers are separated, the aqueous phase is extracted with
diethyl ether (100 mL) and the combined organic phase is washed
with saline (50 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound, NMR
(CDCl.sub.3, 400 MHz) 5.77, 4.05, 3.64, 2.45, 1.48 .delta..
[0239] Step 3:
3,6-Dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinecarbox- ylic
acid 1,1-dimethylethyl ester
[0240] A solution of
1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disi-
lacyclopentane (EXAMPLE 20, Step 1, 19.1 g) in dry tetrahydrofuran
(150 mL) at -78.degree. C. under N.sub.2 is treated with
sec-butyllithium (1.3M in cyclohexane, 60.31 mL) dropwise over ten
minutes, and the resulting mixture is stirred at -78.degree. C. for
2.25 hours. A solution of zinc chloride (0.5M in tetrahydrofuran,
150 mL) is then added over 15 minutes, and the mixture is allowed
to warm to ambient temperature over one hour with stirring. A
solution of 3,6-dihydro-4-[[(trifluoromethyl)-s-
ulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester
(EXAMPLE 20, Step 2, 20.8 g) in dry tetrahydrofuran (63 mL) and
tetrakis(triphenylphosphine)palladium(0) (1.45 g) is added, and the
mixture is degassed, heated up to reflux, refluxed for five
minutes, cooled to ambient temperature and stirred for 12 hours.
The mixture is then diluted with water (150 mL), the layers are
separated, the aqueous phase is extracted with diethyl ether
(2.times.100 mL) and the combined organic phase is washed with
water (100 mL) and saline (100 mL), dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue is
then dissolved in methanol (630 mL) and treated with anhydrous
potassium carbonate (17.3 g), and the mixture is stirred at ambient
temperature for 40 minutes, concentrated under reduced pressure,
diluted with water (100 mL) and extracted with diethyl ether
(2.times.150 mL). The combined organic phase is washed with water
(50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to give the crude product
which is chromatographed on silica gel (230-400 mesh, 1 kg),
eluting with a gradient of ethyl acetate/hexane (15/85-50/50).
Pooling and concentration of those fractions with an R.sub.f=0.17
by TLC (ethyl acetate/hexane, 25/75) gives the title compound, mp
123-125.degree. C.
[0241] Step 4:
4-[4-[[(Phenylmethoxy)carbonyl]amino-2-fluorophenyl-1-piper-
idinecarboxylic acid 1,1-dimethylethyl ester
[0242] A mixture of
3,6-dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinec- arboxylic
acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 3, 11.44 g) and 10%
palladium-on-carbon (4 g) in methanol (400 mL) in four Parr bottles
is shaken on the Parr apparatus under a hydrogen atmosphere at 40
psi for two hours, the catalyst is removed by filtration through
Celite, and the filtrate is concentrated under reduced pressure to
give the 4-[4-amino-2-fluorophenyl]-1-piperidinecarboxylic acid
1,1-dimethylethyl ester intermediate. A mixture of this
intermediate (11.17 g) and sodium bicarbonate (6.57 g) in dry
tetrahydrofuran (390 mL) is treated with benzyl chloroformate (5.86
mL), and the resulting mixture is stirred at ambient temperature
for 15 hours and washed with water (200 mL). The aqueous phase is
extracted with methylene chloride (150 mL), and the combined
organic phase is washed with saline (50 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give the
crude product which is chromatographed on silica gel (70-230 mesh,
800 g), eluting with a gradient of ethyl acetate/hexane
(15/85-25/75). Pooling and concentration of those fractions with an
R.sub.f=0.38 by TLC (ethyl acetate/hexane, 25/75) gives the title
compound, mp 96-98.degree. C.
[0243] Step 5:
(R)-(-)-4-[4-[5-(Hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-flu-
orophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester
[0244] A solution of
4-[4-[[(phenylmethoxy)carbonyl]amino-2-fluorophenyl]--
1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20,
Step 4, 0.500 g) in dry tetrahydrofuran (5.7 mL) at -78.degree. C.
under N.sub.2 is treated with n-butyllithium (0.73 mL, 1.6M in
hexanes) dropwise over five minutes. The resulting mixture is
stirred at -78.degree. C. for 45 minutes and is then treated with
(R)-(-)-glycidyl butyrate dropwise. The resulting solution is
allowed to warm to ambient temperature over approximately 45
minutes and is stirred for an additional 20 hours, after which the
reaction is quenched with saturated aqueous ammonium chloride (10
mL), diluted with water (20 mL) and extracted with ethyl acetate
(2.times.15 mL). The combined organic phase is washed with saline
(10 mL), dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the crude product which is
chromatographed on silica gel (230-400 mesh, 40 g), eluting with
methanol/methylene chloride (1/99). Pooling and concentration of
those fractions with an R.sub.f=0.37 by TLC (methanol/chloroform,
5/95) gives the title compound, mp 120-122.degree. C.
[0245] Step 6:
(R)-(-)-4-[4-[5-[[(Methylsulfonyloxy]methyl]-2-oxo-3-oxazol-
idinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid
1,1-dimethylethyl ester
[0246] A solution of
(R)-(-)-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-
-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester (EXAMPLE 20, Step 5, 970 mg) and triethylamine (0.50 mL) in
dry methylene chloride (9.5 mL) at 0.degree. C. under N.sub.2 is
treated with methanesulfonyl chloride (0.20 mL) dropwise. The
resulting mixture is stirred at 0.degree. C. for one hour, diluted
with methylene chloride (40 mL), washed with water (10 mL),
saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL),
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give the title compound, mp 163-165.degree. C.
[0247] Step 7:
(R)-(-)-4-[4-[5-(Azidomethyl)-2-oxo-3-oxazolidinyl]-2-fluor-
ophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester
[0248] A mixture of
(R)-(-)-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3--
oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 20, Step 6, 13.83 g) and sodium
azide (7.62 g) in dry dimethylformamide (117 mL) under N.sub.2 is
stirred at 60.degree. C. for five hours and at ambient temperature
for 16 hours. The mixture is then diluted with ethyl acetate (200
mL), washed with water (8.times.100 mL) and saline (100 mL), dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure to give the title compound, mp 109-110.degree. C.
[0249] Step 8:
(S)-(-)-4-[4-[5-(Aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluor-
ophenyl]-1-piperidinecarboxylic acid 11-dimethylethyl ester
[0250] A solution of
(R)-(-)-4-[4-[5-(azidomethyl)-2-oxo-3-oxazolidinyl]-2-
-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester
(EXAMPLE 20, Step 7, 12.05 g) in dry tetrahydrofuran (96 mL) under
N.sub.2 is treated with triphenylphosphine (8.29 g) over five
minutes, and the resulting mixture is stirred at ambient
temperature for two hours. The mixture is then treated with water
(3.1 mL), heated up to 40.degree. C., stirred at 40.degree. C. for
five hours and at ambient temperature for 12 hours, and then
concentrated under reduced pressure to give a viscous oil which is
chromatographed on silica gel (70-230 mesh, 500 g), eluting with a
gradient of methanol/methylene chloride (2.5/97.5-15/85). Pooling
and concentration of those fractions with an R.sub.f=0.26 by TLC
(methanol/chloroform, 10/90) gives the title compound, mp
136-137.degree. C.
[0251] Step 9:
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-
-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylether
ester
[0252] A solution of
(S)-(-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-
-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester
(EXAMPLE 20, Step 8, 9.45 g) in dry methylene chloride (96 mL)
under N.sub.2 is treated with pyridine (5.82 mL) and acetic
anhydride (3.40 mL), and the resulting mixture is stirred at
ambient temperature for four hours, diluted with methylene chloride
(25 mL), washed with water (25 mL), saturated aqueous sodium
bicarbonate (25 mL) and saline (25 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the crude
product which is then chromatographed on silica gel (230-400 mesh,
350 g), eluting with a gradient of methanol/chloroform
(2.5/97.5-7.5/92.5). Pooling and concentration of those fractions
with an R.sub.f=0.51 by TLC (methanol/chloroform, 10/90) gives the
title compound, mp 144-146.degree. C.;
[0253] Step 10:
(S)-(-)-N-r[2-Oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-o-
xazolidinyl]methyl]acetamide
[0254] A solution of
(S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazoli- dinyl]-26
fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester
(EXAMPLE 20, Step 9, 10.44 g) in dry methylene chloride (100 mL) at
0.degree. C. under N.sub.2 is treated with trifluoroacetic acid
(24.0 mL) over one minute, and the resulting mixture is stirred at
0.degree. C. for 1.75 hours, concentrated under reduced pressure,
diluted with water (100 mL), cooled in an ice bath, adjusted to pH
11 with saturated aqueous potassium carbonate, and extracted with
methanol/methylene chloride (5/95, 6.times.100 mL). The combined
organic phase is dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound, mp
163-164.degree. C.
EXAMPLE 21
(S)-(-)-N-[[3-[4-[1-[(Benzyloxy)acetyl]-4-piperidinyl]-3-fluorophenyl]-2-o-
xo-5-oxazolidinyl]methyl]acetamide
[0255] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(4-piperi-
dinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]-acetamide (EXAMPLE
20,) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]-methyl]acet-
amide and purifying the crude product by trituration with
chloroform/diethyl ether and filtration, the title compound is
obtained, mp 147-149.degree. C.
EXAMPLE 22
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-
-oxazolidinyl]methyl]acetamide
[0256] A mixture of
(S)-(-)-N-t[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-
-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 21,
5.00 g) and 20% palladium hydroxide on carbon (2.80 g) in methanol
(500 mL) is stirred under a hydrogen atmosphere (balloon) for four
hours, the catalyst is removed by filtration through Celite and the
filtrate is concentrated under reduced pressure, triturated with
methylene chloride/diethyl ether and filtered to give the title
compound, mp 182-183.degree. C.
EXAMPLE 23
(S)-(-)-N-[[3-[4-1-(Indole-2-carbonyl)-4-piperidinyl]-3-fluorophenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide
[0257] A solution of indole-2-carboxylic acid (79 mg) and
1,1'-carbonyldiimidazole (80 mg) in dry tetrahydrofuran (2.0 mL) is
stirred at ambient temperature for one hour, and a solution of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]met-
hyl]acetamide (EXAMPLE 20, 150 mg) in dry tetrahydrofuran (6.0 mL)
is added. The mixture is then stirred at ambient temperature for 19
hours, concentrated under reduced pressure, diluted with methylene
chloride (20 mL), washed with saturated aqueous sodium bicarbonate
(10 mL), water (10 mL) and saline (10 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give the
crude product which is chromagraphed on silica gel (70-230 mesh, 10
g), eluting with methanol/methylene chloride (7.5/92.5). Pooling
and concentration of those fractions with an R.sub.f=0.67 by TLC
(methanol/chloroform, 10/90) and recrystallization from
chloroform/diethyl ether gives the title compound, mp
223-225.degree. C.
EXAMPLE 24
(S)-(-)-N-[[3-[4-[1-(Isoxazole-5-carbonyl)-4-piperidinyl]-3-fluorophenyl]--
2-oxo-5-oxazolidinyl]methyl]acetamide
[0258] A solution of isoxazole-5-carboxylic acid (79 mg) and
1,1'-carbonyldiimidazole (80 mg) in dry tetrahydrofuran (2.0 mL) is
stirred at ambient temperature for one hour, and a solution of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]met-
hyl]acetamide (EXAMPLE 20, 150 mg) in dry tetrahydrofuran (6.0 mL)
is added. The mixture is then stirred at ambient temperature for 19
hours, concentrated under reduced pressure, diluted with methylene
chloride (20 mL), washed with saturated aqueous sodium bicarbonate
(10 mL), water (10 mL) and saline (10 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give the
crude product which is chromagraphed on silica gel (70-230 mesh, 10
g), eluting with methanol/methylene chloride (7.5/92.5). Pooling
and concentration of those fractions with an R.sub.f=0.67 by TLC
(methanol/chloroform, 10/90) and recrystallization from
chloroform/diethyl ether gives the title compound, mp
290-292.degree. C.
EXAMPLE 25
(S)-(-)-N-[[3-[4-[1-(Methylsulfonyl)-4-piperidinyl]-3-fluorophenyl]-2-oxo--
5-oxazolidinyl]methyl]acetamide
[0259] A solution of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl-
]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 125 mg) and pyridine
(60 mL) in dry methylene chloride (1.9 mL) at 0.degree. C. is
treated with methanesulfonyl chloride (32 mL), and the resulting
mixture was stirred at 0.degree. C. for one hour and at ambient
temperature for 16 hours. The reaction mixture is then diluted with
methylene chloride (30 mL), washed with water (10 mL) and saline
(10 mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure, and the residue is recrystallized from methylene
chloride/diethyl ether to give the title compound, mp
240-242.degree. C.
EXAMPLE 26
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl-
]-1-piperidinecarboxylic acid methyl ester
[0260] A mixture of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-
-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20,150 mg) and sodium
bicarbonate (75 mg) in dry tetrahydrofuran (6 mL) at 0.degree. C.
under N.sub.2 is treated with methyl chloroformate (38 mL), and the
resulting mixture is stirred at 0.degree. C. for one hour. The
reaction is then diluted with ethyl acetate (20 mL), washed with
water (10 mL) and saline (10 mL), dried over anhydrous magnesium
sulfate and concentrated under reduced pressure, and the residue is
recrystallized from methylene chloride/diethyl ether to give the
title compound, mp 165-166.degree. C.
EXAMPLE 27
(S)-(-)-N-[[3-[4-[1-(Cyanomethyl)-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide
[0261] A mixture of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-
-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20,150 mg),
chloroacetonitrile (31 .mu.L) and anhydrous potassium carbonate
(124 mg) in dry acetonitrile (4 mL) under N.sub.2 was stirred at
ambient temperature for 20 hours, diluted with methylene chloride
(20 mL), washed with water (10 mL) and saline (10 mL), dried over
anhydrous sodium sulfate and concentrated under reduced pressure,
and the residue is recrystallized from methylene chloride/diethyl
ether to give the title compound, mp 165-167.degree. C.
EXAMPLE 28
(S)-(-)-N-[[3-[4-[1-(2-Fluoroethyl)-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-
-oxazolidinyl]methyl]acetamide
[0262] Following the general procedure of EXAMPLE 27, and making
non-critical variations but substituting 2-flouroethyl
4-toluenesulfonic acid ester for chloroacetonitrile and purifying
the crude product by chromatography on silica gel (70-230 mesh, 30
g), eluting with methanol/methylene chloride, the title compound is
obtained, mp 155-157.degree. C.
EXAMPLE 29
(S)-(-)-N-[[3-[4-[1-(Formyl)-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-oxazol-
idinyl]methyl]acetamide
[0263] A mixture of
(S)-(-)-3-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-
-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20,150 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (171
mg) and formic acid (34 .mu.L) in dry tetrahydrofaran (6 mL) is
stirred at ambient temperature for one hour, diluted with methylene
chloride (10 mL), washed with water (10 mL) and saline (10 mL),
dried over anhydrous sodium sulfate and concentrated under reduced
pressure, and the residue is recrystallized from methylene
chloride/diethyl ether to give the title compound, mp
186-187.degree. C.
EXAMPLE 30
(S)-(-)-4-[4-[5-[[(2,2-Dichloroacetyl)amino]methyl]-2-oxo-3-oxazolidinyl]--
2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester
[0264] A solution of
(S)-(-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-
-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester
(EXAMPLE 20, Step 8, 400 mg) in dry methylene chloride (4.1 mL) at
0.degree. C. under N.sub.2 is treated with triethylamine (0.21 mL)
and dichloroacetyl chloride (0.11 mL), and the resulting mixture is
stirred at 0.degree. C. for three hours, diluted with methylene
chloride (10 mL), washed with water (10 mL), saturated aqueous
sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give the
crude product which is then chromatographed on silica gel (70-230
mesh, 50 g), eluting with methanol/chloroform (5/95). Pooling and
concentration of those fractions with an R.sub.f=0.53 by TLC
(methanol/chloroform, 10/90), trituration with methylene
chloride/diethyl ether and filtration gives the title compound, mp
168-170.degree. C.
EXAMPLE 31
(S)-(-)-2,2-Dichloro-N-[[2-oxo-3-[3-fluoro-4-(4-piperidinyl)phenyl]-5-oxaz-
olidinyl]methyl]acetamide
[0265] Following the general procedure of EXAMPLE 20, Step 10), and
making non-critical variations but substituting
(S)-(-)-4-[4-[5-[[(2,2-dichloroa-
cetyl)amino]methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarb-
oxylic acid phenylmethyl ester (EXAMPLE 30) for
(S)-(-)-4-[4-[5-[(acetylam-
ino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic
acid phenylmethyl ester, the title compound is obtained, NMR
(CDCl.sub.3, 400 MHz) 7.37, 7.22, 7.10, 5.99, 5.29, 4.83, 4.07,
3.78, 3.71, 3.30, 2.98, 2.83, 2.09, 1.81 .delta..
EXAMPLE 32
(S)-(-)-2,2-Dichloro-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-4-piperi-
dinyl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0266] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(S)-(-)-2,2-dichloro-N-[[2-oxo-3-
-[3-fluoro-4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 31) for
(S)-(-)-3-N-[4-(4-piperidinyl)phenyl]-5-acetamidomethyl--
2-oxazolidinone and acetoxyacetyl chloride for benzyloxyacetyl
chloride, the title compound is obtained, NMR (CDCl.sub.3, 400 MHz)
7.42, 7.15, 6.24, 4.77, 4.04, 3.77, 3.68, 3.20, 3.07, 2.71, 2.20,
2.02, 1.88, 1.68 .delta..
EXAMPLE 33
(S)-(-)-2,2-Dichloro-N-[[2-oxo-3-[3-fluoro-4-[1-(hydroxyacetyl)-4-piperidi-
nyl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0267] A mixture of
(S)-(-)-2,2-dichloro-N-[[2-oxo-3-[3-fluoro-4-[1-[(acet-
oxy)acetyl]-4-piperidinyl]phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 32, 110 mg) and anhydrous potassium carbonate (60 mg) in
methanol (8.8 mL) is stirred under N.sub.2 at ambient temperature
for one hour and then concentrated under reduced pressure and
chromatographed on silica gel (70-230 mesh, 10 g), eluting with
methanol/chloroform (10/90). Pooling and concentration of those
fractions with an R.sub.f=0.41 by TLC (methanol/chloroform, 10/90),
repurification by radial chromatography (2000.mu. silica gel plate)
eluting with methanol/methylene chloride, and trituration with
chloroform/diethyl ether gives the title compound, NMR (CDCl.sub.3,
400 MHz) 7.46, 7.39, 7.15, 5.99, 4.84, 4.74, 4.22, 4.09, 3.77,
3.61, 3.10, 2.79, 1.89, 1.65 .delta..
EXAMPLE 34
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-4-piperidinyl]phenyl]-
-5-oxazolidinyl]methyl]acetamide
[0268] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(4-piperi-
dinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE
20,) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]aceta-
mide and acetoxyacetyl chloride for benzyloxyacetyl chloride, the
title compound is obtained, NMR (CDCl.sub.3, 400 MHz) 7.42, 7.15,
6.24, 4.77, 4.04, 3.77, 3.68, 3.20, 3.07, 2.71, 2.20, 2.02, 1.88,
1.68 .delta..
EXAMPLE 35
(S)-(-)-N-[[2-Oxo-3-[4-(4-piperidinyl)-3,5-difluorophenyl]-5-oxazolidinyl]-
methyl]acetamide Step
1:1-(3,5-Difluorophenyl)-2,2,5,5-tetramethyl-1-aza-2-
,5-disilacyclopentane
[0269] Following the general procedure of Step 1 of EXAMPLE 20, and
making non-critical variations but substituting 3,5-difluoroaniline
for 3-fluoroaniline, the title compound is obtained, NMR
(CDCl.sub.3, 400 MHz) 6.38, 6.31, 0.87, 0.17 .delta..
[0270] Step 2:
3,6-Dihydro-4-[4-amino-2,6-difluorophenyl]-1(2H)-pyridineca-
rboxylic acid 1,1-dimethylethyl ester
[0271] Following the general procedure of Step 3 of EXAMPLE 20, and
making non-critical variations but substituting
1-(3,5-difluorophenyl)-2,2,5,5-t-
etramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 35, Step 1) for
1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane,
the title compound is obtained, mp 134-135.degree. C.
[0272] Step 3:
4-[4-[[(Phenylmethoxy)carbonyl]amino-2,6-difluorophenyl]-1--
piperidinecarboxylic acid 1]-dimethylethyl ester
[0273] Following the general procedure of Step 4 of EXAMPLE 20, and
making non-critical variations but substituting
3,6-dihydro-4-[4-amino-2,6-diflu-
orophenyl]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester
(EXAMPLE 35, Step 2) for
3,6-dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinecarb- oxylic
acid 1,1-dimethylethyl ester and purifying the crude product by
trituration with ethyl acetate/hexane and filtration, the title
compound is obtained, mp 153-155.degree. C.
[0274] Step 4:
(R)-(-)-4-[4-[5-(Hydroxymethyl)-2-oxo-3-oxazolidinyl]-2,6-d-
ifluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester
[0275] Following the generel procedure of Step 3 of EXAMPLE 17, and
making non-critical variations but substituting
4-[4-[[(phenylmethoxy)carbonyl]a-
mino-2,6-difluorophenyl]-1-piperidinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 35, Step 3) for
3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl-
]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester,
the title compound is obtained, NMR (CDCl.sub.3, 400 MHz) 7.11,
4.75, 4.22, 3.96, 3.75, 3.06, 2.76, 2.50, 1.98, 1.65, 1.48
.delta..
[0276] Step 5:
(R)-(-)-4-[4-[5-[[(Methylsulfonyloxy]methyl]-2-oxo-3-oxazol-
idinyl]-2,6-difluorophenyl]-1-piperidinecarboxylic acid
11-dimethylethyl ester
[0277] Following the general procedure of Step 4 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-4-[4-[5-(hydroxymethyl)--
2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperidinecarboxylic
acid 1,1-dimethylethyl ester (EXAMPLE 35, Step 4) for
(R)-(-)-3,6-dihydro-4-[4-
-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester, the title compound is obtained, mp
125-126.degree. C.
[0278] Step 6:
(R)-(-)-4-[4-[5-(Azidomethyl)-2-oxo-3-oxazolidinyl]-2,6-dif-
luorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester
[0279] Following the general procedure of step 7 of EXAMPLE 20, and
making non-critical variations but substituting
(R)-(-)-4-[4-[5-[[(methylsulfony-
l)oxy]methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperidinecarbox-
ylic acid 1,1-dimethylethyl ester (EXAMPLE 35, Step 5) for
(R)-(-)-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2-flu-
orophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, the
title compound is obtained, mp 125-127.degree. C.
[0280] Step 7:
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-
-2,6-difluorophenyl]-1-piperidinecarboxylic acid phenylmethyl
ester
[0281] A mixture of
(R)-(-)-4-[4-[5-(azidomethyl)-2-oxo-3-oxazolidinyl]-2,-
6-difluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl
ester ((EXAMPLE 35, Step 6, 1.51 g) and 10% palladium on carbon
(367 mg) in methanol (35 mL) is stirred under a hydrogen atmosphere
(balloon) for 18 hours, the catalyst is removed by filtration
through Celite and the filtrate is concentrated under reduced
pressure to give the 5-aminomethyl-2-oxazolidinone intermediate
(R.sub.f 0.10 by TLC, methanol/chloroform, 5/95). A solution of
this intermediate (1.28 g) and pyridine (2.51 mL) in dry methylene
chloride (31 mL) at 0.degree. C. under N.sub.2 is treated with
acetic anhydride (1.47 mL), and the resulting solution is allowed
to warm to ambient temperature with stirring over 1.5 hours. The
mixture is then diluted with methylene chloride (15 mL), washed
with water (10 mL), saturated aqueous sodium bicarbonate
(2.times.10 mL) and saline (10 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the crude
product which is chromatographed on silica gel (70-230 mesh, 150
g), eluting with a gradient of methanol/methylene chloride
(1/99-4/96). Pooling and concentration of those fractions with an
R.sub.f=0.31 by TLC (methanol/chloroform, 5/95), trituration with
diethyl ether and filtration gives the title compound, NMR
(CDCl.sub.3, 400 MHz) 7.06, 6.56, 4.78, 4.22, 4.00, 3.74, 3.65,
3.05, 2.75, 2.02, 1.96, 1.64, 1.47 .delta..
[0282] Step 8:
(S)-(-)-N-[[2-Oxo-3-[4-(4-piperidinyl)-3,5-difluorophenyl]--
5-oxazolidinyl]methyl]acetamide
[0283] A mixture of
(S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolid-
inyl]-2,6-difluorophenyl]-1-piperidinecarboxylic acid phenylmethyl
ester ((EXAMPLE 35, Step 7, 847 mg) and trifluoroacetic acid (12
mL) maintained at 0.degree. C. under N.sub.2 is stirred for two
hours and then concentrated under reduced pressure to remove excess
trifluoroacetic acid. The residue is diluted with saturated aqueous
potassium carbonate (70 mL) and methylene chloride (50 mL), and the
layers are separated. The aqueous phase is extracted with methylene
chloride (2.times.50 mL), and the combined organic phase is dried
over anhydrous sodium sulfate, concentrated-under reduced pressure,
triturated with diethyl ether and recrystallized from ethyl acetate
to give the title compound, NMR (CDCl.sub.3, 400 MHz) 7.08, 6.10,
4.78, 4.00, 3.74, 3.64, 3.19, 3.07, 2.72, 2.03, 1.99, 1.68
.delta..
EXAMPLE 36
(S)-(-)-N-[[3-[4-[1-[(Benzyloxy)acetyl]-4-piperidinyl]-3,5-difluorophenyl]-
-2-oxo-5-oxazolidinyl]methyl]acetamide
[0284] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(4-piperi-
dinyl)-3,5-difluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE
35) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]a-
cetamide, the title compound is obtained, mp 169.degree.
C.-171.degree. C.
EXAMPLE 37
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-4-piperidinyl]-3,5-difluorophenyl]-2-o-
xo-5-oxazolidinyl]methyl]acetamide
[0285] A mixture of
(S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-
-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE
36, 207 mg) and 10% palladium-on-carbon (100 mg) in methanol (9 mL)
is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi
for 20 hours, the catalyst is removed by filtration through Celite
and the filtrate is concentrated under reduced pressure to give the
crude product which is chromatographed on silica gel (230-400 mesh,
20 g), eluting with a gradient of methanol/methylene chloride
(5/95-10/90). Pooling and concentration of those fractions with an
R.sub.f=0.26 by TLC (methanol/chloroform, 10/90) and
recrystallization from methylene chloride/diethyl ether gives the
title compound, NMR (CDCl.sub.3, 400 MHz) 7.07, 6.80, 4.78, 4.69,
4.18, 3.99, 3.74, 3.63, 3.60, 3.16, 3.06, 2.90, 2.72, 2.00, 1.97,
1.75 .delta..
EXAMPLE 38
(S)-(-)-N-[[2-Oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxa-
zolidinyl]methyl]acetamide
[0286] Step 1:
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-
-2-fluorophenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid
1,1-dimethylethyl ester
[0287] A mixture of
(S)-(-)-N-[[3-[4-trimethylstannyl-3-fluorophenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide (690 mg),
3,6-dihydro-4-[[(trifluorometh-
yl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl
ester (step 2 of EXAMPLE 20, 500 mg),
tris(dibenzylideneacetone)dipalladium(0) (14 mg) and
triphenylarsine (37 mg) in N-methyl-2-pyrrolidinone (7.5 mL) is
degassed, stirred under N.sub.2 at ambient temperature for 4.5
days, diluted with ethyl acetate, washed with water (3.times.40 mL)
and saline (20 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue is chromatographed
on silica gel (230-400 mesh, 120 g), eluting with a gradient of
methanol/methylene chloride (1/99-2/98), and those fraction having
an R.sub.f=0.27 by TLC (methanol/chloroform, 2.times.5/95) are
pooled and concentrated to give the title compound, .sup.1H NMR
(CDCl.sub.3, 400 MHz) 7.39, 7.22, 7.13, 7.01, 5.92, 4.82, 4.06,
3.80, 3.67, 3.61, 2.47, 2.03, 1.49 .delta..
[0288] Step 2:
(S)-(-)-N-[[2-Oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)-3-fluo-
rophenyl]-5-oxazolidinyl]methyl]acetamide
[0289] A solution of
(S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazoli-
dinyl]-2-fluorophenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 38, Step 1, 1.00 g) in dry
methylene chloride (9.2 mL) at 0.degree. C. under N.sub.2 is
treated with trifluoroacetic acid (2.3 mL) over one minute, and the
resulting mixture is stirred at 0.degree. C. for three hours and
added slowly to saturated aqueous potassium carbonate (30 mL) to
neutralize excess trifluoroacetic acid. The resultant slurry is
filtered and the precipitate is chromatographed on silica gel
(70-230 mesh, 60 g), eluting with ammonium
hydroxide/methanol/methylene chloride (0.25/19.75/80). Those
fractions with an R.sub.f=0.08 by TLC (methanol/chloroform, 20/80)
are pooled and concentrated under reduced pressure to give the
title compound, .sup.1H NMR (MeOH-d.sub.4, 400 MHz) 7.41, 7.33,
7.25, 6.02, 4.80, 4.15, 3.83, 3.58, 3.47, 3.04, 2.46, 1.98
.delta..
EXAMPLE 39
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3;6-dihydro-2H-pyridi-
n-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0290] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 38) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolid-
inyl]methyl]acetamide and acetoxyacetyl chloride for
benzyloxyacetyl chloride, the title compound is obtained, mp
188-191.degree. C.
EXAMPLE 40
(S)-(-1-N-[[3-[4-[1-(Hydroxyacetyl)-3,6-dihydro-2H-pyridin-4-yl]-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0291] A mixture of
(S)-(-)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3-
,6-dihydro-2H-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 39, 475 mg), and anhydrous potassium carbonate (303 mg) in
methanol (44 mL) is stirred under N.sub.2 at ambient temperature
for 1.5 hours and then adjusted to pH 7 with aqueous hydrochloric
acid (1M) and concentrated under reduced pressure. The residue is
chromatographed on silica gel (230-400 mesh, 40 g), eluting with a
gradient of methanol/chloroform (5/95-10/90), and those fractions
with an R.sub.f=0.21 by TLC (methanol/chloroform, 10/90) are pooled
and concentrated under reduced pressure. The resulting foam is then
triturated with methylene chloride/diethyl ether and the
precipitate filtered to give the title compound, Anal. calcd for
C.sub.19H.sub.22N.sub.3O.sub.5F: C, 58.31; H, 5.67; N, 10.74.
Found: C, 58.15; H, 5.64; N, 10.72.
EXAMPLE 41
(5S)-N-[[3-[3-Fluoro-4-[1-(phenylmethyl)-3-pyrrolidinyl]phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide
[0292] Step 1:
(S)-(-)-N-[[3-[4-Ethenyl-3-fluorophenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide
[0293] A mixture of
(S)-(-)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and
bis(triphenylphosphine)palladium(II) chloride (303 mg) in
1,4-dioxane (72 mL) under N.sub.2 is degassed, heated up to reflux,
refluxed for seven hours, cooled to ambient temperature and stirred
for 12 hours. The mixture is then diluted with ethyl acetate (40
mL) and water (50 mL) and the layers are separated. The aqueous
phase is extracted with ethyl acetate (2.times.30 mL), and the
combined organic phase is washed with saline (40 mL), dried over
anhydrous magnesium sulfate, concentrated under reduced pressure
and triturated with diethyl ether. The resultant precipitate is
filtered to give the title compound, mp 165-166.degree. C.
[0294] Step 2:
(5S)-N-[[3-[3-Fluoro-4-[f-(phenylmethyl)-3-pyrrolidinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0295] A solution of
(S)-(-)-N-[[3-[4-vinyl-3-fluorophenyl]-2-oxo-5-oxazol-
idinyl]methyl]acetamide (EXAMPLE 41, Step 1, 3.50 g) and
trifluoroacetic acid (0.23 mL) in dry methylene chloride under
N.sub.2 is treated with a solution of N-benzyl-N-(methoxymethyl)
trimethylsilylmethylamine (6.10 g) in dry methylene chloride (50
mL) dropwise over 4.5 hours, and the resulting solution was stirred
at ambient temperature for 17 hours. The reaction mixture is then
washed with saturated aqueous sodium bicarbonate (30 mL), water (30
mL) and saline (30 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give a residue which is
chromatographed on silica gel (230-400 mesh, 350 g), eluting with a
gradient of methanol/methylene chloride (1/99-10/90). Pooling and
concentration of those fractions with an R.sub.f=0.19 by TLC
(methanol/chloroform, 10/90) and trituration with methanol/diethyl
ether gives the title compound, NMR (CDCl.sub.3, 400 MHz) 7.35,
7.25, 7.13, 6.08, 4.78, 4.03, 3.76, 3.69, 3.62, 2.97, 2.78, 2.56,
2.33, 2.02, 1.85 .delta..
EXAMPLE 42
(5S)-N-[[3-[3-Fluoro-4-(3-pyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl-
]acetamide
[0296] A mixture of
(5S)-N-[[3-[3-fluoro-4-[1-(phenylmethyl)-3-pyrrolidiny-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 41, 1.09
g) and 20% palladium hydroxide on carbon (545 mg) in methanol (30
mL) is shaken on the Parr apparatus under a hydrogen atmosphere at
40 psi for 1.5 hours and at 10 psi for 18 hours. The catalyst is
then removed by filtration through Celite, and the filtrate is
concentrated under reduced pressure to give the title compound, NMR
(CDCl.sub.3, 400 MHz) 7.39, 7.24, 7.11, 6.35, 4.78, 4.04, 3.77,
3.67, 3.44, 3.37, 3.18, 3.11, 2.88, 2.21 2.02, 1.86 .delta..
EXAMPLE 43
(5S)-N-[[3-[3-Fluoro-4-[1-[(benzyloxy)acetyl]-3-pyrrolidinyl]phenyl]-2-oxo-
-5-oxazolidinyl]methyl]acetamide
[0297] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(5S)-N-[[3-[3-fluoro-4-(3-pyrrol-
idinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 42)
for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]aceta-
mide, the title compound is obtained,
[0298] HRMS calculated for C.sub.25H.sub.28N.sub.3O.sub.5F:
470.2091. Found: 470.2106.
EXAMPLE 44
(5S)-N-[[3-[3-Fluoro-4-[1-(hydroxyacetyl)-3-pyrrolidinyl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide
[0299] Following the general procedure of EXAMPLE 22, and making
non-critical variations but substituting
(5S)-N-[[3-[3-fluoro-4-[1-[(benz-
yloxy)acetyl]-3-pyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 43) for
(S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-3-
-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, the title
compound is obtained, FAB-HRMS calculated for
C.sub.18H.sub.22N.sub.3O.sub.5F+H: 380.1622. Found: 380.1625.
EXAMPLE 45
(5S)-N-[[3-[3-Fluoro-4-[1-(formyl)-3-pyrrolidinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]acetamide
[0300] Following the general procedure of EXAMPLE 29, and making
non-critical variations but substituting
(5S)-N-[[3-[3-fluoro-4-(3-pyrrol-
idinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 44)
for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]met-
hyl]acetamide, the title compound is obtained, HRMS calculated for
C.sub.17H.sub.20FN.sub.3O.sub.4: 349.1438: Found: 349.1444.
EXAMPLE 46
(5S)-3-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2;
fluorophenyl]-1-pyrrolidinecarboxylic acid methyl ester
[0301] Following the general procedure of EXAMPLE 26, and making
non-critical variations but substituting
(5S)-N-[[3-[3-fluoro-4-(3-pyrrol-
idinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 44)
for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]met-
hyl]acetamide, the title compound is obtained, HRMS calculated for
C.sub.18H.sub.22FN.sub.3O.sub.5: 379.1543. Found: 379.1546.
EXAMPLE 47
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazo-
lidinyl]methyl]acetamide
[0302] Step 1: 3,6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonic
acid ester
[0303] Following the general procedure of Step 2 of EXAMPLE 20, and
making non-critical variations but substituting
tetrahydropyran-4-one for
1-(1,1-dimethylethoxycarbonyl)-4-piperidone, the title compound is
obtained, .sup.1H NMR (CDCl.sub.3, 400 MHz) 5.82, 4.27, 3.90, 2.47
.delta..
[0304] Step 2:
3-Fluoro-4-(3,6-dihydro-2H-pyran-4-yl)benzenamine
[0305] Following the general procedure of Step 3 of EXAMPLE 20, and
making non-critical variations but substituting
3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonic acid ester
(EXAMPLE 47, Step 1) for
3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic
acid 1,1-dimethylethyl ester, the title compound is obtained, mp
86.degree. C.-88.degree. C.
[0306] Step 3:
3-Fluoro-4-(3,6-dihydro-2H-pyran-4-yl)benzenaminecarboxylic acid
phenylmethyl ester
[0307] A mixture of
3-fluoro-4-(3,6-dihydro-2H-pyran-4-yl)benzenamine (EXAMPLE 47, Step
2, 2.28 g) and sodium bicarbonate (1.98 g) in tetrahydrofuran (59
mL) is treated with benzyl chloroformate (1.85 mL), and the
resulting slurry is stirred at ambient temperature for six hours.
The mixture is then washed with water (50 mL), the aqueous phase is
extracted with methylene chloride (50 mL), and the combined organic
phase is washed with saline (25 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue is
then chromatographed on silica gel (70-230 mesh, 80 g), eluting
with ethyl acetate/hexane (15/85), and those fractions with an
R.sub.f=0.45 by TLC (ethyl acetate/hexane, 25/75) are pooled and
concentrated to give the title compound, mp 75-76.degree. C.
[0308] Step 4:
(R)-(-)-3-[3-Fluoro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-5--
hydroxymethyl-2-oxazolidinone
[0309] Following the general procedure of Step 3 of EXAMPLE 17, and
making non-s critical variations but substituting
3-fluoro-4-(3,6-dihydro-2H-pyr- an-4-yl)benzenaminecarboxylic acid
phenylmethyl ester (EXAMPLE 47, Step 3) for
3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridi-
necarboxylic acid phenylmethyl ester, the title compound is
obtained, mp 127-130.degree. C.
[0310] Step 5:
(R)-(-)-3-[3-Fluoro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-5--
[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
[0311] Following the general procedure of Step 4 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[3-fluoro-4-(3,6-dihyd-
ro-2H-pyran-4-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone (EXAMPLE
47, Step 4) for
(R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]p-
henyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester, the title
compound is obtained, mp 166-169.degree. C. (decomp.).
[0312] Step 6:
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-pyran-4-yl)-3-fluorophenyl-
]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0313] Following the general procedure of Step 5 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[3-fluoro-4-(3,6-dihyd-
ro-2H-pyran-4-yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
(EXAMPLE 47, Step 5) for
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)ox-
y]methyl]-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester, the title compound is obtained, mp
148-151.degree. C.
EXAMPLE 48
(S)-(-)-N-[[3-[4-[Tetrahydro-2H-pyran-4-yl]-3-fluorophenyl]-2-oxo-5-oxazol-
idinyl]methyl]acetamide
[0314] A mixture of
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 47, 1.00 g)
and 10% palladium-on-carbon (637 mg) in methanol (60 mL) is shaken
on a Parr apparatus under a hydrogen atmosphere at 40 psi for three
hours, the catalyst is removed by filtration through Celite and the
filtrate is concentrated under reduced pressure to give the title
compound, mp 191-192.degree. C.
EXAMPLE 49
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide
[0315] Step 1: 3,6-Dihydro-2H-thiopyran-4-yl
trifluoromethanesulfonic acid ester
[0316] Following the general procedure of Step 2 of EXAMPLE 20, and
making non-critical variations but substituting
tetrahydrothiopyran-4-one for
1-(1,1-dimethylethoxycarbonyl)-4-piperidone, the title compound is
obtained, NMR (CDCl.sub.3, 400 MHz) 6.01, 3.30, 2.86, 2.62
.delta..
[0317] Step 2:
3-Fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)benzenamine
[0318] Following the general procedure of Step 3 of EXAMPLE 20, and
making non-critical variations but substituting
3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonic acid ester
(EXAMPLE 49, Step 1) for
3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic
acid 1,1-dimethylethyl ester, the title compound is obtained, NMR
(CDCl.sub.3, 400 MHz) 6.98, 6.40, 6.35, 5.94, 3.73, 3.31, 2.84,
2.62 .delta..
[0319] Step 3:
3-Fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)benzenaminecarbox- ylic
acid phenylmethyl ester
[0320] Following the general procedure of Step 3 of EXAMPLE 47, and
making non-critical variations but substituting
3-fluoro-4-(3,6-dihydro-2H-thiop- yran-4-yl)benzenamine (EXAMPLE
49, Step 2) for 3-fluoro-4-(3,6-dihydro-2H--
pyran-4-yl)benzenamine, the title compound is obtained, mp
99-100.degree. C.
[0321] Step 4:
(R)-(-)-3-[3-Fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl-
]-5-hydroxymethyl-2-oxazolidinone
[0322] Following the general procedure of Step 3 of EXAMPLE 17, and
making non-critical variations but substituting
3-fluoro-4-(3,6-dihydro-2H-thiop- yran-4-yl)benzenaminecarboxylic
acid phenylmethyl ester (EXAMPLE 49, Step 3) for
3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyr-
idinecarboxylic acid phenylmethyl ester, the title compound is
obtained, mp 119-122.degree. C.
[0323] Step 5:
(R)-(-)-3-[3-Fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl-
]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
[0324] Following the general procedure of Step 4 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[3-fluoro-4-(3,6-dihyd-
ro-2H-thiopyran-4-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone
(EXAMPLE 49, Step 4) for
(R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidi-
nyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester, the
title compound is obtained, mp 138-141.degree. C.
[0325] Step 6:
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluoroph-
enyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0326] Following the general procedure of Step 5 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[3-fluoro-4-(3,6-dihyd-
ro-2H-thiopyran-4-yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidino-
ne (EXAMPLE 49, Step 5) for
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)-
oxy]methyl]-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester, the title compound is obtained, mp
187-189.degree. C.
EXAMPLE 50
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide S,S-dioxide
[0327] A solution of
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fl-
uorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 49, 300
mg) in water/acetone (25%, 17 mL) is treated with
N-methylmorpholine N-oxide (301 mg) followed by osmium tetroxide
(2.5 wt % in t-butanol, 0.54 mL), and the resulting mixture is
stirred at ambient temperature overnight. The mixture is then
quenched with saturated aqueous sodium bisulfite (10 mL) and
extracted with methylene chloride (2.times.20 mL). The combined
organic phase is washed with saline (10 mL), dried over sodium
sulfate and concentrated under reduced pressure to give the crude
product which is then chromatographed on silica gel (70-230 mesh,
30 g), eluting with a gradient of methanol/methylene chloride
(3/97-5/95). Pooling of fractions with an R.sub.f=0.49 by TLC
(methanol/chloroform, 10/90) and trituration with methylene
chloride/diethyl ether gives the title compound, mp 181-182.degree.
C.
EXAMPLE 51
(S)-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide S,S-dioxide
[0328] Following the general procedure of EXAMPLE 48, and making
non-critical variations but substituting
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-
-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
S,S-dioxide (EXAMPLE 50) for
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-pyran-4-yl)-
-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
recrystallizing the product from methylene chloride/diethyl ether,
the title compound is obtained, mp 199-200.degree. C.
EXAMPLE 52
(S)-(-)-N-[13-[4-(3,6-Dihydro-2H-pyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]acetamide
[0329] Step 1:
4-[4-(Hydoxy)tetrahydro-2H-pyran-4-yl]benzenaminecarboxylic acid
phenylmethyl ester
[0330] Following the general procedure of Step 1 of EXAMPLE 17, and
making non-critical variations but substituting
tetrahydropyran-4-one for N-(carbobenzyloxy)-4-piperidone, the
title compound is obtained, mp 143-145.degree. C.
[0331] Step 2: 4-(3,6-Dihydro-2H-pyran-4-yl)benzenaminecarboxylic
acid phenylmethyl ester
[0332] Following the general procedure of Step 2 of EXAMPLE 17, and
making non-critical variations but substituting
4-[4-(hydroxy)tetrahydro-2H-pyra- n-4-yl]benzenaminecarboxylic acid
phenylmethyl ester (EXAMPLE 52, Step 1) for
4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-piperidineca-
rboxylic acid phenylmethyl ester and recrystallizing the crude
product from ethyl acetate/hexane, the title compound is obtained,
mp 145-148 C.degree..
[0333] Step 3:
(R)-(-)-3-[4-(3,6-Dihydro-2H-pyran-4-yl)phenyl]-5-hydroxyme-
thyl-2-oxazolidinone
[0334] Following the general procedure of Step 3 of EXAMPLE 17, and
making non-critical variations but substituting
4-(3,6-dihydro-2H-pyran-4-yl)ben- zenaminecarboxylic acid
phenylmethyl ester (EXAMPLE 52, Step 2) for
3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridineca-
rboxylic acid phenylmethyl ester and triturating the crude product
with ethyl acetate/hexane (50/50), the title compound is obtained,
Anal. Calcd for C.sub.15H.sub.17NO.sub.4: C: 65.44; H, 6.22; N,
5.09. Found: C: 65.05; H, 6.04; N, 4.91.
[0335] Step 4:
(R)-(-)-3-[4-(3,6-Dihydro-2H-pyran-4-yl)phenyl]-5-[[(methyl-
sulfonyl)oxymethyl]-2-oxazolidinone
[0336] Following the general procedure of Step 4 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[4-(3,6-dihydro-2H-pyr-
an-4-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone (EXAMPLE 52, Step
3) for
(R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]--
1(2H)-pyridinecarboxylic acid phenylmethyl ester, the title
compound is obtained, mp 182-184.degree. C.
[0337] Step 5:
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-pyran-4-yl)phenyl]-2-oxo-5-
-oxazolidinyl]methyl]acetamide
[0338] Following the general procedure of Step 5 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[4-(3,6-dihydro-2H-pyr-
an-4-yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
(EXAMPLE 52, Step 4) for
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-
-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester, the title compound is obtained, NMR
(CDCl.sub.3, 400 MHz) 7.45, 7.36, 6.63, 6.09, 4.77, 4.31, 4.05,
3.92, 3.80, 3.65, 2.48, 2.01 .delta..
EXAMPLE 53
(S)-(-)-N-[[3-[4-[Tetrahydro-2H-pyran-4-yl]phenyl-2-oxo-5-oxazolidinyl]met-
hyl]acetamide
[0339] Following the general procedure of EXAMPLE 48, and making
non-critical variations but substituting
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-
-pyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE
52) for
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxaz-
olidinyl]methyl]acetamide, the title compound is obtained, mp
185.degree. C.-187.degree. C.
EXAMPLE 54
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide
[0340] Step 1:
4-[4-(Hydroxy)tetrahydro-2H-thiopyran-4-yl]benzenaminecarbo- xylic
acid phenylmethyl ester
[0341] Following the general procedure of Step 1 of EXAMPLE 17, and
making non-critical variations but substituting
tetrahydrothiopyran-4-one for N-(carbobenzyloxy)-4-piperidone and
recrystallizing the product from ethyl acetate/hexane, the title
compound is obtained, mp 152-154.degree. C.
[0342] Step 2:
4-(3,6-Dihydro-2H-thiopyran-4-yl)benzenaminecarboxylic acid
phenylmethyl ester
[0343] Following the general procedure of Step 2 of EXAMPLE 17, and
making non-critical variations but substituting
4-[4-(hydroxy)tetrahydrothiopyra- n-4-yl]benzenaminecarboxylic acid
phenylmethyl ester (EXAMPLE 54, Step 1) for
4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-piperidineca-
rboxylic acid phenylmethyl ester and triturating the crude product
with diethyl ether or recrystallizing from ethyl acetate/hexane,
the title compound is obtained, mp 150-152.degree. C.
[0344] Step 3:
(R)-(-)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-5-hydro-
xymethyl-2-oxazolidinone
[0345] Following the general procedure of Step 3 of EXAMPLE 17, and
making non-critical variations but substituting
4-(3,6-dihydro-2H-thiopyran-4-yl- )benzenaminecarboxylic acid
phenylmethyl ester (EXAMPLE 54, Step 2) for
3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridineca-
rboxylic acid phenylmethyl ester and triturating the crude product
with methanol/methylene chloride, the title compound is obtained,
mp 182-184.degree. C. (decomp.).
[0346] Step 4:
(R)-(-)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-5-[(met-
hylsulfonyl)oxy]methyl]-2-oxazolidinone
[0347] Following the general procedure of Step 4 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[4-(3,6-dihydro-2H-thi-
opyran-4-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone (EXAMPLE 54,
Step 3) for
(R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phen-
yl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester and
triturating the crude product with methylene chloride/diethyl ether
(25/75), the title compound is obtained, mp 171-174.degree. C.
(decomp.).
[0348] Step 5:
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-o-
xo-5-oxazolidinyl]methyl]acetamide
[0349] Following the general procedure of Step 5 of EXAMPLE 17, and
making non-critical variations but substituting
(R)-(-)-3-[4-(3,6-dihydro-2H-thi-
opyran-4-yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
(EXAMPLE 54, Step 4) for
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)ox-
y]methyl]-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester and acetonitrile for isopropanol, the title
compound is obtained, mp 169.degree. C.-173.degree. C.
(decomp.).
EXAMPLE 55
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide S,S-dioxide
[0350] Following the general procedure of EXAMPLE 50, and making
non-critical variations but substituting
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-
-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 54) for
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide and triturating the product with
ethyl acetate/methylene chloride, the title compound is obtained,
mp 185-187.degree. C.
EXAMPLE 56
(S)-(-)-N-[[3-[4-[1-(Formyl)-3,6-dihydro-2H-pyridin-4-yl]-3-fluorophenyl]--
2-oxo-5-oxazolidinyl]methyl]acetamide
[0351] Following the general procedure of EXAMPLE 29, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 38) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-
-oxazolidinyl]methyl]acetamide, the title compound is obtained, mp
148-151.degree. C.
EXAMPLE 57
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl-
]-3,6-dihydro-1(2H)-pyridinecarboxylic acid methyl ester
[0352] Following the general procedure of EXAMPLE 26, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 38) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-
-oxazolidinyl]methyl]acetamide, the title compound is obtained, NMR
(CDCl.sub.3, 400 MHz) 7.35, 7.18, 7.10, 6.85, 5.89, 4.78, 4.08,
4.02, 3.78, 3.71, 3.64, 2.45, 2.00 .delta..
EXAMPLE 58
(S)-(-)-N-[[2-Oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl-
]methyl]acetamide
[0353] Step 1:
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-
phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl
ester
[0354] Following the general procedure of step 1 of EXAMPLE 38, and
making non-critical variations but substituting
(S)-(-)-N-[[3-[4-(trimethylstann-
yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide for
(S)-(-)-N-[[3-[4-(trimethylstannyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]-
methyl]acetamide, the title compound is obtained, NMR (CDCl.sub.3,
400 MHz) 7.45, 7.35, 6.55, 6.00, 4.77, 4.05, 3.80, 3.63, 2.49,
2.01, 1.48 .delta..
[0355] Step 2:
(S)-(-)-N-[[2-Oxo-3-[4-(3,6-dihydro-2H-pyridin-4-yl)phenyl]-
-5-oxazolidinyl]methyl]acetamide
[0356] A solution of
(S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazoli-
dinyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 58, step 1, 0.92 g) in dry
methylene chloride (8.8 mL) at 0.degree. C. under N.sub.2 is
treated with trifluoroacetic acid (2.2 mL) over one minute, and the
resulting mixture is stirred at 0.degree. C. for four hours and
added slowly to saturated aqueous potassium carbonate (30 mL) at
0.degree. C. to neutralize excess trifluoroacetic acid. The mixture
is then diluted with water (50 mL) and saline (50 mL), extracted
with methanol/methylene chloride (3.times.150 mL, 25/75), and the
combined organic phase is dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound, mp
164-166.degree. C. (decomp.).
EXAMPLE 59
(S)-(-)-N-[[2-Oxo-3-[4-[1-[(acetoxy)acetyl]-3,6-dihydro-2H-pyridin-4-yl]ph-
enyl]-5-oxazolidinyl]methyl]acetamide
[0357] Following the general procedure of EXAMPLE 18, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 58) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]a-
cetamide and acetoxyacetyl chloride for benzyloxyacetyl chloride,
the title compound is obtained, HRMS calcd for
C.sub.21H.sub.25N.sub.3O.sub.6- : 415.1743. Found: 415.1752.
EXAMPLE 60
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide
[0358] Following the general procedure of EXAMPLE 40, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-[1-[(acet-
oxy)acetyl]-3,6-dihydro-2H-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acet-
amide (EXAMPLE 59) for
(S)-(-)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl-
]-3,6-dihydro-2H-pyridin-4-yl]phenyl]-oxazolidinyl]methyl]acetamide,
the title compound is obtained, HRMS (FAB) calcd for
C.sub.19H.sub.23N.sub.3O- .sub.5+H: 374.1716. Found: 374.1713.
EXAMPLE 61
(S)-(-)-N-[[3-[4-[1-(Formyl)-3,6-dihydro-2H-pyridin-4-yl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide
[0359] Following the general procedure of EXAMPLE 29, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 58) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl-
]methyl]acetamide, the title compound is obtained, mp
149-152.degree. C.
EXAMPLE 62
(S)-(-)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-3,6-dih-
ydro-1(2H)-pyridinecarboxylic acid methyl ester
[0360] Following the general procedure of EXAMPLE 26, and making
non-critical, variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dih-
ydro-0.2H-pyridin-4-yl)phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 58) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolid-
inyl]methyl]acetamide, the title compound is obtained, mp
142-145.degree. C.
EXAMPLE 63
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide S-oxide
[0361] A solution of sodium periodate (192 mg) in water at
0.degree. C. is treated with a slurry of
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-
-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 49,
300 mg) in methanol (10 mL), and the resulting mixture is allowed
to slowly warm to ambient temperature over approximately one hour
and is stirred overnight. The mixture is then concentrated to
remove methanol, diluted with water (20 mL) and extracted with
methanol/chloroform (3.times.30 mL, 5/95). The combined organic
phase is washed with saline (20 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the crude
product which is then chromatographed on silica gel (30 g, 70-230
mesh), eluting with methanol/methylene chloride (5/95). Those
fractions an R.sub.f=0.39 by TLC (methanol/chloroform, 10/90) were
pooled and concentrated and the residue was recrystallized from
methylene chloride/diethyl ether to give the title compound, mp
150-151.degree. C.
EXAMPLE 64
(S)-(-)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidin-
yl]methyl]acetamide S-oxide
[0362] Following the general procedure of EXAMPLE 63, and making
non-critical variations but substituting
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-
-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 54) for
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-ox-
o-5-oxazolidinyl]methyl]acetamide, the title compound is obtained,
mp 158-162.degree. C. (decomp.).
EXAMPLE 65
(S)-(-)-N-[[3-[4-(Tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidiny-
l]methyl]acetamide S,S-dioxide
[0363] A mixture of
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl-
]-2-oxo-5-oxazolidinyl]methyl]acetamide S,S-dioxide (EXAMPLE 55, 75
mg) and 10% palladium-on-carbon (44 mg) in tetrahydrofuran (20 mL)
is stirred under a hydrogen atmosphere (balloon) for one hour, the
catalyst is removed by filtration through Celite, the filtrate is
concentrated under reduced pressure and the residue is
recrystallized from methylene chloride/diethyl ether to give the
title compound, mp 190-192.degree. C. (decomp.).
EXAMPLE 66
3-(4-amino-2-fluorophenyl)pyrrolidine
[0364] Step 1: 2-(2-fluoro-4-nitrophenyl)-dimethylmalonate
[0365] A flame-dried 500 mL round bottom flask equipped with
spinbar and addition funnel was charged with sodium hydride (4.0 g,
0.10 mol). This oil dispersion was washed three times with pentane
(30 mL), dried under house vacuum, diluted with 50 mL of freshly
distilled tetrahydrofuran, and cooled to 0.degree. C. The grey
suspension was drop-wise treated with a 100 mL THF solution of
dimethylmalonate (5.7 mL, 50 mmol) with copious gas evolution. The
resulting thick suspension was treated with a 100 mL THF solution
of 3,4-difluoronitrobenzene, quickly turning golden in color and
was warmed to 50.degree. C. for 16 hours. At this time, the deep
red wine homogenous solution was cooled to RT, quenched with 300 mL
1M hydrochloric acid, and volatiles removed in vacuo. The resulting
aqueous acidic residue was extracted three time with ethyl acetate
(200 mL) with the combined organics washed once with brine (200
mL), dried over Mg SO.sub.4, filtered and concentrated to give
13.58 g of a brown solid. This material was triturated with a
mixture of ethyl acetate/hexane/dichloromethane to afford 7.60 g of
the title compound as a light yellow solid. The filtrate was
concentrated and purified by Prep 500 HPLC on a single silica gel
cartridge eluting with 25% ethyl acetate/hexane to afford and
additional 3.95 g of the title compound. Total yield 10.60 g (78%),
mp 108-109. mp 108-109.degree. C.; R.sub.f 0.38 (25% ethyl
acetate/hexane); IR (mull) 1744, 1736, 1532, 1438, 1357, 1345,
1273, 1243, 1232, 812 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.09 (dt, 1H, J=2.2 & J=7.8 Hz, aromatic), 7.99 (ddd,
1H, J=2.3 & 9.4 Hz, aromatic), 7.74 (dd, 1H, J=7.1 & J=8.6
Hz, aromatic), 5.08 (s, 1H, methine), 3.81 (s, 6H, methyls); Anal.
Calcd for C.sub.11H.sub.10N.sub.1O.sub.6F.sub.1: C, 48.74; H, 3.72;
N, 5.17. Found: C, 48.74; H, 3.84; N, 5.14.
[0366] Step 2:
2-(2-fluoro-4-nitrophenyl)-2-(cyanomethyl)-dimethylmalonate
[0367] An oven-dried 100 mL round bottom flask equipped with
spinbar and reflux condenser was charged with
2-(2-fluoro-4-nitrophenyl)-dimethylmalo- nate (EXAMPLE 66, Step 1,
3.25 g, 12.0 mmol) and 60 mL acetone. This yellow homogenous
solution was treated with a single portion of powdered potassium
carbonate (4.98 g, 36 mmol) instantly turning red in color. This
suspension was added to by bromoacetonitrile (1.3 mL, 18 mmol) and
heated to reflux for 16 hours. At this time, the now brown
suspension was cooled to RT, diluted with 100 mL 1M hydrochloric
acid, and extracted twice with ethyl acetate (150 mL). The combined
organics were washed once with brine (100 mL), dried over
MgSO.sub.4, filtered, and concentrated to give 4.10 g of a crude
brown foam. This material was purified by Prep 500 HPLC on a single
silica gel cartridge eluting with 30% ethyl acetate/hexane to
afford 3.60 g of an off-white solid. This material was
recrystallized from ethyl acetate/hexanes to give 3.14 g (84%) of
the title compound as white needles. mp 137-138.degree. C.; R.sub.f
0.26 (30% ethyl acetate/hexanes); IR (mull) 1749, 1730, 1527, 1355,
1290, 1276, 1262, 1234, 812, 739 cm.sup.-1; .sup.1H NMR (300 MHz,
CDCl.sub.3) 8.12 (ddd, 1H, J.sub.HF=00.8, J=2.2, J=8.6 Hz,
aromatic), 8.01 (dd, 1H, J=2.3 & 10.8 Hz, aromatic), 7.48 (dd,
1H, J=7.5 & J=8.7 Hz, aromatic), 3.92 (s, 6H, methyls), 3.34
(s, 2H, methine); .sup.31C NMR (75 MHz, CDCl.sub.3) 166.5, 159.5
(J.sub.CF=253 Hz), 148.7, 130.2 (J.sub.CF=3 Hz), 129.9 (J.sub.CF=13
Hz), 119.4 (J.sub.CF=3 Hz), 11.9 (J.sub.CF=28 Hz), 58.0, 54.1,
24.2; Anal. Calcd for C.sub.13H.sub.11N.sub.2O.sub.6F.sub.1: C,
50.33; H, 3.57; N, 9.03. Found: C, 50.23; H, 3.73; N, 9.06.
[0368] Step 3:
2-(4-amino-2-fluorophenyl)-2-carbomethoxypyrrolidinone.
[0369] A 500 mL Parr flask was charged with a solution of
2-(2-fluoro-4-nitrophenyl)-2-(cyanomethyl)-dimethylmalonate
(EXAMPLE 66, Step 2, 1.236 g, 4.0 mmol) in 100 mL methanol and 1.17
g 10% palladium on carbon. The black suspension was placed under 40
psi hydrogen with shaking for 64 hours. The Parr was removed from
the hydrogentaor, the reaction mixture was filtered through a pad
of CELITE and concentrated to afford 1.02 g of a white foam. This
material was purified by LC on 70 g (230-400) silica gel eluting
with ethyl acetate to afford 824 mg (82%) of the compound as a
white amorphous solid. R.sub.f 0.20 (75% ethyl acetate/hexanes); IR
(mull) 3359, 3233, 1738, 1695, 1694, 1634, 1515, 1254, 1276, 1128,
cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.15 (t, 1H,
J=9.0 Hz, aromatic), 6.58 (bs, 1H, O.dbd.C--NH), 6.41 (m, 2H,
aromatic), 3.80 (bs, 2H, NH.sub.2), 3.77 (s, 3H, CH.sub.3), 3.49
(m, 1H, N--CH.sub.2A), 3.25 (m, 2H, C--CH.sub.2s), 2.28 (m, 1H,
N--CH.sub.2B); .sup.13C NMR (75 MHz, CDCl.sub.3) 173.6, 170.9,
161.4 (J.sub.CF=245 Hz), 147.7 (J.sub.CF=11 Hz), 128.9 (J.sub.CF=5
Hz), 115.7 (J.sub.CF=14 Hz), 110.2, 102.5, (J.sub.CF=25 Hz), 56.9,
53.2, 39.4, 34.3; K.F. Water=0.87%; Anal. Calcd for
C.sub.12H.sub.13N.sub.2O.sub.3F, with 0.87% water: C, 56.64; H,
5.25; N, 11.01. Found: C, 56.78; H, 5.34; N, 11.01. HRMS Calcd for
C.sub.12H.sub.13N.sub.2O.sub.3F.sub.1: 252.0910. Found:
252.0902.
[0370] Step 4:
2-(4-amino-2-fluorophenyl)-2-carbomethoxypyrrolidinone
[0371] A 100 mL recovery flask containing
2-(4-amino-2-fluorophenyl)-2-car- bomethoxypyrrolidinone (EXAMPLE
66, Step 3, 930 mg, 3.7 mmol) was charged with 26 mL DMSO and
sodium cyanide (542 mg, 11.1 mmol). This rose colored suspension
was heated to 150.degree. C. for 30 minutes becoming reddish/brown
in color with some gas evolution. At this time, the reaction was
cooled to RT, DMSO removed under reduced pressure (approx.
60.degree. C., 0.1 mm Hg), with the resulting residue diluted with
30 mL brine and extracted three times with dichloromethane (30 mL).
The combined organics were washed once with brine (15 mL), dried
over MgSO.sub.4, filtered, and concentrated to give 521 m g of a
red/brown oil. TLC indicated remaining product in the brine layers
and they were combined and extracted three times with ethyl acetate
(30 mL). These combined organics were washed once with brine (15
mL), dried over MgSO.sub.4, filtered, and concentrated to give an
additional 230 m g of a red/brown oil. These crude extracts were
purified by LC on 49 g (230-400) silica gel eluting with 5%
methanol/ethyl acetate to afford 628 mg (88%) of the title compound
as a light yellow solid. mp 157-160.degree. C.; R.sub.f 0.24 (ethyl
acetate); IR (mull) 3465, 3363, 1680, 1630, 1614, 1515, 1447, 1285,
830, 828 cm.sup.-1; .sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 7.73
(bs, 1H, O.dbd.C--NH), 6.85 (t, 1H, J=8.4 Hz, aromatic), 6.31 (m,
2H, aromatic), 5.28 (bs, 2H, NH.sub.2), 3.48 (t, 1H, J=9.4 Hz,
Ph--CH), 3.24 (m, 2H, C--CH.sub.2s), 2.35 (m, 1H, N--CH.sub.2A),
1.95 (m, 1H, N--CH.sub.2B); .sup.13C NMR (75 MHz, CDCl.sub.3)
178.8, 161.9 (J.sub.CF=244 HZ), 147.5 (J.sub.CF=11 Hz), 130.4
(J.sub.CF=6 Hz), 115.7 (J.sub.CF=15 Hz), 111.1 (J.sub.CF=2 Hz),
102.3 (J.sub.CF=25 Hz), 41.5, 40.5, 30.1; HRMS Calcd for
C.sub.10H.sub.11N.sub.2O.sub.1F.sub.1+H: 195.0134. Found:
195.0937.
[0372] Step 5: 3-(4-amino-2-fluorophenyl)pyrrolidine
[0373] 100 mL round bottom flask equipped with spinbar and reflux
condenser was charged with
2-(4-amino-2-fluorophenyl)-2-carbomethoxypyrro- lidinone (EXAMPLE
66, Step 4, 430 mg, 2.2 mmol) and 22 mL freshly distilled THF
followed by cooling to 0.degree. C. This light yellow homogeneous
solution was treated with a 1M solution of lithium aluminumhydride
(11 mL, 11 mmol) instantly becoming an opaque light rose color with
copious gas evolution. The reaction was warmed to RT then heated to
reflux with the formation of a gelatinous precipitate. After 20
hours, the now green/yellow thick suspension was successively
quenched by the addition of 0.42 mL water, 0.38 mL 5N sodium
hydroxide, and 1.5 mL water. The resulting thick gelatinous
suspension was diluted with ethyl acetate, filtered through a pad
of Celite, and concentrated to give 392 mg of a yellow oil. This
material was purified by LC on 25 g (230-400) silica gel eluting
with 2:17:81 sat. NH.sub.4OH:methanol:dichloromethane to afford 295
mg (74%) of the title compound as a light yellow oil. This material
was dissolved in a mixture of methanol/ethylacetate and treated
with gaseous HCl with no observable change. This solution was
concentrated to afford a peach colored foam that failed to
recrystallize from many different solvent combinations. R.sub.f
0.20 (2:17:81 sat NH.sub.4OH:methanol:dichloromethane); IR (mull)
3139, 3042, 3016, 2766, 2562, 1514, 1485, 1444, 12616, 1108
cm.sup.-1; .sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 6.99 (t, 1H,
J=8.2 Hz, aromatic), 6.39 (m, 2H, aromatic), 3.70 (bs, 2H,
Ph-NH.sub.2s), 3.27 (m, 2H, methine, N--CH.sub.2A--CH), 3.11 (m,
2H, N--CH.sub.2s-CH2), 2.80 (dd, 1H, J=6.2 & 8.9 Hz,
N--CH.sub.2B--CH), 2.30 (bs, 1H, NH), 2.14 (m, 1H,
N--CH.sub.2--CH.sub.2A), 1.81 (m, 1H, N--CH.sub.2--CH.sub.2B);
[0374] .sup.13C NMR (75 MHz, CDCl.sub.3) 161.4 (J.sub.CF=243 Hz),
146.0 (J.sub.CF=11 Hz), 128.4 (J.sub.CF=7 HZ), 119.9 (J.sub.CF=152
HZ), 110.5 (J.sub.CF=2 HZ), 102.1 (J.sub.CF=26 HZ), 53.6, 47.0,
38.1, 32.9; Anal. Calcd for C.sub.10H.sub.13N.sub.2F.sub.1: C,
47.45; H, 5.93; N, 11.07. Found: C, 47.10; H, 6.10; N, 10.74. HRMS
Calcd for C.sub.10H.sub.13N.sub.2F.sub.1: 180.1063. Found:
180.1060.
EXAMPLE 67
(S)-(-)-N-[[3-[3-Fluoro-4-(dihydrothien-3-yl)-phenyl]-2-oxo-5-oxazolidinyl-
]methyl]acetamide
[0375] Step 1:
3-Fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenaminec-
arboxylic acid phenylmethyl ester
[0376] A solution of
1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disi-
lacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran
(16 mL) at -78.degree. C. under N.sub.2 is treated with
sec-butyllithium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2
mins, and the resulting mixture is stirred at -78.degree. C. for 2
hrs. The mixture is then treated with a solution of
tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL)
dropwise over 2 mins and is stirred at -78.degree. C., allowing the
cooling bath to expire over 4 hrs. The mixture is then quenched
with saturated aqueous ammonium chloride (25 mL), diluted with
water (25 mL), the layers are separated, and the combined organic
phase is washed with saline (20 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue is
dissolved in methanol (16 mL) and treated with anhydrous potassium
carbonate (1.09 g), and the mixture is stirred at ambient
temperature for 30 mins, concentrated under reduced pressure,
diluted with water (20 mL) and extracted with diethyl ether
(2.times.20 mL). The combined organic phase is washed with saline
(10 mL), dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to give the crude
3-fluoro-4-[3-(hydroxy)tetrahydrothiop- hen-3-yl]benzenamine
intermediate (R.sub.f=0.37 by TLC, ethyl acetate/hexane (50/50)). A
solution of this intermediate in tetrahydrofuran (16 mL) and water
(8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl
chloroformate (0.56 mL), and the resulting mixture is stirred at
ambient temperature for 4 hrs, diluted with water (8 mL), the
layers are separated, and the organic phase is washed with saline
(10 mL), dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue is chromatographed on silica
gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane
(25/75), and those fractions with an R.sub.f=0.19 by TLC (ethyl
acetate/hexane, 25/75) are pooled and concentrated to give the
title compound, mp 134-135.degree. C.
[0377] Step 2: 3-Fluoro-4-(dihydrothien-3-yl)benzenaminecarboxylic
acid phenylmethyl ester
[0378] Following the general procedure of EXAMPLE 17, Step 2, and
making non-critical variations but substituting
3-fluoro-4-[3-(hydroxy)tetrahydr-
othiophen-3-yl]benzenaminecarboxylic acid phenylmethyl ester
(EXAMPLE 67, Step 1) for
4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1-pipe-
ridinecarboxylic acid phenylmethyl ester, the title compound is
obtained as a mixture of the 2,5- and 4,5-dihydro regioisomers. NMR
(CDCl.sub.3, 400 MHz) 7.40, 7.21, 7.14, 7.02, 6.73, 6.69, 6.31,
5.21, 4.10, 3.94, 3.33 and 3.15 .delta..
[0379] Step 3:
(R)-3-[3-Fluoro-4-(dihydrothien-3-yl)phenyl]-5-hydroxymethy-
l-2-oxazolidinone
[0380] Following the general procedure of EXAMPLE 17, Step 3, and
making non-critical variations but substituting
3-fluoro-4-(dihydrothien-3-yl)be- nzenaminecarboxylic acid
phenylmethyl ester (EXAMPLE 67, Step 2, mixture of the 2,5- and
4,5-dihydro regioisomers) for 3,6-dihydro-4-[4-[[(phenylm-
ethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester, the title compound is obtained as a mixture of
the 2,5- and 4,5-dihydro regioisomers. HRMS calculated for
C.sub.14H.sub.14N.sub.1F.su- b.1O.sub.3S.sub.1: 295.0678. Found:
295.0676.
[0381] Step 4:
(R)-3-[3-Fluoro-4-(dihydrothien-3-yl)phenyl]-5-[[(methylsul-
fonyl)oxy]methyl]-2-oxazolidinone
[0382] Following the general procedure of EXAMPLE 17, Step 4, and
making non-critical variations but substituting
(R)-3-[3-fluoro-4-(dihydrothien--
3-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone (EXAMPLE 67, Step 3,
mixture of the 2,5- and 4,5-dihydro regioisomers) for
(R)-(-)-3,6-dihydro-4-[4-[5-
-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester, the title compound is obtained as a
mixture of the 2,5- and 4,5-dihydro regioisomers. HRMS calculated
for C.sub.15H.sub.16N.sub.1F.sub.1O.sub.5S.sub.2: 373.0454. Found:
373.0440.
[0383] Step 5:
(S)-N-[[3-[3-Fluoro-4-(dihydrothien-3-yl)phenyl]-2-oxo-5-ox-
azolidinyl]methyl]acetamide
[0384] Following the general procedure of EXAMPLE 17, Step 5, and
making non-critical variations but substituting
(R)-3-[3-fluoro-4-(dihydrothien--
3-yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
(EXAMPLE 67, Step 4, mixture of the 2,5- and 4,5-dihydro
regioisomers) for
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazoli-
dinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester, the
title compound is obtained as a mixture of the 2,5- and 4,5-dihydro
regioisomers. Anal. calculated for
C.sub.16H.sub.17F.sub.1N.sub.2O.sub.3S- .sub.1: C, 57.13; H, 5.09;
N, 8.33. Found: C, 56.89; H, 5.18; N, 8.24.
EXAMPLE 68
(5S)-N-[[3-[3-Fluoro-4-(2,5-dihydro-1-oxido-3-thienyl)-phenyl]-2-oxo-5-oxa-
zolidinyl]methyl]acetamide (68a) and
(5S)-N-[[3-[3-Fluoro-4-(4,5-dihydro-1-
-oxido-3-thienyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(68b)
[0385] Following the general procedure of EXAMPLE 63, and making
non-critical variations but substituting
(S)-N-[[3-[3-fluoro-4-(dihydroth-
ien-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 67,
Step 5, mixture of the 2,5- and 4,5-dihydro regioisomers) for
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5--
oxazolidinyl]methyl]acetamide and separating the regioisomers by
chromatography on silica gel (230-400 mesh, methanol/methylene
chloride (4/96) eluent), the title compounds are obtained. mp (68a)
208-210.degree. C. (decomp.); NMR (68b) (CDCl.sub.3, 400 MHz) 7.55,
7.46, 7.27, 7.13, 6.11, 4.82, 4.07, 3.82-3.62, 3.43, 3.23, 3.10 and
2.03 .delta..
EXAMPLE 69
(S)-N-[[3-[3-Fluoro-4-(2,5-dihydro-1,1-dioxido-3-thienyl)-phenyl]-2-oxo-5--
oxazolidinyl]methyl]acetamide (69a) and
(S)-N-[[3-[3-Fluoro-4-(4,5-dihydro-
-1,1-dioxido-3-thienyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
(69b)
[0386] Following the general procedure of EXAMPLE 50, and making
non-critical variations but substituting
(S)-N-[[3-[3-fluoro-4-(dihydroth-
ien-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 67,
Step 5, mixture of the 2,5- and 4,5-dihydro regioisomers) for
(S)-(-)-N-[[3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5--
oxazolidinyl]methyl]acetamide and separating the regioisomers by
HPLC (Chiralpak AD, 10% isopropanol/methanol (0.05% diethylamine),
0.5 mL/min), the title compounds are obtained. mp (69a)
183-185.degree. C. (decomp.); (69b) 238-239.degree. C.
(decomp.).
EXAMPLE 70
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-dihydro-2H-pyridin-3--
yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0387] Step 1:
5,6-Dihydro-3-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridi-
necarboxylic acid 1,1-dimethylethyl ester
[0388] Following the general procedure of EXAMPLE 20, Step 2, and
making non-critical variations but substituting
1-(1,1-dimethylethoxycarbonyl)-3- -piperidone for
1-(1,1-dimethylethoxycarbonyl)-4-piperidone and isolating the
desired regioisomer by chromatography on silica gel (70-230 mesh,
ethyl acetate/hexane (10/90) eluent), the title compound is
obtained, NMR (CDCl.sub.3, 400 MHz) 5.92, 14.04, 3.49, 2.30 and
1.47 .delta..
[0389] Step 2:
(S)-3-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-f-
luorophenyl]-5,6-dihydro-1(2H)-pyridine-1-carboxylic acid
1,1-dimethylethyl ester
[0390] Following the general procedure of EXAMPLE 38, Step 1, and
making non-critical variations but substituting
5,6-dihydro-3-[[(trifluoromethyl-
)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl
ester (EXAMPLE 70, Step 1) for
3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1-
(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester, the title
compound is obtained, NMR (CDCl.sub.3, 400 MHz) 7.41, 7.25, 7.17,
6.06, 4.79, 4.19, 4.06, 3.78, 3.75-3.59, 3.57, 2.32, 2.03 and 1.49
.delta..
[0391] Step 3:
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-dihydr-
o-2H-pyridin-3-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0392] A solution of
(S)-3-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidiny-
l]-2-fluorophenyl]-5,6-dihydro-1(2H)-pyridinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 70, Step 2, 158 mg) in dry
acetonitrile under N.sub.2 is treated with iodotrimethylsilane (62
.mu.L) dropwise, and the resulting solution is stirred at ambient
temperature for 50 mins, during which additional
iodotrimethylsilane (25 .mu.L) is added. The reaction is then
treated with methanol (59 .mu.L), stirred for 5 mins and
concentrated under reduced pressure to give the deprotected
intermediate. A mixture of this intermediate and triethylamine
(0.122 mL) in dry methylene chloride (3.6 mL) at 0.degree. C. under
N.sub.2 is treated with acetoxyacetyl chloride (47 .mu.L), and the
resulting mixture is stirred at 0.degree. C. for 2 hrs and at
ambient temperature for 2 hrs and then diluted with methylene
chloride (20 mL), washed with water (10 mL), saturated aqueous
sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
is chromatographed on silica gel (70-230 mesh, 15 g), eluting with
methanol/methylene chloride (5/95), and those fractions with an
Rf=0.5 by TLC (methanol/chloroform, 10/90) are pooled and
concentrated to give the title compound, HRMS calculated for
C.sub.21H.sub.24N.sub.3F.sub- .1O.sub.6+H.sub.1: 434.1727. Found:
434.1741.
EXAMPLE 71
(S)-N-[[3-[4-[1-(Hydroxyacetyl)-5,6-dihydro-2H-pyridin-3-yl]-3-fluoropheny-
l]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0393] A mixture of
(S)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-d-
ihydro-2H-pyridin-3-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 70, Step 3, 105 mg) and anhydrous potassium carbonate (67
mg) in methanol (4.8 mL) is stirred under N.sub.2 at ambient
temperature for 2 hrs and is then neutralized with hydrochloric
acid (1 M), diluted with water (10 mL) and methylene chloride (40
mL), and the layers are separated. The organic phase is washed with
saline (10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the crude product,
which is then chromatographed on silica gel (70-230 mesh, 15 g),
eluting with methanol/methylene chloride (5/95). Pooling and
concentration of those fractions with an R.sub.f=0.30 by TLC
(methanol/chloroform, 10/90) gives the title compound, mp
188-190.degree. C.
EXAMPLE 72
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-dihydro-2H-pyridin-5--
yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0394] Step 1:
3-Hydroxy-3-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophe-
nyl]-1-piperidinecarboxylic acid phenylmethyl ester
[0395] Following the general procedure of EXAMPLE 67, Step 1, and
making non-critical variations but substituting
N-(carbobenzyloxy)-3-piperidone for tetrahydrothiophen-3-one, the
title compound is obtained, mp 137-139.degree. C.
[0396] Step 2:
3,4-Dihydro-5-[4-[[(phenylmethoxy)carbonylamino]-2-fluoroph-
enyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester
[0397] Following the general procedure of EXAMPLE 17, Step 2, and
making non-critical variations but substituting
3-hydroxy-3-[4-[[(phenylmethoxy)-
carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid
phenylmethyl ester (EXAMPLE 72, Step 1) for
4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]a-
mino]phenyl]-1-piperidinecarboxylic acid phenylmethyl ester, the
title compound is obtained, mp 138-139.degree. C.
[0398] Step 3:
(R)-3,4-Dihydro-5-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidiny-
l]-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl
ester
[0399] Following the general procedure of EXAMPLE 17, Step 3, and
making non-critical variations but substituting
3,4-Dihydro-5-[4-[[(phenylmethox-
y)carbonyl]amino]-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester (EXAMPLE 72, Step 2) for
3,6-dihydro-4-[4-[[(phenylmet-
hoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester, the title compound is obtained, HRMS calculated
for C.sub.23H.sub.23N.sub.2F.sub.1O.sub.5: 426.1591. Found:
426.1594.
[0400] Step 4:
(R)-3,4-Dihydro-5-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-
-3-oxazolidinyl]-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid
phenylmethyl ester
[0401] Following the general procedure of EXAMPLE 17, Step 4, and
making non-critical variations but substituting
(R)-3,4-Dihydro-5-[4-[5-(hydroxy-
methyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester (EXAMPLE 72, Step 3) for
(R)-(-)-3,6-dihydro-4-[4-
-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic
acid phenylmethyl ester, the title compound is obtained, NMR
(CDCl.sub.3, 400 MHz) 7.39, 7.27, 7.18, 5.23, 4.93, 4.47, 4.15,
3.95, 3.71, 3.11, 2.44 and 1.97 .delta..
[0402] Step 5:
(S)-(-)-5-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-
-2-fluorophenyl]-3,4-dihydro-1(2H)-pyridinecarboxylic acid
phenylmethyl ester
[0403] Following the general procedure of EXAMPLE 17, Step 5, and
making non-critical variations but substituting
(R)-3,4-Dihydro-5-[4-[5-[[(methy-
lsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1(2H)-pyridine-
carboxylic acid phenylmethyl ester (EXAMPLE 72, Step 4) for
(R)-(-)-3,6-dihydro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazoli-
dinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester, the
title compound is obtained, HRMS calculated for
C.sub.25H.sub.26F.sub.1N.sub.3O- .sub.5: 467.1856. Found:
467.1862.
[0404] Step 6:
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-dihydr-
o-2H-pyridin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0405] Following the general procedure of EXAMPLE 70, Step 3, and
making non-critical variations but substituting
(S)-(-)-5-[4-[5-[(Acetylamino)me-
thyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-3,4-dihydro-1(2H)-pyridinecarb-
oxylic acid phenylmethyl ester (EXAMPLE 72, Step 5) for
(S)-(-)-5-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluoropheny-
l]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl
ester, the title compound is obtained, mp 146-148.degree. C.
EXAMPLE 73
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-3,4-dihydro-2H-pyridin-5-yl]-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0406] A mixture of
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-d-
ihydro-2H-pyridin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 72, Step 6, 238 mg) and anhydrous potassium carbonate (151
mg) in methanol (27 mL) is stirred under N.sub.2 at ambient
temperature for 2 hrs and is then neutralized with hydrochloric
acid (1 M) and concentrated under reduced pressure. The residue is
then diluted with methylene chloride (100 mL) and saline (50 mL)
and the resultant insoluble product is removed by filtration and
dried under reduced pressure. The layers in the filtrate are
separated and the organic phase is dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give additional
quantities of the title compound, mp 171-173.degree. C.
EXAMPLE 74
(S)-(-)-N-[[3-[4-[1-Formyl-4-fluoro-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-
-oxazolidinyl]methyl]acetamide
[0407] Step 1:
4-Hydroxy-4-[2-fluoro-4-r[(phenylmethoxy)carbonyl]amino]phe-
nyl]-1-piperidinecarboxylic acid phenylmethyl ester
[0408] A solution of
1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disi-
lacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran
(9.8 mL) at -78.degree. C. under N.sub.2 is treated with
sec-butyllithium (1.3 M in cyclohexane, 3.64 mL) dropwise over 3
mins, and the resulting mixture is stirred at -78.degree. C. for 2
hrs. The mixture is then treated with a solution of
N-(carbobenzyloxy)-4-piperidone (919 mg) in dry tetrahydrofuran
(3.9 mL) dropwise over 2 mins and is stirred at -78.degree. C. for
2 hrs. The mixture is then warmed to -20.degree. C. over 1 hr and
quenched with saturated aqueous ammonium chloride (5 mL), diluted
with water (20 mL), the layers are separated, the aqueous phase is
extracted with diethyl ether (20 mL), and the combined organic
phase is washed with saline (10 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue is
dissolved in methanol (15 mL) and treated with anhydrous potassium
carbonate (544 mg, 3.94 mmol), and the mixture is stirred at
ambient temperature for 30 mins, concentrated under reduced
pressure, diluted with diethyl ether (30 mL), washed with water (20
mL) and saline (10 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the crude
4-(hydroxy)piperidinyl benzenamine intermediate (R.sub.f=0.25 by
TLC, ethyl acetate/hexane (50/50)). A mixture of this intermediate
and N,N-dimethylaniline (1.00 mL) in tetrahydrofuran (20 mL) is
cooled to -20.degree. C. and treated with benzyl chloroformate
(0.59 mL), and the resulting mixture is stirred at -20.degree. C.
for 1 hr. The mixture is then diluted with saturated aqueous
potassium carbonate (5 mL), water (25 mL) and diethyl ether (25
mL), the layers are separated, and the organic phase is washed with
water (20 mL) and saline (20 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue is
chromatographed on silica gel (230-400 mesh, 150 g), eluting with a
gradient of ethyl acetate/hexane (25/75-50/50), and those fractions
with an R.sub.f=0.47 by TLC (ethyl acetate/hexane, 50/50) are
pooled and concentrated to give the title compound, NMR (400 MHz,
CDCl.sub.3) 7.35, 7.00, 6.92, 5.20, 5.16, 4.10, 3.32, 2.15 and 1.79
.delta. and Anal. calculated for C.sub.27H.sub.27FN.sub.2O.sub.5:
C, 67.77; H, 5.69; N, 5.85. Found: C, 67.44; H, 5.83; N, 5.65.
[0409] Step 2:
4-Fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophen-
yl]-1-piperidinecarboxylic acid phenylmethyl ester
[0410] To a solution of diethylaminosulfur trifluoride (DAST, 0.65
mL) in dry methylene chloride (49 mL) at -78.degree. C. under
N.sub.2 is added a solution of
4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluoropheny-
l]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step
1, 2.25 g) in dry methylene chloride (47 mL) over 2 mins. The
resulting mixture is stirred at -78.degree. C. for 1 hr and at
ambient temperature for 30 mins and is then adjusted to pH 8 with
saturated aqueous sodium bicarbonate (50 mL), diluted with water
(50 mL), and the layers are separated. The organic phase is washed
with water (25 mL) and saline (25 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure, and the residue is
chromatographed on silica gel (230-400 mesh, 150 g), eluting with
methanol/methylene chloride (0.5/99.5). Those fractions with an
R.sub.f=0.27 by TLC (ethyl acetate/hexane, 25/75) are pooled and
concentrated to give the title compound (contaminated with approx.
15% of the elimination side product). An analytical sample is
prepared by radial chromatography (1000.mu. silica gel rotor, ethyl
acetate/hexane (20/80) eluent), mp 116-118.degree. C.
[0411] Step 3:
(R)-4-Fluoro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]--
2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester
[0412] A solution of
4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluo-
rophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE
74, Step 2, 2.03 g, contaminated with the elimination side product)
in dry tetrahydrofuran (21 mL) at -78.degree. C. under N.sub.2 is
treated with n-butyllithium (2.80 mL, 1.6 M in hexanes) dropwise
over 5 mins. The resulting mixture is stirred at -78.degree. C. for
1.25 hrs and is then treated with (R)-(-)-glycidyl butyrate (0.63
mL) dropwise. The resulting solution is stirred at -78.degree. C.
for 1 hr, warmed to ambient temperature and stirred for an
additional 20 hrs, after which the reaction is quenched with
saturated aqueous ammonium chloride (10 mL), diluted with water (10
mL), and the layers are separated. The organic phase is washed with
saline (10 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the crude product which
is chromatographed on silica gel (230-400 mesh, 250 g), eluting
with methanol/methylene chloride (3/97). Pooling and concentration
of those fractions with an R.sub.f=0.51 by TLC
(methanol/chloroform, 10/90) and repurification by silica gel
chromatography (230-400 mesh, 100 g, methanol/methylene chloride
(4/9.6) eluent) gives the title compound (contaminated with the
elimination side product from the starting material). An analytical
sample is prepared by radial chromatography (2000.mu. silica gel
rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz,
CDCl.sub.3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22,
2.25 and 1.90 .delta. and HRMS calculated for
C.sub.23H.sub.24F.sub.2N.sub.2O.sub.5: 446.1653. Found:
446.1660.
[0413] Step 4:
(R)-4-Fluoro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3--
oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid
phenylmethyl ester
[0414] A solution of
(R)-4-fluoro-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidin-
yl]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester
(EXAMPLE 74, Step 3, 0.17 g) and triethylamine (0.080 mL) in dry
methylene chloride (2 mL) at 0.degree. C. under N.sub.2 is treated
with methanesulfonyl chloride (0.031 mL) dropwise. The resulting
mixture is stirred at 0.degree. C. for 12 hrs and at ambient
temperature for 1.5 hrs, diluted with methylene chloride (10 mL),
washed with water (5 mL), saturated aqueous sodium bicarbonate (5
mL) and saline (5 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the title compound,
HRMS calculated for C.sub.24H.sub.26F.sub.2N.sub.2O.s-
ub.7S+H.sub.1: 525.1507. Found: 525.1522.
[0415] Step 5:
(S)-N-[[2-Oxo-3-[4-(4-fluoro-4-piperidinyl)-3-fluorophenyl]-
-5-oxazolidinyl]methyl]acetamide
[0416] A mixture of
(R)-4-fluoro-4-[4-[5-[[(methylsulfonyl)oxy]methyl]-2-o-
xo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid
phenylmethyl ester (EXAMPLE 74, Step 4, 0.190 g) and concentrated
aqueous ammonium hydroxide (2 mL) in isopropanol (1 mL) and
acetonitrile (2 mL) is placed in a sealed tube and immersed in an
oil bath maintained at 95.degree. C. for 18 hrs. The mixture is
then diluted with methylene chloride (20 mL), washed with water (10
mL) and saline (10 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give the crude
5-aminomethyl-2-oxazolidinone intermediate (R.sub.f=0.13 by TLC,
methanol/chloroform, 5/95). A solution of this intermediate and
pyridine (0.088 mL) in dry methylene chloride (3.6 mL) under
N.sub.2 is treated with acetic anhydride (0.051 mL), and the
resulting solution is stirred at ambient temperature for 18 hrs.
The mixture is then diluted with methylene chloride (10 mL), washed
with water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and
saline (5 mL), dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give the crude acetamide intermediate
which, after being combined with approx. 1.5 g of crude product
from previous reaction workups, is chromatographed on silica gel
(230-400 mesh, 150 g), eluting with a gradient of
methanol/methylene chloride (1/99-2/98). Pooling and concentration
of those fractions with an R.sub.f=0.18 by TLC
(methanol/chloroform, 5/95) gives 0.80 g (approx. 70% from the
mesylate) of the product (contaminated with the elimination side
product) as an amorphous, white solid which is used without further
purification. A mixture of this intermediate (0.75 g) and 20%
palladium hydroxide on carbon (200 mg) in methanol (30 mL) is
shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi
for 1 hr, the catalyst is removed by filtration through Celite and
the filtrate is concentrated under reduced pressure. The residue is
chromatographed on silica gel (230-400 mesh, 45 g), eluting with a
gradient of triethylamine/methanol/methylene chloride (Jan. 9,
1990-1/4/95), and those fractions having an R.sub.f=0.19 by TLC
(triethylamine/methanol/chl- oroform, Jan. 9, 1990) are pooled and
concentrated to give the title compound, mp 163-165.degree. C.
[0417] Step 6:
(S)-(-)-N-[[3-[4-[1-Formyl-4-fluoro-4-piperidinyl]-3-fluoro-
phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0418] A mixture of
(S)-3-N-[[2-oxo-3-[4-(4-fluoro-4-piperidinyl)-3-fluoro-
phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 74, Step 5, 205
mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(145 mg) and formic acid (28 .mu.L) in dry tetrahydrofuran (11.6
mL) is diluted with water to solubilize all reactants and stirred
at ambient temperature for 6 hrs. The reaction is then diluted with
methylene chloride (30 mL), washed with water (20 mL) and saline
(20 mL), dried over anhydrous sodium sulfate and concentrated under
reduced pressure, and the residue is chromatographed on silica gel
(230-400 mesh, 40 g), eluting with a gradient of methanol/methylene
chloride (3/97-5/95). Those fractions with an R.sub.f=0.40 by TLC
(methanol/chloroform, 10/90) are pooled and concentrated and the
residue is recrystallized from chloroform/diethyl ether to give the
title compound, mp 180-181.degree. C. (decomp.).
EXAMPLE 75
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-2,3,4,7-tetrahydro-1H-aze-
pin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0419] Step 1:
2,3,4,7-Tetrahydro-5-[[(trifluoromethyl)sulfonyl]oxy]-1H-az-
epine-1-carboxylic acid 1,1-dimethylethyl ester (a) and
2,3,6,7-Tetrahydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1H-azepine-1-carbox-
ylic acid 1,1-dimethylethyl ester (b)
[0420] Following the general procedure of EXAMPLE 20, Step 2, and
making non-critical variations but substituting
1-(1,1-dimethylethoxycarbonyl)-1- ,2,3,5,6,7-hexahydroazepin-4-one
for 1-(1,1-dimethylethoxycarbonyl)-4-pipe- ridone and isolating the
regioisomers by chromatography on silica gel (230-400 mesh, ethyl
acetate/hexane (5/95) eluent), the title compounds are obtained,
(a) NMR (CDCl.sub.3, 400 MHz) 5.87, 3.95, 3.55, 2.57, 1.95 and 1.46
.delta. and (b) NMR (CDCl.sub.3, 400 MHz) 5.90, 3.54, 2.69, 2.35
and 1.47 .delta..
[0421] Step 2:
(S)-5-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-f-
luorophenyl]-2,3,4,7-tetrahydro-1H-azepinecarboxylic acid
1,1-dimethylethyl ester
[0422] Following the general procedure of EXAMPLE 38, Step 1, and
making non-critical variations but substituting
2,3,4,7-tetrahydro-5-[[(trifluor-
omethyl)sulfonyl]oxy]-1(1H)-azepinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 75, Step 1(A)) for
3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy-
]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester, the title
compound is obtained, NMR (CDCl.sub.3, 400 MHz) 7.31, 7.12-6.95,
5.84, 4.76, 4.00, 3.98, 3.76, 3.61, 3.58, 2.51, 1.97, 1.85 and 1.42
.delta..
[0423] Step 3:
(S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-2,3,4,7-te-
trahydro-1H-azepin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0424] Following the general procedure of EXAMPLE 70, Step 3, and
making non-critical variations but substituting
(S)-5-[4-[5-[(acetylamino)methyl-
]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-2,3,4,7-tetrahydro-1H-azepine-1-ca-
rboxylic acid 1,1-dimethylethyl ester (EXAMPLE 75, Step 2) for
(S)-(-)-3-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluoropheny-
l]-5,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl
ester, the title compound is obtained, HRMS calculated for
C.sub.22H.sub.26F.sub.1N.- sub.3O.sub.6: 448.1884. Found:
448.1888.
EXAMPLE 76
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-2,3,4,7-tetrahydro-1H-azepin-5-yl]-3-f-
luorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0425] Following the general procedure of EXAMPLE 71, and making
non-critical variations but substituting
(S)-N-[[2-oxo-3-[3-fluoro-4-[1-[-
(acetoxy)acetyl]-2,3,4,7-tetrahydro-1H-azepin-5-yl]phenyl]-5-oxazolidinyl]-
methyl]acetamide (EXAMPLE 75, Step 3) for
(S)-(-)-N-[[2-oxo-3-[3-fluoro-4--
[1-[(acetoxy)acetyl]-5,6-dihydro-2H-pyridin-3-yl]phenyl]-5-oxazolidinyl]me-
thyl]acetamide, the title compound is obtained, NMR (CDCl.sub.3,
400 MHz, mixture of rotamers) 7.41, 7.09-7.18, 6.07, 6.00, 5.87,
4.78, 4.25, 4.21, 4.05, 3.92, 3.87, 3.78, 3.67, 3.51, 2.63, 2.03
and 1.97 .delta. and HRMS calculated for
C.sub.20H.sub.24F.sub.1N.sub.3O.sub.5: 405.1700. Found:
405.1694.
EXAMPLE 77
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-2,3,6,7-tetrahydro-1H-
-azepin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0426] Step 1:
(S)-4-[4-[5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-f-
luorophenyl]-2,3,6,7-tetrahydro-1H-azepine-1-carboxylic acid
1,1-dimethylethyl ester
[0427] Following the general procedure of EXAMPLE 38, Step 1, and
making non-critical variations but substituting
2,3,6,7-tetrahydro-4-[[(trifluor-
omethyl)sulfonyl]oxy]-1(1H)-azepinecarboxylic acid
1,1-dimethylethyl ester (EXAMPLE 75, Step 1(B)) for
3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy-
]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester, the title
compound is obtained, mp 164-165.degree. C.
[0428] Step 2:
(S)-(-)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-2,3,6,-
7-tetrahydro-1H-azepin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide
[0429] Following the general procedure of EXAMPLE 70, Step 3, and
making non-critical variations but substituting
(S)-4-[4-[5-[(acetylamino)methyl-
]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-2,3,6,7-tetrahydro-1H-azepine-1-ca-
rboxylic acid 1,1-dimethylethyl ester (EXAMPLE 77, Step 1) for
(S)-(-)-3-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluoropheny-
l]-5,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl
ester, the title compound is obtained, NMR (CDCl.sub.3, 400 MHz,
mixture of rotamers) 7.39, 7.15, 6.22, 5.90, 4.79, 4.04, 3.80-3.50,
2.70, 2.50, 2.19 and 2.02 .delta. and Anal. calculated for
C.sub.22H.sub.26F.sub.1N.sub.3O- .sub.6: C, 59.05; H, 5.86; N,
9.39. Found: C, 58.70; H, 5.80; N, 9.43.
EXAMPLE 78
(S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)-2,3,6,7-tetrahydro-1H-azepin-4-yl]-3-f-
luorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0430] Following the general procedure of EXAMPLE 71, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[3-fluoro-4--
[1-[(acetoxy)acetyl]-2,3,6,7-tetrahydro-1H-azepin-4-yl]phenyl]-5-oxazolidi-
nyl]methyl]acetamide (EXAMPLE 77, Step 2) for
(S)-(-)-N-[[2-oxo-3-[3-fluor- o-4-[1-[(acetoxy)acetyl]-5,6-,
dihydro-2H-pyridin-3-yl]phenyl]-5-oxazolidi- nyl]methyl]acetamide,
the title compound is obtained, NMR (CDCl.sub.3, 400 MHz, mixture
of rotamers) 7.41, 7.13, 6.08, 5.90, 4.78, 4.22, 4.04, 3.85-3.59,
3.51-3.41, 2.70, 2.52 and 2.02 .delta. and Anal. calculated for
C.sub.20H.sub.24F.sub.1N.sub.3O.sub.5: C, 59.25; H, 5.97; N, 10.36.
Found: C, 58.91; H, 6.04; N, 10.19.
EXAMPLE 79
(5S)-(-)-N-[[3-[4-[1-(Hydroxyacetyl)hexahydro-1H-azepin-4-yl]-3-fluorophen-
yl]-2-oxo-5-oxazolidinyl]methyl]acetamide (as a Mixture of
Diastereomers)
[0431] Following the general procedure of EXAMPLE 48, and making
non-critical variations but substituting
(S)-(-)-N-[[3-[4-[1-(hydroxyacet-
yl)-2,3,4,7-tetrahydro-1H-azepin-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidiny-
l]methyl]acetamide (EXAMPLE 76, Step 3) for
(S)-(-)-N-[[3-[4-(3,6-dihydro--
2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
and purifying the product by chromatography on silica gel (70-230
mesh, methanol/methylene chloride (7.5/92.5) eluent), the title
compound is obtained, HRMS calculated for
C.sub.20H.sub.26F.sub.1N.sub.3O.sub.5+H.sub- .1: 408.1935. Found:
408.1928.
EXAMPLE 80
(S)-N-[[3-[3-Fluoro-4-(3,4-dihydro-2H-pyran-6-yl)phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]acetamide
[0432] Step 1: 6-(tributylstannyl)-3,4-dihydro-2H-dihydropyran
[0433] A solution of 3,4-dihydro-2H-dihydropyran (2.000 g, 23.8
mmol) and N,N,N',N'-tetramethylethylenediamine (0.50 mL, 3.09 mmol)
under a nitrogen atmosphere was cooled to 0.degree. C. and treated
with n-butyllithium (19.30 mL of a 1.6 M solution in hexane, 30.94
mmol). The mixture was then warmed to ambient temperature
overnight. The resultant mixture was cooled to -78.degree. C., dry
tetrahydrofaran (20 mL) was added, and then tributyltin chloride
(6.40 mL, 23.8 mmol). The mixture was stirred at -78.degree. C. for
1 h and then warmed to ambient temperature for 2 h. The reaction
mixture was diluted with diethyl ether (50 mL), transferred to a
separatory funnel and washed with 5% aqueous ammonnium hydroxide
and brine. The organic layer was then dried, filtered and
concentrated to give a crude product. Distillation of the residue
under reduced pressure afforded 1.80 g (47%) of the title compound
with a purity of 55%.
[0434] Step 2:
(S)-N-[[3-[3-Fluoro-4-(3,4-dihydro-2H-pyran-6-yl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]acetamide
[0435] A solution of
(S)-N-[[3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidiny-
l]methyl]acetamide (0.200 g, 0.53 mmol) in 1-methyl-2-pyrrolidinone
(5 mL) under a nitrogen atmosphere was treated with Pd.sub.2
dba.sub.3 (0.018 g, 0.02 mmol) and tri(2-furyl)phosphine (0.009 g,
0.04 mmol). After stirring 10 min at ambient temperature, the
mixture was treated with
6-(tributylstannyl)-3,4-dihydro-2H-dihydropyran (0.538 g, 55%
purity, 0.80 mmol). The atmosphere was evacuated and filled with
nitrogen three times and then the mixture heated to 90.degree. C.
for 24 h. At this time the reaction mixture was cooled to ambient
temperature and poured into ethyl acetate. A precipitate was
noticed and removed by filtering the mixture through Celite. The
filtrate was transferred to a separatory funnel and washed with
water and brine, dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was chromatographed over silica
gel, eluting with hexane, 20% acetone/hexane, and finally 5%
methanol/dichloromethane. Appropriate fractions were combined and
concentrated in vacuo to give 0.196 g of a material containing a
small amount of 1-methyl-2-pyrrolidinone. Recrystallization
provided 0.128 g (68%) of the title compound. mp 161-163.degree.
C.; MS(EI): m/z 334.
EXAMPLE 81
(S)-N-[[3-[3-Fluoro-4-[r-(carbobenzyloxy)-3-azetidinyl]-phenyl]-2-oxo-5-ox-
azolidinyl]methyl]-acetamide
[0436] Step 1:
3-(4-Amino-2-fluorophenyl)-3-hydroxy-1-(1,1-diphenylmethyl)-
azetidine
[0437] Sec. butyllithium (22.5 mL of a 1.3M solution in
cyclohexane, 29.5 mmol) was added dropwise to a stirred solution of
1-(3-fluorophenyl)-2,2,-
5,5-tetramethyl-t-aza-2,5-disilacyclopentane (Example 20, Step 1)
(6.0 g, 23.7 mmol) at -78.degree. C. under nitrogen in dry THF (75
mL). After 2 hr a solution of 1-(1,1-diphenylmethyl)azetidin-3-one
(5.6 g, 23.6 mmol) in dry THF (60 mL) was added dropwise and
stirring continued at -78.degree. for 2 hr, when the cooling bath
was removed. After reaching room temperature, a solution of
saturated ammonium chloride (75 mL) was added followed by water
(200 mL). The mixture was extracted with ether (500 mL), washed
with brine (100 mL), dried over magnesium sulfate, filtered and
evaporated. The residue was dissolved in methanol (150 mL) and
anhydrous potassium carbonate (6.0 g, 43.5 mmol) added and then
stirred overnight. The suspension was filtered and the filtrate
evaporated. The residue was partitioned between ether (500 mL) and
water (200 mL). The water was extracted with additional ether (200
mL) and the combined ether extracts washed with brine (100 mL),
dried over magnesium sulfate, filtered and evaporated to afford an
orange foam. Chromatography over silica gel (150 g, 40-60 .mu.m)
eluting with 25-50% ethyl acetate-hexane gave the title compound as
a pale yellow foam. .sup.1H NMR .delta. (CDCl.sub.3): 2.62, 3.53,
3.78, 4.41, 6.36, 6.41, 7.03, 7.14-7.30, 7.39-7.47.
[0438] Step 2:
3-(N-Carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxy-1-(1,1-d-
iphenylmethyl)azetidine
[0439] To a solution of
3-(4-amino-2-fluorophenyl)-3-hydroxy-1-(1,1-diphen-
ylmethyl)azetidine (Example 81, Step 1, 5.10 g, 14.7 mmol) in
acetone (75 mL) was added a solution of sodium bicarbonate (2.52 g,
30.0 mmol) in water (40 mL) to give a creamy suspension. Benzyl
chloroformate (2.57 g, 15.1 mmol) was added and stirring continued
overnight. The suspension was filtered and the acetone evaporated.
The residue was partitioned between ethyl acetate (200 mL) and
water (50 mL). The organic layer was washed with brine (50 mL),
dried over magnesium sulfate, filtered and evaporated to leave an
amber foam. Chromatography over silica gel (150 g, 40-60 .mu.M)
eluting with 1-2% methanol-methylene chloride gave the title
compound as a cream foam. HRMS: meas. 483.2087, theory
483.2084.
[0440] Step 3:
N-Carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-
-hydroxyazetidine
[0441] Benzyl chloroformate (3.8 mL, 26.6 mmol) was added to a
solution of
3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxy-1-(1,1-diphenylmethyl)-
azetidine (Example 81, Step 2, 1.60 g, 3.32 mmol) in benzene (30
mL) and then heated under reflux under nitrogen for 2 hr. The
benzene was evaporated and the residue chromatographed over silica
gel (150 g, 40-60 .mu.m) eluting with 20-60% ethyl acetate-hexane.
The title compound was obtained as a white foam. .sup.1H NMR
.delta. (CDCl.sub.3): 3.32, 4.19, 4.42, 5.08, 5.17, 6.98, 7.11,
7.19, 7.24-7.43.
[0442] Step 4:
N-Carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)az-
etidine.
[0443] Triethylsilane (30 mL) and trifluoroacetic acid (12 mL) were
added to a solution of
N-carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl-
)-3-hydroxyazetidine (Example 81, Step 3, 4.3 g, 9.55 mmol) in
methylene chloride (40 mL) and stirred for 2 days. Removal of the
solvents at 45.degree./0.75 mm gave an amber oil. Chromatography
over silica gel (150 g, 40-60 .mu.m) eluting with 1-3%
methanol-chloroform yielded the title compound as a solid, m.p.
950.
[0444] Step 5:
(R)-(-)-N-Carbobenzyloxy-3-[2-fluoro-4-[5-hydroxymethyl-2-o-
xo-3-oxazolidinyl]phenyl]azetidine
[0445] n-Butyllithium (5.25 mL of a 1.6 M solution in hexane, 8.40
mmol) was added dropwise to a stirred solution of
N-carbobenzyloxy-3-(N-carbobe-
nzyloxy-3-fluoroanilin-4-yl)azetidine (Example 81, Step 4, 3.63 g,
8.36 mmol) at -78.degree. under nitrogen in dry THF (30 mL), then
stirred for 2 hr. A solution of R-glycidyl butyrate (1.21 g, 8.40
mmol) in dry THF (3.0 mL) was added and the cooling bath removed
after 15 min. After 18 hr, the solvent was removed and the residue
partitioned between ethyl acetate (150 mL) and saturated ammonium
chloride solution (50 mL). The organic layer was washed with water
(50 mL) and brine (50 mL), dried over magnesium sulfate, filtered
and evaporated leaving an amber oil. Chromatography over silica gel
(150 g, 40-60 .mu.m) eluting with 2-5% methanol-chloroform gave the
title compound as a sticky foam. FAB-HRMS: theory 401.1513 (M+1);
meas 401.1521.
[0446] Step 6:
(R)-(-)-N-Carbobenzyloxy-3-[2-fluoro-4-[5-[[(3-nitrophenyls-
ulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]phenyl]azetidine
[0447] 3-Nitrobenzenesulfonyl chloride (1.70 g, 7.67 mmol) was
added to an ice cooled solution of
(R)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-hydroxym-
ethyl-2-oxo-3-oxazolidinyl]-pheny]azetidine (Example 81, Step 5,
2.79 g, 6.97 mmol) and triethylamine (1.41 g, 14.0 mmol) in
methylene chloride (40 mL). After 16 hr. water (50 mL) and
methylene chloride (100 mL) were added. The organic layer was
washed with brine (50 mL), dried over magnesium sulfate, filtered
and evaporated. The residue was chromatographed over silica gel
(150 g, 40-60 .mu.m) eluting with 25-100% ethyl acetate-hexane to
give the title compound as a sticky foam. FAB-HRMS: theory 586.1290
(M+1); meas 586.1295.
[0448] Step 7:
(S)-(-)-N-Carbobenzyloxy-3-[2-fluoro-4-[5-azidomethyl-2-oxo-
-3-oxazolidinyl]phenyl]azetidine
[0449] A mixture of sodium azide (1.44 g, 22.1 mmol) and
(R)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-[[(3-nitrophenylsulfonyl)oxy]-m-
ethyl]-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 6,
2.60 g, 4.44 mmol) in DMF (30 mL) was stirred for 16 hr, then
filtered. The solvent was removed at 38.degree./0.75 mm and the
residue extracted with ethyl acetate (100 mL) and washed with water
(3.times.50 mL) and brine (50 mL). After drying over magnesium
sulfate, filtration and evaporation gave a yellow oil.
Chromatography over silica gel (150 g, 40-60 .mu.m) eluting with 1%
methanol-methylene chloride gave the title compound as a pale
yellow foam. FAB-HRMS: theory 426.1577 (M+1); meas. 426.1580.
[0450] Step 8:
(S)-(-)-N-Carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-
-3-oxazolidinyl]phenyl]azetidine
[0451] To a stirred solution of
(S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5--
azidomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step
7, 1.63 g, 3.84 mmol) in dry THF (20 mL) was added
triphenylphosphine (1.11 g, 4.23 mmol). After 3 hr, water (0.69 mL,
38.4 mmol) was added and the reaction stirred for 2 days at which
time the solvents were evaporated. The residue was chromatographed
over silica gel (150 g, 40-60 .mu.m) eluting with 5-10%
methanol-chloroform. The title compound was isolated as a viscous
colorless oil. FAB-HRMS: theory 400.1672 (M+1); meas. 400.1676.
[0452] Step 9:
(S)-N-[[3-[3-Fluoro-4-[1-(carbobenzyloxy)-3-azetidinyl]phen-
yl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0453] Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few
crystals of 4-dimethylaminopyridine were added to a stirred
solution of
(S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidiny-
l]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in
methylene chloride (30 mL), then stirred for 1 hr. The solvents
were removed at 38.degree./0.75 mm and the residue chromatographed
over silica gel (50 g, 40-60 .mu.m) eluting with 1-2%
methanol-chloroform. The title compound was isolated as a white
foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
EXAMPLE 82
(S)-N-[[3-[3-Fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ac-
etamide
[0454] A solution of
(S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-3-azetidiny-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 81, Step
9, 1.44 g, 3.26 mmol) in ethyl acetate (25 mL) and absolute ethanol
(50 mL) was added to 10% Pd/C (1.0 g) and hydrogenated at 30 psi
for 7 hr. Filtration and evaporation gave the title compound as a
white glassy solid. FAB-HRMS: theory 308.1410 (M+1); meas.
308.1408.
EXAMPLE 83
(S)-N-[[3-[3-Fluoro-4-[1-(carboxymethyl)-3-azetidinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]acetamide
[0455] Triethylamine (150 .mu.L, 1.08 mmol) and methyl
chloroformate (65 .mu.L, 0.84 mmol) were added to a chloroform (5
mL) suspension of
(S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]a-
cetamide (Example 82, 153 mg, 0.50 mmol) and stirred overnight.
Additional chloroform (25 mL) was added and the solution washed
with water (15 mL) and brine (15 mL). Drying over magnesium
sulfate, filtration, and evaporation gave a foam. Chromatography
over silica gel (50 g, 40-60 .mu.m) eluting with 1-3%
methanol-chloroform gave the title compound as a white solid.
FAB-HRMS: theory 366.1465 (M+1); meas. 366.1468.
EXAMPLE 84
(S)-N-[[3-[3-Fluoro-4-[1-(formyl)-3-azetidinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]acetamide
[0456] N-Formylbenzotriazole (115 mg, 0.78 mmol) was added to a
stirred suspension of
(S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]methyl]acetamide (Example 82, 153 mg, 0.50 mmol) in THF (5
mL) and stirred overnight. The solvent was removed and the residue
chromatographed over silica gel (50 g, 40-60 .mu.m) eluting with
2-5% methanol-chloroform to give the title compound as a white
foam. FAB-HRMS: theory 336.1356 (M+1); meas. 336.1357.
EXAMPLE 85
(S)-(-)-N-[[3-[4-[1-(4-Oxo-2-thiazolinyl)-4-piperidinyl]-3-fluorophenyl]-2-
-oxo-5-oxazolidinyl]methyl]acetamide
[0457] A mixture of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-
-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20,310 mg), methyl
thiocyanatoacetate (121 mg, Bull. Chem. Soc. Jpn. 1972, 45(5),
1507) and glacial acetic acid (55 mg) in absolute ethanol (5 mL) is
stirred at reflux under N.sub.2 for 4 hrs and then cooled to
ambient temperature, diluted with methylene chloride (45 mL),
washed with water (2.times.15 mL) and saline (20 mL), dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue is chromatographed on silica gel (230-400 mesh, 45 g),
eluting with methanol/methylene chloride (4/96), and those
fractions with an R.sub.f=0.47 by TLC (methanol/chloroform, 10/90)
are pooled and concentrated to give the title compound, mp
222-224.degree. C. (decomp.).
EXAMPLE 86
(S)-(-)-N-[[3-[4-[1-(4-Oxo-2-thiazolinyl)-3,6-dihydro-2H-pyridin-5-yl]-3-f-
luorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0458] Following the general procedure of EXAMPLE 85, and making
non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 38) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-
-oxazolidinyl]methyl]acetamide, the title compound is obtained, mp
209-211.degree. C. (decomp.).
EXAMPLE 87
(S)-(-)-N-[[3-[4-[1-[5-Methyl-1,3,4-thiadiazol-2-yl]-4-piperidinyl]-3-fluo-
rophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0459] Step 1: 2-Bromo-5-methyl-1,3,4-thiadiazole
[0460] To a solution of aqueous hydrobromic acid (48%, 40 mL)
containing a trace amount of copper powder at -10.degree. C. is
added a mixture of 2-amino-5-methyl-1,3,4-thiadiazole (2.88 g) and
sodium nitrite (7.76 g) portionwise over 45 mins with vigorous
stirring. The resulting mixture is stirred at -10.degree. C. for
1.5 hrs and at ambient temperature for an additional 1.5 hrs and is
then cooled in an ice bath, neutralized with aqueous sodium
hydroxide (50%), diluted with saturated aqueous sodium
hydrogensulfite till the mixture no longer turns potassium
iodide-starch test paper blue and filtered to remove insoluble
material (rinsing with hot water). The filtrate is extracted with
methylene chloride (4.times.100 mL), and the combined organic phase
is dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the crude product which is then
chromatographed on silica gel (70-230 mesh, 75 g), eluting with
ethyl acetate/hexane (50/50). Pooling and concentration of those
fractions with an R.sub.f=0.78 by TLC (methanol/chloroform, 10/90)
gives the title compound, mp 107-108.degree. C.
[0461] Step 2:
(S)-(-)-N-[[3-[4-[1-(5-Methyl-1,3,4-thiadiazol-2-yl)-3,6-di-
hydro-2H-pyridin-4-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetami-
de
[0462] A mixture of
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-
-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg),
2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and
potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL)
is stirred under N.sub.2 at 100.degree. C. for 2 hrs, cooled to
ambient temperature, diluted with water (20 mL) and extracted with
methylene chloride (3.times.20 mL). The combined organic phase is
washed with water (20 mL) and saline (10 mL), dried over anhydrous
sodium sulfate and concentrated to give the crude product which is
then chromatographed on silica gel (230-400 mesh, 45 g), eluting
with a gradient of methanol/methylene chloride (2/98-3/97). Pooling
and concentration of those fractions with an R.sub.f=0.44 by TLC
(methanol/chloroform, 10/90) gives the title compound, mp
193-195.degree. C.
EXAMPLE 88
(S)-(-)-N-[[3-[4-[1-(5-Methyl-1,3,4-thiadiazol-2-yl)-3,6-dihydro-2H-pyridi-
n-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
[0463] Following the general procedure of EXAMPLE 87, Step 2, and
making non-critical variations but substituting
(S)-(-)-N-[[2-oxo-3-[4-(3,6-dihy-
dro-2H-pyridin-4-yl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide
(EXAMPLE 38) for
(S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-
-oxazolidinyl]methyl]acetamide, the title compound is obtained, mp
229-231.degree. C. (decomp.). 3 45 6 7 8 9 10 11 12 13
* * * * *