Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PROCESS FOR PREPARING LINEZOLID
FIELD OF INVENTION
The present invention relates to a novel process to prepare an oxazolidinone
antibacterial agent. Particularly, the present invention relates to a novel
process to prepare
linezolid.
BACKGROUND OF THE INVENTION
Antibacterial resistance is a global clinical and public health problem that
has
emerged with alarming rapidity in recent years and undoubtedly will increase
in the near
future. Resistance is a problem in the community as well as in health care
settings, where
transmission of bacteria is greatly amplified. Because multiple drug
resistance is a growing
problem, physicians are now confronted with infections for which there is no
effective
therapy. As a result, structurally novel antibacterial agents with a new mode
of action have
become increasingly important in the treatment of bacterial infections.
Among newer antibacterial agents, linezolid is a recent synthetic class of
antimicrobials active against a number of pathogenic microorganisms. Linezolid
[(S)-N-[[3-
[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is
disclosed in
U.S. Patent No. 5,688,792. It is marketed in the United States by Pfizer, Inc.
as an injection,
tablets, and oral suspensions under the name ZYVOX . Processes for preparation
of
linezolid are described in U.S. Patent No. 5,688,792, U.S. Patent No. 5,837,
870, PCT
publication WO 99/24393, PCT publication WO 2006/004922, J. Med. Chem. 39(3),
673-
679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
We have discovered and developed a novel process to prepare linezolid. The
process
has the potential to significantly lower the cost of commercial production of
linezolid. It is a
highly convergent three-step process with a much shorter cycle time. It is
environmentally
friendly because it reduces the large solvent volumes used in the currently
known processes.
We also discovered rapidly crystallized key intermediates for the process of
the present
invention.
INFORMATION DISCLOSURE
US 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773 disclose the
synthesis of 5-hydroxymethyloxazolidinones from amines.
J. Med. Cltern., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and US Patent
4,948,801 disclose a method of producing oxazolidinones.
PCT Publications W093/09103, W093109103, W095/07271 and W093/23384;
PCT applications PCT/US95/12751 and PCT/US95/10992 disclose the reaction of a
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2
carbamate with n-butyllithium, lithium diisopropylamide or lithium
hexamethyldisilazide.
International Publication W095/07271 discloses the ammonolysis of 5R-
methylsuifonyloxymethyl substituted ox.azolidinones.
US Patent 4,476,136 discloses a method of transforming 5-hydroxymethyl
substituted
oxazolidinones to the corresponding 5(S)-aminomethyl substituted
oxazolidinones.
US patent 5,332,754 discloses racemic oxazolidinone-CH2-NH-Ac can be
synthesized in one step by condensation of a carbamate with racemic glycidyl
acetamide.
US patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-
substituted
oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
1.0
SUMMA.RY OF THE INVENTION
The present invention provide a process to prepare linezolid
F o
o N ! ~ ~O H
N,,jr
0
Linezolid
which comprises:
a) reacting a compound of structure (1)
HO
Cl N~~~ x
(1)
wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
with a compound of structure (2)
F 0
p N / \ NO_R
(2)
at a temperature in a range from ambient temperature to about 65 C, wherein R
is benzyl or
CI.8alkyl to provide a compound of structure (3);
0
O lN N~O
N4~X
(3)
where X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl;
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b) hydrolyzing the compound of structure (3) and subsequent acylation to
provide
linezolid.
Other aspects of the present invention are the compounds of structures (1) and
(3) as
shown above, their crystal structures, and their methods of crystallizations.
DETAILED DESCRIi'TION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and
claims
have the meanings given below:
The carbon atom content of various hydrocarbon-containing moieties is
indicated by
a prefix designating the minimum and maximum number of carbon atoms in the
moiety, i.e.,
the prefix C;_j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive.
Thus, for example, Ci_$ alkyl refers to alkyl of one to eight carbon atoms,
inclusive.
The term alkyl refers to both straight and branched groups, but reference to
an
individual radical such as "propyl" embraces only the straight chain radical,
a branched chain
isomer such as "isopropyl" being specifically referred to. Specifically, alkyl
is C14alkyl.
More specifically, alkyl is tert-butyl.
The term "ambient temperature" refers to a temperature in a range from about
20 C
to 30 C.
SCHEME I
0
ON OH ~N ~ O ~
X + ~ i JL .R F N O
F ~ O
(1) (3) X
~ O N
--=
~ ~ (i ~
F N O ~'N O
1__~NH2 t.inezoiici 1__~NH
HCI O
As shown in Scheme I (wherein X and R are defined above), the synthesis begins
with coupling the substituted imine moiety (1) (preferably 1 to 3 eq, most
preferably 1.5 to 2
eq) with a carbamate (2) to provide the corresponding (S)-oxazolidinone imine
(3). The
reaction is carried out preferably at a temperature in a range from ambient
temperature to
about 65 C in the presence of a base with pKa greater than 12, preferably a
tertiary alkoxide
base, most preferably lithium t-butoxide and an aprotic non-nucleophilic
solvent (preferably
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4
DMF, DMAc, THF, Acetonitrile, C1.6 linear, branched and cyclic ethers and/ or
chlorinated
solvents and/ or mixtures of these solvents, most preferably MTBE or methylene
chloride).
Most preferably, the temperature is from about 30-60 C and the reaction time
is 2 to 24
hours. Preferably, the (S)-oxazolidinone imine (2), after an aqueous
extractive workup, is
crystallized and isolated by filtration from a weakly polar organic solvent,
such as an alcohol
(including C1.6 branched and linear alcohols and polyols) or ether (including
MTBE, THF,
and other Cl_6 linear, branched and cyclic ethers); most preferably
isopropanol. Hydrolysis
of compound (3) with an aqueous acidic solution and subsequent acylation
provides crude
linezolid. Compound (3) is best hydrolyzed with a mixture of water and a
strong acid such as
hydrochloric acid and the substituted benzaldehyde byproduct removed by
extraction with a
water immiscible organic solvent (preferably toluene, MTBE, methylene chloride
and ethyl
acetate), most preferably ethyl acetate. The resulting aqueous solution of
Amine
hydrochloride (4) is preferably acylated with acetic anhydride, preferably in
the presence of
water and a water immiscible organic solvent (most preferably methylene
chloride), The
conversion of Amine hydrochloride (4) to linezolid is well known in the
literature (Brickner,
S.J.; et. al. J. Med. Chem. 1996 39 (3) 673-679, US Patent 5,837,870, US
5,688,792).
SCHEME II
o,,, OH
~~ GI + XNr'O ----~- CI~~N X
H
il)
As shown in Scheme IT (wherein X is defined above), the key strating material
(1)
can be prepared by reacting (S)-epichlorohydrin with a mixture of the
appropriately
substituted benzaldehyde derivative (preferably 0.5 to 2 eq, most preferably I
eq) and
aqueous ammonia (preferably 0.5 to 3 eq, most preferably 1.5 eq). The reaction
is best
performed in both protic and aprotic non-nucleophilic and non-electrophilic
solvents such as
alcohols (including C1.6 branched and linear alcohols and polyols), ethers
(including MTBE,
THF, and other C1.6 linear, branched and cyclic ethers) as well as chlorinated
solvents such as
methylene chloride. MTBE is a preferred solvent. Temperatures can be in a
range from
about 15 to about 60 C are preferred, preferably between 30 to 50 C most
preferred. After
extractive isolation and concentration, the imine moiety (1) is obtained. It
is then crystallized
from a second liquid phase, in the presence of non-polar aprotic hydrocarbon
solvents such
as, but not limited to, alkanes, mixtures of alkanes (hexane, heptane, octane,
isooctane and
commercially available alkane mixtures), optionally in the presence of aprotic
polar solvents,
preferably ethereal solvents such as MTBE or aromatic solvents such as toluene
or
chlorinated solvents such as methylene chloride or mixtures thereof. Preferred
solvents are a
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mixture of MTBE and heptane or a mixture of toluene and heptane. The
crystallization
process can be conducted in a temperature in a range from ambient temperature
(about 18-25
C) to about 55 C, preferably in a range of 30 to 50 C, more preferably in a
range of 38 to
45 C. This crystallization provides surprisingly high yield and with
significantly improved
5 enantiomeric purity after isolation by filtration.
EXAMPLES
In the discussion above and in the examples below, the following abbreviations
have
the following meanings. If an abbreviation is not defined, it has its
generally accepted
meaning.
bm - broad multiplet
BOC tert-butoxycarbonyl
bd -- broad doublet
bs = broad singlet
iS CDI -- 1, 1 0-carbodiimidazole
d - doublet
dd -- doublet of doublets
dq = doublet of quartets
dt = doublet of triplets
DMF dimethylformamide
DMAP dimethylaminopyridine
DMSO - dimethyl sulfoxide
eq. - equivalents
g grams
h hours
HPLC - high pressure liquid chromatography
HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-
1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate N-oxide
LG - leaving group
m - multiplet
M - molar
M% - mole percent
max maximum
meq = milliequivalent
mg = milligram
mL - milliliter
mm = millimeter
mmol - millimol
MTBE = methyl t-butyl ether
q = quartet
s - singlet
t or tr -- triplet
TBS -- tributylsilyl
TFA = trifluoroacetic acid
THF - tetrahydrofuran
TLC ~ thin layer chromatography
p-TLC - preparative thin layer chromatography
L - microliter
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N normality
MeOH methanol
DCM -- dichloromethane
HCl = hydrochloric acid
ACN - acetonitrile
MS _ mass spectrometry
rt - room temperature
EtOAc ethyl acetate
EtO = ethoxy
Ac - acetate
NMP - 1-methyl-2-Pyrrolidinone
L - microliter
J - coupling constant
NMR - Nuclear magnetic resonance
MHz - megahertz
Hz = hertz
m/z - mass to charge ratio
min = minutes
Boc tert-butoxycarbonyl
CBZ - benzyloxycarbonyl
DCC - 1,3-dicyclohexylcarbodiimide
PyBop -- benzotriazole-l-yl-oxy-trispyrrolidinophosphonium
hexafluorophosphate
Example 1 Preparation of (S)=1-chloro-3-[(4-chloro-E-benzylidene)-aminol-
propan-2-ol
cI CI
o NN3 ,` FIO i I
+
a
Method A
A 5L three neck round bottom flask equipped with a mechanical stirrer,
thermocouple, reflux condenser and heating mantel is charged with 4-
chlorobenzaldehyde
(351. g, 2.5 mol, 1.0 eq.). MTBE (1.5 L) is then charged into the round bottom
to give a
homogeneous solution. Aqueous ammonia (28 wt%, 252.98 mL, 3.75 mol, 1.5 eq.)
is added
in a single portion resulting in a white precipitate that turned into a thin
slurry within 15
minutes of stirring. (S)-(+)-epichlorohydrin (> 99 % ee, 196.0 mL, 2.5 mol,
1.0 eq.) is then
slowly charged into the vessel. After 40 minutes, the contents are then slowly
heated to
43 C. The reaction is stirred at 40 C for 18 hours at which time 8.4% area of
epichorohydrin
remained by GC. Upon cooling to rt, the reaction mixture is transferred to a
separatory funnel
and the layers are separated. The lower aqueous layer is discarded. The
organic layer is
transferred to a 3L round bottom flask, concentrated in vacuo to about half
the volume (800-
900 mL) at which time iso-octanes is slowly added from a feed tube (-750 mL)
until
cloudiness is observed. The biphasic mixture is seeded with - 4 mgs of the
title compound.
The reaction is cooled with an ice bath for 45 minutes while stirring. The
precipitate is
collected and rinsed with cold iso-octane (500 mL). The solid is dried for 18
hours at 50 C
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under vacuum to give the title compound as a white crystalline in solid. GC
assay: 100%,
99,7% ee by Chiral SFC). GC (conditions: column - 30 meter HP-1, 0.25mm ID and
0.25
micron film and 15 psi head pressure, 1.0 l injection size; T;,,; = 70 C,
ramp of 20 C/min)
Ta (epichlorohydrin) = 2.4 min, Ta (4-chlorobenzaldehyde) = 4.8 min and TR
(title
compound) = 9.7min; HPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column,
eluting
with 70% CO.2/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound]
= 3.9
min; TR (enantiomer of title compound) = 2.8 min; 'H NMR (400 MHz, CDC13) S
3.69 (bs, 2
H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41. (d, J= 8 Hz, 2 H), 7.69 (d, J = 8 Hz,
2 H), 8.33 (s, I H);
"C NMR (CDCI3) 8 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30;
IR (KBr
Pellet) 1630 cm``;
X-ray crystal structure: crystal system = monoclinic, space group = P2(l),
unit cell
dimensions a 8.791(2) A, b = 4.6556(11) A, c = 14.372(3) A, oc= 90 , (3=
106.819(4) , y=
90 , Volume = 563.0(2) A3; Z =2; F(000) = 240; Ortep' Drawing:
C3
: =r~,
f.=...
õ Qlt C2 '''.....r
C4 r.iu
C12
= .. C10 CS
7
Ce
r. =>.t
\/~K1iJ
`..../
Method B
A 5L three neck round bottom flask equipped with a mechanical stirrer,
thermocouple, reflux condenser and heating mantel is charged with 4-
chlorobenzaldehyde
(375 g, 2.67 mol, 1.0 eq.). Methanol or THF is added and mixture warmed from
10 to 23 C.
Aqueous ammonia (28.4 wt%, 264 mL, 3.95 mol, 1.5 eq.) is added in a single
portion
resulting in a biphasal solution forming after stirring for 15 minutes at 23
to 26 C. (S)-(+)-
epichlorohydrin ( 99.3 % ee, 207 mL, 2.64 mol, 1.0 eq.) is then added in one
portion. The
reaction mixture is stirred at 23-24 C for 18 h, then warmed to 40 to 45 C
and stirred for 2.5
h at which time 0.26% area of S-epichorohydrin remains by GC (GC conditions,
0.050 ml
reaction mixture in 1 ml acetonitrile, inject 1 microliter; 15 M DB-1 column,
0.25mm ID and
0.25 micron film and 15 psi head pressure, 1.0p1 injection size; T; = 38 C,
ramp of 10
C/min) TR (epichlorohydrin) = 1.1 min, TR (4-chlorobenzaldehyde) = 6.9 min and
Ta (title
compound) = 16.0 min). The mixture is concentrated in vacuo to a total volume
of 1250 ml.
Toluene (250 ml) is added and the mixture concentrated in vacuo to a total
volume of 1250
ml. Toluene (250 ml) is added and the mixture concentrated in vacuo to a total
volume of
1145 ml. Toluene (355 m.l) is added and the mixture concentrated in vacuo to a
total volume
of 900 ml. Toluene (600 ml) is added and the mixture concentrated in vacuo to
a total
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8
volume of 1120 ml. While maintaining 45 to 50 C, heptane (1500 ml) is added.
The
resulting biphasal solution is cooled to 45 C and seeded. The mixture is then
further cooled
to 38 C over 1/2 h while seeding after every I degree of cooling. The mixture
is then further
allowed to slowly cool to 23 C over 16 h. The white crystals are then
collected by vacuum
filtration and washed with room temperature heptane (180 ml). The product is
dried in a
nitrogen stream to give the title compound. IAPLC 95 area% [Kromasil 150 mm X
4.6 mm
column, 254 nm, flow rate 1.5 ml! m'rn; A=1000 ml water + 0.52 ml
trifluoroacetic acid +
1.20 ml triethylamine; B = acetonitrile; Isocratic 47: 53 A: B for 5 min then
gradient to 100%
B over 5 min TR [title compound] = 2.1 min,; TR (4-chlorobenzaldehyde) = 2.3
min];
99.72% ee by Chiral SFC. Chiral BPLC conditions: Chiralpak AD-H 250 nm X 4.6
nm
column, eluting with 70% CO2/ 30%MeOH at 3.0 mLlmin, detecting at 255 nm. TR
[title
compound] = 3.9 min; TR (enantiomer of title compound) = 2.8 m.in;'H NMR (400
MHz,
CDCl3) & 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41 (d, J = 8 Hz, 2
H), 7.69 (d, J = 8
Hz, 2 H), 8.33 (s, 1 H); "C IVMR (CDC13) & 47.05, 63.09, 70.82, 128.93,
.129.39, 134.08,
137.07, 162.30.
Method C
A 5L three neck round bottom flask equipped with a mechanical stirrer,
thermocouple, reflux condenser and heating mantel is charged with 4-
chlorobenzaldehyde
(375 g, 2.67 mol, 1..0 eq.). MTBE (1.50 L) is then added to give a homogeneous
solution
after warming from 9 to 24 C. Aqueous ammonia (28.4 wt%, 265 mL, 3.97 mol,
1.5 eq.) is
added in a single portion resulting in a biphasal solution forming after
stixring for 15 minutes
at 23 to 26 C. (S)-(+)-epichlorohydrin ( 99.3 % ee, 209 mL, 2.67 mol, 1.0
eq.) is then added
in one portion. The reaction mixture is stirred at 23-24 C for 3 days. The
phases are
separated and the upper phase concentrated under atmospheric pressure from
2000 to 1000
ml total volume (boiling point 58 to 67 C). While maintaining 45 to 50 C,
heptane (1700
ml) is added. The resulting biphasal solution is cooled to 45 C and seeded.
The mixture is
then further cooled to 38 C over 1/2 h while seeding after every i degree of
cooling. The
mixture is then further allowed to slowly cool to 23 C over I h. The white
crystals are then
collected by vacuum filtration and washed with room temperature heptane (180
ml). The
product is dried in a nitrogen stream to give the title compound. HPLC 94
area% [Kromasil
150 nm X 4.6 nm column, 254 nm, flow rate 1.5 ml/ min; A = 1000 ml water +
0.52 ml
trfluoroacetic acid + 1.20 ml triethylamine; B = acetonitrile Isocratic 47: 53
A: B for 5 min
then gradient to 100% B over 5 min TR [title compound] = 2.1 min,; TR (4-
chlorobenzaldehyde) = 2.3 min]; 99.92% ee by Chiral SFC. Chiral HPLC
conditions:
Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% COZ/ 30%MeOH at 3.0
mL/min, detecting at 255 nm. TR [title compound] = 3.9 min; Tk (enantiomer of
title
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9
compound) = 2.8 min; EH NMR (400 MHz, CDC13) S 3.69 (bs, 2 H), 3.80 (m, 2 H),
4.15 (s, I
H), 7.41 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, i H); 13C NMR
(CDCI3) S 47.05,
63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30.
Example 2 Preparation of (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-
fluoro-4-
morpholin-4-yl-ph.enyl)-oxazolidin-2-one
Ao-' ~H cl ~N \ O
F + cl ,~irv F ! ~' N,~,
C)
. \ ~
Method A
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (20 g, 60.05
mmoles, 1 eq) is added lithium t-butoxide (12.11 g, 151.4 mmoles, 2.5 eq),
followed by
methylene chloride (80 mL) and the mixture stirred at room temperature. To the
resultant
suspension is added (S)-1-chloro-3-[(4-chloro-benzylidene)-amino]-propan-2-ol
(21.07 g,
90.81 mmoles, 1.5 eq) in methylene chloride (40 mL) in one portion. The
resulting thin
suspension is heated to reflux (41 C) for 5h. After cooling to room
temperature, the organic
layer is washed with water (1 x 100 mL, 1 x 50 mL), these aqueous washes are
then
discarded. The organic phase is concentrated in vacuo to about 1/2 volume, at
which time
isopropy). alcohol (200 mL) is added and the concentration continued to a
volume of less than
200 mL. The resultant suspension is cooled to -i0 C to -20 C and the solids
isolated by
filtration and washed with cold isopropyl alcohol (less than 100 mL) then
dried at 55 C under
vacuum to afford the title compound as a crystalline in solid. SFC achiral
assay indicates a
purity of 99.4 area% and SFC chiral assay identified 0.11 % of the (R)
enantiomer. HPLC
conditions: YMC 5 ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water +
0.1%
TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR
[(3-
fluoro-4-morpholin-4-yl-phenyi)-carbamic acid benzyl ester] = 8.5 min; TR
(title compound)
= 7.9 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting
with 75%
C02/ 25%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.8
min; TR
(enantiomer of title compound) = 4.4 min; tH NMR (400 MHz, CDC13) $ 3.05 (d,
J= 4 Hz, 4
H), 3.87 (d, J= 4 Hz, 4 H), 3.90 (m, 2 H), 4.12 (m, 2 H), 4.95 (m, I H), 6.92
(t, J= 8 Hz, 1
H), 7.12 (d, J= 2 Hz, I H), 7.36 (d, J= 8 Hz, 2 H), 7.44 (dd, J= 16, 4 Hz, I
H); 7.63 (d, J= 8
Hz, 2 H), 8.34 (s, 1 H); "C NMR (CDC13) S 48.23, 51.00, 63.19, 66.94, 71.69,
107.42 (d, J =
27 Hz), 113.88, 118.74, 128.93, 129.50, 133.36 (d, J= 11 Hz),133.94,
136.30,137.22, 154.46,
155.48 (d, J = 244 Hz), 163.46.
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Method B
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (372 g, 1.13
mol, 1
eq) is added lithium t-butoxide (225 g, 2.81 mol, 2.5 eq), followed by
methylene chloride (2.2
L) and the mixture stirred at room temperature. To the resultant suspension is
added (S)-1-
5 chloro-3-[(4-chloro-benzylidene)-amino.]-propan-2-ol (400 g, 1.72 mol, 1.5
eq) in one
portion. The resulting thin suspension is heated to reflux (41 C) for 10 h.
The resultant
slurry is added to a solution of acetic acid (85.2 g, 1.42 mol, 1.26 eq) in
methanol (800 ml)
while maintaining reflux and rinsed in with methanol (40 ml). The resultant
slurry is
concentrated via atmospheric distillation to a total volume of 3200 ml.
Methanol (2500 ml)
l0 is added while concentrating via atmospheric distillation to maintain a
total volume of 3200-
3800 ml. The resultant slurry is cooled to 3 C and the precipitate collected
by vacuum
filtration, washed with methanol and dried in a nitrogen stream to give the
title compound as
crystalline in solid. (HPLC conditions: Kromasil C18 3.5 micron 250 mm X 4.6
mm column,
mobile phase A = 0.52 ml TFA, 1.20 ml~ triethylamine, 1000 ml water; mobile
phase B
acetonitrile, isocratic 53: 47 A:B for 5 min then gradient to 100% B over 5
min at 1.5
mL/min, detecting at 254 nm; TR [title compound] = 6.66 min.
Example 3 Preparation of (S)-N-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-
oxazolidin-5-ylmethyl]-acetamide (Linezolid)
o
N)~ 0 vN I ~
~FN~
\ GI F NNH I I
NH
Method A
To (S)-5-{ [(4-chloro-benzylidene)-amino]-methyl }-3-(3-fluoro-4-morpholin-4-
yl-
phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate
(935 rnL) and
water (935 mL). To the heterogeneous mixture is added 12M aq. HCI (51.58 mL,
620 mmol,
2.0 eq.). Within minutes, the solid went into solution and the reaction
mixture is biphasic.
After stirring the emulsion at ambient temperature for 2 hours, HPLC assay
showed the
hydrolysis reaction to be complete (HFLC conditions: YMC 5 ODS-AM 150 nm X
4.6 nm
column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8
min
at 0.5 mL/min, detecting at 254nm. Retention time of (S)-N-[3-(3-fluor.o-4-
morpholin-4-yl-
phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are
separated, the
organic layer is discarded, and the aqueous layer is washed with ethyl acetate
(500 mL).
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CH2Cl2 (900 mL) is added and the pH is adjusted to 6.7 with - 25 mL aq. 50%
aq. NaOH.
With constant stirring, Ac20 (58.49 mL, 620 mmol, 2.0 eq.) is added in one
portion and the
pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is
adjusted to
ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is
extracted with
CH2,CI2 (800 mL) and the organics are combined and concentrated to -IL in
volume. Ethyl
acetate (1L) is added and the volume is reduced to 1.5 L under vacuum. Another
1L of ethyl
acetate is added and volume is reduced again to 1L under vacuum. The resultant
slurry is
cooled to 0 C and the precipitate collected by vacuum filtration. The
resulting solid is
washed with ethyl acetate (250 mL). The crude product is dried under vacuum at
50 C for 2
hours to give the title compound as linezolid crystalline Form I.
Method B
N ~
F I/N~_-~ CI F'~ kNH2 HCF`: NCI
NH
a
Following the general procedure of method A and making non-critical
variations, but
substituting (S)-5-{ [2,4-dichloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-
morpholin-4-yl-
phenyl)-oxazolidin-2-one (example 11.) for (S)-5-{ [(4-chloro-benzylidene)-
amino]-
methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin 2-one, the title
compound
is obtained.
Method C
N N
/ 8r F N
N HCI
N NH2 NH
O
Following the general procedure of method B and making non-critical
variations, but
substituting (S)-5-{ [4-bromo-benzylidene)-amino]-methyl }-3-(3-fluoro-4-
morpholin-4-yl-
phenyl)-oxazolidin-2-one (example 9) for (S)-5- { [(4-chloro-benzylidene)-
arnino]-
methyl}-3-(3-luoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one, the title
compound
is obtained.
Example 4 Trituration (convert linezolid crystalline Form I to linezolid
crystalline Form
Ii) The product from Example (89.18 g) is transferred to a 3L round bottom
flask equipped
with a mechanical stirrer, thermocouple and heating mantel. Ethyl acetate
(2.23 L, 15 mL/g)
is added and seeded with Linezolid form II crystals and the slurry is heated
to ca. 50 C. A
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12
slight exotherm of 3 C is observed. After 30 minutes of heating the form
change is
observable as the solid is changing to long needles. Stirring is continued for
2 hours at 50 C,
at which time the contents are cooled to ambient temperature and stirred for
an additional 30
minutes. The contents are then cooled to 3 C for 1.5 hours, filtered and
washed with cold
ethyl acetate (300 mL total). The resultant solids are dried under vacuum at
50 C for 18
hours to give Linezolid (78.12 g) Form R by XRD, 99.8 wt%, 99.9% ee. HPLC
conditions:
YMC 511 ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA
from
20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR
(Linezolid) =
4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with
90% C02/
10%MeOH at 3.0 mLlmin, detecting at 255 nm. Tx [title compound] = 3.6 min; TR
(enantiomer of title compound) = 4.1 min.
Example 5 Preparation of (S)-1-chloro-3-[(4-bromo-benzylidene)-amino]-propan-2-
ol
Br
A + + NH3 ,= HO =~ ~
Cl
To a solution of 4-bromobenzaldehyde (20,8 g, 112 mmol) in MTBE (48 g) is
added
ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal
mixture
is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108
mmol, 1.0 eq.)
is added. The mixture is stirred for 3 days at room temperature and the phases
separated.
The organics layer is dried on MgSO4 (2 g) clarified with an MTBE rinse (10
ml) and isopar
C (100 m.l) is added to the filtrate. The solution is concentrated- in vacuo
to 75 ml total
volume and the resultant precipitate collected by vacuum filtration at room
temperature and
washed with isooctanes. Drying in a nitrogen stream afforded the title
compound as
crystalline in solid. 'H NMR (400 MHz, CDC13) S 3.69 (m, 2 H), 3.77 (dd, J =
6,13 Hz, I H),
3.84 (dd, J = 13, 5 Hz, 1 H), 4.15 (m, 1 H), 7.57 (d, J= 8 Hz, 2 H), 7.62 (d,
J= 8 Hz, 2 H),
8.31 (s, I H);13C NMR (CDC13) 5 47.05, 63.11, 70.80, 129.60, 131.89, 134.49,
137.36,
162.41.
Example 6 Preparation of (S)-I-chloro-3-[(4-nitro-benzylidene)-amino]-propan-2-
ol
/ I
~ + NO* NH3 ~-~- WO NO2
CI~_,N
O
To a mixture of 4-nitrobenzaldehyde (2.69 g, 17.8 mmol), THF (10 ml), and
aqueous
ammonia (28%, 1.80 ml, 26.7 mmol, 1.5 eq) at 18 C is added (S)-(+)-
epichlorohydrin (> 99
% ee, 1.39 mL, 17.8 mmol, 1.0 eq.). The mixture is stirred at 40 C for 18 h
then
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13
concentrated to in vacuo to provide the title compound as oil. GC (column - 30
meter HP-1,
0.25mm ID and 0.25 micron film and 15 psi head pressure, I.0 1 injection size;
Tir,; = 70 C,
ramp of 20 C/min) Ta (title compound) =11.16 min, 64 area%.
Example 7 Preparation of (S)-1-chloro-3-[(2,4-dimethoxy-benzylidene)-aminol-
propan-2-ol
/ OMe OMe
HO / I
0 + \ ~ + NH3 30
CI~,N ~ \
I
0 OMe OMe
To a solution of 2,4-dimethoxybenzaldehyde (18.0 g, 112 mmol) in MTBE (48 g)
is
added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The
biphasal
mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5
mL, 108 mmol,
1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and
the phases
separated. The organics layer is dried on MgSO4(2 g) clarified with an MTBE
rinse (10 ml)
and isopar C (100 ml) is added to the filtrate. The solution is concentrated
in vacuo to 75 ml
total volume. The resultant biphasal mixture is allowed to stand at room
temperature for 24
hours. The resultant waxy solid is collected by vacuum filtration at room
temperature and
washed with isooctanes. Drying in a nitrogen stream to provide the title
compound
1H NMR (400 MHz, CDC13) 8 3.74 (rn, 4 H), 3.85 (s, 6 H), 4.11 (m, 1 H), 6.44
(s, I H), 6.53
(q, J = 12 Hz, 1 H), 7.89 (d, J= 8 Hz, 1 H), 8.68 (s, 1 H); "C NMR (CDC13) S
47.11, 55.44,
55.46, 63.39; 13C NMR (CDC13) 8 71.07, 97.94, 105.32, 117.40, 128.45, 159.1.3,
1.60.20,
163.35.
Example 8 Preparation of (S)-1-chloro-3-[(2,6-dichloro-benzylidene)-aminol-
propan-2-ol
Cf
A + ` I F NH3 ----^-- Hd ~f / ~
~!/C{ CI~~,N~ \
O CI CI
To a solution of 2,6-dichlorobenzaldehyde (18.9 g, 112 mmol) in MTBE (48 g) is
added
ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal
mixture
is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108
mmol, 1.0 eq.)
is added. The mixture is stirred for 3 days at room temperature and the phases
separated.
The organics layer is dried on MgSOa (2 g) clarified with an MTBE rinse (10
ml) and isopar
C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to
give the title
compound as oil. 'H NMR (400 MHz, CDC13) S 3.74 (m, 4 H), 3.85 (s, 6 H), 4.11
(m, 1. H),
6.44 (s, 1 H), 6.53 (q, J = 12 Hz, 1 H), 7.89 (d, J = 8 Hz, 1 H), 8.68 (s, 1
H); 13C NMR
(CDC13) S 47.11, 55.44, 55.46, 63.39; "C NMR (CDC13) 8 71.07, 97.94, 105.32,
117.40,
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14
128.45, 159.13, 160.20, 163.35.
Example 9 Preparation of (S)-5-{[4-bromo-benzylidene)-aminoj-methyl}-3-(3-
fluoro-4-
morphol in-4-yl-phenyl)-oxazol idin-2-one
~ 6r
~.N OH
~/ II + CI~~N~ ~~ F
F NJ~
I
Br
H
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.51 g, 22.7
mmol,' 1 eq) is added lithium t-butoxide (4.64 g, 57.9 mmol, 2.55 eq),
followed by methylene
chloride (45 ml) and the mixture stirred at room temperature. To the resultant
suspension is
added (S)- 1-chloro-3-[(4-bromo-benzylidene)-amino]-propan-2-ol (8.55 g, 30.9
mmol, 1..36
eq) in one portion. The resulting thin suspension is heated to reflux (41 C)
for 21. h. The
resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol,
1.29 eq) in methanol
(46 g) and rinsed in with methanol (24 g). The resultant slurry is
concentrated via
atmospheric distillation to a total volume of 100 ml. The resultant slurry is
cooled to 3 C
and the precipitate collected by vacuum filtration, washed with methanol and
dried in a
nitrogen stream to give the title compound as crystalline in solid. 1H NMR
(CD.CII) S 3.05
(t, J = 5 Hz, 4 H), 3.87 (t, J= 5 Hz, 4 H), 3.90 (dd, J = 5, 14 Hz, 1 H), 3.96
(dd, J= 5, 13 Hz,
1 H), 4.04 (dd, J= 6, 9 Hz, 1 H), 4.12 (t, J- 9 Hz, I H), 4.95 (p, J= 5 Hz, I
H), 6.92 (t, J= 9
Hz, I H), 7.13 (dd, J= 10, 2 Hz, H), 7.43 (dd, J= 14, 3 Hz, 1 H), 7.52 (d, J=
9 Hz, 2 H),
7.56 (d, J = 9 Hz, 2 H), 8.33 (s, 1 H);13C NMR (CDC13) S 48.05, 50.84 (JC-F =
4 Hz), 63.03,
66.77, 71.49, 107.25 (Jc.F = 26 Hz), 113.70 (JC.r = 4 Hz), 118.60, 125.56,
129.54, 131.72,
133.18 (Jc_F = 10 Hz), 134.20, 136,09 (Jc.F = 6 Hz), 154.30, 155.32 (Jc_r =
245 Hz), 163.41.
Example 10 Preparation of (S)-1-chloro-3-[(2,4-dichloro-benzylidene)-amino}-
propan-2-ol
, CI
CI HO
A + + NH3 ----~- ~
."'CI CI"Y' N~
0 Cf ci
To a solution of 2,4-dichlorobenzaldehyde (112 g, 639 mmol) in MTBE (267 g) is
added ammonia (28 wt%, 63,0 ml, 943 mmol, 1.48 eq) at room temperature. The
biphasal
mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 50.0
mL, 639 mmol,
1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and
the phases
separated. The organics layer is dried on MgSOd (2 g) clarified with an MTBE
rinse (50 ml)
and the solution concentrated to 200 ml. Heptane (300 ml) is added and the
resultant
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precipitate collected by vacuum filtration at room temperature and washed with
heptane.
Drying in a nitrogen stream to provide the title compound as crystalline in
solid. 'H NMR
(CDC13) S 3.66 (dd, J= 6, 1 1 Hz, 1 H), 3.70 (dd, J= 5, 1 1 Hz, 1 H), 3.80
(ddd, J= i, 6, i 3
Hz, 1 H), 3.86 (ddd, J= 2, 5, 13 Hz, 1 H), 4.14 (p, J= 6 Hz, 1 H), 7.28 (dd,
J= 2, 8 Hz, 1 H),
5 7.40 (d, J = 2 Hz, I H), 7.96 (d, J = 8 Hz, 1 H), 8.71 (s, 1 H); 13C NMR
(CDCl3) S 46.98,
63.21, 70.66, 127.37, 128.95, 129.49, 131.06, 135.64, 137.22, 159.13.
Example 11 Preparation of (S)-5-{ (2,4-dichloro-benzylidene)-arnino]-methyl}-3-
(3-
fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one
N
N ~ O OH Ci I\ J'~
~{~, N i' O + CI~/N~ p ~ N O
H~ ci
=l
10 ci
To (3-fluoro-4=morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.59 g, 23.0
mmol, 1 eq)
is added lithium t-butoxide (4.69 g, 58.5 mmol, 2.55 eq), followed by
methylene chloride (45
ml) and the mixture stirred at room temperature. To the resultant suspension
is added (S)-1-
15 chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol (8.24 g, 30.9 mmol,
1.35 eq) in one
portion. The resulting thin suspension is heated to reflux (41 C) for 21 h.
The resultant
slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.27 eq) in
methanol (46 g)
and rinsed in.with methanol (24 g). The resultant mixture is concentrated via
atmospheric
distillation to 51 g net weight. The resultant slurry is cooled to 0 C and the
precipitate
collected by vacuum filtration, washed with methanol and dried in a nitrogen
stream to give
the title compound as crystalline in solid. 'H NMR (CDC13) 8 3.05 (t, J = 4
Hz, 4 H), 3.87 (t,
J= 4 Hz, 4 H), 3.98 (t, J= 4 Hz, 1 H), 4.04 (dd, J= 6,9 9 Hz, 1 H), 4.13 (t,
J= 9 Hz, 1 H),
4.97 (p, J= 5 Hz, 1 H), 6.92 (t, J= 9 Hz, I H), 7.14 (dd, J= 2, 9 Hz, 1 H),
7.22 (dd, J= 2, 9
Hz, 1 H), 7.39 (d, J= 2 Hz, I H), 7.44 (dd, J= 3, 14 Hz, 1 H), 7.87 (d, J= 2
Hz, 1 H), 8.75 (s,
1 H); 13C NMR (CDCl3) $ 48.03, 50.83, 63.16, 66.78, 71.44, 107.20 (Jc_F = 26
Hz), 113.62,
118.59, 1.27.37, 129.05, 129.46, 130.93, 133.16 (JC.F = 11 Hz), 135.71, 136.09
(Jc_r = 9 Hz),
137.38, 154.26, 155.32 (3C.F = 245 Hz), 160.24.
