A convenient synthesis of oxazolidinone derivatives linezolid and eperezolid from (S)-glyceraldehyde acetonide

Article abstract of DOI:10.1002/hc.20435

A new convenient method for the synthesis of oxazolidinone antibacterials Linezolid and Eperezolid from readily available (S)-glyceraldehyde acetonide was developed. The key steps include reductive amination of arylamine and (S)-glyceraldehyde acetonide in the presence of NaBH₄ and 4 A sieve, followed by hydrolysis and regioselective cyclization.

Full text of DOI:10.1002/hc.20435

Heteroatom Chemistry
Volume 19, Number 3, 2008
A Convenient Synthesis of Oxazolidinone
Derivatives Linezolid and Eperezolid from
(S)-Glyceraldehyde Acetonide
Guangyu Xu,1 Yi Zhou,1 Chunhao Yang,2 and Yuyuan Xie2
1Institute of Chemistry and Chemical Engineering, Hunan Normal University,
Changsha 410081, People’s Republic of China
2Shanghai Institute of Materia and Medica, Chinese Academy of Sciences,
Shanghai 201023, People’s Republic of China
Received 7 June 2007; revised 26 August 2007
cillin resistant Staphylococcus aureus) and VRE
ABSTRACT: A new convenient method for the syn-
thesis of oxazolidinone antibacterials Linezolid and
Eperezolid from readily available (S)-glyceraldehyde
acetonide was developed. The key steps include reduc-
tive amination of arylamine and (S)-glyceraldehyde
(Vancomycin-resistant Enterococci) [2–4]. Linezolid
has recently received approval for the treatment of
community- and hospital-acquired pneumonia and
skin structure infections.
Several methods are available for the synthe-
sis of Linezolid and Eperezolid. Brickner et al. [2]
and Schaus and Jacobson [5] reported separately a
route to oxazolidinones with good yields. However,
in these methods for the synthetic key step to oxazo-
lidinone ring, severe conditions with low tempera-
ture (−78◦C) and an air-sensitive base (n-BuLi) were
required, which limit the large-scale production in
the industry. Lohray et al. [6] offered another possi-
bility to oxazolidinones via asymmetric bis-epoxide
using D-mannitol as a starting material. However,
the synthesis of asymmetric bis-epoxide suffers from
a long-synthetic route and was reported without any
optical data.
˚
acetonide in the presence of NaBH4 and 4 A sieve,
followed by hydrolysis and regioselective cycliza-
ꢀ
C
tion.
2008 Wiley Periodicals, Inc. Heteroatom Chem
19:316–319, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20435
INTRODUCTION
Oxazolidinones as a new class of synthetic an-
timicrobial agents are active against numerous
multidrug-resistant Gram-positive organisms [1].
Linezolid 1a and Eperezolid 1b (Fig. 1), which are
well known as the promising candidates of this fam-
ily, work effectively against numerous serious Gram-
positive human pathogens such as MRSA (Methi-
We wish to report herein a very convenient
and efficient method for the synthesis of Line-
zolid and Eperezolid, using readily available (S)-
glyceraldehyde acetonide as a chiral-building block.
Correspondence to: Guangyu Xu; e-mail: gyxu@hunnu.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
RESULTS AND DISCUSSION
Contract grant number: 20602010.
Contract grant sponsor: Hunan Provincial Natural Science
Foundation of China.
The synthesis of Linezolid and Eperezolid share
a common route, as detailed in Scheme 1. (S)-
Glyceraldehyde acetonide (3) was easily obtained
Contract grant number: 06JJ50024.
c
ꢀ
2008 Wiley Periodicals, Inc.
316

Convenient Synthesis of Oxazolidinone Derivatives Linezolid and Eperezolid from (S)-Glyceraldehyde Acetonide 317
manipulation [2] provided the targeted antibacterial
Eperezolid with good yield. The final product’s melt-
ing points and specific rotation data were identical
to those reported in the literature.
In summary, we describe herein a simple, mild,
FIGURE 1 Linezolid (1a) and Eperezolid (1b).
and facile synthesis of Linezolid and Eperezolid
from (S)-glyceraldehyde acetonide with reductive
amination and regioselective cyclization as key steps
with good yields.
from L-ascorbic acid (vitamin C) via hydrogena-
tion [7], acetonation, and oxidative cleavage [8,9].
Reductive amination of fluoroarylamine 2 with 3 in
˚
the presence of NaBH4 and 4 A molecular sieve at
EXPERIMENTAL
room temperature afforded dioxolanes 4 with good
yields. The yields were considerably poor when Pd/C
or Raney Ni was used as a catalyst in the reductive
amination step, because unstable (S)-glyceraldehyde
acetonide may polymerize during long reaction time.
The addition of molecular sieve to NaBH4 system
could shorten the reaction time and minimize the
polymerization of glyceraldehyde acetonide in the
solvent. After hydrolysis of dioxolanes 4 in aqueous
HCl/methanol, the regioselective cyclization with
triphosgene in the presence of K2CO3 afforded ox-
azolidinones 5. However, if NaOH [10] or triethy-
lamine was used as an acid scavenger, the byprod-
uct 5c could form. The key intermediate 5 was ac-
tivated as mesylate and then displaced with NaN3
to give 6. Hydrogenation of the azide 6a over Pd/C
and then treatment with Ac2O provided the targeted
antibacterial Linezolid. In our laboratory, we tried
to synthesize 1a via direct displacement of mesy-
late by acetamide anion in DMF or THF, and the
yield was very low (10%) because 5a mesylate was
unstable and degraded under this condition. Reduc-
tive acetylation of azide 6b with thioacetic acid [11]
gave acetamide 7. The compound 7 after side-chain
Melting points were determined with a Bu¨chi 510
melting point apparatus and are uncorrected. 1H
and 13C NMR spectra were recorded in CDCl3 on a
Bruker-300 NMR spectrometer, and chemical shifts
δ are in ppm (TMS was used as an internal stan-
dard). EI mass spectra were accomplished at 70 eV,
using a MAT 90 spectrometer. Microanalyses were
performed on a Leco CHN-2000 elemental analyzer.
Optical rotations were taken on a Perkin-Elmer 341
polarimeter at the sodium-D line. Purification by col-
umn chromatography was carried out with silica gel
60 (70–230).
N-[4(R)-(2,2-Dimethyl-1,3-dioxolane-4-yl)methyl]-
3-fluoro-4-morpholinylaniline (4a). A solution of
2a (5.00 g, 25.5 mmol) and 3 (6.00 g, 46.1 mmol)
in 25 mL THF and 25 mL methanol was added
˚
6.25 g of molecular sieves (4 A), then NaBH4 (0.97 g,
25.6 mmol) was added portionwise. The mixture
was stirred for 10 h at room temperature, ice water
(150 mL) was added, and the molecular sieves were
removed by filtration. The filtrate was extracted
+
˚
SCHEME 1 Reagents and conditions: (a) NaBH4, MeOH, 4 A MS, r.t., 78%; (b) (i ) H3O , MeOH, r.t.; (ii) K2CO3, triphosgene,
CH2Cl2, 30◦C, 80%; (c) CH3SO2Cl, triethylamine, CH2Cl2, 0◦C → r.t., 88%; (d) NaN3, DMF, 80◦C, 90%–92%; (e) (i) Pd/C, H2,
EtOH, r.t.; (ii) pyridine, Ac2O, r.t., 51%; (f) CH3COS H, r.t., 75%; (g) Pd/C, MeOH/EtOAc, r.t.; (h) ClCOCH2OBn, triethylamine,
CH2Cl2, 0◦C → r.t.; (i) Pd/C, H2, MeOH, 73%.
Heteroatom Chemistry DOI 10.1002/hc

318 Xu et al.
with ethyl acetate (50 × 3 mL) was and dried with
Na2SO4. After removal of the solvent, 6.74 g of 4a
as a pale yellow oil was obtained without further
purification. The analytic sample was obtained by
chromatography on a silica-gel column (mobile
phase PE/EtOAc from 6:1 to 4:1). [α]2D0–1.7◦ (c 4.54,
the residue was purified by crystallization from
ethyl acetate and petroleum ether to provide 2.84
g (56% from 2a) of 5a as a light gray amorphous
solid. mp 114–116◦C, [α]D20–53◦ (c 0.69, CHCl3) (lit.
1
[2] mp 112–114◦C, [α]D20–54◦ (c 0.990, CHCl3)); H
NMR(CDCl3): δ 7.47 (dd, 1H, J = 2.1, 14.4 Hz), 7.12
(dt, 1H, J = 2.4, 8.9 Hz), 7.00 (br s, 1H), 4.75 (m,
1H), 3.95 (m, overlapping, 3H), 3.88 (t, 4H, J = 4.7
Hz), 3.76 (d, 1H, J = 13.1 Hz), 3.08 (t, 4H, J = 4.2
Hz), 2.35 (br s, 1H); MS: m/z 296 (100, M+), 238
(55), 149 (20), 57 (36); Anal. calcd for C14H17FN2O4:
C, 56.75; H, 5.78; N, 9.45. Found: C, 57.02; H, 5.78;
N, 9.28.
1
CHCl3); H NMR(CDCl3): δ 6.84 (t, 1H, J = 8.2 Hz),
6.39 (m, 2H), 4.35 (m, 8 lines, 1H), 4.09 (dd, 1H,
J = 7.1, 8.3 Hz), 3.84 (t, 4H, J = 4.7 Hz), 3.75 (dd,
1H, J = 6.0, 8.2 Hz), 3.24 (dd, 1H, J = 3.7, 12.3 Hz),
3.13 (dd, 1H, J = 6.6, 12.5 Hz), 2.95 (br s, 4H), 1.44
(s, 3H), 1.37 (s, 3H); 13C NMR (CDCl3): δ 25.24,
26.86, 46.92, 51.73, 67.07, 67.12, 74.32, 101.70 (d,
J = 24.35 Hz), 108.50, 109.50, 120.25, 130.99, 144.77
(d, J = 9.56 Hz), 156.94 (d, J = 244.71 Hz); MS: m/z
310 (61, M+), 219 (12), 209 (100), 151 (16).
(R)-[N-3-[3-Fluoro-4-[N-1-(4-carbobenzoxy)pipe-
razinyl]-phenyl]-2-oxo-5-oxazolidinyl]methanol (5b).
Yield 78%, mp 155–157◦C, [α]D20–35◦ (c 1.01, CHCl3),
(lit. [2] mp 156–157◦C, [α]D20–32◦ (c 0.991, CHCl3));
1H NMR (CDCl3): δ 7.52 (d, 1H, J = 14.4 Hz), 7.36
(m, 5H), 7.12 (m, 2H), 5.16 (s, 2H), 4.75 (m, 1H),
4.00 (m, 3H), 3.73 (m, 5H), 3.07 (br s, 4H).
Compounds 4b was prepared by using the
method described for the preparation of 4a except
that the 4b was recrystallized from petroleum ether
and ethyl acetate.
N-[4(R)-(2,2-Dimethyl-1,3-dioxolane-4-yl)methyl]-
3-fluoro-4-(N-carbobenzoxypiperazinyl) Aniline (4b).
Yield 78%, mp 92.5—94◦C, [α]D20–1.0◦ (c 1.14, CHCl3);
1H NMR (CDCl3): δ 7.35 (m, 5H), 6.81 (t, 1H, J = 7.6
Hz), 6.36 (m, 2H), 5.16 (s, 2H), 4.35 (m, 8 lines,
1H), 4.10 (dd, 1H, J = 6.4, 8.3 Hz), 3.91 (br s, 1H),
3.76 (dd, 1H, J = 6.1, 8.2 Hz), 3.63 (br s, 4H), 3.25
(dd, 1H, J = 4.2, 12.5 Hz), 3.13 (dd, 1H, J = 6.7,
12.6 Hz), 2.89 (br s, 4H), 1.45 (s, 3H), 1.37 (s,
3H); 13C NMR (CDCl3): δ 25.24, 26.86, 44.00, 46.86,
51.33, 67.06, 67.16, 74.29, 101.57 (d, J = 24.35
Hz), 108.51, 109.52, 120.88, 127.89, 128.02, 128.48,
130.71, 136.61, 145.09, 155.18, 157.03 (d, J = 245.06
Hz); MS: m/z 443 (96, M+), 342 (25), 245 (66), 187
(27), 151 (24), 127 (20), 91 (100); Anal. calcd for
C24H30FN3O4: C, 64.99; H, 6.82; N, 9.47. Found: C,
65.02; H, 6.79; N, 9.39.
6a and 6b were prepared according to the
method described in [2].
(R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl]methyl Azide (6a). Yield 79% (from
1
5a). H NMR (CDCl3): δ 7.45 (dd, 1H, J = 2.5, 14.3
Hz), 7.13 (ddd, 1H, J = 1.1, 2.6, 8.9 Hz), 6.95 (t, 1H,
J = 9.1 Hz), 4.78 (m, 1H), 4.05 (t, 1H, J = 8.8 Hz),
3.88 (t, 4H, J = 4.6 Hz), 3.83 (dd, 1H, J = 6.2, 8.8
Hz), 3.71 (dd, 1H, J = 4.6, 13.3 Hz), 3.59 (dd, 1H,
J = 4.3, 13.1 Hz), 3.06 (t, 4H, J = 4.6 Hz).
(R)-[N-3-[3-Fluoro-4-[N-1-(4-carbobenzoxy)pipe-
razinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl
Azide
(6b). Yield 81% (from 5b). 1H NMR (CDCl3): δ 7.46
(dd, 1H, J = 2.6, 14.3 Hz), 7.35 (m, 5H), 7.12 (ddd,
1H, J = 0.8, 2.5, 8.6 Hz), 6.93 (t, 1H, J = 9.1 Hz),
4.78 (m, 8 lines, 1H), 4.05 (t, 1H, J = 8.8 Hz), 3.83
(dd, 1H, J = 6.3, 8.9 Hz), 3.68 (m, 5H), 3.59 (dd, 1H,
J = 4.4, 13.2 Hz), 3.01 (br s, 4H); MS: m/z 454 (14,
M+), 424 (38), 329 (32), 289 (16), 165 (16), 91 (100),
56 (37).
(R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl]methanol (5a). A solution of benza-
mine (4a, 4.56 g) in dry HCl methanol (4 M, 40 mL)
was added 0.5 mL of water, the mixture was stirred
at room temperature for 8 h, and concentrated
with rotary evaporator, the residue was diluted with
methyl chloride (35 mL) then added aq. Na2CO3
solution (15%, 40 mL, 56.5 mmol). The mixture was
cooled to 0◦C and treated dropwise with a solution of
triphosgene (1.30 g, 4.38 mmol) in methyl chloride
(35 mL) for 30 min. After being stirred for 24 h at
room temperature, the water phase was separated
and extracted with methyl chloride (50 × 2 mL). The
combined organic phase was washed with water
(25 × 2 mL) and dried with anhydrous Na2SO4. The
solvent was evaporated at reduced pressure, and
(S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl]methyl]acetamide (1a, Linezolid). 1a
was prepared according to the method described in
[2], except that the solvent was replaced by ethanol
when reductive hydrogenation of azide 6a. Yield
51% (from 6a). mp 179–180.5◦C, [α]D20–10◦ (c 1.52,
CHCl3) (lit. [2] mp 181.5–182.5◦C, [α]D20–9◦ (c 0.919,
1
CHCl3); H NMR (CDCl3): δ 7.46 (dd, 1H, J = 2.2,
14.6 Hz), 7.08 (dd, 1H, J = 1.8, 9.1 Hz), 6.96 (t, 1H,
J = 9.1 Hz), 6.05 (t, 1H, J = 6.0 Hz), 4.77 (m, 1H),
Heteroatom Chemistry DOI 10.1002/hc

Convenient Synthesis of Oxazolidinone Derivatives Linezolid and Eperezolid from (S)-Glyceraldehyde Acetonide 319
4.02 (t, 1H, J = 8.9 Hz), 3.88 (t, 4H, J = 4.5 Hz),
REFERENCES
3.73 (dd, 1H, J = 1.8, 7.0 Hz), 3.69 (dd, 1H, J = 3.2,
5.9 Hz), 3.61 (dt, 1H, J = 5.5, 8.5 Hz), 3.07 (t, 4H,
J = 4.6 Hz), 2.02 (s, 3H); MS: m/z 337 (27, M+), 293
(25), 234 (20), 209 (26), 149 (50), 91 (100); Anal.
calcd for C16H20FN3O4: C, 56.97; H, 5.98; N, 12.46.
Found: C, 57.16; H, 6.03; N, 12.22.
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(S)-N-[[3-[3-Fluoro-4-[N-1-(4-hydroxyacetyl)pipe-
razinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]aceta-
mide (1b, Eperezolid). 1b was prepared from 6b
according to the method described in [2,11], yield
55% (from 6b). mp 172–174◦C, [α]D20–20◦ (c 0.93,
DMSO), (lit. [2] mp 175–176◦C, [α]D20–21◦ (c 0.853,
1
DMSO); H NMR (CDCl3): δ 7.50 (dd, 1H, J = 2.5,
14.0 Hz), 7.08 (d, 1H, J = 8.7 Hz), 7.00 (t, 1H, J = 9.0
Hz), 6.06 (t, 1H, J = 2.7 Hz), 4.77 (m, 1H), 4.21 (s,
2H), 4.02 (t, 1H, J = 9.0 Hz), 3.87 (t, 2H, J = 5.1
Hz), 3.75 (dd, 1H, J = 6.8, 9.1 Hz), 3.62 (m, 2H),
3.48 (t, 2H, J = 5.0 Hz), 3.09 (t, 4H, J = 4.3 Hz), 2.01
(s, 3H); MS: m/z 394 (28, M+), 350 (56), 306 (27),
165 (26), 56 (100). Anal. calcd for C18H23FN4O5 C,
54.82; H, 5.88; N, 14.21. Found: C, 54.86; H, 5.99; N,
13.98.
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Heteroatom Chemistry DOI 10.1002/hc