A new practical synthesis of linezolid: An antibacterial drug

Article abstract of DOI:10.2174/157017810790533878

A novel and practical asymmetric synthesis of (S)-N-[[3-(3-fluoro-4- morpholinyl phenyl)-2-oxo-5-oxazo- lidinyl]methyl]acetamide has been developed by a new approach without recourse to chromatography and it is employed for the synthesis of Linezolid. This involves the reaction of (R)-epichlorohydrin with N-arylcarbamates and subsequent regioselective epoxide ring opening of resulted intermediate by sodium azide.

Full text of DOI:10.2174/157017810790533878

Letters in Organic Chemistry, 2010, 7, 45-49
45
A New Practical Synthesis of Linezolid: An Antibacterial Drug
Ganta Madhusudhan Reddy*, Akula Ramulu and Padi Pratap Reddy
Research and Development, Innovation Plaza, Integrated Product Developement, Dr. Reddy’s Laboratories Ltd., Survey
Nos 42, 45,46 and 54, Bachupally, Qutubullapur, R. R. Dist. 500 072, India
Received August 21, 2009: Revised November 23, 2009: Accepted November 24, 2009
Abstract: A novel and practical asymmetric synthesis of (S)-N-[[3-(3-fluoro-4-morpholinyl phenyl)-2-oxo-5-oxazo-
lidinyl]methyl]acetamide has been developed by a new approach without recourse to chromatography and it is employed
for the synthesis of Linezolid. This involves the reaction of (R)-epichlorohydrin with N-arylcarbamates and subsequent
regioselective epoxide ring opening of resulted intermediate by sodium azide.
Keywords: Linezolid, antibacterial drug, asymmetric synthesis, regioselective epoxide ring opening, one pot synthesis.
INTRODUCTION
(5R)-(hydroxymethyl)-2-oxazolidinone (7). Activation as the
mesylate 8 and then displacement with NaN3 yielded azide
derivative 9, whose catalytic hydrogenolysis of azide
derivative 9 with 10% Pd/C followed by acetylation with
acetic anhydride yielded 1.
Bacterial resistance development has become a very
serious clinical problem for many classes of antibiotics. The
3-aryl-2-oxazolidinones are a relatively new class of
synthetic antibacterial agents, having a new mechanism of
action which involves very early inhibition of bacterial
protein synthesis [1,2]. Only the oxazolidinone enantiomer
F
O
with
a
(5S)-acetamidomethyl configuration possesses
N
O
antibacterial activity [3]. They have potent activity against a
variety of Gram-positive bacterial pathogens including
methicillin-resistant Staphylococcus aureas (MRSA) and
vancomycin-resistant Enterococci (VRE) [4]. Linezolid (1,
Zyvox®, Pharmacia Upjohn) is currently the only
antibacterial agent which can be administered orally (as well
as intravenously) with strong activity against MRSA. It may
be particularly useful as an alternative to vancomycin, in
patients whose renal function is impaired, in cases of patients
with poor or lack of intravenous access and in patients who
require outpatient therapy, or who do not tolerate
N
O
NH
O
1
This process suffers from disadvanges such as (a) a
multistep synthesis for compound 1 (8 steps from compound
2); (b) The use of (R)-glycidylbutyrate reagent is expensive
and reaction has to be carried out at -78 °C and (c) addition
of n-BuLi via syringe, which on large scale manufacturing
process may pose handling difficulties.
glycopeptides [5-8]. The oxazolidones have
a novel
mechanism of action that involves inhibition of protein
synthesis as an early and unique step [2,9]. For these
reasons, much attention has been given to the synthesis of
these classes of compounds.
Several other methods are available for the synthesis of
linezolid and eperezolid. Gregory et al. [3] reported a
method of producing oxazolidinones, which comprises
reacting an isocyanate (R-N=C=O) with (R)-glycidylbutyrate
in the presence of a catalytic amount of lithium bromide-
tributylphosphine oxide complex to produce the corres-
ponding 5(R)-butyryloxymethyl substituted oxazolidinone.
The process was performed at 135-145 °C. The relative high
cost and/or availability of the isocyanate starting material
and requirement of high temperature detract significantly
from the attractiveness of this method.
Linezolid (1) was earlier prepared by a route described in
Scheme 1 [1,10]. The synthesis involves nucleophilic
aromatic displacement (SNAr reaction) of the 4-fluoro group
of 2 with excess morpholine (3) in the presence of N,N-
diisopropylethylamine to give 3-flouro-4-morpholinylnitro
benzene (4). The nitro functionality of 4 was reduced using
10% Pd/C and ammonium formate to produce 3-flouro-4-
morpholinylaniline (5) and subsequent attachment of a
carbobenzyloxy (Cbz) to the arylamines
intermediate 6. Deprotonation of carbamate 6 with n-BuLi in
THF at -78 °C and reaction with (R)-glycidylbutyrate yielded
5 provided
Fischer and Sweden [11] disclosed a method for
converting primary alcohols to amines in a sealed reaction
vessel under high pressure. It is also known that the
mesylates of primary alcohols react with aqueous ammonia
to give the corresponding primary amines, but high
temperature and high pressure (85 psg) are required [11].
Normally this process cannot be used in ordinary general
purpose reactors and must be run in special reactors rated for
high pressure.
*Address correspondence to this author at the Research and Development,
Innovation Plaza, Integrated Product Developement, Dr. Reddy’s
Laboratories Ltd., Survey Nos 42, 45,46 and 54, Bachupally, Qutubullapur,
R. R. Dist. 500 072, India; Tel: +91 9959098098;
E-mail: madhusudanrg@drreddys.com
DRL-IPD Communication number. IPDOIPM-00108.
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

46
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Reddy et al.
O
N
O
N
O
N
F
F
O
F
F
F
a
b
c
+
N
H
NO2
NH2
HN
O
NO2
2
5
3
4
O
6
O
N
O
N
O
N
O
N
O
N
F
F
F
F
F
g
f
e
d
h
N
N
N
O
N
N
O
O
O
O
O
O
O
O
O
N3
NH
OH
OMS
NH2
O
7
10
8
9
1
Scheme 1. Reagents and conditions: (a) N, N-diisopropylethylamine, EtOAc, CH2Cl2, 25-30 °C, overnight; (b) HCOONH4, Pd/C, THF, 0
°C, 2 h; (c) NaHCO3, benzylchloroformate, acetone, 0 °C, overnight; (d) (R)-glycidyl butyrate, n-BuLi, THF, -78 °C, 35 min; (e)
methanesulfonyl chloride, TEA, CH2Cl2, 0 °C, 20 min; (f) NaN3, DMF, 75 °C, 16 h; (g) 10% Pd/C, 24 h, 25-30 °C; (f) pyridine, Ac2O,
EtOAc, 0 °C, 30 min then 25-30 °C, 1 h.
Dostert et al. [12] reported a method of transforming 5-
hydroxymethyl substituted oxazolidinones to the
commercially available raw materials and reagents. To the
best of our knowledge, this new route is economically
advantageous over the earlier reported methods owing to the
use of less expensive raw materials like (R)-epichlorohydrin
thus circumventing the use of (R)-glycidylbutyrate.
corresponding 5(S)-aminomethyl substituted oxazolidinones
that involves treatment with methanesulfonyl chloride
followed by potassium phthalimide then treating with
hydrazine. This reaction sequence produces by-products (for
example 2,3-dihyro-1,4-phthalazinedione) which are difficult
to separate from the desired product.
Process for 3-fluoro-4-morpholinylnitrobenzene (4)
without Using of Base
Schaus and Jacobson reported [13]
a route to
In our approach, reaction has been conducted without
any base and avoided lot of multi solvent organic
extractions. The workup is simple and it involves that once
the reaction is completed, cool the reaction to 0-5 °C
followed by filteration at same temperature.
oxazolidinones with good yields. However, in these methods
for the synthetic key step to oxazolidinone ring, harsh
conditions with low temperature (-78 °C) and air sensitive
bases (n-BuLi or NaH) were required [14], which limit the
large-scale production in the industry. Lohary et .al. [15]
offered another possibility to oxazolidinones via asymmetric
bis-epoxide using D-mannitol as a starting material. Though,
the synthesis of asymmetric bis-epoxide suffers from a long-
synthetic route and was reported without any optical data.
Process for N-carboethyloxy intermediate (7) via (R)-
epichlorohydrin
We opted ethylchloroformate and (R)-epichlorohydrin as
key raw materials due to its commercial availability and low
cost. In our approach, attachment of an ethylchloroformate to
the aryl amines 5, deprotonation of carbamate 6 with
potassium carbonate in acetone at 50-55 °C and then reaction
with (R)-epichlorohydrin provided a novel intermediate 12.
RESULTS AND DISCUSSION
On the basis of above limitations, we devised a safe,
economically competitive new synthetic route for 1, which
was obtained from 2 in six steps using inexpensive,

A New Practical Synthesis of Linezolid
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
47
Process for Azide Derivative 9 via One Pot Synthesis
from 12
absorption spectrums were obtained using Perkin Elmer,
Spectrum One FT IR spectrophotometer with substances
being pressed in a KBr pellet. The mass analysis was
performed on AB-4000 Q-trap LC-MS mass spectrometer.
The melting points were determined by using the capillary
method on POLMON (Model no. M96). Solvent removal
was accomplished by a rotator evaporator operating at in-
house vacuum (40-50 Torr). The solvents and reagents were
used without further purification.
A general method for the preparation of oxazolidinone
derivative from the N-carboethyl oxyepoxide derivative was
developed. We have chosen to form an uncyclised 13
intermediate in situ and thus avoided the isolation of that
intermediate. We belived this would give the simplest
process for the intermediate 9. In our approach, a solution of
carboethyloxy intermediate 12 in methanol was added to a
mixture of ammonium chloride and sodium azide in water at
80-85 °C, so that regio selective epoxide ring opens and
followed by cyclisation takes place.
3-Fluoro-4-morpholinylnitrobenzene (4)
To a solution of 3 (81.6 g, 0.93 mol) in 2-propanol (250
mL) was added 2 (50 g, 0.31 mol) via an addition funnel
over a period of 4 h at 45-50 °C. The resulting suspension
was stirred at 35-40 °C for an additional 7 h. The progress of
the reaction was monitored by thin layer chromatography
(vide TLC) and then reaction mass was cooled to 0-5 °C.
Filtered the solid and washed with chilled 2-propanol (100.0
mL). Dried in vacuum oven to give a yellow solid 4 (Yield
65.6 g, 92 %). mp 121-126 °C; IR: (KBr, cm-1); 3023
(Aromatic C-H), 2909 (Aliphatic C-H), 1604 (Aromatic
Synthesis of Linezolid 1 via One Pot Synthesis from 9
A general method for the synthesis of N-acetylated
compound 1 from the azide derivative 9 was developed. In
our approach, isolation of amine intermediate 10 was
avoided, so that number of steps was reduced.
EXPERIMENTAL SECTION
1
C=C), 1516, 1328 (NO2); H NMR (CDCl3, 200 MHz): ꢀ
1
The H NMR spectra were measured in DMSO-d6 and
7.97 (ddd, J = 9.2 Hz, J’ = 2.6 Hz, J’’ = 2.6, 1H), 7.88 (dd, J
= 12.8 Hz, J’ = 2.6, 1H), 6.92 (t, J = 8.6 Hz, 1H), 3.88 (t,
4H), 3.28 (t, 4H); MS: m/z 227.4 [M+ + H].
CDCl3 using 200 MHz and 400 MHz on a Varian Gemini FT
NMR spectrometer; The 1H chemical shift values are
reported on the ꢀ ppm, relative to TMS (ꢀ = 0.00). Coupling
constants (J) are reported in hertz (Hz). The infrared
O
O
N
O
N
N
F
F
b
F
F
F
O
c or c'
O
d
a
+
N
H
NO2
NO2
NH
NH2
4
2
3
5
11
O
O
N
O
N
O
N
O
N
F
F
F
F
f
e
N
O
N
O
O
O
N
HO
13
O
N
O
NH
O
N3
O
O
N3
O
9
1
12
Scheme 2. Reagents and conditions: (a) i-PrOH, 45-50 °C, 7 h, 92%; (b) Raney Ni, H2 , EtOAc, 25-30 °C, 10 h, 93%; (c)
ethylchloroformate, K2CO3, acetone, 25-30 °C, 1.5 h, 90% or (c’) ethylchloroformate, TEA, DCM, 2 h, 25-30 °C, 87%; (d) (R)-
epichlorohydrin, K2CO3, acetone, 50-55 °C, 24 h, 60%; (e) NH4Cl, NaN3, MeOH, water, 80-85 °C, 2 h, 76%; (f) Raney Ni, H2, Ac2O, TEA,
EtOAc, 25-30 °C, 7 h. 77%.

48
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Reddy et al.
3-Fluoro-4-morpholinylaniline (5)
(S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazo-
lidinyl]methyl]acetamide (1)
To a solution of compound 4 (150 g, 0.66 mol) in
methanol (1500 mL) was added Raney Ni (8.1 g) and water
(21 mL), hydrogenated the solution for 10 h at 25-30 °C. On
completion of the reaction (vide TLC), the reaction mixture
was filtered through hyflow bed and distilled off ethyl
acetate up to 30 % of mass left in the round bottom flask.
The resulting mass was cooled to 10-15 °C and solid was
collected by filtration, dried in vacuum oven to afford 5 as a
brown solid (Yield 120.9 g, 93%).
To a solution of compound 9 (5.0 g 74 5.5 mmol), acetic
anhydride (2.0 g, 19 mmol) and triethylamine (3.2 g,
31mmol) in ethyl acetate (50 mL) was added Raney Ni (0.8
g) and the reaction mixture was hydrogenated in autoclave at
25-30 °C under hydrogen gas pressure 3 kg/cm2 over 7 h. On
completion of reaction (vide TLC), MeOH was added (25
mL) to the reaction mass and filtered through hyflow bed.
The clear filtrate was partially concentrated under reduced
pressure and the precipitated solid was filtered. This solid
was purified from a mixture of ethyl acetate and acetonitrile.
Dried the solid in a vacuum oven (20 mbr, 50 °C) to afford 1
as a white solid (Yield 3.67 g, 70%). mp. 181-182 °C {lit. [1]
mp: 181.5-182.5 °C} ; (KBr, cm-1): 3343 (N-H), 1741 (C=
O, Oxazolidinone); MS: m/z 338 [M+ + H], 360.1 [M+ + Na];
N-Carboethyloxy-3-fluoro-4-morpholinylaniline (11)
To a mixture of compound 5 (50 g, 0.25 mol) and sodium
carbonate (27 g, 1.0 mol) in DCM (200 mL) was added
ethylchloroformate (30 g, 0.27 mol) at 10-15 °C, and the
reaction mixture was stirred for 1.5 h at 25-30 °C. On the
completion of the reaction (vide TLC), the reaction mixture
was poured into water (200 mL) and extracted with DCM (2
X 250 mL). The organics portions were dried over
anhydrous sodium sulphate. Organics was distilled off
completely and the solid was isolated from n-hexane to
obtain 11 as a gray-purple solid (Yield 61.0 g, 90%). mp.
123-124 °C; IR (KBr, cm-1): 3248 (NH), 1717 (C=O) 1600,
20
SOR = [ꢀ] 20D= -9.4° (c 0.919 CHCl3) {lit. [1] [ꢀ] D = -9° (c
1
0.919 CHCl3)}; H NMR (CDCl3, 200 MHz): ꢀ 8.23 (t, J =
5.4 Hz, 1H), 7.48 (dd, J = 14.0 Hz, J’ = 2.4 Hz, 1H), 7.18
(dd, J = 8.8 Hz, J’ = 2.4 Hz, 1H), 7.05 (t, J = 9.4 Hz, 1H),
4.64-4.70 (m, 1H), 4.07 (t, J = 8.8 Hz, 1H), 3.69-3.73 (m,
4H), 3.4 (t, J = 5.2 Hz, 3H), 2.95 (t, J = 4.6 Hz, 4H), 1.83 (s,
3H); 13C NMR (DMSO-d6, 50 MHz) 22.39, 42.23, 47.28,
50.67 (d, J =3.05 Hz) 66.13, 71.52, 106.61 (d, J =26.2 Hz),
114.04 (d, J =3.0 Hz), 119.20 (d, J = 4.2 Hz), 133.41 (d, J =
10.6 Hz), 135.50 (d, J = 9.0 Hz), 154.02, 156.99 (d, J =
246.44 Hz), 169.98.
1510 (Aromatic C=C); MS m/z 269.0 [M+ + H] ; H NMR
(CDCl3, 200 MHz): ꢀ 7.27 (m, 1H), 6.93 (m, 2H), 6.59 (s,
1H), 4.21 (q, J = 14.2 Hz, J’ = 7 Hz, 2H), 3.86 (t, J = 4.2 Hz,
4H), 3.03 (t, J = 4.8 Hz, 4H), 1.30 (t, J = 7.2 Hz, 3H).
1
(R)-N-(3-Fluoro-4-morpholinylphenyl)oxiranylmehtyl
carbamic acid ethylester (12)
ACKNOWLEDGEMENT
We thank the management of Dr. Reddy’s Laboratories
Ltd for supporting this work. Authors wish to acknowledge
the colleagues of Analytical Research Department of Dr.
Reddy’s Laboratories Ltd for their excellent cooperation.
To a heterogeneous mixture of 11 (100 g, 0.37 mol) and
K2CO3 (160 g, 1.14 mol) in acetone (1000 mL) was added
(R)-epichlorohydrin (100 mL, 1.14 mol) over period of 1 h at
50-55 °C. Reaction was stirred over night at 50-55 °C, on
completion of reaction (vide TLC), the resulting mass was
filtered trough hyflow and filtrate was distilled off under
reduced pressure. The crude was extracted with n-hexane (4
X 800 mL) and the combined extractions were concentrated
to dryness below 50 °C to provide titled the compound as
crude. The solid was isolated from 2-propanol (150 mL) by
filtration and dried to afford 12 as a light yellow solid (Yield
73.0 g, 60%). IR (KBr, cm-1): 3546 (NH), 1698 (C=O); MS:
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