A convenient synthesis of the antibacterial agent linezolid

Article abstract of DOI:10.1016/j.tetlet.2015.10.082

Starting with 3,4-difluorobenzoic acid (8) and (S)-epichlorohydrin (13) a convergent synthesis of linezolid (1) was developed that is attractive for large scale preparation of the drug. The synthetic strategy involves a 1+3 cycloaddition reaction between the chiral epoxide 11 (prepared from 13) and isocyanate 3 (obtained from 8) that was generated in situ by a Curtius rearrangement. The resulting Schiff base precursor of linezolid (12) crystallized from the reaction mixture and was readily converted to linezolid by an acid-catalyzed hydrolysis followed by an acetylation.

Full text of DOI:10.1016/j.tetlet.2015.10.082

Tetrahedron Letters 56 (2015) 6846–6847
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient synthesis of the antibacterial agent linezolid
⇑
James R. McCarthy
Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting with 3,4-difluorobenzoic acid (8) and (S)-epichlorohydrin (13) a convergent synthesis of line-
zolid (1) was developed that is attractive for large scale preparation of the drug. The synthetic strategy
involves a 1+3 cycloaddition reaction between the chiral epoxide 11 (prepared from 13) and isocyanate
3 (obtained from 8) that was generated in situ by a Curtius rearrangement. The resulting Schiff base pre-
cursor of linezolid (12) crystallized from the reaction mixture and was readily converted to linezolid by
an acid-catalyzed hydrolysis followed by an acetylation.
Received 17 September 2015
Revised 16 October 2015
Accepted 26 October 2015
Available online 27 October 2015
Keywords:
Linezolid
Ó 2015 Elsevier Ltd. All rights reserved.
Curtius rearrangement
1+3 cycloaddition
Introduction
Linezolid (1) is a member of the first new class of antibacterial
agents, the oxazolidinones, to be placed on the market in the last
quarter century. Linezolid is active against most Gram-positive
organisms and vancomycin-resistant enterococcus. The drug inhi-
bits protein synthesis early in the biosynthesis process and utilizes
a new mechanism for its antibacterial activity.1 For these reasons
much attention has been given to developing new and efficient
routes for the synthesis of linezolid.2 Most reported methods start
with hazardous 3,4-difluoronitrobenzene that is converted to iso-
cyanate 3 or the benzyl carbamate 4 via the aniline 2 (Fig. 1).3
The synthesis of isocyanate 3 requires phosgene and the issues
involved are discussed by Perrault.2 Routes that utilize 4 require
conversion of this material to the anion with potassium t-butoxide
or n-butyl lithium.3,4
We wish to report a facile route to linezolid that utilizes 3,4-
difluorobenzoic acid5 (8) as a starting material, avoids the isolation
of an isocyanate and utilizes a 1+3 cycloaddition6 to form the oxa-
zolidinone core structure (Scheme 1). Treatment of 3,4-difluo-
robenzoic acid with excess morpholine at reflux provides 9 as a
white precipitate on acidification of the reaction in 77% yield after
recrystallization. We found this method to be complementary to
the report by Sumoto and co-workers3d but eliminates the use of
DMSO on a large scale. The acid (9) was readily converted to
3-fluoro-4-morpholinobenzoyl azide (10), which was isolated as
a white crystalline solid in 92% yield. For the next step in the
synthesis it was envisioned that benzoyl azide 10 would undergo
Figure 1. Intermediates in published syntheses of linezolid.
a Curtius rearrangement, forming the isocyanate 3 in the reaction
mixture, and undergo a 1+3 cycloaddition with epoxide 11.
Indeed treatment of a mixture of 10 and 11 in refluxing xylene
with lithium bromide and tri-n-butylphosphine oxide gave the
desired N-aryloxazolidone 122 as a highly crystalline mass on cool-
ing the reaction mixture in 71% yield. This convergent step in the
synthesis offers a substantial advantage for this route to the drug3
(Scheme 1). The epoxide 11 (Scheme 2) was prepared by treating
(S)-epichlorohydrin (13) with 4-chlorobenzaldehyde and ammo-
nium hydroxide to give the intermediate chlorohydrin 142 in 75%
yield as a crystalline solid. Chlorohydrin 14 was converted to epox-
ide 11 in quantitative yield. It should be noted that treatment of
⇑
Corresponding author. Tel.: +1 317 274 3642; fax: +1 317 274 4701.
E-mail address: jarmccar@iupui.edu
http://dx.doi.org/10.1016/j.tetlet.2015.10.082
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. R. McCarthy / Tetrahedron Letters 56 (2015) 6846–6847
6847
In summary we have developed a convergent synthesis of line-
zolid (1), four steps from 8 with two additional steps to prepare
chiral epoxide 11, utilized for the synthesis of 12 (at the conver-
gent step). The synthesis proceeds in an overall yield of 44% from
commercially available 3,4-difluorobenzioic acid. The pivotal inter-
mediate, Schiff base 12, was obtained by a 1+3 cycloaddition utiliz-
ing the Curtius rearrangement to generate the isocyanate in situ
and react with the chiral epoxide 11. The Schiff base 12 was iso-
lated as a crystalline solid from the reaction mixture and no col-
umn chromatography was required for the synthesis.9
Acknowledgements
The author is thankful to Professor Martin J. O’Donnell and Dr.
Geno Samaritoni for helpful discussions and encouragement.
Supplementary data
Supplementary data (synthetic procedures and spectral data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.10.082.
Scheme 1. Synthesis of linezolid (1): Reagents and conditions: (a) morpholine,
reflux 3 h, acidify (77%); (b) (i) PCl5, CH2 Cl2; (ii) NaN3, acetone water (86%); (c)
xylene, LiBr, n-Bu3P@O (71%); (d) (i) aq HCl, CH2Cl2; (ii) Ac2O (84%).
References and notes
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Barbachyn, M. R.; Hutchinson, D.; Manninen, P. R. J. Med. Chem. 2008, 51, 1981–
1990.
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R. J.; Anderson, R. M.; Ghazal, N.; Secreast, S. L.; Pearlman, B. A. The Development
of a Convergent Green Synthesis of Linezolid, an Oxazolidinone Antibacterial
Agent. In Scalable Green Chemistry; Koenig, S. G., Ed.; Pan Stanford: Singapore,
2013. Chapter 7.
3. (a) Zhang, X.; Zhao, C.; Gu, Y. J. Heterocycl. Chem. 2012, 49, 1143–1146; (b)
Reddy, G. M.; Ramulu, A.; Reddy, P. P. Lett. Org. Chem. 2010, 7, 45–49; (c) Zhang,
X.; Chen, W.; Li, C.; Wu, X. J. Chem. Res. 2009, 739–740; (d) Fujisaki, F.; Abe, N.;
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O.; Rajesh, T.; Ramanatham, J.; Dubey, P. F. K. Tetrahedron Lett. 2008, 49, 3060–
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Scheme 2. Synthesis of 11. Reagents and conditions: (a) 4-chlorobenzaldehyde,
NH4OH, EtOH, 40 °C, 6 h (75%); (b) K2CO2, MeOH, rt, 2 h (100%).
epoxide 11 with isocyanate 3 under similar reaction conditions as
with 10 also gave 12.
Our approach to the oxazolidinone core structure (i.e., 12)
avoids a CuI-catalyzed Buchwald coupling protocol that yields 67
4. See: Manninen, P. R.; Brickner, S. J. Org. Synth. 2004, 8, 112–120. for an example
and discussion on the utilization of N-aryl carbamates to prepare
oxazolidinones.
or 7.3f Conversion of
6 to linezolid required four steps to
introduce the N-acetyl amide and two column purifications.7 The
conversion of 7 to linezolid utilized a reductive acylation with
thioacetic acid.3g Intermediate 6 was also prepared3h utilizing the
anion of benzyl carbamate 4 generated with n-butyl lithium
followed by treatment with (R)-glycidyl butyrate.
5. AmplaChem Inc.
6. Herweh, J. E.; Kauffman, W. J. Tetrahedron Lett. 1971, 809–812
It should be noted that that epoxide 11 has to be opened with bromide before
the cycloaddition can occur and the reaction is therefore a two-step process.
7. Mallesham, B.; Rajesh, B. M.; Reddy, P. R.; Srinivas, D.; Trehan, S. Org. Lett. 2003,
5, 963–965.
8. See Supplementary data for the synthesis of (R) linezolid.
9. McCarthy, J. R. Processes for Preparing Linezolid. U.S. Patent Appl. 20130053557,
Feb 28, 2013.
The N-aryloxazolidone 12 was converted to linezolid (1) (99%
ee) in 84% yield by an acid catalyzed hydrolysis of the Schiff base
followed by an acetylation with acetic anhydride. Enantiomeric
purity of 1 was determined by chiral chromatography utilizing
(R)-linezolid as a reference standard.8