A novel synthesis of oxazolidinone derivatives (A key intermediate of linezolid)

Article abstract of DOI:10.13005/ojc/290322

Oxazolidinone derivatives a very key intermediate of Linezolid 7(a-e) have been synthesized from 3-fluoro-4-morpholinyl aniline 2 in good yield.The structures of all the compounds were confirmed by IR, ¹H NMR, ¹³C NMR and Mass Spectral data.

Full text of DOI:10.13005/ojc/290322

ISSN: 0970-020 X
CODEN: OJCHEG
2013, Vol. 29, No. (3):
Pg. 1015-1019
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Est. 1984
A Novel Synthesis of Oxazolidinone Derivatives
(A Key Intermediate of Linezolid)
PINGILI KRISHNA REDDY1-2, K. MUKKANTI2 and DODDA MOHAN RAO1*
1Symed Research Centre, Plot No. 89/A, Phase-I, Shapoornagar, IDA Jeedimetla, Hyderabad, India
2Center for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, India
*Corresponding author E-mail: kreddysymed@yahoo.com
DOI: http://dx.doi.org/10.13005/ojc/290322
(Received: July 03, 2013; Accepted: August 20, 2013)
ABSTRACT
Oxazolidinone derivatives a very key intermediate of Linezolid 7(a-e) have been
synthesized from 3-fluoro-4-morpholinyl aniline 2 in good yield.The structures of all the compounds
1
were confirmed by IR, H NMR,C13 NMR and Mass Spectral data.
Key words: Oxazolidinone, epichlorohydrin, Antibacterial, Linezolid.
INTRODUCTION
coagulase-negative staphylococci, VRE, and
penicillin-resistant pneumococci, as well as the
perceived looming threat of a vancomycin-resistant
staphylococcus aureus7-9.
The increasing incidence of bacterial
resistance to a large number of antibacterial agents
such as β-lactam antibiotics, macrolides,
quinolones and vancomycin is becoming a major
issue1-4. For the past several years, vancomycin has
been considered the last line of defence against
Gram-positive infections and there is no suitable
therapy available for treating diseases that have
become resistant to vancomycin5.
The oxazolidinones are a class of totally
synthetic antibacterial agents. They have a novel
mechanism of action that involves the inhibition of
bacterial protein synthesis at a very early stage,
prior to chain initiation10.
Linezolid (7a) is a sucessful agent of this
class and has already gained the permission of the
FDA and come into the market.Reffering to the
structure activity relationship studies and the
synthesis of Linezolid , we have reported a very
simple and efficient synthesis of Linezolid (7a) and
other oxazolidinone derivaitives 7(b-e) strating
from 3-fluoro -4-morpholinyl aniline (2).
This growing problem has recently
rekindled interest in the search for new antibiotic
structural classes that inhibit or kill by novel
mechanisms6. Clearly this encourages the
scientists for discovery and development of effective
agents against the emerging problematic Gram-
positive pathogens MRSA, methicillin-resistant

1016
REDDY et al., Orient. J. Chem., Vol. 29(3), 1015-1019 (2013)
RESULTS AND DISCUSSION
H bending), 1301 (C-N stretching), 1273 (C-O
bending), 1259, 1225 (C-F bending), 1167, 1112
The synthetic strategy is shown in (aliphatic C-C stretching), 744 (C-Cl stretching); 1H
Scheme-1. The R-epichlorohydrin (2) reacted with NMR (DMSO-d6) δ ppm: 6.88 (m, 1H), 6.43 (m, 2H),
3-fluoro-4-marpholinyl aniline (1) in methanol at 60- 3.94 (m, 1H), 3.80 (m, 4H), 3.62 (m, 2H), 3.26 (m,
o
65 C and the crude adduct was allowed to react 1H), 3.10 (m, 1H), 2.93 (m, 4H); MS: 289 (M+ +H).
with carbonyl diimidazole in dichloromethane at (5R)-5-(Chloromethyl)-3-[3-fluoro-4-(4-
ambient temperature to furnish the compound (4) morpholinyl)phenyl]-2-oxazolidinone (4):
which upon condensation with potassium
phthalimide in dimethylformamide at reflux
Carbonyl diimidazole (3.2 g, 0.019 mol)
temperature afforded oxazolidinone phthalimide (5). was added to a solution of N-[3-Chloro-2-(R)-
By the treament of (5) with hydrazinehydrate and hydroxypropyl]-3-fluoro-4-morpholinylaniline (3)
the corresponding anhydrides and acid chlorides (5.7g,0.019mol) in dichloromethane (60mL).The
produced Linezolid derivatives 7(a-e).
reaction mixture was then stirred at room
temperature for 20 h.The solution was washed with
In conclusion, we have achieved a general water (60 mL) and concentrated to afford compound
and very reliable synthesis of Linezolid and its (5R)-5-(Chloromethyl)-3-[3-fluoro-4-(4-
derivatives via., chiral oxazolidinones starting from morpholinyl)phenyl]-2-oxazolidinone (4). Yield:
3-fluoro-4-morpholinyl aniline (1) with a cheap and 77%.
readily available (R)-epichlorohydrin (2) in good
yields (Table-1).The structures of all the target (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-
1
compounds were confirmed by IR, H NMR, C13 oxo-5-oxazolidinyl]methyl]phthalimide (5)
NMR and Mass Spectral data.
A solution of (5R)-5-(Chloromethyl)-3-[3-
fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone (4)
(6.0 g, 0.019 mol) in N,N-Dimethylformamide (40
mL) was added potassium phthalimide (4.0 g, 0.021
EXPERIMENTAL
Melting points were determined on Stuart mol), and the reaction mixture was heated to reflux
SMP-30 apparatus and are uncorrected. The IR and stirred for 5 h. The reaction mixture was cooled
spectra were recorded in the solid state as KBr to ambient temperature and diluted with water (200
dispersion media using a Perkin-Elmer model 1600 mL).The precipitated solid was filtered off and dried
Fourier
transform
infrared
(FT)-IR to give compound (5).Yield:62%.IR(KBr, cm-1):3026
spectrophotometer. 1H NMR and 13C NMR spectra (aromatic C-H stretching), 2982, 2952, 2908
were recorded using a 300-MHz Bruker Avance (aliphatic C-H stretching), 1737, 1716 (C=O
spectrometer. Chemical shifts values are expressed stretching), 1628, 1571, (aromatic C=C stretching),
in δ (ppm) using TMS as the internal standard. The 1475, 1466 (aliphatic C-H bending), 1385, 1325
liquid chromatography-mass spectrometry (LC-MS) (C-N stretching), 1276, 1253 (C-O stretching), 1170,
was performed on a 2010 EV mass spectrometer.
1115 (C-F stretching), 1050,1006 (aromatic C-H
bending).1H NMR (DMSO-d6) δ ppm: 7.88 (m, 4H),
Procedure for N-[3-Chloro-2-(R)-hydroxypropyl]- 7.43 (m, 1H), 7.15 (m, 1H), 7.06 (m, 1H), 4.93 (m,
3-fluoro-4-morpholinylaniline (3) 1H), 4.04 (m, 4H), 3.46 (m, 4H), 2.95 (m, 4H); MS:
3-Fluoro-4-morpholinyl aniline (1) (1.08 g, 426 (M+ +H).
0.005 mol) was added to a stirred solution of R-
epichlorohydrin (2) (0.46 g, 0.005 mol) in methanol (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-
(10 mL). The mixture was heated to reflux for 16 h oxo-5-oxazolidinyl]methyl]amine (6)
and concentrated to give thick liquid (3).
Hydrazine hydrate (2.0g, 0.04 mol) was
added to a solution of (S)-N-[[3-[3-Fluoro-4-[4-
I R (KBr, cm-1): 3382 (O-H stretching), 3068 morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]
(aromatic C-H stretching), 2960 (aliphatic C-H phthalimide (5) (4.0 g, 0.009 mol) in methanol (25
stretching), 1582 (aromatic C=C stretching), 1520, mL).The reaction mixture was heated to reflux and
1451 (N-H, O-H bending), 1377, 1319 (aliphatic C- stirred for 1 h. The mass was cooled to ambient

REDDY et al., Orient. J. Chem., Vol. 29(3), 1015-1019 (2013)
1017
temperature, and diluted with water (50 mL) and
extracted with dichloromethane (30 mLx2). The
combined organic extracts were washed with water
(30 mL) and concentrated to give (6).Yield: 90%. IR
(KBr, cm-1): 3579, 3377, (N-H stretching), 3293
(aromatic C-H stretching), 2954, 2893, 2846,
(aliphatic C-H stretching), 1734 (C=O stretching),
1625, 1572 (aromatic C=C stretching), 1519, 1480
(N-H bending), 1381, 1332 (aliphatic C-H bending),
1273, 1256, 1231 (C-N stretching), 1194, 1176 (C-
O stretching), 1114 (C-F stretching), 1066, 1048
(aromatic C-H bending). 1H NMR (DMSO-d6) δ ppm:
7.51 (m, 1H), 7.20 (m, 1H), 7.05 (t, 1H), 4.59 (m,
1H), 3.92 (m, 2H), 3.73 (m, 4H), 2.95 (m, 4H), 2.80
(m, 2H), 1.63 (s, 2H); MS: 296 (M+ +H).
dropwise to a stirred solution of (S)-N-[[3-[3-Fluoro-
4 - [ 4 - m o r p h o l i n y l ] p h e n y l ] - 2 - o x o - 5 -
oxazolidinyl]methyl]amine (6) (2.5 g, 0.008 mol) in
ethyl acetate (20 mL) at ambient temperature and
the reaction mixture was allowed to stirred for 1 h.
The reaction mixture was cooled to 0-5°C. The
precipitated solid was filtered off and re-crystallized
from methanol (20 mL) to give the corresponding
compounds (7a-b).
N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-
oxo-5-oxazolidinyl]methyl]acetamide (7a)
IR (KBr, cm-1):3338 (N-H stretching), 3117,
3066 (aromatic C-H stretching), 2971, 2863, 2818
(aliphatic C-H stretching), 1738, 1662 (C=O
stretching), 1545, 1516,1453 (aromatic C=C
stretching), 1425 (C-N stretching), 1381 (aliphatic
C-H bending), 1334 (C-F stretching), 1274 (C-O
stretching), 1198, 1177 (C-N bending), 1117, 1081
(aromatic C-H bending).1H NMR (CDCl3) δ ppm:
7.44 (m, 1H), 7.26 (m, 1H), 6.99 (m, 1H), 6.01 (t,1H),
4.76 (m, 1H), 4.02 (m, 2H), 3.80 (m, 4H), 3.61(m,
2H), 3.05 (m, 4H), 2.02 (t, 3H): C13NMR(CDCl3) δ
ppm: 171.33, 156.87, 154.44, 136.40, 132.84,
General procedure for N-[[(5S)-3-[3-fluoro-
4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl] acetamide (7a) and N-[[(5S)-3-[3-fluoro-4-
(4-morpholinyl)phenyl)
-2-oxo-5-oxazolidinyl]methyl]propanamide(7b)
A solution of acetic anhydride and
propionic anhydride (0.020 mol) was added
Scheme 1:

1018
REDDY et al., Orient. J. Chem., Vol. 29(3), 1015-1019 (2013)
118.67, 113.81, 107.52, 71.96, 66.76, 50.79, 47.46, (CDCl3) δ ppm: 173.86, 156.23, 154.09, 135.46,
41.68, 22.81. MS: 338 (M++H);
119.15, 113.99, 106.42, 71.62, 66.19, 50.13, 47.31,
41.42, 28.40, 9.91. MS: 352 (M++H);
N-[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl)-2-
oxo-5-oxazolidiny]methyl}propanami de(7b)
General procedure for (S)- N-(3-[3-fluoro-4-
IR (KBr, cm-1): 3342 (N-H stretching), 3073 morpholinophenyl]-2-oxo-5-oxazolidinyl]
(aromatic C-H stretching), 2896, 2857, 2824 methyl]amides 7(c-e)
(aliphatic C-H stretching), 1743, 1660 (C=O
To a stirred mixutre of (S)-N-[[3-[3-Fluoro-
stretching), 1543, 1516 (aromatic C=C stretching), 4-[4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl]
1467, 1423 (NH bending), 1334 (aliphatic C-H methyl]amine (6) ( 0.001 mol) in toluene(15 mL)
bending), 1272, 1256 (C-N stretching), 1228 (C-F was added triethylamine slowly at room
stretching), 1196 (C-O stretching), 1118 (C-C temperature. Added corresponding acid chlorides
1
stretching). H NMR (CDCl3) δ ppm: 8.14-8.28 (m, (valeryl chloroide, n-hexanoyl chloride and n-
0
1H), 7.45-7.51 dd, 1H), 7.15 -7.19 (m, 1H), 7.03- heptanoyl chloride) (0.001 mol) at 0-5 C . The
7.09 (m,1H), 4.68-4.73 (m, 1H), 4.04 - 4.10 (t, 1H), reaction mixture was stirred for 3 h at room
3.67-3.74 (m, 5H), 3.38-3.42 (m, 2H), 2.93-2.96 (t, temperature. The separated solid was filtered and
4H), 2.05-2.12 (q, 2H), 0.92-0.97 (t, 3H). C13 NMR washed with toluene (15 mL). The resulting solid
Table 1: Characterization data of linezolid dervatives 7(a-e)
Compound
R
Mol.Formula
Mp / 0C
Yield / %
7a
7b
7c
7d
7e
-CO-CH3
-CO-CH2CH3
-CO-(CH2)3CH3
-CO-(CH2)4CH3
-CO-(CH2)5CH3
C16H20FN304
C17H22FN304
C19H26FN304
C20H28FN304
C21H30FN304
181-182
174-176
152-158
152-154
156-158
87
67
65
60
65
was recrystallized from methanol produced the (S)- N-(3-[3-fluoro-4-morpholinophenyl]-2-oxo-5-
corresponding compounds 7(c-e).
oxazolidinyl]methyl]hexanamide 7(d)
IR (KBr, cm-1): 3339 (N-H stretching), 3061
(S)-N-(3-[3-fluoro-4-morpholinophenyl]-2-oxo-5- (aromatic C-H stretching), 2950, 2934, 2861
oxazolidinyl]methyl]pentanamide 7(c) (aliphatic C-H stretching), 1742, 1660 (C=O
IR (KBr, cm-1): 3344 (N-H stretching), 3100 stretching), 1547, 1518 (aromatic C=C stretching),
(aromatic C-H stretching), 2955, 2934, 2863 1466, 1427 (N-H bending), 1381,1334 (aliphatic
(aliphatic C-H stretching), 1741, 1660 (C=O C-H bending), 1274, 1256 (C-N stretching), 1227
stretching), 1547, 1519 (aromatic C=C stretching), (C-F stretching), 1196,1180(C-O stretching), 1116
1445, 1427 (N-H bending), 1380,1334 (aliphatic (C-C stretching). 1H NMR (CDCl3) ´ ppm: 8.19-8.23
C-H bending), 1273, 1256 (C-N stretching), 1228 (t, 1H), 7.46 -7.51 (m, 1H), 7.14 -7.17 (m, 1H), 7.03-
(C-F stretching), 1195,1177(C-O stretching), 1116 7.09 (m, 1H), 4.70-4.74 (m, 1H), 4.05 - 4.11 (t, 1H),
(C-C stretching). 1H NMR (CDCl3) δ ppm: 7.41-7.46 3.66 -3.73 (m, 5H), 3.43-3.51 (m, 2H), 2.93-2.95 (m,
(dd, 1H), 7.11 (s, 1H), 7.04 -7.07 (m, 1H), 6.87-6.93 4H), 2.04-2.09 ( t, 2H), 1.36-1.46 (m, 2H), 1.14-1.18
(t, 1H), 4.76-4.83 (m, 1H), 4.02 - 4.06 (t, 1H), 3.84- (m, 4H), 0.74-0.79 (t, 3H). C13 NMR (CDCl3) δ ppm:
3.87 (t, 4H), 3.69-3.81(m, 1H), 3.57-3.61 (m, 2H), 173.23, 156.26, 154.09, 135.41, 133.43, 119.16,
3.02-3.04 (t, 4H), 2.20-2.25 (t, 2H),1.49-1.59(m, 113.86, 106.30, 71.65, 66.20, 50.73, 47.15, 41.23,
2H),1.20-1.32(m, 2H), 0.80-0.84 (t, 3H). C13 NMR 35.30, 30.83, 25.08, 21.90, 13.75: MS:394 (M++H).
(CDCl3) δ ppm: 174.47, 156.78, 154.38, 136.05,
132.74, 118.50, 113.58, 106.94, 71.93, 66.66, (S)- N-(3-[3-fluoro-4-morpholinophenyl]-2-oxo-5-
50.70, 47.33, 41.46, 35.83, 27.60, 22.08, 13.49: MS: oxazolidinyl]methyl]heptanamide 7(e)
380 (M++H);
IR (KBr, cm-1): 3348 (N-H stretching), 3060

REDDY et al., Orient. J. Chem., Vol. 29(3), 1015-1019 (2013)
1019
(aromatic C-H stretching), 2954, 2864, 2821
(aliphatic C-H stretching), 1744, 1660 (C=O
stretching), 1546, 1517 (aromatic C=C stretching),
1448, 1425 (N-H bending), 1379,1333 (aliphatic
C-H bending), 1274, 1252 (C-N stretching), 1227
(C-F stretching), 1197,1177(C-O stretching), 1115
(C-C stretching). 1H NMR (CDCl3) δ ppm: 8.19-8.22
(t, 1H), 7.46 -7.52 (dd, 1H), 7.14 -7.17 (m, 1H), 7.02-
7.08 (m,1H), 4.70-4.74 (m, 1H), 4.04 - 4.10 (t, 1H),
3.71 -3.74 (m, 4H), 3.66-3.69 (m, 1H), 3.43-3.52
(m, 2H), 2.93-2.96 (m, 4H), 2.04-2.08 (t, 2H),1.38-
1.40 (m, 2H), 1.13 (m, 6H), 0.77-0.82 (t, 3H). C13
NMR (CDCl3) δ ppm: 173.24, 156.26, 154.07,
135.39, 133.42, 119.08, 113.81, 106.27, 71.66,
66.21, 50.75, 47.13, 41.19, 35.35, 31.09, 28.33,
25.38, 21.97, 13.91: MS: 408 (M++H).
ACKNOWLEDGMENTS
We wish to thank Dr.B.Parthasarathi
Reddy, Chairman, Hetero Drugs for constant
encouragement and Hetero Analytical Department
for providing spectra.
REFERENCES
1.
2.
Chu, D. T.W.; Plattner, J. J.; Katz, L. New
Directions in Antibacterial Research. J. Med
Chem. 39: 3853-3874 (1996).
Swartz, M. N. Hospital-acquired Infections:
Diseases with Increasingly Limited
Therapies. Proc. Natl. Acad. U.S.A. 91: 2420-
2427 (1994).
Tomasz, A. Multiple-Antibiotic-Resistant
Pathogenic Bacteria. N. Engl. J. Med., 330:
1247-1251 (1994).
Fekete, T. Bacterial Genetics, Antibiotic
Usage, and Public Policy: The Crucial
Interplay in Emerging Resistance. Perspect.
Biol. Med. 38: 363-382 (1995).
emerging resistance. Perspect. Biol. Med.
1995, 38, 363-382.
Brumfitt, W.; Hamilton-Miller, J. M. T. The
7.
challenge
of
methicillin-resistant
Staphylococcus aureus. Drugs Exp. Clin.
Res. 20: 215-224 (1994).
8.
9.
Neu, H. C. Quinolone Antimicrobial Agents.
Annu. Rev. Med. 43: 465-468 (1992).
Blumberg, H. M.; Rimland, P.; Carroll, D. J.;
Terry, P.; Wach-smuth, I. K. Rapid
Development of Ciprofloxacin Resistance in
Methicillin-Susceptible and -Resistant
Staphylococcus aureus. J. Infect. Dis., 163:
1279-1285 (1991).
3.
4.
5.
6.
Spera, Jr, R. V.; Farber, B. F. Multidrug-
Resistant Enterococcus faecium: An
Untreatable Nosocomial Pathogen. Drugs.
48: 678 (1994).
Fekete, T.Bacterial genetics, antibiotic usage
and public policy; the crucial interplay in
10.
Eustic, D.C.;Feldman, P.A.;Zajac, I.;Slee, A.
M. Mechanism of action of DuP 721:
inhibition of an early event during initiation
of protein synthesis. Antimicrob. Agents
Chemother. 32: 1218-1222 (1988).