The synthesis of N-aryl-5(S)-aminomethyl-2-oxazolidinone antibacterials and derivatives in one step from aryl carbamates

Article abstract of DOI:10.1021/op034028h

Since 1993, a significant process research and development effort directed towards the large-scale synthesis of oxazolidinone antibacterial agents has been ongoing in both Early Chemical Process Research and Development, and Chemical Process Research and Development at Pharmacia. This work has led to the successful development of the current commercial process to produce Zyvox (linezolid), recently approved by the FDA as an antibacterial. While this synthesis is appropriate for the preparation of linezolid in particular, a more convergent and versatile synthesis was developed for the rapid preparation of numerous other oxazolidinone analogues. Toward this end, economical methods for the large-scale preparation of N-[(2S)-2-(acetyloxy)-3-chloropropyl]acetamide 3 and tert-butyl [(2S)-3-chloro-2-hydroxypropyl]carbamate 27 from commercially available (S)-epichlorohydrin via the common intermediate (2S)-1-amino-3-chloro-2-propanol hydrochloride 2a were developed. Also, general methods for coupling these reagents with N-aryl carbamates to give N-aryl-5(S)-aminomethyl-2-oxazolidinone derivatives in one step were developed. These reagents and procedures have proven widely applicable in the preparation of a diverse array of oxazolidinone analogues such as 23 and 28 in both process and medicinal chemistry research.

Full text of DOI:10.1021/op034028h

Organic Process Research & Development 2003, 7, 533−546
The Synthesis of N-Aryl-5(S)-aminomethyl-2-oxazolidinone Antibacterials and
Derivatives in One Step from Aryl Carbamates
William R. Perrault,*,§ Bruce A. Pearlman, Delara B. Godrej, Azhwarsamy Jeganathan,§ Koji Yamagata,§
Jiong J. Chen,§ Cuong V. Lu,§ Paul M. Herrinton,§ Robert C. Gadwood,† Lai Chan,‡ Mark A. Lyster,§ Mark T. Maloney,§
Jeffery A. Moeslein,§ Meredith L. Greene,† and Michael R. Barbachyn†
Early Chemical Process Research and DeVelopment, Chemical Process Research and DeVelopment, and
Medicinal Chemistry Research, Pharmacia Corporation, Kalamazoo, Michigan 49001, U.S.A.
Abstract:
lithium anion of the carbamate was required to obtain a useful
yield of the desired oxazolidinone. Using potassium or
sodium cations leads to formation of a mixture of 5- and
4-hydroxymethyl oxazolidinones as well as an unusual
4-arylaminomethyl-2-oxazolidinone.3 It was subsequently
found that (S)-chloropropanediol could be used as a substitute
for (R)-glycidyl butyrate with lithium tert-butoxide as base
and DMF or DMAc as solvent. Numerous methods of
activating the resulting hydroxyl and displacing with an
amine have been developed. The best method from a
commercial standpoint uses 3-nitrobenzenesulfonyl chloride
for the activation and a large excess of ammonia for the
subsequent displacement reaction.4 The nosylate leaving
group sufficiently accelerates the ammonia displacement
reaction to allow it to proceed at atmospheric pressure and
low temperature (40-50 °C). The low cost of aqueous
ammonia allows it to be used in large excess (∼100 equiv),
thus suppressing competing dimer formation and eliminating
the need for nitrogen protection and deprotection steps.
To reduce the number of steps from the aryl carbamate
to the desired 5(S)-aminomethyloxazolidinones, we began
exploring convergent early amination approaches. In these
routes a protected nitrogen is substituted for the hydroxyl in
the glycidol used in Manninen’s procedure, thus obviating
the need for the hydroxyl activation and ammonia displace-
ment steps. The benzylidene 1, was synthesized from
commercial Daiso (S)-epichlorohydrin, generally following
a literature procedure for preparing the racemate (Scheme
1).5 Monoacetylation and base treatment yielded the epoxy-
acetamide 5. We were then pleased to find that coupling
epoxide 5 (in racemic form) with 1.3 equiv of the methyl
carbamate 76 under the Manninen conditions gave a 78%
yield of linezolid based upon 5. The requirement for an
excess of urethane and the moderate yield was attributed to
the competitive formation of the oxazoline 6. These con-
vergent routes were not explored extensively until 1999 in
favor of the linear chloropropanediol/nosylate route due to
the then prohibitive cost of commercial (S)-epichlorohydrin.
In 1996, Jacobsen published an alternative synthesis of 5
using a kinetic resolution approach with azide as the
Since 1993, a significant process research and development
effort directed towards the large-scale synthesis of oxazolidinone
antibacterial agents has been ongoing in both Early Chemical
Process Research and Development, and Chemical Process
Research and Development at Pharmacia. This work has led
to the successful development of the current commercial process
to produce Zyvox (linezolid), recently approved by the FDA as
an antibacterial. While this synthesis is appropriate for the
preparation of linezolid in particular, a more convergent and
versatile synthesis was developed for the rapid preparation of
numerous other oxazolidinone analogues. Toward this end,
economical methods for the large-scale preparation of N-[(2S)-
2-(acetyloxy)-3-chloropropyl]acetamide 3 and tert-butyl [(2S)-
3-chloro-2-hydroxypropyl]carbamate 27 from commercially
available (S)-epichlorohydrin via the common intermediate (2S)-
1-amino-3-chloro-2-propanol hydrochloride 2a were developed.
Also, general methods for coupling these reagents with N-aryl
carbamates to give N-aryl-5(S)-aminomethyl-2-oxazolidinone
derivatives in one step were developed. These reagents and
procedures have proven widely applicable in the preparation
of a diverse array of oxazolidinone analogues such as 23 and
28 in both process and medicinal chemistry research.
Introduction
Linezolid represents the first antibacterial with a new
mechanism of action to be approved by the FDA in over 30
years. The oxazolidinones have a novel mechanism of action
that involves inhibition of protein synthesis at an early and
unique step.1 Initial preparations of the active S-isomers were
done using the elegant chemistry developed by Manninen
in which an aryl carbamate in THF is deprotonated with
butyllithium and reacted with (R)-glycidyl butyrate to give
the corresponding 5(S)-hydroxymethyloxazolidinone.2 While
developing this chemistry, Manninen observed that the
* Corresponding author E-mail: william.r.perrault@pfizer.com.
§ Early Chemical Process Research and Development.
Chemical Process Research and Development.
† Medicinal Chemistry Research.
‡ Summer Intern.
(1) Shinabarger, D. Expert Opin. InVest. Drugs 1999, 8, 1195. Aoki, H.; Ke,
L. Z.; Poppe, S. M.; Poel, T. J.; Weaver, E. A.; Gadwood, R. C.; Thomas,
R. C.; Shinabarger, D. L.; Ganoza, M. C. Antimicrob. Agents Chemother.
2002, 46, 1080.
(2) Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.;
Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D.
S.; Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673.
(3) Manninen, P. R.; Little, H. A.; Brickner, S. J. Book of Abstracts; 212th
ACS National Meeting, Orlando, FL, August 25-29, 1996; American
Chemical Society: Washington, DC, 1996; ORGN-389. AN 1996: 415294.
(4) Pearlman, B. A.; Perrault, W. R.; Barbachyn, M. R.; Manninen, P. R.; Toops,
D. S.; Houser, D. J.; Fleck, T. J. U.S. Patent 5,837,870, November 17, 1998.
(5) Paul, R.; Williams, R. P.; Cohen, E. J. Org. Chem. 1975, 40, 1653-1656.
(6) Pearlman, B. A. U.S. Patent 6,107,519, August 22, 2000.
10.1021/op034028h CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003
Vol. 7, No. 4, 2003 / Organic Process Research & Development
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533

Scheme 1
nucleophile.7 In his report, Jacobsen also demonstrated the
conversion of an aryl carbamate to a 5(S)-acetamidomethyl-
oxazolidinone using the reagent 5, obtaining a 95% yield in
the coupling reaction using 2 equiv of 5 relative to carbamate.
An excess of epoxide was tolerable in Jacobsen’s approach
since his method should arguably make it the less expensive
reagent. Also, significantly, Jacobsen demonstrated that the
intermediate 3 was crystalline in enantiopure form making
it an attractive synthetic target for large-scale synthesis.
In 1999, Chirex began making tonne quantities of (S)-
epichlorohydrin from cheap racemic epichlorohydrin using
Jacobsen’s hydrolytic kinetic resolution technology (HKR).8
Our interest in early amination routes to the oxazolidinones
was thus renewed due to the cheap cost of (S)-epichloro-
hydrin and the crystallinity of 3.
of 2a (77%) was obtained by running the ammonia displace-
ment at 35-40 °C.
The most significant difficulty seen in the largest pilot-
scale run was that by cooling to -28 °C to precipitate all of
the product, some impurities came out which caused the
product cake to be hard and difficult to package. Also some
product may have transiently dissolved in the residual mother
liquor, perhaps contributing to the hard cake. This also led
to a long drying time with room-temperature nitrogen (4 days
to reach 1.73% LOD). An approach to improving the
crystallization is to form other salts besides the hydrochloride,
2a. Six salts were prepared in a parallel reactor and isolated
by solvent swap from water to acetonitrile or 2-propanol.
We had hopes that one of these might prove significantly
more crystalline than 2a and thus lead to a higher yield due
to reduced filtrate losses. However, none gave better yields,
although the mesylate gave a near equivalent yield. The
camphorsulfonate salts were tried mainly with an eye towards
possibly doing a diastereomeric salt resolution of racemic
2. However, considering the low cost of (S)-epichlorohydrin,
it is unlikely that a resolution approach will ever be
competitive.
Process Development for Preparing N-[(2S)-2-(Acetyl-
oxy)-3-chloropropyl]acetamide, 3. In our initial attempt to
prepare reagent 3 by scalable means, 2a was diacylated with
triethylamine and acetic anhydride in THF. Unfortunately,
some of the starting 2a was occluded by the precipitated
triethylamine hydrochloride in this system, resulting in only
a 53.8% isolated yield of 3. We therefore repeated the
acetylation in acetonitrile. An homogeneous solution was
obtained on warming the reaction mixture to 44 °C. After
removal of triethylamine hydrochloride via precipitation from
toluene/THF and an extractive workup, an isolated yield of
90.0% was obtained. A small demonstration pilot run was
done which gave a 92.5% yield.
Results and Discussion:
(2S)-1-Amino-3-chloro-2-propanol
Hydrochloride,
2a: Process Development. With minor variation, we have
continued to use the original benzaldehyde/ammonia process
for the preparation of 2a (Scheme 1). The yield, although
not ideal, has remained consistent at ∼70% as the process
has been scaled up as long as the original stoichiometries
were used. Variations in time and temperature do not seem
to greatly affect the yield. A pilot-scale reaction was done
at 35-40 °C for 90 min and then 20-25 °C for 3 days, a
subsequent larger pilot run was done at 35-41 °C for 12 h,
and both gave a similar yield (67 and 74%). In some early
runs, we tried using excesses of ammonia or benzaldehyde
to try to improve the yield. However, these tended to give
lower yields, presumably due to competing direct condensa-
tion of ammonia with benzaldehyde to form hydrobenz-
amide.9 Due to the low cost of (S)-epichlorohydrin and the
high throughput of the process (7.1 L/kg, 1.5 M peak
volume), it remains the most economical method for the
preparation of 2a. Our highest lab yield for the preparation
In the process of considering further scale-up, some
difficulties presented themselves. The waste triethylamine
hydrochloride that is filtered off gives a voluminous cake
which would have required excessive filtering capacity. Also,
running the acylation in acetonitrile solvent would have
(7) (a) Jacobsen, E. N.; Schaus, S. E. Tetrahedron Lett. 1996, 37, 7937. (b)
Jacobsen, E. N.; Schaus, S. E. U.S. Patent 5,929,232, July 27, 1999.
(8) Jacobsen, E. N.; Tokunaga, M. WO 0009463, February 24, 2000.
(9) Karupaiyan, K.; Srirajan, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1998, 54, 4375.
534
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Figure 1.
Figure 2.
required a tedious solvent swap to arrive at the desired
methylene chloride solution for the extractive isolation. We
tried to address all of these concerns via a Schotten-Bauman
type diacylation of 2a that would have allowed us to omit
the troublesome 2a crystallization and lead directly to a
solution of 3 in methylene chloride. Acylation of a secondary
alcohol in the presence of water is normally not achievable,
and this secondary alcohol is expected to be relatively
unreactive as proximate amides reduce the nucleophilicity
of alcohols.10 Still, we had hoped that running in a two-
phase system could have made the process feasible for this
case. Thus far, we have been unsuccessful at fully diacylating
2a in the presence of significant amounts of water.
In another approach, we speculated it might be possible
to selectively diacylate 2a in 2-propanol as solvent. A
diacylation of 2a in methylene chloride and 2-propanol (3
mL/g each) and triethylamine as base was tried. With 2.5
equiv of acetic anhydride, the reaction stalled at 4.4%
monoacetylated intermediate, showing that the 2-propanol
was competing to a certain extent. However, adding another
1 equiv of acetic anhydride (3.5 equiv total) gave complete
conversion. Therefore, it was practical to consider the one
isolation process from epichlorohydrin to 3. Thus, a slurry
of crude 2a in 2-propanol, prepared without isolation from
(S)-epichlorohydrin, was treated with pyridine (2.5 equiv)
and acetic anhydride (3.5 equiv) in methylene chloride to
give, after extractive workup, a solution of crude 3 in toluene.
Crystallization by addition of isooctanes afforded a poor
57.1% yield of 3, of only 93.3 wt % purity by external
standard GC analysis. The mother liquor was chromato-
graphed and an additional 23.2% yield of 3 obtained (total
yield ) 76.5%) along with the dimeric and trimeric byprod-
ucts 9 and 10 in impure form (Figure 1). Analysis of the
mixture by GC indicated 6.9 area % 9 and 1.4 area % 10
total were formed, for a mass balance of about 85% overall
from (S)-epichlorohydrin. Clearly, isolating at the 2a stage
is better for removal of these overalkylation products, and
we thus abandoned the one-pot process.
oil collected in the filter flask. NMR and GC analysis of
this oil showed it to contain 5.4% in yield of 3 along with
acetic acid and pyridine in a molar ratio of 1.9:0.5:1.0 acetic
acid:pyridine:3. Clearly some acetic acid carried through the
extractions and prevented complete azeotropic removal of
pyridine with toluene during the isolation. Crystallizations
spiked with a high level of acetic acid also gave a sticky
oil. Thus, a higher pH extraction was done during the
isolation to ensure complete acetic acid removal, and this
eliminated the oiling problem.
During further development work, we succeeded in
isolating the principal impurity responsible for oiling during
the final crystallization of 23 (see below) and showed it to
be the bis-adduct 11 (Figure 2). A correlation was then found
between the level of this impurity in a given lot of compound
23 and the level of a 12.4-min retention time impurity (GC
15 M-DB-1, 70 °C 2 min, then 10 °C/min) in the lot of
reagent 3 used to prepare it. Attempts to isolate this 12.4-
min impurity by chromatography and fully characterize it
have so far been unsuccessful due to its high polarity and
its instability to silica gel. However, we are fairly confident
it is the incompletely acetylated dimer 12 (Figure 2) as GC
data suggests that the 12.4-min impurity is an intermediate
in the triacetate’s formation. This incompletely acetylated
impurity partitions preferentially in the aqueous phases. Thus,
an extra aqueous sodium chloride wash was added to the
isolation of 3, reducing the level of this impurity from the
2.0% obtained with the original procedure to only 0.36% in
a pilot lot. GC analysis of this extra waste stream showed it
contained only 2.5% reagent 3. A use test then showed this
new material gave only 0.25% dimer in crude 23, instead of
about 1.0% with the original procedure.
One-Pot Conversion of N-Aryl Carbamates to N-Aryl-
5(S)-acetamidomethyl-2-oxazolidinones. A general method
for the preparation of N-aryl-5(S)-acetamidomethyl-2-ox-
azolidinones from N-aryl carbamates was then developed
(Scheme 2). While Jacobsen had chosen to preform and
chromatograph 5 by treating 3 with methanol and potassium
carbonate, we chose to form 5 in situ and thus avoid the
isolation of this unstable intermediate. We chose to apply
the lithium tert-butoxide/DMF chemistry developed for the
reaction of (S)-chloropropanediol with aryl carbamates as
we believed this would give the simplest process. Methanol
was added to act as a nucleophile for the in situ deacetylation.
We used 2 equiv of 3 to increase the conversion following
the precedent of Jacobsen. Thus, a solution of 82 in DMF (2
mL/g), methanol (2.02 equiv), and lithium tert-butoxide (3.0
equiv, in THF) was simply treated at 5-21 °C for 21 h with
To simplify the workup due to the high water solubility
of reagent 3 we chose to use methylene chloride as solvent.
Thus, to avoid occlusion, a base whose hydrochloride salt
is soluble in methylene chloride was needed. Reactions using
tributylamine as base gave complex mixtures by GC;
however, clean conversion was seen with as little as 1.5 equiv
of pyridine. Upon scale-up of the pyridine process, however,
a difficulty was observed. During drying in a nitrogen stream,
the product cake became difficult to break up, and a brown
(10) Szabo`, L.; Li, Y.; Polt, R. Tetrahedron Lett. 1991, 32, 585.
Vol. 7, No. 4, 2003 / Organic Process Research & Development
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535

Scheme 2
3 (2.00 equiv). HPLC showed a clean 87% conversion to
linezolid. After extractive workup and crystallization from
xylenes, a 72.1% yield of 98.0 wt % purity linezolid was
obtained. HPLC analysis of the filtrate showed an additional
9.7% recoverable linezolid.
Table 1: Substrate and concentration effects on reactions
with 3
Pilot-Scale Preparation of Oxazolidinone 15. The first
large-scale application of this convergent oxazolidinone
synthesis was in the preparation of 15. When we substituted
sulfone 13 for the linezolid substrate 8 in the corresponding
reaction with 3, a lower yield was obtained (68.4 norm %
vs 80.3 norm %). The yield in this reaction was considerably
increased by substituting solid lithium tert-amylate for
lithium tert-butoxide in THF to increase the desired coupling
reaction rate (second order) in the face of the undesired
decomposition of 5 to 6 (first order) by taking advantage of
the concentration effect. This reaction gave an 84% conver-
sion of starting material and a 75% HPLC external standard
yield of 1512 after extractive workup. Numerous unknowns
observed by HPLC accounted for the balance of the yield.
Results for other substrates and conditions appear in Table
1.
On the basis of the results of these experiments, it appears
that a para nitrogen substituent on the aromatic ring of the
linezolid substrate was increasing the yield relative to the
sp3 carbon substituent in the 15 series substrates. Changing
to an sp2 hybridized center by using the unsaturated substrate
17 increased the yield about 8-9%. We had hoped to use a
reduced substrate in the coupling to avoid performing a
hydrogenation as the last step in the synthesis; however, the
increased yield seen with 17 outweighed this concern.
A simple, high-yielding, streamlined procedure for the
coupling of 3 with 17 to give 18 (a known intermediate in
the synthesis of 15)12 was then developed (Scheme 3).
Tertiary alcohol 2113 was dehydrated with trifluoroacetic acid
and the water and trifluoroacetic acid removed via azeotropic
distillation with toluene. To this solution was then added a
solution of 3 in DMF, followed by 2 equiv of methanol. The
toluene was then extracted into a separate phase by the
addition of isooctanes. Lithium tert-butoxide in isooctanes
(3 equiv) was then added to effect the desired oxazolidinone
Scheme 3
formation. Acetic acid was added to quench the reaction,
and the product was extracted from the upper nonpolar phase
with methanol and water. The product was then extracted
from the methanol/water phase with methylene chloride.
After a solvent swap to methanol, the product was precipi-
tated with toluene and water. Our best laboratory run of this
process afforded a 76.4% purity corrected isolated yield of
18 from 21. Only 1.9% product was lost to the isolation,
and 13.5% was lost as residual 17. A variety of low-level
unknown impurities accounted for the remaining 8.1% in
yield. Upon piloting, this process afforded a 75% yield of
18, in accord with laboratory expectations.
Several important variables were identified in the reaction
of carbamate 17 with reagent 3. It is important to add a
sufficient amount of an immiscible hydrocarbon to the crude
17 solution to extract out the toluene from the DMF phase
(11) Mbappe, M. A.; Sicsic, S. Tetrahedron: Asymmetry 1993, 4, 1035.
(12) Thomas, R. C.; Poel, T. J. U.S. Patent 6,358,942, March 19, 2002.
(13) (a) Gage, J. R.; Perrault, W. R.; Poel, T. J.; Thomas, R. C. Tetrahedron
Lett. 2000, 41, 4301. (b) Herrinton, P. M.; Owen, C. E.; Gage, J. R. Org.
Process Res. DeV. 2001, 5, 80.
536
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Vol. 7, No. 4, 2003 / Organic Process Research & Development

Scheme 4
Table 2: Order of addition and substrate effects on
reactions with reagent 3
where the reaction occurs, or else lower yields are obtained.
Also, we tried to substitute commercial 2 M lithium tert-
butoxide in THF for lithium tert-butoxide in hexanes.
Although this was observed to reduce the yield in earlier
experiments, we had hoped that adding isooctanes would
extract enough of the THF out of the reactive phase to restore
the yield. However, the yield was still depressed by over
6% to 69.9%. In one run, we also tried adding all of the
lithium tert-butoxide in one portion at <0 °C and then
warming to 13 °C; we obtained a conversion nearly identical
to that from the normal slow-addition process. This was not
a useful variant for the pilot-plant processing, but it did
simplify the laboratory procedure considerably. A preparation
of 18 was done in which the lithium tert-butoxide was added
in 12 portions, instead of a constant syringe pump addition,
and a normal yield (77.2%) was obtained. This showed that
minor changes in the flow rate during the lithium tert-
butoxide addition do not affect the yield in this reaction.
Pilot-Scale Preparation of Oxazolidinone 23. Our
convergent oxazolidinone synthesis was also applied on pilot
scale to the sulfone 23, using the isobutyl carbamate 2214 as
substrate (Scheme 4). Our initial oxazolidinone preparation
conditions closely mimicked those developed for the prepa-
ration of 18 above. However, the increased acidity of the
carbamate proton caused by the additional aromatic fluorine
substituent on 22 resulted in conversions as high as 92%, as
opposed to 88% with 17. The reactions were also cleaner,
giving none of the minor byproducts seen with 17. The higher
conversions proved somewhat irreproducible, and conver-
sions as low as 82% were also obtained. We then found that
we could reproducibly obtain conversions of 92-95% by
adding the lithium tert-butoxide to the carbamate 22 and then
adding 3 slowly as a solution in DMF.
To further explore this inverse addition observation,
several oxazolidinone formation reactions were run on a
parallel reactor using variants of this inverse addition and
several different substrates (Table 2). In all of the runs except
entries 2, 7, and 8, the reactions were slurries prior to
beginning the addition of reagent 3 due to the small amount
of DMF used to dissolve the substrate. Reactions 2 and 7
gave the highest conversions, suggesting that substrate
solubility is the key variable in achieving high conversions
with this procedure. It is not surprising that entry 8 gave a
somewhat poor conversion despite the substrate solubility
as 2-propanol should be slow to transesterify reagent 3. Little
effect was seen upon varying methanol from 1 to 3 equiv,
showing that the process is robust with respect to the amount
of alcohol used for the transesterification.
a 3 equiv of lithium tert-butoxide solid added last at 0-5 °C, then reaction
warmed to rt. b 3 equiv of lithium tert-butoxide in THF added last at 0-5 °C,
then reaction warmed to rt.
Table 3: Solvent effects in the preparation of 23
solvent
ratio 23:22
observations
THF
CH3CN
CH2Cl2
2-propanol
ethanol
81:19
86:14
72:28
N/A
sticky LiCl plug formed
sticky LiCl plug formed
substrate forms sticky ball
unstirrable sludge formed
substrate insoluble
4:96
1:1 CH3CN:THF
1:1 CH3CN:CH2Cl2
1:1 THF:CH2Cl2
sec-BuOH
glyme
83:17
79:21
83:17
22:78
63:37
homogeneous solution
LiCl precipitates, but not sticky
sticky LiCl plug formed
substrate insoluble
substrate marginally soluble
amount of solids were formed at the bottom of the reactor,
which was not evident during lab development. The removal
of DMF proved very tedious and challenging during product
isolation. To improve the process for this step and circumvent
these challenges, we had hoped to eliminate the use of DMF
and increase reaction solubility to prevent the solid precipita-
tion. Subsequently, it was found that THF could be substi-
tuted for DMF in the coupling reaction, though with a slight
reduction in conversion. Also, it was found that this THF
procedure is applicable to less acidic substrates as applying
it to 8 yielded linezolid with a 91% conversion and a 73%
isolated yield.
A series of reactions involving different solvents were
then studied; as Table 3 indicates, the highest level of
conversion was obtained with acetonitrile as solvent. How-
ever, a sticky salt plug was observed during the reaction.
By using a 1:1 mixture of acetonitrile/THF as solvent, a
slightly lower level of conversion was obtained compared
to using only acetonitrile (83.4% vs 86.2%) but the reaction
was completely homogeneous throughout the reaction. All
In an initial pilot run to prepare compound 23 using DMF
as solvent, several challenges were encountered. A significant
(14) Chen, J. J.; Lu, C. V. WO 02085865, October 31, 2002.
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
537

Scheme 5
of the runs in Table 3 were done at 10 mL total volume/g of
22 at 4-22 °C overnight. The lithium tert-butoxide (3 equiv)
was added last in one portion to a mixture of 22, reagent 3
(2 equiv), and methanol (2 equiv) dissolved in the indicated
solvent.
upon rapid cooling and crystallization of the anhydrous
product, an unfilterable solid was obtained. By slowing the
cooling rate to ca. 5 °C per hour and utilizing seed crystals,
nice filterable solids were obtained. Two multikilogram pilot
campaigns proceeded as expected using the new procedure
with no major problems, and 80% isolated yields were
obtained in each.
Upon scaling up to 20 g starting material, using 1:1 THF/
acetonitrile under lower temperature (16 °C) and higher
concentration (5 mL/g total volume), the level of conversion
increased to 87.4% by calibrated HPLC. At this concentra-
tion, towards the end of the reaction and especially after the
acetic acid quench, the reaction mixture became somewhat
viscous and sticky. To avoid this problem, a lower concen-
tration reaction was performed at 6.9 mL/g at 16 °C
overnight. As expected, the viscosity, after the acid quench,
was greatly reduced without any significant conversion loss
(87.0% vs 87.4%). Other conditions for the oxazolidinone
formation were also screened. The use of lithium ethoxide
as the base under standard conditions resulted in a signifi-
cantly decreased level of conversion (76% vs 90-95%). It
was rationalized that the reduced basicity of lithium meth-
oxide relative to ethoxide was increasing the stability of the
epoxyacetamide 5. Also, the use of additional methanol (3
equiv) was found to not significantly increase the level of
conversion but did provide a sticky reaction mixture.
After switching to the THF/acetonitrile solvent system,
conditions for the removal of unreacted starting material still
needed to be defined. Through partitioning studies, we found
that 23 partitions preferentially at ca. 85% in the aqueous
phase of a toluene/water mixture. However, the processing
volume required was too large (ca. 60 L/kg) due to the low
water solubility of 23. By using a water miscible cosolvent,
we had hoped to increase the solubility of the product to
decrease the processing volume. At the refluxing tempera-
tures needed to dissolve the product, methanol was found to
be the best cosolvent with our toluene/water system. Under
the new toluene/water/methanol system, nonpolar impurities
such as 22 and most of the colored impurities were
effectively removed. The preferential partitioning of 22 for
the toluene layer also allowed the starting material to be
recovered for reuse.
In hopes of increasing the yield and reducing the amount
of excess 3 required in the reaction, we explored the use of
other carbamates besides the isobutyl carbamate 22 for
preparing 23. We speculated that, since the acidity of the
carbamate is key to favoring alkylation over isoxazoline
formation, using a more acidic carbamate should favor the
desired reaction. However, this proved generally not to be
the case, at least in this series. One modest success we did
have was in substituting trichloroethanol for methanol and
the trichloroethyl carbamate, 25, for the isobutyl carbamate
22 (Scheme 5). Here we saw a minor conversion increase
to 66% with 1.25 equiv of 3 vs a 58% conversion with the
standard reagents. Other combinations of carbamates and
alcohols did not give an improvement. Carbamates tried
included isopropenyl, trifluoroethyl, and phenyl. The car-
bamates were prepared via reaction of the aniline 2414 with
the corresponding commercially available chloroformate.
Most of these alternative carbamates gave poor results. For
example, the phenyl carbamates gave gross mixtures when
reacted with isolated 5 and lithium tert-butoxide. When the
phenyl carbamates were reacted with methanol and 3, the
methyl carbamate was formed, and it reacted to give poor
yields of 23.
Recently, (S)-N-[2-(acetyloxy)-3-bromopropyl]acetamide
has become commercially available from Samsung Fine
Chemicals,16 and we have shown that it performs equivalently
to 3 in the synthesis of 23.
Preparation and Use of tert-Butyl [(2S)-3-Chloro-2-
hydroxypropyl]carbamate, 27. We also desired a reagent
which would be useful for the synthesis of 5(S)-amino-
methyloxazolidinone derivatives other than acetamide. Sev-
eral other amines besides acetamide were explored as
substrates for the Manninen conditions and all of these
substrates failed to give useful yields. However, Bayer
recently found that the BOC-protected (S)-glycidylamine 26
could be used to alkylate anilines, and the resulting amino
alcohols cyclized to the desired oxazolidinones with CDI,
although only in poor to moderate yields (Scheme 6).17
Residual toluene needed to be removed from the aqueous
product-containing layer to meet ICH toluene specifications
for the final product. Computer simulations15 involving the
distillation of toluene from a mixture of water and methanol
showed that toluene removal was extremely efficient in this
system. After reducing the total volume of the crude extracts
by ∼10%, analysis of the mixture by GC indicated no
detectable toluene remaining in the still residue. However,
(16) Roh, K. R.; Lee, J. H.; Hwang, D. I.; Lee, W. J.; Kim, K. I. WO 9952855,
October 21, 1999.
(17) Raddatz, S.; Bartel, S.; Guarnieri, W.; Rosentreter, U.; Ruppelt, M.; Wild,
H.; Endermann, R.; Kroll, H. P.; Henninger, K. WO 9940094, August 12,
1999; Bartel, S.; Guarnieri, W.; Habich, D.; Raddatz, S.; Riedl, B.;
Rosentreter, U.; Ruppelt, M.; Stolle, A.; Wild, H.; Endermann, R.; Kroll,
H. P. WO 9937641, July 29, 1999.
(15) The commercial BDIST-SimOpt software from Batch Process Technologies
(www.bptech.com) and the freeware VLECALC by William D. Kovats
(my.net-link.net/∼wdkovats) gave qualitatively similar predictions.
538
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development

Scheme 6
fully BOC-protected 1,3-diamino-2-propanol, obviously de-
rived from the corresponding diamine in the starting material.
Apparently, the expected impurities derived from the di-
alkylation of ammonia with epichlorohydrin, which were
difficult to remove from diacetate 3, were easily removed
while crystallizing reagent 27. This diamino impurity was
slowing the crystallization, as lower levels of it were
associated with faster precipitations of 27.
Scheme 7
Conclusions
Methods were developed for the preparation and use of
the valuable reagents 3 and 27.18 In addition to the pilot-
scale preparations described herein, these reagents have
proven widely applicable to the rapid synthesis of numerous
other pharmaceutically active aryl oxazolidinone analogues
in medicinal chemistry at Pharmacia.19
Scheme 8
Experimental Section
(2S)-1-Amino-3-chloro-2-propanol Hydrochloride (2a).
To a solution of benzaldehyde (59.54 g, 0.561 mol, 1.03
equiv) in ethanol (150 mL) at 18 °C was added aqueous
ammonia (28.8 wt %, 49.9 g, 0.861 mol, 1.58 equiv) followed
by an ethanol rinse (6 mL). (S)-Epichlorohydrin (50.5 g,
0.546 mol) was added, and rinsed in with ethanol (22 mL).
The reaction mixture was allowed to exotherm from 19 to
40 °C over 1 h; it was then stirred at 35-40 °C for 6 h and
then at 20-25 °C for 13.5 h. GC showed 1.4% residual (S)-
epichlorohydrin and 80.7% compound 1 (identity confirmed
vs racemic GC standard5). The solution was concentrated in
vacuo to 133 mL, and toluene (115 mL) was added. While
a temperature of 36-41 °C was maintained, a solution of
hydrochloric acid (37 wt %, 80.6 g, 0.827 mol, 1.52 equiv)
and water (77 mL) was added over 5 min. The two-phase
mixture was stirred at 35-45 °C for 3 h, and the phases
were settled and separated. The upper phase was washed
with water (28 mL), the aqueous was combined, and ethanol
(28 mL) was added. The mixture was concentrated to 95
mL, and ethanol (7 × 38 mL) was added, concentrating to
95 mL after each addition. Ethanol (95 mL) was added, and
the slurry was warmed to reflux and then cooled to and
maintained at -25 °C for 18 h. The product was collected
by vacuum filtration, washed with -28 °C ethanol (28 mL)
and dried in a room-temperature nitrogen stream to afford a
white solid (61.4 g, 77.0%, mp ) 125-136 °C): 1H NMR
(CD3OD, 400 MHz) δ 4.85 (s, 4H), 4.2-4.0 (m, 1H), 3.66-
3.57 (m, 2H), 3.22 (dd, J ) 17.2, 3.6 Hz, 1H), 2.94(dd, J )
12.4, 16.8 Hz, 1H); 13C NMR (CD3OD, 100 MHz) d 43.53
(t), 46.90 (t), 68.74 (d); MS (CI, NH3) m/z (relative intensity)
112 (43), 110 (100); [R]25D ) -22 (c ) 1.02, water); Anal.
Calcd for C3H9Cl2NO: C, 24.68; H, 6.21; N, 9.59; found:
C, 24.30; H, 6.36; N, 10.01; GC for 1 (tR) 17.5 min) and
(S)-epichlorohydrin (tR ) 1.23 min): 15 M-DB-1 capillary
column, Tinj ) 250 °C, Tini ) 28 °C for 2 min, Tfin ) 250
°C, rate ) 10 °C/min.
We therefore tried the corresponding chlorohydrin reagent
27 and found that it performed very well using DMF as the
solvent and lithium tert-butoxide as the only base (Scheme
7). We obtained the desired BOC-protected linezolid deriva-
tive 28 analytically pure in 87.5% yield after chromatogra-
phy. With 2 equiv of 27, the reaction was driven to 99.5%
conversion and 94 crude HPLC area % 28 as compared to
only 86.8% conversion with 2 equiv of 3. This prompted us
to try reducing the equivalents of 27 to only 1.26, and this
very low loading still gave a 95% conversion.
Compounds 29 and 30, potential intermediates for prepar-
ing thiopyran oxazolidinone 15, were also prepared with
reagent 27 (Scheme 8). Both compounds 13 and 1413 were
somewhat poorer substrates for this chemistry with reagent
27 than they were for reagent 3 (Table 1). With 1.26 equiv
of 27, only 83.0 area % 29 and 85.0 area % 30, respectively,
were formed under conditions which had afforded 94 area
% 28 in the linezolid series. This was due both to lower
conversion and to an increase in the level of some unknowns.
In the preparation of 27, a scalable procedure for the clean
bocylation of 2a with 1.05 equiv of di-tert-butyldicarbonate
in methanol/aqueous potassium bicarbonate proved simple
to develop. However, subsequent crystallization of the
product after extractive isolation was somewhat problematic.
Even with seeding (∼50 mg of seeds for 20 g run), the
product precipitated very slowly from toluene/heptane (over-
night stirring was required to reach complete precipitation
at room temperature). When the isolated material was
recrystallized, the precipitation was complete within a matter
of hours suggesting that the impurities in the crude reaction
mixture were causing the slow crystallization. GC analysis
of various lots of the crude product showed them to contain
1-4% of a late-eluting impurity, which did not affect use
of the reagent. This impurity was isolated and identified as
(18) Perrault, W. R.; Gadwood R. C. WO 0232857, April 25, 2002; Perrault,
W. R.; Pearlman, B. A.; Godrej, D. B. WO 0285849, October 31, 2002.
(19) Johnson, P. D.; Aristoff, P. A.; Poel, T. J.; Thomasco, L. M. WO 0259115,
August 1, 2002.; Barbachyn, M. R.; Zurenko, G. E. WO 0198297, December
27, 2001.
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
539

Table 4: Alternative (2S)-1-amino-3-chloro-2-propanol salts
Anal. Calcd for C10H16O4S‚C3H8ClNO: C, 45.67; H, 7.08;
N, 4.10. Found: C, 45.36; H, 7.11; N, 4.07.
crystallization
yield/ % of
1
2f: H NMR (300 MHz, CD3OD) δ 1.23 (s, 3 H), 1.78
salt
acid
g
theory
solvent
temperature
(t, J ) 12 Hz, 1 H), 2.05 (d, J ) 13 Hz, 1 H), 2.44 (m, 2 H),
2.87 (m, 1 H), 3.70 (s, 4 H), 6.10 (d, J ) 6 Hz, 2 H), 6.58
(d, J ) 9 Hz, 2 H); 13C NMR (75 MHz, CD3OD) δ 20.24
(q), 42.43 (t), 45.79 (t), 67.66 (d), 125.84 (d), 128.79 (d),
140.74 (s), 142.29 (s); [R]25D ) -13 (c ) 0.86, water). Anal.
Calcd for C7H8O3S‚C3H8ClNO: C, 42.63; H, 5.72; N, 4.97.
Found: C, 42.59; H, 5.76; N, 4.96.
2b methanesulfonic
2c benzenesulfonic
2d (1R)-10-camphorsulfonic 8.1
2e (1S)-10-camphorsulfonic 6.8
5.3
6.6
75
72
70
58
59
acetonitrile
acetonitrile
2-propanol
2-propanol
2-propanol
-23
-23
0
0
-23
2f p-toluenesulfonic
5.6
(2S)-1-Amino-3-chloro-2-propanol Salts. To a sample
of crude 1 concentrate (9.0 g) derived from (S)-epichloro-
hydrin (3.15 g, 34 mmol) following the procedure for
preparing 2a above was added toluene (20 mL), water (20
mL), and the indicated acid (41 mmol, 1.2 equiv, Table 4).
The mixture was stirred at room temperature for ∼18 h on
a parallel synthesizer, and the phases were separated. The
upper was washed with water (10 mL). The aqueous phase
was concentrated to an oil in vacuo and the crystallization
solvent added twice, concentrating to a thick slurry or oil
after each addition. The crystallization solvent was added,
and the slurries were cooled to the indicated temperatures;
the products were collected by vacuum filtration and dried
in a nitrogen stream to give a white solid in the indicated
(S)-N-[2-(Acetyloxy)-3-chloropropyl]acetamide (3). To
a slurry of 2a (200.2 g, 1.371 mol) in methylene chloride
(465 mL) was added acetic anhydride (322 g, 3.153 mol,
2.30 equiv). The slurry was warmed to 38 °C, and pyridine
(140 g, 1.731 mol, 1.26 equiv) was added while maintaining
the temperature at 36-38 °C, followed by a methylene
chloride (32 mL) rinse. The resulting solution was stirred at
37-40 °C for 5 h and then at 20-25 °C for 14 h. GC [(15
M-DB-1 capillary column, Tinj ) 250 °C, Tini ) 70 °C for 2
min, Tfin ) 250 °C, rate ) 10 °C/min; tR (3) ) 8.66 min; tR
(4) ) 6.87 min] showed 0.90% residual intermediate 4. The
mixture was cooled to 25 °C, and water (240 mL) was added.
The mixture was cooled to 6 °C, and a solution of aqueous
potassium carbonate (47 wt %, 800 g, 2.72 mol, 1.98 equiv)
was added over 7 min, while maintaining the temperature at
5-7 °C. Water (622 mL) and methylene chloride (240 mL)
were added; the phases were separated, and the aqueous was
washed with methylene chloride (2 × 120 mL). The
combined organics were washed with a solution of sodium
chloride (26 g) in water (792 mL). The wash was back-
extracted with methylene chloride (2 × 120 mL), and the
combined organics were concentrated in vacuo to 540 mL.
Toluene (2 × 400 mL) was added and the mixture concen-
trated to 540 mL after each addition. The solution was cooled
to 28 °C to give a slurry, and 900 mL of isooctanes was
added. The slurry was cooled to 3 °C and the product
collected by pressure filtration, washed with isooctanes (280
mL), and dried in a nitrogen stream to give a white solid
(220.3 g, 82.9%): mp ) 66 °C; 1H NMR (CDCl3, 400 MHz)
δ 6.20 (bs, 1H), 5.09 (p, J ) 4.8 Hz, 1H), 3.70 (dd, J )
12.0, 4.8 Hz, 1H), 3.64-3.47 (m, 3H), 2.12 (s, 3H), 2.00 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 20.93 (q), 23.12 (q),
amounts.
1
2b: H NMR (300 MHz, CD OD) δ 1.19 (s, 3 H), 1.42
3
(t, J ) 12 Hz, 1 H), 1.67 (d, J ) 13 Hz, 1 H), 2.08 (dd, J
) 3, 6 Hz, 2 H), 2.52 (m, 1 H), 3.32 (s, 4 H); 13C NMR (75
MHz, CD3OD) δ 38.49 (q), 42.45 (t), 45.86 (t), 67.67 (d);
[R]25D ) -16 (c ) 0.92, water); Anal. Calcd for C3H8ClNO‚
CH4O3S: C, 23.36; H, 5.88; N, 6.81. Found: C, 22.86; H,
6.04; N, 6.76.
1
2c: H NMR (300 MHz, CD3OD) δ 1.35 (t, J ) 12 Hz,
1 H), 1.60 (d, J ) 13 Hz, 1 H), 2.00 (dd, J ) 4, 6 Hz, 2 H),
2.45 (m, 1 H), 3.35 (s, 4 H), 5.86 (d, J ) 5 Hz, 3 H), 6.26
(t, J ) 5 Hz, 2 H); 13C NMR (75 MHz, CD3OD) δ 42.40
(t), 45.77 (t), 67.61 (d), 125.77 (d), 128.27 (d), 130.33 (d),
144.96 (s); [R]25D ) -12 (c ) 0.95, water). Anal. Calcd for
C6H6O3S‚C3H8ClNO: C, 40.38; H, 5.27; N, 5.23. Found:
C, 38.97; H, 5.42; N, 4.53.
1
2d: H NMR (300 MHz, CD3OD) δ 0.86 (s, 3 H), 1.11
(s, 3 H), 1.42 (m, 1 H), 1.64 (td, J ) 6, 9 Hz, 1 H), 1.90 (d,
J ) 18 Hz, 1 H), 2.07 (m, 2 H), 2.31 (m, 1 H), 2.62 (m, 1
H), 2.78 (d, J ) 15 Hz, 1 H), 2.96 (dd, J ) 12, 15 Hz, 1 H),
3.23 (dd, J ) 12, 15 Hz, 1 H), 3.29 (d, J ) 15 Hz, 1 H),
3.61 (m, 2 H), 4.05 (m, 1 H), 4.83 (s, 4 H);13C NMR (75
MHz, CD3OD) δ 19.05 (q), 19.24 (q), 24.69 (t), 26.71(t),
42.50 (t), 42.58 (t), 42.95 (d), 45.89(t), 47.70 (t), 58.48 (s),
67.69 (d), 217.38 (s); [R]25D ) -24 (c ) 0.96, water). Anal.
Calcd for C10H16O4S‚C3H8ClNO: C, 45.67; H, 7.08; N, 4.10.
Found: C, 43.70; H, 7.21; N, 3.98.
40.52 (t), 43.53 (t), 71.98 (d), 170.46 (s), 170.63 (s). [R]25
D
) -10 (c ) 0.94, methylene chloride) Anal. Calcd for C7H12-
ClNO3: C, 43.42; H, 6.25; N, 7.23. Found: C, 43.37; H,
6.29; N, 7.18. GC for: DSC: stable to 152 °C.
N-(3-Chloro-2-hydroxypropyl)acetamide [(() 4]. To a
slurry of (()-2a (47.71 g, 326.7 mmol) in THF at -40 °C
was added triethylamine (36.50 g, 360.8 mmol, 1.10 equiv)
followed by acetic anhydride (35.01 g, 342.9 mmol, 1.05
equiv) while maintaining <-30 °C. The mixture was stirred
15 min at -30 °C, then allowed to warm to 20 °C over 1 h.
The mixture was stirred at 20-25 °C for 3 h, and then the
precipitate was removed by vacuum filtration and the product
rinsed through with THF (175). The filtrate was concentrated
to 80 g net weight, toluene (195 mL) was added, and the
mixture was concentrated to 86 g and toluene (250 mL)
added. The mixture was concetrated to 68 g and toluene (250
1
2e: H NMR (300 MHz, CD3OD) δ 0.86 (s, 3 H), 1.11
(s, 3 H), 1.42 (m, 1 H), 1.64 (m, 1 H), 1.90 (d, J ) 18 Hz,
1 H), 2.07 (m, 2 H), 2.31 (m, 1 H), 2.62 (m, 1 H), 2.78 (d,
J ) 15 Hz, 1 H), 2.96 (m, 1 H), 3.23 (m, 1 H), 3.29 (d, J )
15 Hz, 1 H), 3.61 (m, 2 H), 4.05 (m, 1 H), 4.83 (s, 4 H); 13
C
NMR (75 MHz, CD3OD) δ 19.05 (q), 19.24 (q), 24.70 (t),
26.71(t), 42.51 (t), 42.58 (t), 42.95 (d), 45.89(t), 47.10 (t),
58.48 (s), 67.69 (d), 217.35 (s); [R]25D ) 5 (c ) 0.98, water).
540
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development

mL), methanol (40 mL), and ethyl acetate (10 mL) were
added. The mixture was cooled to -20 °C, seeded, and
cooled to -30 °C, and heptane (200 mL) was added. The
precipitate was collected by vacuum filtration at -33 °C,
washed with heptane (100 mL), and dried. The crude solid
was redissolved in toluene (250 mL) and methanol (120 mL)
and was concentrated under reduced pressure to 233 g net
weight. The solution was cooled to -30 °C and seeded, and
heptane (180 mL) was added. The precipitate was collected
by vacuum filtration at -30 °C, washed with heptane (100
mL), and dried in a nitrogen stream to give a white solid
(32.25 g, 66.3%); silica gel TLC (95:5 methylene chloride:
ammonium chloride (5.0 mL) was added followed by water
(30 mL), saturated aqueous sodium chloride (20 mL), and
methylene chloride (20 mL). The phases were separated and
the aqueous washed with methylene chloride (3 × 20 mL).
The organics were dried on magnesium sulfate and concen-
trated to an oil in vacuo (4.209 g). Xylenes A.R. (25 mL)
was added, and the product was crystallized by seeding and
sonicating (initially gave a gel which broke up to give a
slurry). The product was collected by vacuum filtration,
washed with xylenes A.R. (10 mL) and dried in a nitrogen
stream to afford a white solid (0.6509 g, 61.8%). The filtrate
was concentrated in vacuo to an oil and xylenes (15 mL)
added. The second crop was crystallized by seeding and
sonicating (initially gave a gel which broke up to give a
slurry). The product was collected by vacuum filtration,
washed with xylenes A.R. (10 mL), and dried in a nitrogen
stream to a white solid (0.1085 g, 10.3%). HPLC analyses
showed the first and second crops to be 98.9 and 94.6 wt %
linezolid, respectively, with <0.2% enantiomer in each; also,
an additional 9.7% yield of linezolid was detected in the
filtrate by external standard HPLC (total ) 80.6%). Analysis
1
methanol, iodine char) Rf ) 0.23; H NMR (300 MHz,
CDCl3) δ 1.97 (s, 3 H), 3.33 (p, J ) 6 Hz, 1 H), 3.54 (d, J
) 6 Hz, 2 H), 3.95 (s, 1 H), 4.73 (s, 1 H), 6.94 (s, 1 H); 13
C
NMR (75 MHz, CDCl3) δ 23.01, 43.32, 46.46, 70.72, 172.37;
MS (Cl, NH3) 154 (34); 152 (100) Anal. Calcd for C5H10-
ClNO2: C, 39.62; H, 6.65; N, 9.24. Found: C, 39.63; H,
6.69; N, 9.13.
(()-N-(Oxiranylmethyl)acetamide [(()-5]; (()-(2-
Methyl-4,5-dihydro-1,3-oxazol-5-yl)methanol [(()-6]. To
a solution of (()1-acetamido-2-hydroxy-3-chloropropane,
(()-4 (1.00 g, 6.59 mmol), in THF (2.0 mL) at -40 °C was
added potassium tert-butoxide in THF (1.0 M, 6.3 mL, 6.3
mmol, 0.95 equiv). The mixture was warmed to 0 °C; then
the solution was filtered through silica gel (1.7 g) and rinsed
through with 10 mL of 5:95 methanol:methylene chloride.
The filtrate was concentrated to dryness, redissolved in
methylene chloride, then chromatographed on 34 g of silica
gel, eluting with 880 mL of ethyl acetate then 220 mL each
of 5, 10, and 20% methanol in ethyl acetate. The appropriate
fractions were combined and concentrated to give two
compounds (()-5 (0.487 g, 64.2%): silica gel TLC Rf )
1
data for 1st crop material: mp ) 73-76 °C; H NMR
(CDCl3, 400 MHz) δ 7.43 (dd, J ) 14.4, 2.4 Hz, 1H), 7.07
(dd, J ) 8.8, 2.0 Hz, 1H), 6.91 (t, J ) 8.8 Hz, 1H), 6.43 (br
t, 1H), 4.77 (m, 1H), 4.02 (t, J ) 9.2 Hz, 1H), 3.86 (t, J )
4.4 Hz, 4H), 3.76 (dd, J ) 8.8, 6.8 Hz, 1H), 3.66 (m, 2H),
3.05 (t, J ) 4.8 Hz, 4H), 2.02 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 23.07 (q), 41.93 (t), 47.66 (t), 51.00 (t), 66.95
(t), 71.99 (d), 107.56 (dd, JC-F ) 26.16 Hz), 113.97 (dd,
JC-F ) 3.02 Hz), 118.85 (dd, JC-F ) 4.03 Hz), 132.90 (sd,
JC-F ) 4.03 Hz), 136.58 (sd, JC-F ) 9.06 Hz), 154.42 (s),
155.50(sd, JC-F ) 246.53 Hz), 171.19 (s) MS (EI) m/z
(relative intensity) 337 (90), 293 (81), 209 (100); [R]25
)
D
1
0.50 (iodine char, 95:5 methylene chloride:methanol); H
-16 (c ) 1.05, ethanol). Anal. Calcd for C16H20FN3O4: C,
56.97; H, 5.97; N, 12.46; found: C, 56.86; H, 6.05; N, 12.44.
Linezolid (THF as solvent). To 8 (5.006 g, 15.15 mmol)
and lithium tert-butoxide (3.621 g, 45.23 mmol, 2.99 equiv)
was added THF (15 mL) yielding a beige solution after a
moderate exotherm from 24 to 31 °C. The mixture was
cooled to 14 °C and methanol (0.9691 g, 30.25 mmol, 2.00
equiv) added with an exotherm to 20 °C. The resulting
solution was cooled to 7 °C, yielding a thick slurry. 3 (5.885
g, 30.39 mmol, 2.01 equiv) was added and the mixture stirred
at 15-18 °C for 15 h at which point HPLC showed a 90.9%
conversion of 8 to linezolid. Acetic acid (1.73 mL, 30.22
mmol, 2.00 equiv) was added with an exotherm from 13 to
27 °C, followed by water (20 mL) and methylene chloride
(20 mL). The phases were separated and the aqueous washed
with methylene chloride (2 × 10 mL). The combined
organics were dried on magnesium sulfate and then concen-
trated in vacuo to a net weight of 18 g. The resulting oil
was seeded and ethyl acetate (28 g) added to yield a thin
slurry. The slurry was concentrated to 29 g and ethyl acetate
(30 g) added. The slurry was cooled to -25 °C and the
product collected by vacuum filtration, washed with -25
°C ethyl acetate (2 × 5 mL), and dried in a nitrogen stream
to give a white solid (3.725 g, 72.9%): HPLC (99.0 wt %,
98.9 area % linezolid, tR 1.60 min) conditions: Inertsil
NMR (300 MHz, CDCl3) δ 2.01 (s, 3 H), 2.59 (dd, J ) 3,
5 Hz, 1 H), 2.80 (t, J ) 5 Hz, 1 H), 3.11 (m, 1 H), 3.25 (dt,
J ) 6, 15 Hz, 1 H), 3.70 (ddd, J ) 3, 6, 15 Hz, 1 H), 6.44
(s, 1 H); 13C NMR (75 MHz, CDCl3) δ 23.01, 40.75, 45.21,
50.63, 170.69; MS (CI+) 116 (M + H)+ and (()-6 (0.071
g, 9.4%): silica gel TLC Rf ) 0.30 (iodine char, 95:5
methylene chloride:methanol); 1H NMR (300 MHz, CDCl3)
δ 1.98 (s, 3 H), 3.53-3.84 (m, 5 H), 4.60-4.65 (m, 1 H);
13C NMR (75 MHz, CDCl3) δ 13.92, 55.88, 63.87, 80.19,
165.39; MS (CI+) 116 (M + H)+. Note: Treating a solution
of (()-5 (0.1532 g, 1.331 mmol) in THF (1.54 mL) at 0 °C
with lithium tert-butoxide (0.1199 g, 1.498 mmol, 1.13 equiv)
for 1 h gave (()-6 as the major product by TLC.
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-
5-oxazolidinyl]methyl]acetamide: Linezolid: Zyvox. (DMF
as solvent) To a solution of 82 (1.032 g, 3.125 mmol) in
DMF (2.0 mL) and methanol (0.202 g, 6.32 mmol, 2.02
equiv) at 20 °C was added a solution of lithium tert-butoxide
in THF (4.16 g of an 18.1 wt % solution, 9.39 mmol, 3.00
equiv) while keeping less than 24 °C with an ice bath. The
solution was cooled to 5 °C and 3 (1.207 g, 6.234 mmol,
2.00 equiv) was added. The resulting solution was allowed
to stand at 21 °C for 21 h at which point HPLC showed an
86.8% conversion of 8 to linezolid. Saturated aqueous
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
541

ODS-2 5.0 µm 150 mm × 4.6 mm, flow rate ) 2.0 mL/
min, gradient elution from 40:60 A:B to 80:20 A:B over 10
min; A ) acetonitrile; B ) water. External standard HPLC
analysis of the filtrate showed 12.9% and 7.6% yield of
linezolid and 8, respectively.
detection at 254 nm, isocratic elution solvent: 479.5 of g
buffer (1 L of water, 1.57 g of ammonium formate, formic
acid to pH ) 3.2) and 409.1 g of acetonitrile; 1H NMR (400
MHz, CDCl3) δ 2.21 (s, 3 H), 3.17 (s, 8 H), 3.61 (s, 8 H),
3.6-4.2 (m, 8 H), 4.93 (q, J ) 9 Hz, 2 H), 7.1-7.2 (m, 4
H); MS (CI, NH3) m/z 748 [100, (M + H)+], 765 [31, (M +
NH4)+].
(1S)-2-{Acetyl[(2S)-2-(acetyloxy)-3-chloropropyl]amino}-
1-(chloromethyl)ethyl Acetate(9); (1S)-2-{Bis[(2S)-2-
(acetyloxy)-3-chloropropyl]amino}-1-(chloromethyl)eth-
yl Acetate (10). A crude slurry of 2a in 2-propanol was
prepared by the procedure above starting with (S)-epichlo-
rohydrin (19.34 g, 209 mmol) and substituting 2-propanol
for ethanol in the final solvent exchange. The crude slurry
was concentrated to 34 g net weight and methylene chloride
(92 mL) was added. The mixture was cooled to <0 °C and
acetic anhydride (69 mL, 731 mmol, 3.5 equiv) was added
followed by pyridine (42 mL, 519 mmol, 2.48 equiv). The
mixture was allowed to exotherm to 46 °C, stirred 1.5 h at
42 °C, and then cooled to 18 °C. GC showed a mixture of
91.7% 3 (tR ) 8.5 min), 6.9% 9 (tR ) 14.7 min), and 1.4%
10 (tR ) 17.4 min); conditions: 15 M-DB-1 capillary
column, Tinj ) 250 °C, Tini ) 70 °C for 2 min, Tfin ) 250
°C, rate ) 10 °C/min. A solution of potassium bicarbonate
(50.08 g, 495.3 mmol, 2.37 equiv) in water (166 mL) was
added. The phases were separated and the aqueous washed
with methylene chloride (3 × 50 mL). The organics were
concentrated to an oil and chased with toluene (4 × 80 g).
The oil was dissolved in toluene (93 g), seeded with 3 and
isooctanes (44 g added) to give a slurry. The precipitate was
collected at room temperature and washed with isooctanes
to give 3 (23.11 g, 57.1%) (98.1 area % 3 by GC, 1.5 area
% 9, 0.4 area % 10. The mother liquour was concentrated
to an oil and loaded on a silica gel column (287 g) packed
with methylene chloride and eluted with 1000 mL each of
0, 1, 2, 4, 8, 16% methanol in methylene chloride, collecting
14 fractions. Fraction 8 was concentrated to yield 9 (77 area
% purity, 553 mg, 1.6%) MS (CI+) m/z 234 (100), 236 (49),
328 (65), 330 (43), 332 (8.7); fraction 2 was concentrated
N-{[(5S)-3-(3-Fluoro-4-tetrahydro-2H-thiopyran-4-yl-
phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (16).
To a slurry of 14 (1.9543 g, 6.275 mmol) and 3 (2.4312 g,
12.555 mmol, 2.00 equiv) in DMF (3.00 mL) and methanol
(0.3974 g, 12.403 mmol, 1.98 equiv) was added lithium tert-
amylate (1.7765 g, 18.88 mmol, 3.01 equiv) at 2 °C. The
mixture was warmed and stirred at 18-23 °C for 18 h. The
solution was cannulated into a mixture of saturated am-
monium chloride (10 mL) and water (10 mL) while
maintaining 5-15 °C and rinsed in with toluene (20 mL)
and water (10 mL). Heptane (15 mL) was added and the
mixture cooled to 2 °C. The precipitate was collected by
vacuum filtration, washed with water (20 mL) and heptane
(5 mL), and dried in a nitrogen stream to give a white solid
(1.634 g, 73.9%): 1H NMR (400 MHz, DMSO-d6) δ 1.77
(q, J ) 10 Hz, 2 H), 1.84 (s, 3 H), 1.99 (d, J ) 12 Hz, 2 H),
2.65 (d, J ) 14 Hz, 2 H), 2.82 (t, J ) 12 Hz, 3 H), 3.41 (t,
J ) 6 Hz, 2 H), 3.73 (dd, J ) 6, 9 Hz, 1 H), 4.10 (t, J ) 9
Hz, 1 H), 4.73 (m, 1 H), 7.23 (dd, J ) 8, 10 Hz, 1 H), 7.33
(t, J ) 8 Hz, 1 H), 7.44 (dd, J ) 2, 13 Hz, 1 H), 8.23 (t, J
) 6 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) d 22.38 (q),
28.21 (t), 33.49 (t), 35.90 (d), 41.36 (t), 47.13 (t), 71.59 (d),
105.11 (dd, JC-F ) 28), 113.76 (dd, JC-F ) 3), 127.88 (sd,
JC-F ) 15), 128.25 (dd, JC-F ) 4), 137.89 (sd, JC-F ) 12),
153.96 (s), 159.46 (dd, JC-F ) 241), 169.97 (s); MS (EI)
m/z (relative intensity) 352 (100); [R]25 ) -13 (c ) 0.80,
D
methylene chloride). Anal. Calcd for C17H21FN2O3S: C,
57.94; H, 6.01; N, 7.95. Found: C, 57.64; H, 6.13; N, 7.65.
(S)-N-[[3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluo-
rophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (18). To
a slurry of 21 (21.9 g, 66.89 mmol) and 2,6-di-tert-butyl-
4-methylphenol (150 mg, 0.68 mmol, 0.01 equiv) in toluene
(120 mL) was added trifluoroacetic acid (14.07 g, 123.4
mmol, 1.85 equiv. The solution was stirred at 35-37 °C for
6 h. The solution was concentrated in vacuo to 60 mL and
toluene (4 × 56 mL) added, concentrating to 50 mL after
each addition, then to a final volume of 56 mL. Reagent 3
(24.36 g, 125.80 mmol, 1.88 equiv), DMF (37.5 mL), and
isooctanes (38 mL) were added followed by methanol (3.994
g, 124.5 mmol, 1.86 equiv). A solution of lithium tert-
butoxide (15.00 g, 187.4 mmol, 2.80 equiv) in isooctanes
(141 mL) was added over 2 h while maintaining 15 °C and
was rinsed in with isooctanes (10 mL). The mixture was
stirred for 12 h at 15-19 °C at which point HPLC showed
12% residual 17. Acetic acid (7.57 g, 126.06 mmol, 1.89
equiv) was added followed by methanol (32 mL). The phases
were separated and the upper phase washed twice with a
mixture of methanol (32 mL) and water (10 mL). To the
combined lower phases were added water (80 mL) and
methylene chloride (80 mL). The phases were separated, and
the upper was washed twice with methylene chloride (32
1
to yield 10 (78 mg, 0.27%) H NMR (400 MHz, CDCl3) δ
2.09 (s, 9 H), 2.76 (dd, J ) 6, 14 Hz, 3 H), 2.93 (dd, J ) 6,
14 Hz, 3 H), 3.65 (dd, J ) 5, 7 Hz, 3 H), 3.70 (dd, J ) 5,
7 Hz, 3 H), 5.10-5.17 (m, 3 H); MS (CI+) m/z 292 (100),
294 (42), 298 (56), 300 (52), 326 (48), 328 (40), 330 (11),
420 (54), 422 (57), 424 (16) Anal. Calcd for C12H19Cl2NO5:
C, 43.92; H, 5.84; N, 4.27. Found: C, 44.08; H, 6.01; N,
4.71.
N,N-Bis({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-
difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-
acetamide (11). The preparation of 23 below (run in DMF
as solvent) was repeated on 27 g of carbamate 22 (74.5
mmol) with minor changes. The lot of reagent 3 used was
assayed by GC as containing 2.1 area % 12 and 0.45 area %
9. When the crude product 23 was redissolved in refluxing
water/toluene a small amount of an oily third phase was
observed. The water and toluene phases were decanted off
to leave behind the oil which was chromatographed on silica
gel with acetonitrile eluent to afford a solid (10 mg) HPLC
(82 area % 11 tR ) 4.51 min) procedure: Inertsil ODS-2
5.0 µm 150 mm × 4.6 mm, flow rate ) 1.0 mL/min,
542
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Vol. 7, No. 4, 2003 / Organic Process Research & Development

mL). The combined lower phases were concentrated in vacuo
to 122 mL, and methanol (2 × 75 mL) was added,
concentrating to 80 mL after each addition. Toluene (71 mL)
was added; then water (71 mL) was added dropwise over
0.5 h while maintaining 21 °C. Isooctanes (61 mL) was added
and the slurry cooled to -1 °C. The product was collected
by vacuum filtration, washed with water (24 mL) and
isooctanes (24 mL), and dried in a nitrogen stream to afford
a brown solid (19.43 g, 76.9%): (HPLC: 90.2 wt % 18);
1H NMR (400 MHz, CDCl3) δ 2.02 (s, 3 H), 2.62 (s, 2 H),
2.85 (t, J ) 6 Hz, 2 H), 3.32 (s, 2 H), 3.67 (t, J ) 5 Hz, 2
H), 3.79 (t, J ) 9 Hz, 1 H), 4.05 (t, J ) 9 Hz, 1 H), 4.80
(m, 1 H), 6.00 (s, 1 H), 6.59 (s, 1 H), 7.13 (dd, J ) 2 Hz,
J ) 9 Hz, 1 H), 7.19 (t, J ) 8 Hz, 1 H), 7.37 (dd, J ) 2 Hz,
J ) 13 Hz, 1 H);13C NMR (100 MHz, CDCl3) δ 22.97 (q),
25.05 (t), 25.82 (t), 29.28 (t), 41.78 (t), 47.37 (t), 72.04 (d),
106.15 (dd, JC-F ) 29 Hz), 113.23 (dd, JC-F ) 3 Hz), 124.58
(d), 126.95 (dd, JC-F ) 15 Hz), 129.73 (dd, JC-F ) 5 Hz),
134.14(s), 137.99 (sd, JC-F ) 10 Hz), 154.25 (s), 159.73
(sd, JC-F ) 245 Hz), 171.29 (s); MS (EI) m/z 350 (M+, 100);
JC-F ) 241), 169.97 (s). Anal. Calcd for C12H13FN2O3: C,
57.14; H, 5.19; N, 11.11; found: C, 56.99; H, 5.21; N, 11.09;
[R]25 ) -40 (c ) 1.05, acetonitrile). A second crop was
D
collected from the filtrates (46.8 g, 13.1%, total yield )
76.1%).
N-[[(5S)-3-[4-(1,1-Dioxido-4-thiomorpholinyl)-3,5-di-
fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (23).
(DMF as SolVent). To a mixture of 22 (330 g, 910 mmol)
and lithium tert-butoxide (218.7 g, 2.73 mol, 3.00 equiv)
were added isooctanes (1200 mL), DMF (300 mL), and
methanol (58.4 g, 1.82 mol, 2.00 equiv). A solution of
reagent 3 (353 g, 1.82 mol, 2.00 equiv) in DMF (300 mL)
was added over 4 h while maintaining 15-20 °C. The
mixture was stirred at 20 °C for 17 h at which point HPLC
showed a 91% conversion of 22 to 23. Acetic acid (104 mL,
1.82 mol, 2.0 equiv) was added while maintaining 14-20
°C followed by methanol (900 mL) and water (150 mL).
The phases were separated, and the upper was washed twice
with a mixture of methanol (488 mL) and water (163 mL).
To the combined lower extracts were added methylene
chloride (1 L) and water (1 L). The phases were separated,
and the upper was washed with methylene chloride (3 × 1
L). The extracts were concentrated in vacuo to 300 mL total
volume. 2-Propanol (2000 mL) was added, and the resultant
slurry was stirred at 20-25 °C for 5 h and the product
collected by vacuum filtration, washed with 2-propanol (1500
mL), and dried in a 50 °C vacuum oven to afford crude 23
as a yellow solid (259.4 g). Crude 23 was slurried in water
(6.0 L); the slurry was warmed to 100 °C and then cooled
to 25 °C; the product was collected by vacuum filtration,
washed with water (2 × 500 mL), and dried in a 60 °C
vacuum oven to afford an off-white solid (230.2 g, 62.7%):
HPLC: 99.5 area % 23, tR ) 2.96 min; 11, 0.13%, tR )
3.87 min; 22, 0.26%, tR ) 10.83 min (HPLC procedure:
Inertsil ODS-2 5.0 µm 150 mm × 4.6 mm, flow rate ) 1.0
mL/min, detection at 254 nm, isocratic elution solvent: 409.1
g of acetonitrile and 479.5 g of a mixture of 1 L of water,
1.57 g of ammonium formate, and formic acid to pH ) 3.2);
1H NMR (300 MHz, DMSO) δ 1.83 (s, 3H), 3.20-3.24 (m,
4H), 3.40 (t, J ) 5.6 Hz, 2H), 3.47-3.51 (m, 4H), 3.70 (dd,
J ) 9.0 Hz, J ) 7.9 Hz, 1H), 4.09 (t, J ) 9.0 Hz, 1H),
4.69-4.78 (m, 1H), 7.29 (s, 1H), 7.32 (s, 1H), 8.21 (t, J )
5.6 Hz, 1H); 13C NMR (75.5 MHz, DMSO) δ 22.32 (s),
41.23 (s), 47.08 (s), 49.79 (s), 51.89 (s), 71.63 (s), 101.95
(d, JC-F ) 29.1 Hz), 121.93 (dd, JC-F ) 14.5 Hz), 135.71
(dd, JC-F ) 14.5 Hz), 153.76 (s), 157.92 (dd, JC-F ) 244.95
Hz), 169.90 (s); IR (mull) 1741, 1643, 1558, 1520, 1421,
1311, 1289, 1279, 1245, 1233, 1224, 1211, 1134, 1123, 849
cm-1; KF ) 0.00%; [R]25D ) -23 (c ) 0.96, DMSO); UV
Σmax 253 (17500, 95% EtOH); Melt Solvate: 0.06% DMF;
ROI 0.04%. Anal. Calcd for C16H19F2N3O5S: C, 47.64; H,
4.75; N, 10.42; S, 7.95; F, 9.42. Found: C, 47.58; H, 4.77;
N, 10.41; S, 7.94; F, 9.36.
[R]25 ) -14 (c ) 0.90, methylene chloride). Anal. Calcd
D
for C17H19FN2O3S: C, 58.27; H, 5.47; N, 7.99. Found: C,
58.27; H, 5.52; N, 7.92. HPLC for 18 (tR ) 2.70 min); 17
(tR ) 8.75 min); 21 (tR ) 5.60 min): Phenomenex Luna 5.0
µm C-8(12) 150 mm × 4.6 mm, flow rate ) 2.0 mL/min,
gradient elution from 40:60 A:B to 73.3:26.7 A:B over 15
min; A ) acetonitrile; B ) water.
(S)-N-[[3-(3-Fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]-
acetamide (20). To a mixture of 1913a (300.0 g, 1.42 mol),
3 (556.1 g, 2.87 mol, 2.02 equiv), methanol (90.03 g, 2.81
mol, 1.98 equiv), and DMF (500 mL) was added a slurry of
lithium tert-amylate (401.3 g, 4.27 mol, 3.00 equiv) in
heptane (1 L) while maintaining -4 to 7 °C, followed by
heptane (100 mL). The mixture was then stirred at 19-20
°C for 21 h. The reaction mixture was then added to a
mixture of ammonium chloride (228 g, 4.26 mol, 3.00 equiv),
water (2.0 L), and toluene (1.0 L) while maintaining 8-10
°C. The reaction mixture was rinsed in with a mixture of
water (100 mL), saturated ammonium chloride (50 mL), and
toluene (100 mL). The precipitate was collected by vacuum
filtration and washed with heptane (1 L) and water (1 L)
and dried in a nitrogen stream to give 252.4 g of crude
product. This was triturated in acetonitrile (1 kg) at 90 °C
and the slurry concentrated under reduced pressure to 800
mL total volume. Toluene (1900 mL) was added while
concentrating to maintain 800 mL total volume. Water (1
L) and heptane (1 L) were added, and the precipitate was
collected by vacuum filtration, washed with water (750 mL)
and heptane (250 mL), and dried in a nitrogen stream to
give a white solid (225.7 g, 63.0%): 1H NMR (400 MHz,
CDCl3) δ 1.84 (s, 3 H), 3.35 (s, 1 H), 3.43 (t, J ) 6 Hz, 2
H), 3.76 (dd, J ) 6, 9 Hz, 1 H), 4.13 (t, J ) 9 Hz, 1 H),
4.75 (m, 1 H), 6.96 (td, J ) 2, 8 Hz, 1 H), 7.31 (dd, J ) 1,
8 Hz, 1 H), 7.43 (q, J ) 8 Hz, 1 H), 7.50 (dt, J ) 2, 14 Hz,
1 H), 8.25 (t, J ) 6 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 22.36 (q), 41.33 (t), 71.62 (d), 104.91 (dd, JC-F ) 27),
109.86 (dd, JC-F ) 21), 113.52 (dd, JC-F ) 2), 130.53 (dd,
JC-F ) 10), 140.10 (dd, JC-F ) 11), 153.95 (s), 161.22 (sd,
Alternate Preparation of 23 (THF/Acetonitrile as sol-
Vent). To a slurry of 22 (300 g, 828 mmol) and 3 (321 g,
1.656 mol, 2.00 equiv) in acetonitrile (600 mL) and methanol
(53 g, 1.656 mol, 2.0 equiv) was added a slurry of lithium
tert-butoxide (199.6 g, 2.48 mol, 3.00 equiv) in THF (500
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
543

mL) over 0.5 h while maintaining 4-11 °C followed by a
THF (100 mL) rinse. The reaction mixture was then stirred
for 15 h at 16 °C, and a solution of glacial acetic acid (95
mL, 1.656 mol, 2.0 equiv) in water (1.33 L) was added over
15 min at 5 °C followed by water (330 mL). The mixture
was concentrated in vacuo to 2.4 L. Toluene (1.8 L) and
methanol (600 mL) were added and the phases separated at
70 °C. The organic was washed with water (1.2 L) and
methanol (300 mL) at 67 °C. The combined aqueous layers
were washed with toluene (1.8 L) at 67 °C. The upper toluene
layer was re-extracted with water (1.2 L) and methanol (300
mL) at 60-65 °C. The combined aqueous layers were
extracted with methylene chloride (2 × 1.5 mL). The
organcics were clarified, and water (5.0 L) and methanol
(2.5 L) were added. The mixture was concentrated via
atmospheric distillation to a pot temperature of 85 °C. The
solution was then cooled to 65 °C, seeded, and then slowly
cooled at 5-10 °C/h to 2 °C. The white slurry was then
filtered; the cake was washed with a mixture of water (1.1
L) and methanol (360 mL) and dried at 60 °C for ca. 3 days
to give a white solid (259.2 g, 77.6%) HPLC tR ) 3.06 min
(98.7% 23) (column ) Inertsil OSD-2, 150 mm × 4.6 mm,
flow rate: 1.0 mL/min, detection at 254 nm, isocratic elution
solvent: 409.1 g of acetonitrile and 479.5 g of a mixture of
1 L of water, 1.57 g of ammonium formate, and formic acid
to pH ) 3.2).
Alternate Preparation of 23 (Carbamate 25 as Sub-
strate). To a solution of 25 (0.971 g, 2.22 mmol), 3 (0.539
g, 2.78 mmol, 1.26 equiv), and trichloroethanol (0.31 mL,
3.23 mmol, 1.45 equiv) in acetonitrile (2 mL) and THF (2
mL) at 0 °C was added lithium tert-butoxide (0.402 g, 5.02
mmol, 2.27 equiv). The mixture was allowed to warm to
room temperature and stir for 16 h. HPLC analysis showed
66% 23, 26.5% 25: tR (23) ) 1.7; tR (25) ) 13.9 min, Inertsil
ODS-2 5.0 µm 250 mm × 4.6 mm, flow rate ) 2.0 mL/
min, detection at 254 nm, isocratic elution solvent: 479.5 g
buffer (1 L of water, 1.57 g of ammonium formate, formic
acid to pH ) 3.2) and 409.1 g of acetonitrile.
2,2,2-Trichloroethyl 4-(1,1-dioxido-4-thiomorpholinyl)-
3,5-difluorophenylcarbamate (25). To a slurry of 24
hydrochloride salt (4.06 g, 13.59 mmol) and potassium
carbonate (3.38 g, 24.4 mmol, 1.80 equiv) in THF (40 mL)
was added 2,2,2-trichloroethyl chloroformate (2.44 mL, 17.7
mmol, 1.31 equiv) and the mixture warmed to 45 °C.
Methylene chloride (30 mL) was added, and the salts were
filtered off with a methylene chloride wash (40 mL). The
filtrate was washed with saturated sodium bicarbonate
solution, and the aqueous was back-extracted with methylene
chloride (50 mL). The organics were dried on magnesium
sulfate; 100 mL of isooctanes was then added, and the
mixture was concentrated to a slurry. Isooctanes (100 mL)
was again added, and the precipitate was collected by vacuum
filtration and dried in a nitrogen stream to give a white solid
Alternate Preparation of 23 (Bromo Analogue of 3 as
Reagent). 22 (2.5 g, 6.9 mmol), (S)-N-[2-(acetyloxy)-3-
bromopropyl]acetamide (3.27 g, 13.8 mmol, 2.0 equiv), and
methanol (0.56 mL, 13.8 mmol, 2.0 equiv) were stirred in
acetonitrile (5 mL). A slurry of lithium tert-butoxide (1.7 g,
20.7 mmol, 3.0 equiv) in THF (5 mL) was prepared and
added to the carbamate/acetamide mixture while maintaining
a temperature less than 20 °C. The cloudy light yellow/brown
solution was stirred at 15-16 °C for 16 h. The reaction was
quenched with a solution of concentrated acetic acid (0.8
mL, 13.6 mmol, 2.0 equiv) in THF (1.8 mL) while maintain-
ing a temperature less than 20 °C. Water (7 mL) was added
to the mixture. The mixture was concentrated to ap-
proximately 20 mLvolume and washed with toluene (15 mL)
and methanol (7 mL) while maintaining temperature above
60 °C. The phases were separated, and the upper layer was
washed twice with a mixture of water (20 mL) and methanol
(5 mL) while maintaining temperature above 60 °C. The
combined lower phases were washed twice with methylene
chloride (2 × 20 mL) and were concentrated to ap-
proximately 25 mL volume. Water (35 mL) was added, and
the slurry was concentrated to approximately 45 mL volume
and slowly cooled to 0 °C. The precipitate was collected by
vacuum filtration, washed with a cold solution of water (10
mL) and methanol (2.5 mL), and dried in a nitrogen stream
to give a white solid (2.32 g, 83%). HPLC tR ) 1.83 min
(column ) Phenomenex IB-SIL Phenyl BD, 150 mm × 4.6
mm, flow rate: 1.0 mL/min, detection at 254 nm, isocratic
elution solvent: 350 mL of acetonitirile and 650 mL of a
solution of 0.7 mL of triethylamine in 1 L of water adjusted
to pH 3.5 with phosphoric acid).
1
(5.54 g, 93%); H NMR (400 MHz, CDCl3) δ 3.21 (t, J )
5 Hz, 4 H), 3.46 (s, 4 H), 4.95 (s, 2 H), 7.21 (d, J ) 11 Hz,
2 H), 10.46 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 49.82,
51.94, 73.46, 95.55, 102.28 (JC-F ) 29 Hz), 121.71, 136.02,
151.53, 158.06(JC-F ) 243 Hz, JC-F ) 9 Hz).
[(2S)-Oxiranylmethyl]carbamic Acid, 1,1-Dimethyl-
ethyl Ester (26). To a solution of 27 (19.98 g, 95.29 mmol)
in methanol (50.0 mL) at 13 °C was added lithium tert-
butoxide (8.40 g, 104.9 mmol, 1.10 equiv) while maintaining
less than 22 °C. The mixture was stirred at 8-20 °C for 15
min, and water (200 mL) followed by methylene chloride
(200 mL) was added. The phases were separated, and the
aqueous was washed with methylene chloride (135 mL). The
combined organics were dried on magnesium sulfate and
concentrated to an oil. Column chromatography on silica gel
(0 to 4% methanol in methylene chloride eluent) gave the
title compound as a white solid (14.26 g, 86.4%): mp )
1
45-49 °C; H NMR (400 MHz, CDCl3) δ 1.448 (s, 9 H),
2.59 (s, 1 H), 2.78 (t, J ) 4 Hz, 1 H), 3.09 (s, 1 H), 3.20 (dt,
J ) 14, 6 Hz, 1 H), 3.53 (d, J ) 15 Hz, 1 H), 4.85 (s, 1 H);
13C NMR (CDCl3) δ 28.28 (q), 41.72 (t), 45.04 (t), 50.85
(d), 79.61 (s), 155.96 (s); MS (CI+) for C8H15NO3 m/z 174
(M + H)+; [R]22D (-13, C ) 1.0, methylene chloride). Anal.
Calcd for C8H15NO3: C, 55.47; H, 8.73; N, 8.09. Found:
C, 55.17; H, 8.54; N, 8.00.
tert-Butyl-(2S)-3-chloro-2-hydroxypropylcarbamate (27).
To a slurry of 2a (900 g, 6.16 mol) and di-tert-butyldicar-
bonate (1.470 kg, 6.74 mol, 1.09 equiv) in methanol (3.6 L)
was added a solution of potassium bicarbonate (702 g, 7.01
mol, 1.14 equiv) in water (2.1 L) over 45 min while
maintaining 28-30 °C. The mixture was stirred at 28 °C
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Vol. 7, No. 4, 2003 / Organic Process Research & Development

for 1 h at which point GC showed 3.4 area % residual di-
tert-butyl dicarbonate. Methylene chloride (3.6 L) and water
(1.8 L) were added and the phases separated. The organic
was washed with water (900 mL), and both aqueous were
serial back-extracted with methylene chloride (2.25 L). The
combined organics were concentrated in vacuo to 2.7 L total
volume. Toluene (2.7 L) was added and the solution
concentrated to 3.0 L total volume. Isooctanes (4.2 L) was
added, the resultant two-phase solution seeded with 27 and
stirred at 22 °C for 20.5 h. The resultant slurry was cooled
to 4 °C and stirred for 3 h. The product was collected by
vacuum filtration and washed with isooctanes (900 mL) and
dried in a 30 °C vacuum oven to afford a white solid (1162
g, 90.0%): GC 96.0 area % 27; mp ) 48-52 °C; 1H NMR
(CDCl3, 400 MHz) δ 5.13 (bs, 1H), 3.92 (m, 1H), 3.76 (bs,
1H), 3.60-3.51 (m, 2H), 3.42 (m, 1H), 3.24 (m, 1H), 1.45
(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 28.26 (q), 43.81 (t),
C, 57.71; H, 6.63; N, 10.63; found: C, 57.63; H, 6.81; N,
10.32.
tert-Butyl-{(5S)-3-[4-(1,1-dioxohexahydro-1lambda6-
thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-
yl}methylcarbamate (29). To a slurry of 1313a (1.0037 g,
2.92 mmol), and 27, (0.7608 g, 3.629 mmol, 1.24 equiv) in
DMF (1.80 mL) in an ice bath was added lithium tert-
butoxide in THF (18.07 wt % solution, 2.7465 g, 6.20 mmol,
2.12 equiv). The mixture was allowed to stand at 20-25 °C
for 37 h. Toluene (10 mL), saturated aqueous ammonium
chloride (5 mL), water (5 mL) and heptane (10 mL) were
added and the precipitate collected by vacuum filtration,
washed with water (13.2 g) and toluene (10.2 g) and dried
in a nitrogen stream to give a white solid, 1.1507 g
(89.0%): HPLC tR ) 3.0 min (column ) Phenomenex Luna
C8 5 µm, 150 mm × 4.6 mm, flow rate ) 2.0 mL/min,
gradient elution from 40:60 A:B to 100:0 A:B over 15 min;
A ) acetonitrile; B ) water); 1H NMR (400 MHz, DMSO-
d6) δ 1.35 (s, 9 H), 2.07 (m, 2 H), 2.17 (q, J ) 13 Hz, 2 H),
3.10 (d, J ) 12 Hz, 2 H), 3.20 (t, J ) 12 Hz, 1 H), 3.28 (t,
J ) 5 Hz, 1 H), 3.30 (m, 3 H), 3.80 (dd, J ) 6, 9 Hz, 1 H),
4.11 (t, J ) 9 Hz, 1 H), 4.71 (m, 1 H), 7.20 (t, J ) 6 Hz, 1
H), 7.24 (d, J ) 8 Hz, 1 H), 7.37 (t, J ) 9 Hz, 1 H), 7.47
(dd, J ) 2, 13 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) δ
28.05 (q), 29.91 (t), 33.49 (d), 42.88 (t), 47.06 (t), 50.45 (t),
71.53 (d), 78.07 (s), 105.18 (dd, JC-F ) 28 Hz), 113.78 (d),
125.32 (sd, JC-F ) 15), 128.13 (dd, JC-F ) 6), 138.41 (sd,
JC-F ) 11), 153.98 (s), 157.17 (sd, JC-F ) 241), 160.8 (s);
MS (EI) m/z (relative intensity) 442 (2), 342 (21), 243 (31),
46.42 (t), 71.19 (d), 80.09 (s), 157.17 (s); [R]25 ) -22 (c
D
) 0.94, methylene chloride). Anal. Calcd for C8H16ClNO3:
C, 45.83; H, 7.69; N, 6.68; Cl, 16.91. Found: C, 46.12; H,
7.73; N, 6.76; GC for 27 (tR) 8.3 min): 15 M-DB-1 capillary
column, Tinj ) 250 °C, Tini )70 °C for 2 min, Tfin ) 250
°C, rate ) 10 °C/min.
tert-Butyl-{(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-
2-oxo-1,3-oxazolidin-5-yl}methylcarbamate (28). To a
solution of 8 (0.8758 g, 2.651 mmol) and 27, (0.7011 g,
3.344 mmol, 1.26 equiv) in DMF (1.7 mL) in an ice bath
was added a solution of lithium tert-butoxide in THF (2.82
g of an 18.1 wt % solution, 6.37 mmol, 2.40 equiv). The
resultant solution was allowed to stand at 20 °C for 44 h
(HPLC showed 95.0% conversion after 20 h and 97.8%
conversion after 44 h). Saturated aqueous ammonium
chloride (5.0 mL), water (10 mL), and methylene chloride
(12 mL) were added and the phases separated. The aqueous
was washed with methylene chloride (12 mL), and the
combined organics were dried on magnesium sulfate and
concentrated to an oil (2.4574 g). External standard HPLC
showed the oil to contain 0.9397 g (89.6%) of 28. HPLC
retention time ) 4.97 min (column ) Zorbax SB-C8 3.5
µm 150 mm × 4.6 mm, flow rate ) 2.0 mL/min, gradient
elution from 30:70 A:B to 90:10 A:B over 15 min; A )
969:30:1 acetonitrile:THF:trifluoroacetic acid; B ) 949:50:1
water:THF:trifluoroacetic acid). An analytical sample of 28
isolated by column chromatography (ethyl acetate/hexanes
eluent) had the following physical properties: mp ) 46.2-
48.0 °C; 1H NMR (CDCl3, 400 MHz) δ 7.43 (dd, J ) 14.4,
2.4 Hz, 1H) 7.09 (dd, J ) 8.8, 2.0 Hz), 6.92 (t, J ) 9.2, 1H)
5.11 (bs, 1H), 4.73 (bs, 1H), 4.00 (t, J ) 8.8, 1H), 3.86 (t,
J ) 4.4, 4H), 3.80 (t, J ) 6.8, 1H), 3.50 (m, 2H), 3.04 (t, J
) 4.8, 4H), 1.41 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
28.25 (q), 43.27 (t), 47.53 (t), 51.03 (dt, JC-F ) 3.02 Hz),
66.95 (t), 71.99 (d), 80.19 (s), 107.50 (dd, JC-F ) 26.16 Hz),
113.93 (dd, JC-F ) 3.02 Hz), 118.83 (dd, JC-F ) 4.03 Hz),
133.18 (sd, JC-F ) 11.07 Hz), 136.45 (sd, JC-F ) 9.06 Hz),
154.29 (s), 155.55 (sd, JC-F ) 241.50 Hz), 156.30 (s). MS
151 (100); [R]25 ) -23 (c ) 0.93, methylene chloride).
D
Anal. Calcd for C20H27FN2O6S: C, 54.29; H, 6.15; N, 6.33.
Found: C, 54.09; H, 6.20; N, 6.41.
[[(5S)-3-[3-Fluoro-4-(tetrahydro-2H-thiopyran-4-yl)-
phenyl]-2-oxo-5-oxazolidinyl]methyl]carbamic Acid 1,1-
Dimethylethyl Ester (30). To a solution of 1413a (0.915 g,
2.94 mmol) and 27 (0.768 g, 3.66 mmol, 1.25 equiv) in DMF
(1.8 mL) and THF (3.0 mL) at 0 °C was added lithium tert-
butoxide (0.697 g, 8.71 mmol, 2.97 equiv). The mixture was
allowed to room to room temperature over 16 h. Saturated
aqueous ammonium chloride (5 mL), water (5 mL), toluene
(10 mL) and isooctanes (20 mL) were added and the phases
separated. The aqueous was washed with toluene (10 mL)
and the combined organics dried on MgSO4 and concentrated
to an oil. Column chromatography (gradient from 0 to 70%
ethyl acetate in hexanes) afforded a hard oil (0.920 g,
1
76.3%): H NMR (400 MHz, CDCl3) δ 1.41 (s, 9 H), 1.86
(q, J ) 13 Hz, 2 H), 2.06 (d, J ) 15 Hz, 2 H), 2.69 (d, J )
14 Hz, 2 H), 2.86 (t, J ) 14 Hz, 3 H), 3.52 (m, 2 H), 3.83
(t, J ) 7 Hz, 1 H), 4.01 (t, J ) 9 Hz, 1 H), 4.75 (s, 1 H),
5.03 (s, 1 H), 7.14-7.22 (m, 2 H), 3.39 (d, J ) 12 Hz, 1
H); 13C NMR (100 MHz, CDCl3) δ 28.16, 29.17, 33.80,
36.35, 47.33, 71.98, 80.20, 105.96 (JC-F ) 29 Hz), 113.54
(JC-F ) 3 Hz), 127.89 (JC-F ) 6 Hz), 129.02 (JC-F ) 15
Hz), 137.37(JC-F ) 11 Hz), 154.18, 156.22, 160.18 (JC-F
)
(EI) m/z (relative intensity) 395 (100), 339 (85); [R]25
)
243 Hz). Anal. Calcd for C20H27FN2O4S: C, 58.52; H, 6.63;
D
-36 (c ) 0.71, acetonitrile). Anal. Calcd for C19H26FN3O5:
N, 6.82. Found: C, 58.20; H, 6.74; N, 6.66.
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545

Acknowledgment
Roger Ericks, Rusty Colvin, Daniel Alphenaar, Timothy
Bowers, James Garlock, Michael Veley, Kenneth Whitney,
John Burt. David Anderson, Thomas Judge, Paul Johnson,
and Yan Hao from medicinal chemistry participated in
insightful discussions of this technology.
Jeffrey Smith and Mark Krook have been a significant
source of practical advice on the application of this technol-
ogy. Donald Knoechel, Sean Lapekas, and Steve Snyder
performed hazards analyses on each of the piloted steps. The
following technicians were instrumental in solving the many
technical issues associated with the scale-up of these
processes: Richard Hohler, Ronald Newhouse, Walter Por-
trum, Hector Jimenez, David Soderquist, Harold Gleaves,
Robert Soderquist, Douglas Grevenstuk, Matthew Eckman,
Received for review February 17, 2003.
OP034028H
546
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