PROCESSES FOR THE PREPARATION OF LINEZOLID
Field of the Invention
The present invention relates to the improved processes for the preparation of
linezolid. In particular, the present invention is directed to a novel process for the
preparation of linezolid, which avoids the use of sodium azide in the reaction. The
present invention also includes preparation of linezolid going through a novel
intermediate of Formula XIa.
The present invention also includes the processes of preparation of linezolid, free of
bis-linezolid impurity. Also, the present invention further relates to preparation of
linezolid by preparing azide intermediate, and converting it into linezolid in one-pot.
It also provides linezolid with high yield and high chemical purity without the use of
tedious, complicated purification steps, such as chromatography.
Background of the Invention
Linezolid, (S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]
acetamide is an antimicrobial agent. Linezolid is an oxazolidinone, having the
empirical formula C!6H20FN3O4 and the following structure (I):
(I)
US Patent No. 5,688,792 claims linezolid and its use for the treatment of microbial
infections. Various processes for preparation of linezolid are described in US
5,688,792; US 7,291,614; US2009093631 and Tetrahedron Lett 40(26), 4855, 1999.
The synthesis of linezolid (Scheme-I) given in US 5,688,792, is also disclosed in
Bricker, et al., J. Med. Chem., 39, 673-679 (1996) and is given as follows:
Scheme-I
MeS02CI
Et N
In the above described synthesis the intermediate azide, (R)-N-[[3-(3-fluoro-4-
mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]azide (X) is being prepared by (R)-
N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate
(IX) using sodium azide as one of the critical reagents.
Moreover, it is disclosed in US 2006/0252932 that when the said azide intermediate
(X) is reduced to its corresponding amine, (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-
2-oxo-5-oxazolidinyl] methyl] amine (XI) in the solvent ethyl acetate by
hydrogenation using hydrogen gas and a palladium/carbon catalyst, production of
undesirable level of reaction by-products occur. The reaction is followed by
acetylation of the intermediate amine (XI) to linezolid (I), and undesirably high levels
of bis-linezolid (XII), as an impurity, are also obtained in linezolid.
(XII)
Due to the formation of high levels of impurity, the purification becomes critical,
resulting in poor yield of linezolid. Purification techniques such as chromatography is
utilized to obtain pure linezolid resulting in low yields of linezolid.
Thus, it is desirable to have a simple, safe and efficient industrial process for
producing pure intermediate amine (XI) used to prepare linezolid (I), which
overcomes the drawbacks disclosed in the prior art.
Summary of the Invention
The present invention seeks to overcome the prior art limitations and provide a cost
effective and industrially favorable process for the preparation of linezolid.
In one embodiment, the invention encompasses a process for preparation of linezolid
comprising: (a) condensation of 3,4-difluoronitrobenzene (III) with morpholine (II) to
obtain 3-fluoro-4-morpholinyl nitrobenzene (IV); (b) reduction of IV obtained in step
'a' to 3-fluoro-4-morpholinyl aniline (V); (c) protection of amino group of V
obtained in step 'b' to generate a carbamate derivative like ethyl carbamate (Via) or
benzyl carbamate (VIb); and the like (d) conversion of carbamate Via or VIb as
obtained in step 'c' into oxazolidinone derivative, (R)-N-[3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol (VIII); (e) further, conversion of
the hydroxy group of VIII as obtained in step 'd' into a leaving group e.g. mesylate,
nosylate, tosylate, triflate, besylate or a halo compound. If the leaving group is
tosylate the compound generated is (R)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl]methyl /?-toluenesulfonate (IXa); (f) conversion of IXa as obtained in
step 'e' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine./?-TSA salt (XIa), a novel intermediate compound, which
helps in providing linezolid in high yield, it also helps in avoiding the use of sodium
azide and hence the formation of X and (g) acetylation of XIa as obtained in step ' f
to provide linezolid (I), free of bis-linezolid (XII).
In another embodiment, the present invention provides a process for preparing a
linezolid comprising acetylating (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine.^-TSA salt (XIa) in presence of a base and solvent.
In another embodiment, the present invention provides a novel intermediate (S)-N-
[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine . -TSA salt
of formula XIa.
In yet another embodiment, present invention provides a novel polymorph Form J of
(S)-N-[[3 (3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine./?-TSA
salt (XIa), which is characterized by a powder X-Ray diffraction pattern with peaks at
about 4.1, 15.6, 20.6, 22.7, 23.4 ±0.2° 2Q, as depicted in Figure I .
In another embodiment, present invention provides a novel polymorph Form J of (S)-
N-[[3-(3-fluoro-4-mo holinylphenyl)- -oxo-5-oxazolidinyl]methyl amine. -TSA
salt (XIa), which is characterized by Infrared spectrum having main bands at about
3440, 1746, 1518, 1421, 1224, 1153, 680 and 564 cm 1, as depicted in Figure II.
In another embodiment, present invention provides a novel polymorph Form J of (S)-
N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]amine.p-TSA
salt (XIa), which is characterized by DSC thermogram as depicted in Figure III and
TGA as depicted in Figure IV.
In yet another embodiment of the present invention the reaction occurs in a similar
fashion as in the first embodiment till the formation of (R)-N-[[3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa). Further,
the reaction comprises (a) treatment of IXa with benzylamine leading to the formation
of compound (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl] benzylamine (XIII) (b) hydrogenolysis of XIII as obtained in
step 'a' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine (XI), i.e. an amine intermediate and (c) acetylation of XI
as obtained in step 'b' to provide linezolid (I).
Use of sodium azide is avoided in the reaction and as the azide intermediate (X) is not
being formed so I formed by following the said process is free of XII.
In another embodiment of the present invention, the reaction occurs in a similar
fashion as in the earlier embodiment till the formation of (R)-N-[[3-(3-fluoro-4-
morpholinylphenyi)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa). Further,
the reaction comprises of: (a) conversion of IXa into corresponding (S)-N-[[3-(3-
fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]azide (X) and (b) the azide
intermediate X obtained in step 'a' is reduced as well as acetylated simultaneously in
one pot to form linezolid (I) avoiding the formation of bis linezolid (XII).
In another embodiment, present invention provides linezolid having a total purity of at
least about 98%. Preferably, the total purity is at least about 99%, more preferably,
total purity is at least about 99.8%.
Linezolid prepared by following the above processes is obtained in high chemical
purity without the use of tedious, complicated purification steps, such as
chromatography or repeated recrystallization.
Description of the Drawings
Figure I : PXRD pattern of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine . 7-TSA salt
Figure II: IR spectrum pattern of (8)-N-[[3-(3-ί qGq -4^ o 1 1r16^1)-2- o o-5-
oxazolidinyl]methyl]amine.p-TSA salt
Figure III: DSC thermogram of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine . 7-TSA salt
Figure IV: TGA of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine.p - A salt
Detailed Description of the Invention
In one embodiment of the present invention linezolid (I) is prepared comprising the
steps of:
a) condensation of 3, 4-difluoronitrobenzene (III) with morpholine (II) in presence
of a base and a solvent to ield 3-fluoro-4-morpholinyl nitrobenzene (IV).
The base may be selected from a group comprising of an organic or inorganic base.
Organic base is selected from the group comprising of N,N-diisopropylethylamine,
triethylamine, tributylamine, triisopropylamine, pyridine, diazabicyclo-[5.4.0]-undec-
7-ene (DBU), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (4-DMAP) and
mixtures thereof. The inorganic base is selected from group comprising of carbonates,
bicarbonates, hydroxides of alkali and alkaline earth metals and the like. Preferably
the inorganic base is selected from sodium bicarbonate, potassium bicarbonate,
sodium carbonate and the like. More preferably the base is sodium bicarbonate. The
solvent as defined herein is selected from the group comprising of alcohols, nitriles,
ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the
mixtures thereof. Alcohols are selected .from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol and the like. Nitriles are selected from the
group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
Ketones are selected from the group comprising of acetone, methyl ethyl ketone,
methyl isobutyl ketone and the like. Esters are selected from the group comprising of
ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the
group comprising of dichloromethane (DCM), chloroform, dichloroethane,
chlorobenzene and the like. Ethers are selected from the group comprising of diethyl
ether, Methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF),
dioxane and the like. Amides are selected from the group comprising of
dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone
and the like. Dialkylsulfoxides are selected from the group comprising of dimethyl
sulfoxide (DMSO), diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
Preferred solvent is water; thus making the process more cost effective.
b) reduction of the nitro derivative (IV) by hydrogenation or by metal hydrogen
transfer like formic acid / alkali metal or ammonium salts in a suitable solvent to
provide 3-fluoro-4-morpholinyl aniline (V).
The solvent as defined herein is selected from the group comprising of alcohols,
esters^ chlorinated solvents, ethers or mixtures thereof. Alcohols are selected from the
group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the
like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and
the like. Chlorinated solvents are selected from the group comprising of
dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like.
Ethers are selected from the group comprising of diethyl ether, diisopropyl ether,
MTBE, THF, dioxane and the like. The hydrogenation is carried out in presence of
suitable catalyst, but not limited to Raney-Ni/H 2, Palladium-C/H 2 and the like;
c) carboxylation of an amino compound (V) with alkyl chloroformate or alkaryl
chloroformate in an organic solvent in presence of base to yield carbamate derivative
(VI). For example reaction of V with ethyl chloroformate or benzyl chloroformate in
an organic solvent in presence of base to yield ethyl carbamate derivative
nomenclatured as N-carboethoxy-3-fluoro-4-morpholinylaniline (Via) or benzyl
carbamate nomenclatured as N-carbobenzoxy-3-fluoro-4-morpholinylaniline (VIb)
respectively.
R is alkyl or alkaryl group
(Vlb)
Organic base is selected from the group comprising of N,N-diisopropylethylamine,
triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DBN, DABCO, 4-
DMAP and mixtures thereof. The inorganic base is selected from group comprising of
carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.
Preferably the inorganic base is selected from sodium bicarbonate, potassium
bicarbonate, sodium carbonate and the like. More preferably the base is sodium
bicarbonate. The solvent as defined herein is selected from the group comprising of
nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water
or the mixtures thereof. Nitriles are selected from the group comprising of
acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected
from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone
and the like. Esters are selected from the group comprising of ethyl acetate, propyl
acetate and the like. Chlorinated solvents are selected from the group comprising of
DCM, chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected
from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane
and the like. Amides are selected from the group comprising of dimethylformamide,
dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl
sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is DCM for ethyl
carbamate and acetone for benzyl carbamate derivates.
d) condensation of ethyl carbamate derivative (Via) or benzyl carbamate derivative
(VIb) with (R)-glycidyl butyrate in a suitable solvent in presence of a base to yield
(R)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl]methanol (VIII).
(VIb)
The base may be selected from a strong base selected from the group comprising of
organometallic or non-nucleophilic hindered base. Metal from organometallic base is
selected from Li, Na, K and the like. It may be preferably selected from base
containing Li ion e.g. n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium
diisopropyl amide, lithium bis(trimethylsilyl) amine, lithium t-butoxide or lithium
amyloxide. The solvent may be selected from non protic inert polar solvents. The
preferable non protic inert polar solvent is selected from a group comprising of
tetrahydrofuran (THF), diethylether, dioxan, methyl tertiary butyl ether and the like;
e) treatment of methanol derivative (VIII) with suitable reagent to convert the
alcoholic group into a leaving group selected from the group comprising of: tosylate,
mesylate, nosylate, triflate, besylate, halo and the like. The reaction except for halo
derivative takes place in an organic solvent in presence of a base to yield (R)-N-[[3-
(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]derivative (IXb) having
LG as a leaving group. Methanol derivative on treatment with thionyl halide provides
halo derivatives. Preferably the reaction is carried out with tosyl chloride to yield (R)-
N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]/?-
toluenesulfonate (IXa).
For example:
The base may be selected from a group comprising of an organic or inorganic base.
Organic base is selected from the group comprising of N,N-diisopropylethylamine,
triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-
DMAP and mixtures thereof. The inorganic base is selected from group comprising of
carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.
Preferably the inorganic base is selected from sodium bicarbonate, potassium
bicarbonate, sodium carbonate and the like. The organic solvent as defined herein is
selected from the group comprising of nitriles, ketones, esters, chlorinated solvents,
ethers, amides, dialkylsulfoxides or mixtures thereof. Nitriles are selected from the
group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
Ketones are selected from the group comprising of acetone, methyl ethyl ketone,
methyl isobutyl ketone and the like. Esters are selected from the group comprising of
ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the
group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
Ethers are selected from the group comprising of diethyl ether, diisopropyl ether,
MTBE, THF, dioxane and the like. Amides are selected from the group comprising of
dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone
and the like. Dialkylsulfoxides are selected from the group comprising of dimethyl
sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred
solvent is selected from group comprising of DCM, chloroform, THF, dioxan or
mixture thereof;
f) reaction of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]p-toluenesulfonate (IXa) with amine source which may be
dissolved in solvent like water or alcohol. Preferred amine source is ammonium
hydroxide. Reaction occurs in presence of a solvent to provide an amine intermediate
(XIa). XIa is a novel intermediate compound, which helps in providing linezolid in
high yield.
The solvent as defined herein is selected from the group comprising of alcohols,
nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water
or the mixtures thereof. Alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol (IPA), n-butanol and the like. Nitriles are selected
from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile
and the like. Ketones are selected from the group comprising of acetone, methyl ethyl
ketone, methyl isobutyl ketone and the like. Esters are selected from the group
comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are
selected from the group comprising of DCM, chloroform, dichloroethane,
chlorobenzene and the like. Ethers are selected from the group comprising of diethyl
ether, diisopropyl ether, MTBE, THF, dioxane and the like. Amides are selected from
the group comprising of dimethylformamide, dimethylacetamide, N-methyl
formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from
.
the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide,
sulfolane and the like. Preferred solvent is selected from THF and IPA;
g) acetylation of the intermediate amine (XIa) in the form of p-TSA salt, in presence
of a base and a solvent provides linezolid (I) in high yields in comparison to the
conversion into free amine and further free amine providing linezolid. Moreover, the
preparation of intermediate XIa is economically and industrially more viable and is
operationally safe.
The acetylating agent may be selected from acetic anhydride or acetyl chloride,
preferably acetic anhydride. The base may be selected from a group comprising of an
organic or inorganic base. Organic base is selected from the group comprising of
N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine,
DBU, DABCO, DBN, 4-DMAP and mixtures thereof. The inorganic base is selected
from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline
earth metals and the like. The solvent as defined herein is selected from the group
comprising of water, nitriles, ketones, esters, hydrocarbons, chlorinated solvents,
ethers, amides, dialkylsulfoxides or mixtures thereof. Nitriles are selected from the
group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
Ketones are selected from the group comprising of acetone, methyl ethyl ketone,
methyl isobutyl ketone and the like. Esters are selected from the group comprising of
ethyl acetate, propyl acetate and the like. Hydrocarbons are selected from toluene,
xylene, cyclohexane and the like. Chlorinated solvents are selected from the group
comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene
and the like. Ethers are selected from the group comprising of diethyl ether,
diisopropyl ether, MTBE, THF, dioxane and the like. Amides are selected from the
group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide,
N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from the group
comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and
the like. The solvent may be preferably selected from hydrocarbons, halogenated
hydrocarbons, C2-4 acetates, water or mixtures thereof. More preferably the solvent is
selected from DCM, ethyl acetate, chloroform, toluene or water and mixture thereof.
The present method involves the direct conversion of tosylate derivative (IXa) in to an
amine salt (XIa), which is a novel intermediate used for the preparation of linezolid.
The said process, avoids the usage of sodium azide, formation of azide intermediate
(X), the use of hydrogen gas, high hydrogen pressure and moreover, reducing the
number of the steps of the reaction and making the process cost effective as well as
environment friendly. The crude linezolid formed can be obtained with high purity
just by recrystallization avoiding cumbersome purification techniques.
In another embodiment, present invention provides linezolid having a total purity of at
least about 98%. Preferably, the total purity is at least about 99%, more preferably,
total purity is at least about 99.8%.
In another embodiment, the present invention provides a novel intermediate (S)-N-
[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl]methyl] amine.p-TSA salt
of formula XIa.
In yet another embodiment, present invention provides a novel polymorph Form J of
(S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine . -TSA
salt (XIa), which is characterized by a powder X-Ray diffraction pattern with peaks at
about 4.1, 15.6, 20.6, 22.7, 23.4 ±0.2° 2Q, further characterized by 12.3, 18.8 and 24.1
±0.2° 2Qor as depicted in Figure I.
In another embodiment, present invention provides a novel polymorph Form J of (S)-
N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]amine.p-TSA
salt (XIa), which is characterized by Infrared spectrum having bands at about 3440,
1746, 1518, 1421, 1224, 1153, 680 and 564 cm 1, further characterized by 2970,
1195, 1175,1058, 801 cm 1 or as depicted in Figure II.
In another embodiment, present invention provides a novel polymorph Form J of (S)-
N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine./>-TSA
salt (XIa), which is characterized by DSC thermogram as depicted in Figure III and
TGA as depicted in Figure IV.
In yet another embodiment of the invention, the (R)-N-[[3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa) is treated
with benzylamine to provide S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]benzylamine (XIII), which on hydrogenolysis leads to formation
of S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (XI),
which is further converted to linezolid (I).
Starting from IXa the reaction comprises of the following steps:
a) reaction of the compound having a leaving group e.g. tosylate derivative (IXa) with
benzylamine to yield N-benzyl methyl amine derivative of oxazolidinone compound
i.e. (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]benzylamine (XIII);
b) hydrogenolysis of N-benzyl methylamine derivative of oxazolidinone (XIII) in
presence of catalysts and a reducing agent in an organic solvent to provide (S)-N-[[3-
(3-fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (XI)
The catalysts may be selected from the group comprising of zinc, nickel, platinum,
palladium and the like. The metal catalyst may be provided on an inert support such
as carbon, activated carbon or alumina. The reducing agent may be selected from
formic acid and salts or acetic acid and salts thereof. The organic solvent is selected
from the group comprising of alcohols, esters, chlorinated solvents, ethers, amides,
dialkylsulfoxides, or the mixtures thereof. Alcohols are selected from the group
comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like.
Esters are selected from the group comprising of ethyl acetate, propyl acetate and the
like. Chlorinated solvents are selected from the group comprising of DCM,
chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the
group comprising of diethyl ether, MTBE, diisopropyl ether, THF, dioxane and the
like. Amides are selected from the group comprising of dimethylformamide,
dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl
sulfoxide, dibutyl sulfoxide, sulfolane and the like.
Preferred solvent is selected from methanol, ethanol, toluene, DCM and the like;
c) acetylation of the intermediate amine (XI) in presence of a base and a solvent to
form linezolid (I).
The acetylating agent may be selected from acetic anhydride or acetyl chloride,
preferably acetic anhydride. The base may be selected from a group comprising of an
organic or inorganic base. Organic base is selected from the group comprising of
N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine,
DBU, DABCO, DBN, 4-DMAP and mixtures thereof. The inorganic base is selected
from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline
5 earth metals and the like. The solvent as defined herein is selected from the group
comprising of nitriles, ketones, esters, hydrocarbons, chlorinated solvents, ethers,
amides, dialkylsulfoxides, or mixtures thereof. Nitriles are selected from the group
comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
Ketones are selected from the group comprising of acetone, methyl ethyl ketone,
10 methyl isobutyl ketone and the like. Esters are selected from the group comprising of
ethyl acetate, propyl acetate and the like. Hydrocarbons are selected from toluene,
- xylene, cyclohexane and the like. Chlorinated solvents are selected from the group
comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like. Ethers
are selected from the group comprising of diethyl ether, MTBE, diisopropyl ether,
15 THF, dioxane and the like. Amides are selected from the group comprising of DMF,
dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
Dialkylsulfoxides . are selected from the group comprising of DMSO, diethyl
sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is selected from
DCM, ethyl acetate, chloroform or toluene.
20
The benefit of preparing the N-benzyl methyl amine derivative is that it avoids the
usage of sodium azide. Accordingly, the formation of azide intermediate as well as
bis-linezolid (XII) is avoided and linezolid (I) formed can be purified just by
recrystallization. Thus, the process provides linezolid in purified form.
25
In yet another embodiment of the present invention, (R)-N-[[3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa) is
converted into corresponding (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]azide (X). The azide intermediate X is reduced as well as
30 acetylated simultaneously in one pot to produce linezolid (I) avoiding the formation of
bis-linezolid (XII).
Starting from IXa the reaction comprises of the following steps:
a) reaction of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]p-toluenesulfonate (IXa) with sodium azide in presence of a
solvent to yield an azide intermediate (X);
The solvent may be selected from the group of aprotic polar solvents comprising of
nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides or the
mixtures thereof. Nitriles like acetonitrile etc., ketones like acetone, l-methyl-2-
pyrrrolidinone etc., esters like ethyl acetate etc., chlorinated solvents like DCM etc.,
ethers like THF etc., amides like dimethylformamide (DMF) etc., dialkylsulfoxides
like DMSO and the like. Preferred solvents are selected from DMF, l-methyl-2-
pyrrrolidinone or DMSO.
b) reaction of the azide intermediate (X) with a reducing agent in presence of
acetylating agent in a solvent to form linezolid (I) in one pot avoiding the
formation of an amine intermediate (XI).
The reducing agent may be selected from the group of catalysts comprising of zinc,
nickel, platinum, palladium and the like combined with H2 source. The metal catalyst
may be provided on an inert support such as carbon, activated carbon or alumina. The
acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably
acetic anhydride. The solvent as defined herein is selected from the group comprising
of esters, chlorinated solvents, hydrocarbons, ethers, amides, dialkylsulfoxides or
mixtures thereof. Esters are selected from the group comprising of ethyl acetate,
propyl - acetate and the like. Chlorinated solvents are selected from the group
comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
Hydrocarbons are selected from benzene, toluene, cyclohexane and the like. Ethers
are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE,
THF, dioxane and the like. Amides are selected from the group comprising of DMF,
dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
Dialkylsulfoxides . are selected from the group comprising of DMSO, diethyl
sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvents are selected
from benzene, toluene, DCM, chloroform, ethyl acetate.
The present method involves the conversion of azide intermediate (X) directly to
linezolid (I). The amine intermediate (XI) is formed in one pot and further produces
converts into linezolid avoiding the formation of bis-linezolid. The crude linezolid
formed can be obtained with high purity just by recrystallization avoiding
cumbersome purification techniques.
The process disclosed above are further demonstrated in the examples illustrated
below. These examples are provided as illustration only and therefore should not be
construed as limitation of the scope of the invention.
Examples
Example-1: Preparation of 3-fluoro-4-morpholinylnitrobenzene (IV)
3, 4-Difluoronitrobenzene (100 g) was dissolved in water (100 ml), to it was added
sodium bicarbonate (105.6 g). To the resulting suspension morpholine (60.2 g) was
added under stirring at room temperature. The mixture was heated at 80-85°C for 18h.
After the completion of reaction it was cooled to room temperature. The precipitated
solid mass was filtered, washed with water and dried to obtain the titled compound
(139 g) with 98% yield.
Example-2: Preparation of 3-fluoro-4-morpholinylaniline (V)
3-Fluoro-4-morpholinylnitrobenzene (100 g) was dissolved in a mixture of methanol
(900 ml) and ethanolamine (10 ml). To the resulting solution, Raney nickel (20 g) was
added. Hydrogenation was carried out under 5 kg/cm2 hydrogen pressure at room
temperature. After the completion of reaction, the reaction mass was filtered and
washed with methanol. The filtrate was concentrated. To the resulting residue water
(100 ml) was added and concentrated. The residue was cooled to room temperature
and diluted with water (500 ml). The resulting suspension was stirred for lh. The
solid mass was filtered, washed with water and dried to obtain the titled compound
(78 g) with 90% yield.
Example-3: Preparation ofN-carboethoxy-3-fluoro-4-morpholinylaniline (Via)
3-Fluoro-4-morpholinylaniline (100 g) and sodium bicarbonate (107 g) was dissolved
in DCM (575 ml). To the suspended mixture was added ethyl chloroformate (66.4 g)
at 5-1 0°C over a period of 2h. The mixture was slowly warmed up to 25°C and stirred
for 12h. After completion of the reaction, it was concentrated under atmospheric
pressure at 35-40°C. To the resulting residue water (1500 ml) was added and was
further concentrated. The mixture was warmed to 50°C and stirred for lh. The solid
mass was filtered, washed with water and dried to obtain the titled compound (133 g)
with 97% yield.
Example-4: Preparation of N-carbobenzoxy-3-fluoro-4-morpholinylaniline (VIb)
3-Fluoro-4-morpholinylaniline (100 g) was dissolved in a mixture of acetone (400 ml)
and water (200 ml). To the resulting solution sodium bicarbonate (85.6 g) was added
at 5-10°C followed by the addition of benzyl chloroformate (226g, 50%w/w solution
in toluene). The mixture was warmed up to 25-30°C and stirred for lh. After
completion of the reaction, water (1000 ml) was added and stirred for lh. The
precipitated solid mass was filtered, washed with water and suck dried completely.
The solid obtained was washed with cyclohexane and suck dried. The suck dried
material was suspended in cyclohexane (1400 ml) and stirred at room temperature for
lh. The solid material was filtered, washed with cyclohexane and dried to obtain the
titled compound ( 157 g) with 94% yield.
Example-S(a): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5-
oxazolidinyljmethanol (VIII) starting from N-carboethoxy-3-fluoro-4-
morpholinylaniline
N-carboethoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (500 ml).
To the resulting solution, n-butyllithium (245 ml in hexane) was added under nitrogen
at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate
(53.75 g, in THF (100 ml)) was added. The resulting solution was stirred at -78°C for
2h, further it was warmed to room temperature and stirred for overnight. To the
resulting thick slurry, saturated ammonium chloride (345 ml) was added followed by
the addition of water (300 ml). It was stirred at room temperature for 30 min and was
concentrated. Further, water (500 ml) was added and the suspension was again stirred
at 50-55°C for l h and then at 25-30°C for next lh. The solid mass was filtered,
washed with water and suck dried for lh. The filtrate was extracted with toluene. To
the combined toluene layer, the suck dried material obtained above was added and
heated to reflux and further concentrated. The concentrated solution was cooled to
room temperature and stirred for lh. The solid mass was filtered, washed with toluene
and dried to obtain the titled compound ( 110 g) with 80% yield.
ExampleS(b): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5-
oxazolidinyljmethanol (VIII) starting from N-carboethoxy-3-fluoro-4-
morpholinylaniline
N-carboethoxy-3-fluoro-4-morpholinylaniline (50 g) was dissolved in THF (300 ml).
To the resulting solution, n-butyllithium (122.5 ml in hexane) was added under
nitrogen at -78°C over 30 min and stirred for 2h, further a solution of R-(-)-glycidyl
butyrate (29.5 g, in THF (50 ml)) was added and stirred at -78°C for 2h. It was
warmed to room temperature and stirred overnight. To the resulting thick slurry
saturated ammonium chloride (173 ml) was added followed by the addition of water
(50ml). The reaction mixture was stirred at room temperature for 30 min and further
ethyl acetate (400 ml) was added to it, which was stirred for 15 min. Organic layer
was separated and aqueous layer was extracted with ethyl acetate. The combined
organic layer was washed with water. The organic layer was concentrated under
vacuum at 45-50°C, which resulted into an oily mass that was diluted with a mixture
(1:1) of ethyl acetate and hexanes (750 ml). The suspended solution was warmed to
60°C and further stirred at 55-60°C for 30 min. The resulting clear solution was
cooled to room temperature and stirred for 3h. The solid mass was filtered, washed
with a mixture (1:1) of ethyl acetate and hexanes and suck dried. The suck dried
material was suspended in ethyl acetate (380 ml) and heated to 80°C, which was
further stirred at 75-80°C for 30 min. To the resulting clear solution, hexanes (380 ml)
were added at 75-80°C and stirred at the same temperature for 15 min, further cooled
to room temperature and stirred for lOh. The solid mass was filtered, washed with a
mixture (1:1) of ethyl acetate and hexanes and dried to obtain the titled compound
(30.5 g) with 55% yield.
Example-6(a): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyI]methanol (VIII) starting from N-carbobenzoxy-3-fluoro-4-
morpholinylaniline
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (50 g) was dissolved in THF (400
ml). To the resulting solution, n-butyllithium (99.5 ml in hexane) was added under
nitrogen at -78°C over 40 min and stirred for 2h, further a solution of R-(-)-glycidyl
butyrate (24 g in THF (50 ml)) was added and stirred for 2h. The reaction mixture
was warmed to room temperature and stirred for overnight. To the resulting thick
slurry saturated ammonium chloride (173 ml) was added and stirred for 30 min
followed by the addition of water (50 ml). It was stirred at room temperature for next
30 min and concentrated. The resulting solution was cooled to room temperature and
water (200 ml) was added. The obtained suspension was stirred at 50-55°C for 30 min
and then at 25-30°C for next 30 min. The solid mass was filtered, washed with water
and suck dried for 30 min. The filtrate was extracted with toluene. To the toluene
layer, the suck dried material obtained above was added and heated to reflux. The
resulting solution was concentrated and further cooled to room temperature and
stirred for 15h. The solid mass was filtered, washed with toluene and dried to obtain
the titled compound (24.6 g) with 55% yield.
Example-6(b): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methanol (VIII) starting from N-carbobenzoxy-3-fluoro-4-
morpholinylaniline
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (800
ml). To the resulting solution, n-butyllithium (208 ml in hexane) was added under
nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl
butyrate (52.3 g in THF (100 ml)) was added and stirred for 2h. The reaction mixture
was warmed to room temperature and stirred for overnight. To the resulting thick
slurry saturated ammonium chloride (345 ml) was added followed by the addition of
water (50 ml). It was stirred at room temperature for 10 min and THF layer was
separated from aqueous layer. Aqueous layer was extracted with ethyl acetate (2 x
250 ml). The combined ethyl acetate layer was washed with water and concentrated to
get a residue in which THF layer was added and further concentrated completely. The
solid mass obtained was cooled to room temperature and ethyl acetate (600 ml) was
added. The reaction mixture was heated to 60-65°C and was stirred for 30 min, which
was further cooled to 40-45 °C. The cooled reaction mixture was filtered and was
washed with ethyl acetate (100 ml). To the filtrate cyclohexane (450 ml) was added at
25-35°C in 5 min. The resulting mixture was stirred for 12h. The precipitated solid
was filtered, washed with a mixture (1:1) of ethyl acetate and cyclohexane and dried
to obtain the titled compound (62 g) with 70% yield.
Example-7: Preparation of (R)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl] p-toluenesulfonate (IXa)
(R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5-oxazolidinyl]methanol (100 g)
and £>-toluenesulfonyl chloride (97 g) were dissolved in DCM (600 ml). The resulting
solution was cooled to 0-5°C and to the cold solution; triethylamine (58 g) was added.
The obtained solution was warmed to room temperature and stirred for 18h. After the
completion of reaction, water (300 ml) was added and stirred for 10 min. DCM layer
was collected and concentrated. Further, methanol (500 ml) was added in the reaction
mass and was stirred at room temperature for 30 min. The solid was filtered, washed
with methanol and dried to obtain the titled compound (130 g) with 85% yield.
Example-8: Preparation of (R)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl] 4-methylmethanesulfonate (IX)
(R)-[N-3-(3-fluoro-4-mo holinylphenyl)-2- oxo-5-oxazolidinyl] methanol (6.5 g) and
methanesulfonyl chloride (3.78 g) were dissolved in DCM (60 ml). The resulting
solution was cooled to 0-5°C and to the cold solution; triethylamine (3.76 g) was
added. The obtained solution was warmed to room temperature and stirred for lOh.
After the completion of reaction, it was concentrated. In the resulting reaction mass,
water (50 ml) was added and stirred at 50-55°C for l h and further at 25-30°C for next
lh. The solid obtained was filtered, washed with water and suck dried. The suck dried
material was suspended in methanol (65 ml) and heated to 60°C. The suspension was
stirred at 55-60°C for 2h and further at room temperature for lh. The solid was
filtered, washed with methanol at room temperature and dried to obtain the titled
compound (6 g) with 73% yield.
Example-9: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl]amine p-TSA salt (XIa)
(R)- [[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] -p-toluene
sulfonate (60 g) was dissolved in a mixture of (1:1:1) THF/IPA/aqueous ammonium
hydroxide (900 ml) and heated in an autoclave to 85°C, further stirred at 80-85°C for
24 h. After completion of reaction, it was cooled to room temperature. The reaction
mass was filtered. The filtrate was concentrated to dryness. Residual moisture was
removed by using IPA (120 ml) followed by recovery. To the resulting residue IPA
(180 ml) was added, heated to 50-55°C for 2h and cooled to room temperature. The
solid mass was filtered and dried under vacuum at 50°C. To the above obtained solid,
DCM was added and heated to reflux for 2h. Further, cooled to room temperature and
stirred the obtained suspension for lh. The solid mass was filtered, washed with DCM
and dried under vacuum at 50-55°C for overnight to obtain the titled compound (45 g)
with 72% yield.
Example-10: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-
oxazolidinyljmethyl] benzylamine (XIII)
(R)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl]methyl]-p-toluene
sulfonate (5 g) was added to benzylamine (17.8 g) and heated to 70°C and further,
stirred for 5h. After completion of reaction it was cooled to room temperature and
diluted with toluene (50 ml). The solution was successively washed with 10% sodium
bicarbonate solution, 10% ammonium chloride solution and water. Toluene layer was
concentrated to obtain the titled compound as oil.
Example-11: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl]amine (XI)
(S)-[[N-3-(3-fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]
benzylamine (5 g) was dissolved in methanol (55 ml). To the resulting solution
ammonium formate (4.5 g) was added. Further, 10% Pd/C (0.55 g) was added to the
resulting mixture. The mixture was heated to 65°C and stirred for 8 h. After
completion of reaction it was cooled to room temperature. The solution was filtered
and washed with methanol. The filtrate was concentrated under vacuum at 50-55°C to
obtain the titled compound as oil.
Example-12: Preparation of (S)-N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl azide (X)
Dissolved (T<)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl-4-
methylbenzene sulfonate (50 g) in DMF (150 ml), added sodium azide (14.44 g) to
the solution, heated to 80-85°C and stirred at the same temperature for 4 h. After
completion of reaction, it was cooled to room temperature and diluted with water (300
ml). Further, solution was stirred for lh. The solid mass was filtered, washed with
water and dried to obtain the titled compound (32 g) with 90% yield.
Example-13(a): Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinylJmethyl]aminep-TSA salt
(S)-[P^-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine -TSA
salt (5 g) obtained in example 9 and triethylamine (2.56 g) were dissolved in DCM
(25 ml). The solution was cooled to 5°C and acetic anhydride (2.07 g) was added. The
resulting reaction mixture was warmed to room temperature and stirred for 5h. After
completion of reaction, water (50 ml) was added in reaction mixture and stirred for 30
min. Separation of DCM and aqueous layers was carried out. Aqueous layer was
extracted with DCM. The combined DCM layers were washed with 10% sodium
bicarbonate solution followed by washing with water. DCM layer was concentrated
under vacuum at 35-40°C. Toluene (30 ml) was added into the residue and heated to
70°C. The suspended solution was stirred at 65-70°C for 30 min and further at room
temperature for lh. The solid mass was filtered, washed with toluene and dried to
obtain the titled compound (3 g) with 80% yield.
Example-13(b): Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]aminep-TSA salt
(S)- [[N-3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] amine p -
TSA salt (50 g) obtained in example 9 was suspended in water (500 ml). To the
resulting suspension, 6N hydrochloric acid (50 ml) was added at room temperature to
adjust its pH to -0.5. Ethyl acetate (500 ml) was added in the above solution and
further pH was readjusted to 4.5-4.7 using 10% sodium hydroxide solution. After
separating ethyl acetate layer aqueous layer was washed with ethyl acetate. To the
acidic aqueous layer, DCM (500 ml) and acetic anhydride (21.84 g) were added. The
pH of the biphasic reaction mixture was adjusted to 4.5-4.7 using 10% sodium
hydroxide solution (100 ml). The resulting reaction mixture was stirred at room
temperature for 3h at the same pH. After completion of reaction pH of the reaction
mixture was raised to -7-7.5 using 10% sodium hydroxide solution. Separation of
DCM and aqueous layers was carried out. Aqueous layer was extracted with DCM
(500 ml). The combined DCM layer was washed with water. DCM layer was
concentrated and ethyl acetate (400 ml) was added in the concentrated DCM solution.
The solvent was recovered completely to obtain a solid mass which was dissolved in
ethyl acetate (1400 ml) at 60-65°C and then cooled to 35-40°C. To a cold (-15°C)
mixture of cyclohexane (1575 ml) and ethyl acetate (175 ml) was added the above
ethyl acetate solution at -15 to 0°C in 3-5 min. Further, the suspended solution was
cooled down to -15°C and stirred for 2h. The solid mass was filtered, kept under
suction for l h and dried to obtain the titled compound (23 g) with 63% yield.
Example-14: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine
(S)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (3 g)
obtained in example 11 and triethylamine (1.54 g) were dissolved in DCM (15 ml).
The solution was cooled to 5°C and acetic anhydride (1.25 g) was added. The
resulting reaction mixture was warmed to room temperature and stirred for 4h. After
completion of reaction, water (50 ml) was added in reaction mixture and stirred for 30
min. Separation of DCM and aqueous layers was carried out. Aqueous layer was
extracted with DCM. The combined DCM layers were washed with 10% sodium
bicarbonate solution followed by washing with water. DCM layer was concentrated
under vacuum at 35-40°C. Toluene (20 ml) was added into the residue and heated to
70°C. The suspended solution was stirred at 65-70°C for 30 min and further at room
temperature for lh. The solid mass was filtered, washed with toluene and dried to
obtain the titled compound (2. 1 g) with 60% yield.
Example-15: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-N-3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl azide
(S^-N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl azide (10 g)
obtained in example 12, and acetic anhydride (4.8 g) were dissolved in DCM (100
ml). To the resulting solution, 10% Pd/C (50% wet, 1.0 g) was added. The reaction
mixture was hydrogenated under 1.5 kg/cm2 hydrogen pressure for 6h. After the
completion of reaction, catalyst was removed by filtration. The filtrate was washed
with water. The DCM layer was concentrated completely under vacuum at 35-40°C.
To the resulting residue toluene (50 ml) was added and heated to 80°C. The
suspended solution was stirred at 80-85°C for lh and further at room temperature for
next lh. The solid mass was filtered, washed with toluene and dried to obtain the
titled compound (8.0 g) with 80% yield.
Example-16(a): Purification of Linezolid
Linezolid (I) (2 g) was dissolved in ethyl acetate (50 ml) and heated to 65°C, further,
was stirred at 60-65°C for 15 min. To the clear solution obtained hexanes (8 ml) were
added at 50-55°C. The resulting solution was cooled to room temperature and stirred
for lh. The solid mass was filtered, washed with a 1:1 mixture of ethyl acetate and
hexanes (4 ml) and dried to obtain pure linezolid (1.6 g) with 70% yield.
Example-16(b): Purification of Linezolid
Linezolid (I) (10.Og) was dissolved in methanol (100 ml) and heated to 65°C, further,
was stirred at 60-65°C for 30 min. The resulting solution was cooled to room
temperature and stirred for 2h. The solid mass was filtered, washed with methanol (10
ml) and dried to obtain pure linezolid (8 g) with 80% yield.
Having described the invention with reference to particular preferred embodiments
and illustrative examples, those in the art would appreciate modifications to the
invention as that do not depart from the spirit and scope of the invention as disclosed
in the specification. The examples are set forth to aid in understanding the invention
but are not intended to, and should not be construed to limit its scope in any way. The
examples do not include detailed descriptions of conventional methods. Such methods
are well known to those of ordinal skill in the art and are described in numerous
publications. All references mentioned herein are incorporated in their entirety.

We Claim:
1. A process for preparation of linezolid comprising:
a) condensation of 3, 4-difluoronitrobenzene (III) with morpholine (II) to
yield 3-fluoro-4-morpholinyl nitrobenzene (IV);
(IV)
reduction of IV to provide 3-fluoro-4-morpholinyl aniline (V);
c) carboxylation of V with alkyl chloroformate or aryl chloroformate to
provide N-carboalkoxy or N-carboalkaryloxy-3-fluoro-4-
morpholinylaniline derivative (VI);
(VI)
R is alkyl or aryl group
d) condensation of carbamate derivative (VI) with (R)-glycidyl butyrate
to yield (R)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methanol (VIII);
(viii)
e) conversion of VIII to (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-
oxo-5-oxazolidinyl]methyl]derivative (IXb) containing a leaving group
(LG);
f)conversion of IXb to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
I oxazolidinyl]methyl]amine./?-TSA salt (XIa); and
(XIa)
g) acetylation of XIa to yield linezolid (I).
2. A process according to claim 1, wherein the condensation in step (a) occurs in
presence of base and a solvent to yield 3-fluoro-4-morpholinyl nitrobenzene
(IV).
3. A process according to claim 2, wherein the solvent is water and base is
sodium bicarbonate.
4. A process according to claim 1, wherein the reduction in step (b) occurs either
by hydrogenation or by metal hydrogen transfer to yield 3-fluoro-4-
morpholinyl aniline (V).
5. A process according to claim 1, wherein the carboxylation source in step(c) is
ethyl chloroformate or benzyl chloroformate.
6. A process according to claim 1, wherein the carboxylation in step(c) occurs in
presence of a base selected from organic or inorganic base.
7. A process according to claim 6, wherein the base is sodium bicarbonate.
8. A process according to claim 1, wherein the condensation in step (d) occurs in
presence of a strong base selected from organometallic or non-nucleophilic
hindered base.
9. A process according to claim 8, wherein the strong base is n-butyl lithium.
10. A process according to claim 1, wherein the leaving group in step (e) is
selected from the group comprising of mesylate, nosylate, tosylate, triflate,
besylate or a halo group.
11. A process according to claim 10, wherein the leaving group is a tosylate
group.
12. A process according to claim 1, wherein the acetylation in step (g) occurs in
presence of acetic anhydride or acetyl chloride and a base.
13. (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]amine . -TSA salt (XIa)
(XIa)
A compound according to claim 13, characterized by x-ray powder
diffraction spectrum with peaks at peaks at about 4.1, 15.6, 20.6, 22.7, 23.4
±0.2° 20 or as depicted in Figure I.
15. A compound according to claim 13, further characterized by an IR spectrum
having main bands at about 3440, 1746, 1518, 1421, 1224, 1153, 680 and
564 cm or as depicted in Figure II.
16. A compound according to claim 13, further characterized by DSC thermogram
as depicted in Figure III.
17. A compound according to claim 13, further characterized by TGA as
depicted in Figure IV.
18. A process for preparation of linezolid, wherein the process for preparation of
IXb is same as provided in claim 1, further comprising of:
a) reaction of IXb with benzylamine to produce (S)-N-[[3-(3-fluoro-4-
morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]benzylamine (XIII);
(XIII )
b) hydrogenolysis of XIII in presence of catalyst and a reducing agent or by
hydrogenation to yield (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl] methyl]amine (XI);
(XI)
c) acetylation of XI to yield linezolid (I).
19. A process according to claim 18, wherein the catalyst employed in step (b) is
selected from zinc, nickel, platinum or palladium.
20. A process according to claim 19, wherein the catalyst employed is Pd/C.
21. A process according to claim 18, wherein the reducing agent in step (b) is
selected from formic acid and its salts or acetic acid and its salts.
22. A process according to claim 21, wherein the reducing agent is ammonium
formate.
23. A process according to claim 18, wherein the acetylation in step (c) occurs in
presence of acetic anhydride or acetyl chloride and a base.
24. A process according to claim 23, wherein the acetylation occurs in presence of
acetic anhydride and triethylamine.
25. A process for preparation of linezolid, wherein the process for preparation of
IXb is same as provided in claim 1, further comprising of:
a) reaction of IXb with sodium azide in presence of a solvent to provide
(S)-N-3-(3-Fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]
methyl azide (X);
b) reaction of X with a reducing agent and acetylating agent in one-pot to
provide linezolid.
26. A process according to claim 25, wherein the solvent for step (a) is selected
from amides or sulfoxides.
27. A process according to claim 26, wherein the solvent is dimethylformamide.
28. A process according to claim 25, wherein the reducing agent in step (b) is
selected from zinc, nickel, platinum or palladium combined with hydrogen
source.
29. A process according to claim 25, wherein the acetylating agent is selected
from acetic anhydride or acetyl chloride.
30. A process for preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-
oxo-5-oxazolidinyl]methyl]amine. -TSA salt (XIa) comprising of : reaction
of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl]p-toluenesulfonate (IXa) with aqueous or alcoholic
ammonia in presence of a solvent.
31. A process according to claim 30, wherein the solvent is selected from
alcohols, tetrahydrofuran, dioxan, acetonitrile, dimethylsulfoxide or
mixtures thereof.
32. A process according to claim 3 1 wherein the solvent is mixture of
tetrahydrofuran and isopropylalcohol.
33. A process according to claim 30, wherein the preferable reagent is aqueous
ammonia.
34. A process for preparing a linezolid comprising acetylating (S)-N-[[3-(3-
fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine.p-TSA
salt (XIa) in presence of a base and solvent.
The process according to claim 34, wherein the acetylation is performed in
presence of a acetylating agent selected from acetic anhydride or acetyl
chloride, preferably acetic anhydride.
The process according to claim 34, wherein the base is selected from a group
comprising of an organic or inorganic base.
The process according to claim 36, wherein the organic base is selected from
the group comprising of N,N-diisopropylethylamine, triethylamine,
tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-DMAP
and mixtures thereof and the inorganic base is selected from group
comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline
earth metals and the like.
The process according to claim 34, wherein the solvent is selected from the
group comprising of nitriles, ketones, esters, hydrocarbons, chlorinated
solvents, ethers, amides, dialkylsulfoxides, or mixtures thereof.