A facile synthesis of the oxazolidinone antibacterial agent linezolid

Article abstract of DOI:10.1016/j.cclet.2013.01.039

A facile synthetic route of linezolid 1 has been developed. Using commercially available (R)-epichlorohydrin as the starting material, 1 was obtained through a sequence of cyclization, substitution, a Goldberg coupling, aminolysis and acetylation reactions. The synthetic route is easy to perform and can be scaled up.

Full text of DOI:10.1016/j.cclet.2013.01.039

Chinese Chemical Letters 24 (2013) 230–232
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Chinese Chemical Letters
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Original article
A facile synthesis of the oxazolidinone antibacterial agent linezolid
*
Yan-Wu Li, Yan Liu, Yun-Can Jia, Jian-Yong Yuan
Institute of Life Science & Pharmacy College, Chongqing Medical University, Chongqing 400016, China
A R T I C L E I N F O
A B S T R A C T
facile synthetic route of linezolid
Article history:
A
1 has been developed. Using commercially available (R)-
epichlorohydrin as the starting material, 1 was obtained through a sequence of cyclization, substitution,
a Goldberg coupling, aminolysis and acetylation reactions. The synthetic route is easy to perform and can
Received 7 December 2012
Received in revised form 13 December 2012
Accepted 8 January 2013
be scaled up.
Available online 7 March 2013
ß 2013 Jian-Yong Yuan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Linezolid
Synthesis
Goldberg coupling reaction
1. Introduction
could be obtained from aryl isocyanides (4) and (R)-glycidylbu-
tyrate (3). The preparation of aryl isocyanate is cumbersome from
The alarming rate of emerging and reemerging microbial
threats coupled with the increasing antibacterial resistance in
hospitals is major concerns to the public health and scientific
communities worldwide, especially with regard to the multidrug-
resistant Gram-positive bacteria [1–3]. The N-aryloxazolidinones
represent a latest class of antibacterials that emerged in the last
four decades, having potent activity against multidrug-resistant
Gram-positive bacteria [4,5]. Linezolid (1) is an important
representative of the N-aryloxazolidinones. Extensive research
efforts led to the discovery and introduction of linezolid (1) (Fig. 1)
in clinical use against hospital- and community-acquired pneu-
monia, skin infections and diabetic foot infections caused by Gram-
positive bacterial strains [6]. For these reasons, much attention has
been given to the synthesis of linezolid and several synthetic
methods for linezolid were developed.
Most methods reported involve the construction of the
oxazolidinone as a key step in the synthesis of 5-substituted
3-aryloxazolidinones [7–12]. A common strategy for the prepara-
tion of 5-aminomethyl-3-aryl oxazolidinone in the linezolid is to
deprotonate the aryl carbamate (2) with BuLi and react the
resulting anion with (R)-glycidylbutyrate (3) to give the corre-
sponding 5(S)-hydroxymethyl oxazolidinone. The lithium anion of
the carbamate was necessary to obtain a useful yield of the desired
oxazolidinone. In an alternative strategy, the aryl oxazolidinone
aryl amines. Other methods reported in literature [13,14] involve
metal-catalyzed coupling reactions between aryl halides (5) and
oxazolidinone (6). This strategy took advantage of the pioneering
work by Buchwald and Hartwig [15,16]. Recently, Buchwald
reported a landmark development in the Goldberg coupling
reaction using CuI for the amidation of aryl halides [17,18]. The
procedure, in addition to being cost-effective, could also tolerate
some functional groups that would be otherwise problematic in
palladium-catalyzed coupling reactions. But the reactions reported
in which oxazolidinone were coupled with aryl iodides using CuI
gave only modest yields [19]. To generalize the Goldberg coupling
reaction using CuI for the amidation of aryl halides, Trehan has
developed an efficient and higher yielding CuI-mediated
N
arylation of oxazolidinone using the Buchwald protocol [20]. To
overcome these limitations, a convenient synthetic method of
linezolid by the Goldberg coupling reaction from commercially
available (R)-epichlorohydrin and aryl bromide as the key step is
reported in this paper (Scheme 1).
2. Experimental
(R)-5-(Chloromethyl)oxazolidin-2-one (8): A mixture of 120 g
(0.1 mol) of magnesium sulfate and 1 g (1 mmol) of sodium
cyanate in 500 mL water at 60 8C was added 46.3 g (0.5 mol) of (R)-
epichlorohydrin dropwise over 30 min, keep the warm for 1 h, the
water was removed under reduced pressure and then added ethyl
acetate (500 mL), the mixture was filtered and the filter cake was
washed with ethyl acetate (2ꢀ 200 mL), the combined ethyl
* Corresponding author.
E-mail address: enediyne@163.com (J.-Y. Yuan).
1001-8417/$ – see front matter ß 2013 Jian-Yong Yuan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.039

Y.-W. Li et al. / Chinese Chemical Letters 24 (2013) 230–232
231
O
F
with ethyl acetate (3ꢀ 40 mL), the combined organic layers were
dried (Na2SO4) and the concentrate was purified by chromatogra-
phy on silica gel column (ethyl acetate:hexane = 1:2) to give 16.2 g
O
F
O
O
R
O
1
O
N
N
H
N
O
R
O
N
NH
Ac
(76%) of 10, mp 204–206 8C. 1H NMR (300 MHz, CDCl3):
d 3.05
3
Linezolid 1
F
2
(t, 4H, J = 3.4 Hz), 3.85–3.89 (m, 5H), 3.98 (dd, 1H, J1 = 10.6 Hz,
J2 = 4.3 Hz), 4.09 (t, 1H, J = 6.6 Hz), 4.14 (dd, 1H, J1 = 10.6 Hz,
J2 = 5.0 Hz), 4.98 (m, 1H), 6.92 (t, 1H, J = 6.8 Hz), 7.11 (dd, 1H,
J1 = 6.8 Hz, J2 = 1.9 Hz), 7.41 (dd, 1H, J1 = 10.6 Hz, J2 = 1.9 Hz), 7.78
(m, 2H), 7.88 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 40.8, 48.5, 51.1,
67.1, 69.7, 107.6 (d, J = 19.5 Hz), 114.1 (d, J = 2.3 Hz), 118.9
(d, J = 3 Hz), 123.8, 131.8, 133.1 (d, J = 8.2 Hz), 134.6, 136.6
(d, J = 6.7 Hz), 153.9, 155.5 (d, J = 183.7 Hz), 168.1.
O
F
NH
O
N
N C O
O
N
X
R
2
6
4
5
Fig. 1. Structures of linezolid and compounds 2–6.
acetate were dried (Na2SO4) and concentrated to give a yellow
liquid, which was cooled to 0 8C and crystallized of 8 as a white
solid, the obtained solid was recrystallized from ethyl acetate to
(S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazo-
lidin-2-one (11): A solution of 8.5 g (0.02 mol) of 10 in 100 mL
methanol was added 6.9 g (0.11 mol) of 80% hydrazinium
hydroxide, the mixture was heated at reflux temperature for 1 h
and cooled to ambient temperature (the reaction produced a large
white byproduct). The mixture was filtered and the filtrate
removed the methanol in vacuo, extracted with methylene
dichloride (3ꢀ 30 mL) and water (50 mL). The combined organic
layers were dried (Na2SO4) and the concentrate was purified by
chromatography on silica gel column (ethyl acetate:metha-
nol = 10:1) to give 4.2 g (71%) of 11. 1H NMR (300 MHz, CDCl3):
give 46 g (67.8%). mp 64–65 8C. 1H NMR (300 MHz, CDCl3):
d 3.48
(dd, 1H, J1 = 6.6 Hz, J2 = 4.6 Hz), 3.56 (t, 1H, J = 6.6 Hz), 3.80 (dd, 1H,
J1 = 8.9 Hz, J2 = 3.7 Hz), 3.89 (dd, 1H, J1 = 8.9 Hz, J2 = 3 Hz), 4.84 (m,
1H), 7.62 (s, 1H), 7.88 (m, 2H). 13C NMR (75 MHz, CDCl3):
43.8, 73.4, 168.1.
d 40.8,
(R)-2-((2-Oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (9): A
solution of 27 g (0.2 mol) of 8 in 500 mL DMF was treated with
40.8 g (0.22 mol) of potassium phthalimide, the mixture was
heated to 80 8C for 12 h, the reaction was cooled to ambient
temperature, diluted with 2 L of water and extracted with
methylene dichloride (3ꢀ 200 mL), the combined organic layer
was washed with saturated sodium chloride solution followed and
then dried (Na2SO4), the solution was evaporated in vacuo to
obtained a white solid, which was stirred with ethyl acetate and
petroleum ether to get product 34.4 g (70%) of 9 as a white solid,
d
1.47 (s, 2H), 2.98 (dd, 1H, J1 = 10.3 Hz, J2 = 4.3 Hz), 3.05 (t, 4H,
J = 3.5 Hz), 3.11 (dd, 1H, J1 = 10.3 Hz, J2 = 3 Hz), 3.82 (t, 1H,
J = 6.1 Hz), 3.87 (t, 4H, J = 3.5 Hz), 4.01 (t, 1H, J = 6.1 Hz), 4.68
(m, 1H), 6.93 (t, 1H, J = 6.8 Hz), 7.14 (dd, 1H, J1 = 6.8 Hz, J2 = 1.8 Hz),
7.45 (dd, 1H, J1 = 10.1 Hz, J2 = 1.8 Hz). 13C NMR (75 MHz, CDCl3):
d
45.1, 47.8, 51.1, 67.1, 73.9, 107.4 (d, J = 20.2 Hz), 113.8 (d, J = 3 Hz),
118.9 (d, J = 3 Hz), 133.5 (d, J = 22.5 Hz), 136.4 (d, J = 3.7 Hz), 154.7,
155.6 (d, J = 183.7 Hz), 171.4.
mp 195–197 8C. 1H NMR (300 MHz, CDCl3):
d 3.2 (dd, 1H,
J1 = 6.6 Hz, J2 = 4.3 Hz), 3.72 (t, 1H, J = 6.6 Hz), 3.91 (dd, 1H,
J1 = 10.6 Hz, J2 = 4.2 Hz), 4.10 (dd, 1H, J1 = 10.6 Hz, J2 = 5.2 Hz),
4.97 (m, 1H), 7.75 (m, 2H), 7.88 (m, 2H). 13C NMR (75 MHz, CDCl3):
(S)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-
yl)methyl)acetamide (1): A mixture of 2.95 g (10 mmol) of 11 and
2 g (20 mmol) of triethylamine in 50 mL methylene dichloride was
added slowly 0.95 g (12 mmol) of acetyl chloride at 0 8C, the
reaction remove the room temperature for 1 h. The mixture was
washed with water (50 mL) and dried (Na2SO4). The concentrate
was purified by chromatography on silica gel column (ethyl
acetate:methanol = 10:1) to give 2.86 g (85%) of 1 as a white solid,
d
42.6, 46.3, 73.9, 158.2.
(S)-2-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-
yl)methyl)isoindoline-1,3-dione (10): A mixture of 14.8 g (60 mmol)
of 9 in 300 mL of anhydrous dioxane under nitrogen was added
13 g (50 mmol) of 4-(4-bromo-2-fluorophenyl)-morpholine, 0.48 g
(2.5 mmol) of CuI, 0.58 g (5 mmol) of (+)-trans-1,2-diaminocyclo-
hexane and 13.9 g (0.1 mol) anhydrous potassium carbonate, the
mixture was allowed to stir at reflux for 20 h. The solution was
cooled to ambient temperature, which was filtered and the filtrate
concentrated in vacuo, diluted with water (100 mL) and extracted
mp 181–183 8C. 1H NMR (300 MHz, CDCl3):
d 2.02 (s, 3H), 3.05
(t, 4H, J = 3.4 Hz), 3.59–3.69 (m, 2H), 3.75 (dd, 1H, J = 6.7 Hz,
J = 1.7 Hz), 3.87 (t, 4H, J = 3.4 Hz), 4.02 (t, J = 6.7 Hz, 1H), 4.48 (m,
1H), 6.36 (t, 1H, J = 4.6 Hz), 6.92 (t, 1H, J = 6.8 Hz), 7.06 (dd, 1H,
J1 = 6.8 Hz, J2 = 1.8 Hz), 7.42 (dd, 1H, J1 = 10.7 Hz, J2 = 1.8 Hz). 13C
NMR (75 MHz, CDCl3):
d 23.1, 41.9, 47.7, 51.0, 67.1, 72.1, 107.6
(d, J = 20.2 Hz), 114.0 (d, J = 3 Hz), 118.9 (d, J = 3.7 Hz), 133.0
(d, J = 7.5 Hz), 136.6 (d, J = 6.7 Hz), 154.4, 155.5 (d, J = 183.8 Hz),
171.4.
O
O
O
O
a
b
O
O
Cl
NH
NH
N
Cl
O
7
8
3. Results and discussion
O
9
F
After a detailed survey of the previous results, we chose
commercially available chiral (R)-epichlorohydrin (7) as a starting
material (Scheme 1), which was reacted with NaOCN to afford (R)-
chloromethyl-2-oxazolidinone (8) as a key intermediate. Follow-
ing a classical method [21] for the introduction of amino groups,
the compound (8) was reacted with potassium phthalimide by an
SN2 nucleophile substitution reaction to produce the correspond-
ing phthalimide (9). A Goldberg coupling reaction between amide
(9) and aryl halide (4-(4-bromo-2-fluorophenyl)morpholine) using
CuI as a catalyst afforded the coupled product (10). Amine (11) was
obtained by the deprotection of the phthalimide (10) using
aqueous NH2NH2. Finally, treatment of the amine (11) with Ac2O in
the presence of pyridine provided linezolid (1). The physical and
spectroscopic data of linezolid (1) were in complete agreement
with the reported values.
O
c
O
d
O
N
N
N
10
O
O
O
F
F
e
O
O
O
N
N
O
N
N
H2N
HN
Linezolid1
11
Ac
Scheme 1. (a) NaOCN, 60 8C; (b) potassium phthalimide, DMF, 80 8C; (c) 4-(4-
bromo-2-fluorophenyl)morpholine, CuI (5 mmol%), (Z)-1,2-diaminocyclo-hexane
(10 mol%), dioxane, K2CO3, 110 8C; (d) hydrazine hydrate (80%), MeOH, reflux; (e)
methylene dichloride, Et3N, DCM, r.t.

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Y.-W. Li et al. / Chinese Chemical Letters 24 (2013) 230–232
the potential treatment of multidrug-resistant gram-positive bacterial infections,
4. Conclusion
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(2006) 1264–1268.
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In conclusion, we have developed an efficient and facile
synthetic method to synthesize linezolid 1 using the Goldberg
coupling reaction as a key step from (R)-2-(chloromethyl)oxirane
in five steps in a total yield of 22%. Compared to the known
methods, this route is more straightforward to operate with a
lower cost of goods.
Acknowledgment
This work was supported by Natural Science Foundation Project
of CQ CSTC.
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