JOURNAL OF CHEMICAL RESEARCH 2009
DECEMBER, 739–740
RESEARCH PAPER 739
An efficient and practical synthesis of antibacterial linezolid
Xingxian Zhang*, Wei Chen, Cheng Li and Xiang Wu
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310032, P. R. China
A convergent and efficient synthesis of linezolid was developed using the cycloaddition of commercially available
(R)-epichlorohydrin with morpholine substituted phenylisocyanate catalysed by MgI2 or MgBr2 etherate as the key
step in the 50% overall yield.
Keywords: (R)-epichlorohydrin, isocyanate, MgI2 etherate, linezolid
Oxazolidinones,a new class of synthetic antibacterial agents,
exhibit activity against a large number of Gram-positive
organisms and vancomycin-resistant enterococcus.1,2 Their
mode of action is by inhibition of protein synthesis at an early
step.3,4 Linezolid (1), the only oxazolidinone approved by the
FDA, became the first compound commercialised worldwide
from the oxazolidinone class of antibacterials.5-8 Linezolid
(Zyvox) was introduced into the market which led to the
need for a high-yielding, economical and environmentally
sound process.
In conclusion, we have described a highly-efficient and gentle
method for the preparation of antibacterial linezolid using
the cycloaddition of (R)-epichlorohydrin with substituted
phenylisocyanate 4 catalysed by MgI2 or MgBr2 etherate as
the key step. Further synthetic application of MgI2 or MgBr2
etherate-catalysed cycloaddition of epoxide with isocyanate
into natural producuts and drugs is ongoing in our lab.
Experimental
For product purification by flash column chromatography, silica
gel (200–300 mesh) and light petroleum ether (PE, b.p. 60–90°C)
were used. 1H NMR spectra were taken on a Bruker Avance-500
spectrometer with TMS as an internal standard and CDCl3 as solvent.
The reactions monitoring was accomplished by TLC on silica gel
polygram SILG/UV 254 plates. Melting points were measured on
BUCHI B-540 and uncorrected. FT-IR was recorded on a Bruker
The first synthesis of linezolid from (5S)-5-(hydroxymethyl)
oxazolidin-2-one, which was obtained by the reaction of
aryl carbamate with (R)-glycidyl butyrate in the presence
of butyllithium, was reported by Manninen.1 A modified
synthetic method via (2S)-1-amino-3-chloropropan-2-
ol coupling with aryl carbamates to give (5S)-N-aryl-5-
(aminomethyl)oxazolidin-2-one promoted by lithium tert-
butoxide has been developed.9 Very recently, BF3•Et2O-
promoted regioselective and stereospecific intramolecular
ring opening of 2-(boc-aminomethyl)aziridines was applied
to the preparation of enantiopure linezolid.10 However, not
all methods are practical on a large scale, due primarily to
the overall low yields, high costs of reagents, large number
of steps involved, or poor conversion of the oxazolidinone
cyclisation. Thus, development of a more convergent, practical
and rapid preparation of linezolid was highly desirable.
As shown in Scheme 1, treatment of morpholine with
3,4-difluoronitrobenzene in ethanol under reflux produced
compound 2, which was followed by hydrogenation. Amine
3 reacted with bis(trichloromethyl)carbonate (triphosgene,
BTC) to give isocyanate 4. Cycloaddition of isocyanate 4
with (R)-epichlorohydrin catalysed by 50 mol% MgI2 etherate
or MgBr2 etherate at 65°C in THF exclusively afforded the
desired enantiopure cycloadduct 5 in 96% yield. Then 5 was
transformed into azide 6 under treatment of sodium azide
in 86% yield. Azide 6 was subjected to hydrogenation and
acetylation to provide linezolid 1 in 90% yield over two steps.
1
Tensor 27 spectrometer. All compounds were identified by H NMR
and are in good agreement with those reported.
3-fluoro-4-(morpholin-4-yl)phenylisocyanate (4):11 To a solution
of 3-fluoro-4-(morpholin-4-yl-aniline 3 (30 mmol, 5.88 g) in toluene
(150 mL) was added dropwise a solution of bis(trichloromethyl)
carbonate (16.5 mmol, 4.9 g) in 50 mL toluene at room temperature.
Then the reaction mixture was refluxed for 4 h. After removal of the
solvent, the residue was distilled to give the desired product 4 (5.35 g)
under reduced pressure in 80% yield. IR (film) υ (cm−1) 3072, 2970,
2837, 2321(N=C=O), 1648 (C=O), 1518, 1451, 1239(C–O), 1115 (C–F).
(5R)-5-(chloromethyl)-3-(3-fluoro-4-(morpholin-4-yl)phenyl)
oxazolidin-2-one (5):12 To a stirred solution of freshly prepared
MgI2 etherate (2.5 mmol) in THF (10 mL) was added dropwise
(R)-epichlorohydrin (508 mg, 5.5 mmol) followed by addition of
substituted phenylisocyanate 4 (1.11 g, 5 mmol) at room temperature
under nitrogen. After addition, the reaction mixture was allowed
to warm to 65°C and continued to be stirred for 4 h. The resulting
homogeneous reaction mixture was quenched with saturated
Na2SO3 aqueous solution. Extractive workup with CH2Cl2 and flash
chromatographic purification of the crude product on silica gel gave
the compound 5 (931 mg) in 96% yield. White solid, m.p. 117.3–
118.3°C. dH 3.06 (t, J = 5.0 Hz, 4H), 3.73–3.81 (m, 2H), 3.87 (t,
J = 5.0 Hz, 4H), 3.91 (dd, J = 6.0, 9.0 Hz, 1H), 4.12 (t, J = 9.0 Hz,
1H), 4.84–4.89 (m, 1H), 6.94 (t, J = 9.0 Hz, 1H), 7.14 (dd, J = 2.0,
9.0 Hz, 1H), 7.44 (dd, J = 2.5, 14.5 Hz, 1H). m/z (EI): 314 ([M]+,
100), 316 ([M + 2]+, 33), 256 (67), 177 (52), 149 (51). HRMS (EI)
Calcd for C14H16ClFN2O3: 314.0833, found for [M] +: 314.0816.
F
F
F
F
ii
iii
i
O
O
N
NH2
O
N
N C O
O
NH
+
O
N
NO2
F
NO2
80%
85%
98%
4
2
3
F
O
F
F
O
vi
iv
v
O
N
N
O
O
N
N
O
N
N
O
O
96%
86%
90%
Cl
NH
N3
1
5
6
O
Scheme 1 Reagents and conditons: i, EtOH, reflux; ii, H2, 5%Pd-C, EtOH, room temperature; iii, BTC, toluene, reflux;
iv, (R)-epichlorohydrin, MgI2 etherate or MgBr2 etherate, THF, 65°C; v. NaN3, DMF, 85°C; vi, (1) H2, 5%Pd–C, EtOAc;
(2) Ac2O, Et3N, room temperature.
* Correspondent. E-mail: zhangxx@zjut.edu.cn
PAPER: JC090731
JCR_12_2009 Book.indb 739
11/12/2009 15:36