AU2016403208A1

AU2016403208A1 - An improved process for the preparation of Linezolid

Info

Publication number: AU2016403208A1
Application number: AU2016403208A
Authority: AU
Inventors: Srinivas Reddy Desi Reddy; Subba Reddy PEKETI; Dnyandev Ragho Rane; Srinivasa Rao VELIVELA
Original assignee: Optimus Drugs Pvt Ltd
Current assignee: Optimus Drugs Pvt Ltd
Priority date: 2016-04-21
Filing date: 2016-05-23
Publication date: 2018-05-10
Anticipated expiration: 2036-05-23
Also published as: NZ741891A; KR101832115B1; AU2016403208B2; RU2766082C1; EP3250568A1; WO2017182853A1; EP3250568A4; KR20170128485A; RU2766082C9

Abstract

The present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide and (

Description

The present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide and (5)-glycidyl phthalimide intermediates, which are used in the preparation of Linezolid.

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AN IMPROVED PROCESS FOR THE PREPARATION OF LINEZOLID

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide and (5)-glycidylphthalimide intermediates, which are used in the preparation of Linezolid .

BACKGROUND OF THE INVENTION:

Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA).The antibacterial effect of oxazolidinones is by working as protein synthesis inhibitors, targeting an early step involving the binding of N-formylmethionyl-t-RNA to the ribosome.

Linezolid is marketed by Pfizer under the trade names “Zyvox”and it is chemically known as (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] acetamide having the formula (I).

Linezolid is first disclosed in L.S. Pat. No. 5,688,792 and its process describes by using of R -glycidylbutyrate which results in the formation of (R) - N-[[3-[3-fluoro-4morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol which in the subsequent stages

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PCT/IB2016/053003 has to be converted to various intermediary compounds to finally form Linezolid. The said process also encompasses intermediary azide compound, which is difficult to handle at an industrial level, which is depicted in the scheme-I given below:

NH₄HCO₂110% Pd/C

-►

F

THF/ n-butyl lithium (Ti)-Glycidyl butyrate

OH ·<-

O

V?

NaN₃1 DMF ▼

O

o

V?

o

O

N·

O

O aq.methylamine o

(I)

Scheme-I

WO 1999/24393 Al discloses a process for the preparation of oxazolidinone derivatives, which is depicted in the scheme-II given below:

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Roxa-NH-CO-O-Xj +

Ο

X₂- CH₂- C*H(OH)_ h₂C- N

O

Lithium cation and base (or)

O

O

R„x_a- RING- CH₂- N | — O— ch₂- (Ml- h₂c- n

O acetic anhydride ,, tri(alkylamine)

Roxa- RING- CH₂- NH- CO- R_N

Scheme-II

Where R_oxa is phenyl substituted with one fluoro and one substituted amino group, wherein the substituted amino groups include 4-(benzyloxycarbonyl)- 1-piperazinyl, 4morpholinyl and 4-hydroxyacetylpiperazinyl

X iis C1-C20 alkyl;

X2 is CI, Br

Rn is C1-C5 alkyl # indicates that the atoms marked with a (^#) are bonded to each other resulting in the formation of ring and RING is

N O

However, WO’ 393 does not disclose any specific examples or suitable conditions for the preparation of Linezolid.

WO 2005/099353 A2 discloses a process for the preparation of Linezolid, which is depicted in the scheme-III given below:

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PCT/IB2016/053003 °L>^^CI o

^{lp A z THF}

Ml,

OH

.ME

CDI / MDC

Scheme-Ill

WO 2006/008754 Al discloses a process for the preparation of Linezolid, which is depicted in scheme-IV given below

Scheme-IV

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W02007116284 discloses a process for preparing Linezolid by reacting a compound of structure (1) with a compound of structure (2) at a temperature range from ambient temperature to about 65 °C to provide a compound of structure (3), which is hydrolyzed and subsequently acylated to give Linezolid, which is depicted in the scheme-V below:

Scheme-V

The disadvantages of this process are it involves additional reaction for preparation of compound of structure (1), Schiff s bases are sensitive to water that may not lead to formation of pure compound (1), which enhances impurity and byproducts formation.

(6)-Glycidyl phthalimide or alternatively known as 2-[(20)-Oxiran-2-ylmethyl]-l/7isoindole-l,3(277)-dione of formula (IX) is a key intermediate used in all synthetic routes of Linezolid.

2-[(2)-Oxiran-2-ylmethyl]-l/7-isoindole-l,3(277)-dione (I) first described in Compt. rend. 1930, 190, 495-6 and also describes process for the preparation of2-[(2)-oxiran2-ylmethyl]-l/7-isoindole-l,3(277)-dione comprising reaction of potassium phthalimide with epibromohydrin in presence of gaseous or aqueous hydrohalogen acids. The above process is schematically shown as below:

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ΝΚ θ Epibromohydrin

Potassium phthalimide

Gaseous or aq. hydrohalogen acids

US 5,608,110 discloses process for the preparation of 2-[(25)-oxiran-2-ylmethyl]-177isoindole-l,3(277)-dione (I) comprising, reaction of phthalimide with (S)-(+)epichlorohydrin under reflux in nitrogen atmosphere, ethyl acetate/hexane to get (5)-110 chloro-3-phthalimido-2-propanol which is cyclized in presence of NaH/THF.

The above process is schematically shown as below:

	NH	O, +	Reflux under nitrogen, Hexane, ethyl acetate, Silica gel
7) Phthalimide	(5)-(+)-Epichlorohydrin

O (S)-l-Chloro-3-phthalimido

2-propanol

US 6,875,875 discloses a process for the preparation of 2-[(25)-oxiran-2-ylmethyl]-177isoindole-l,3(277)-dione (I) comprising reaction of phthalimide with (5)epichlorohydrin in presence of alkali metal carbonate, alkali metal hydrogen carbonate or a quaternary ammonium salt to get (5)-1 -chioro-3-phthalimido-2-propanol which is cyclized in presence of metal alkoxides.

The above process is schematically shown as below:

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Π		O„ iX^CI	o
	4-,	Alkali metal carbonate or
Phthalimide	a quaternary ammonium salt	o (S)-l-Chloro-3-phthalimido-

2-propanol

Metal alkoxide

According to the above prior art processes, since the optical purity is lowered and allowed to reflux an optically active epichlorohydrin of the amount of the solvent, there is a problem in that the optical purity of the results the product is reduced. The waste in the prior art processes a large amount of generated, in order to obtain these by removing pure desired product is complicated purification process such as silica gel column chromatography becomes essential, industrially producing it is difficult.

Hence, the use of gaseous or aqueous hydro halogen acids or alkali metal carbonates, alkali metal hydrogen carbonate or a quaternary ammonium salt may not feasible and not economical for industrial production in the preparation of (5)-glycidyl phthalimide.

In order to evaluate the eco-friendly, industrial feasible process for preparing (S)15 glycidyl phthalimide, our inventors surprisingly found with the use of secondary amines in the condensation reaction.

None of the above prior-art processes teaches nor suggests the use of primary or secondary organic bases.

There is consequently a need for an alternative method for the preparation of Linezolid and its intermediates which does not involves the problems described above.

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Therefore there is a need in the art for a simple and facile process for Linezolid and our inventors have developed a cost-effective and industrially viable process for preparing Linezolid.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide cost-effective and commercially feasible process for the preparation of Linezolid.

Another objective of the present invention is to provide a process for the preparation of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] phthalimide and (5)-glycidyl phthalimide intermediates, which employs less expensive, easily available and eco-friendly reagents.

SUMMARY OF THE INVENTION

In one aspect of the present invention provides an improved process for the preparation of (S)- N- [[3 - [3 -fluoro-4- [4-morpholinyl]phenyl] -2-oxo-5-oxazolidinyl] methyljphthalimide of formula (IV)

Which comprises reacting carbamate compound of formula (III)

R represents hydrogen, C1-C5 alkyl, aryl, aralkyl;

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PCT/IB2016/053003 with (S)-glycidyl phthalimide of formula (IX)

in the presence of alkali metal iodides (or) metal hydrides (or) in the presence of lithium tertiary butoxide in the range 0.2-0.4 mole equivalents based 10 on carbamate compound of formula (III)

In another aspect of the present invention is to provide an improved process for the preparation of compound of formula (I) comprising the steps of;

a) reacting the compound of formula(III) with (S)-Glycidyl Phthalimide of formula (IX) in presence of alkali metal iodides (or) metal hydrides to give a compound of formula(VI)

b) subjecting the compound of formula(VI) with aqueous methyl amine or hydrazine hydrate,

c) acylating the product of step b), and

d) isolating the compound of formula (I).

The above synthetic process is illustrated as per the following Scheme

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In yet another aspect of the present invention, provides an improved process for the 5 preparation of 2-[(25')-oxiran-2-ylmethyl]-l //-isoindole-1,3(2//)-dione of formula (IX), comprising the steps of:

a) l//-isoindole-l,3(2//)-dione or phthalimide reacted with (5)-epichlorohydrin in presence of organic base in an organic solvent to obtain (5)-1-chioro-3phthalimido-2-propanol.

O

Phthalimide

O, [>^C1

(.S’)-(+)-Epichloroh

Organic base /

Organic solvent

-►

(S)-l-Chloro-3-phthalimido 2-propanol

Wherein, the organic base is primary or secondary alkyl amines having C1-C5 carbon atoms.

b) (5)-1 -chioro-3-phthalimido-2-propanol is cyclized in presence of alkali metal 15 alkoxides to obtain 2-[(25)-oxiran-2-ylmethyl]-l//-isoindole-l,3(2//)-dione

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(A)-l-Chloro-3-phthalimido2-propanol

Cyclization

2-[(2.$')-Oxiran-2-vlmethvl|-l H-isoindole l,3(2H)-dione (I)

Detailed Description of the Invention

In an embodiment of the present invention provides an improved process for the preparation of (S)- N- [[3 - [3 -fluoro-4- [4-morpholinyl]phenyl] -2-oxo-5oxazolidinyl] methyl] Phthalimide of formula (IV)

Which comprises reacting carbamate compound of formula (III)

R represents hydrogen, C1-C5 alkyl, aryl, aralkyl;

with (S)-glycidyl phthalimide of formula (IX)

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PCT/IB2016/053003 in the presence of alkali metal iodides (or) metal hydrides (or) in the presence of lithium tertiary butoxide used in the range 0.2-0.4 mole equivalents based on carbamate compound of formula (III)

In another embodiment, the reaction is carried using an alkali metal iodides and in the presence or absence of a solvent at a temperature in the range of 60 to 120°C. The reaction is carried out for a period of 10 to 14 hours.

In another embodiment, the reaction is carried using a lithium tertiary butoxide used in the range 0.2-0.4 mole equivalents in presence of a suitable solvent at a temperature in the range of 40 to 100°C. The reaction is carried out for a period of 4 to 12 hours.

According to the embodiment of the present invention, wherein suitable alkali metal iodides used is selected from lithium iodide, sodium iodide, potassium iodide and the like ; Suitable solvent used is selected from alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, and the like; ethers, such as 1,4-dioxane, tetrahydrofuran, and the like; and amides such as N,N- dimethylformamide, Ν,Ν-dimethyl acetamide and the like or dimethylsulfoxide or mixture of solvents thereof.

In yet embodiment of the present invention is to provide an improved process for the preparation of compound of formula (I) comprising the steps of;

a) reacting the compound of formula(III) with (S)-Glycidyl phthalimide of formula(IX) in presence of alkali metal iodides or metal hydrides to give a compound of formula(VI),

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c) acylating the product of step b), and

d) isolating the compound of formula (I).

According to the embodiment, the reaction between formula (III) with (S)-Glycidyl 5 phthalimide of formula(IX) is carried out in presence of suitable alkali metal iodides (or) metal hydrides and solvent at suitable temperature to give a compound of formula(VI); further it is subjected to deprotection with hydrazine hydrae (or) aqueous methyl amine to give (S)-5-Aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)oxazolidin-2-one,which is subsequently acylated with acetic anhydride or acetyl chloride to give (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5oxazolidinyljmethyl] acetamide (Linezolid) of formula I.

According to the embodiment, the reaction between formulas (III) with (S)-Glycidyl phthalimide of formula (IX) is carried out in presence of suitable metal hydrides and solvent at suitable temperature to give a compound of formula (VI); the reaction is completed within a less span of time and provides good quantity of yield with high purity

According to the embodiment, the alkali metal iodides is selected from lithium iodide, sodium iodide, potassium iodide and the like; metal hydrides is selected from sodium hydride, lithium hydride or magnesium hydride.

According to the embodiment, the suitable solvent used is selected from alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as di chloromethane, ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, and the like; ethers, such as 1,4-dioxane, tetrahydrofuran, and the like; and amides such as N,N- dimethylformamide, N,N30 dimethyl acetamide and the like or dimethyl sulfoxide or mixture of solvents thereof

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In an embodiment, the present invention further involves conversion of compound of formula (VI) to Linezolid of formula (I), which involves conversion of phthalimide compound of formula (VI) to amine, followed by acylation to yield Linezolid using conventional methods known in the prior arts.

According to the embodiment, the acylation is carried out in presence of acetic anhydride or acetyl chloride.

The reaction is performed at or below boiling temperature of the solvent used, more preferably between 10°C and boiling temperature of the solvent used and even more preferably at boiling temperature of the solvent used. Time required for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried.

According to the embodiment, the present invention relates to an improved process for the preparation of2-[(25)-oxiran-2-ylmethyl]-l/Z-isoindole-l,3(2//)-dione of formula IX comprising the steps of:

a) Phthalimide reacted with (5)-(+)-Epichlorohydrin in presence of organic base in an organic solvent at the temperature of 60° C to obtain (5)-1-chioro-3phthalimido-2-propanol.

NH +

O,

Organic base I Organic solvent

Cl

Phthalimide

CS')-(+)-Epichlorohydrin (S)-l-Chloro-3-phthalimido 2-propanol

The organic base is selected from primary or secondary alkyl amines having CiC5 carbon atoms such as methylamine, ethylamine, ethyl methylamine, diethylamine, dipropylamine, dibutylamine, preferably diethylamine.

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The organic solvent is selected from the group comprising of alcohols, ethers, esters, nitriles having C1-C4 carbon atoms. Preferably alcohols.

The alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol; the ether solvents are selected from diethyl ether, tetrahydrofuran etc.; the ester solvents are selected from ethyl acetate, methyl acetate, etc.; nitriles are selected from acetonitrile, propionitrile, butyronitrile etc.

b) (5)-1 -chioro-3-phthalimido-2-propanol is cyclized in presence of alkali metal alkoxides to obtain 2-[(25)-oxiran-2-ylmethyl]-177-isoindole-l,3(277)-dione

(A)-l-Chloro-3-phthalimido- 2-[(2.$')-Oxiran-2-vlmcthvl|-l H-isoindolc ₁₀ 2-propanol l,3(2H)-dione (I)

Cyclization of (5)-1 -chioro-3-phthalimide-2-propanol will produce the 2-[(2S)oxiran-2-ylmethyl]-177-isoindole-l,3-(277)-dione.

Cyclization is carried out in presence of alkali metal alkoxides as the procedure described in US 6,875,875.

Linezolid produced according to the present invention may be in the form of amorphous or crystalline form I and form II.

According to the present invention, the compound of formula (I) or Linezolid having HPLC purity is not less than 99%.

Advantages of the present invention:

1. The present invention is simple, operation friendly and industrial applicable process.

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2. The process is commercially viable and results the compounds in high yield, which makes the process cost effective

3. The present invention reaction is carried out in less span of time

4. The present invention provides high purity compound of formulas (I), (VI) and (IX) with very less impurities profile.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Experimental procedure:

Example-1:

Preparation of 2-[(2>y)-oxiran-2-vlmethvll-l//-isoindole-l,3(2//)-dione :

To a suspension of l/Z-isoindole-l,3(2//)-dione (100 g, 0.68 moles) and methylamine (10 g) in isopropanol (200 ml), X-epichlorohydrin (100 g 1.08 moles) was added and the mixture was heated to 60°C and maintained for 5 h at the same temperature. 30% Sodium methoxide in methanol (160 g) was added portion wise at 10-15°C to the reaction mass, the temperature was raised to 25-30°C and the reaction mass was stirred for 2-3 h at the same temperature. After completion of the reaction, water (600 ml) was added, stirred forlO min, filtered the solid and washed with water to obtained titled compound.

Weight: 107 g (77.5%)

Example-2:

Preparation of 2-[(2A)-oxiran-2-ylmethyl]-l//-isoindole-l,3(2//)-dione :

To a suspension of l/7-isoindole-l,3(2//)-dione (100 g, 0.68 moles) and diethyl amine (10 g) in ethanol (200 ml), X-epichlorohydrin (100 g 1.08 moles) was added and the mixture was heated to 60°C and maintained for 5 h at the same temperature. 30% sodium methoxide in methanol (160 g) was added portion wise at 10-15°C to the reaction mass, the temperature was raised to 25-30°C and the reaction mass was stirred

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PCT/IB2016/053003 for 2-3 h at the same temperature. After completion of the reaction, water (600 ml) was added, stirred forlO min, filtered the solid and washed with water to obtained titled compound.

Weight: 107 g (77.5%)

Example-3:

Preparation of (S) 2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5ylmethyl] -isoindole-1, 3-Dione

A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (50 g, 0.196 moles) in Ethyl acetate (100 ml) and stirred for 10 min at 25 to 30°C. 2-[(2S)-oxiran-2-ylmethyl]lH-isoindole-1, 3(2H)-Dione (50 g, 0.246 moles) and Lithium tertiary but oxide (5.0 gm,0.0624 moles ) was added in one lot at 25 to 30°C, and the temperature was slowly raised to 70-75°C and maintain at the same temperature for about 6-8 hrs. The reaction mixture was cooled to ambient temperature, ethyl acetate (50 ml) was added, and resultant slurry was stir for 30 min at 25-30 ° C & filtered the solid. The resultant crude solid was added to ethyl acetate ( 250 ml) at 25-30°C and heated to 70-75°C, stirred for 15-20 min, cooled the slurry to 25-30°C & Stir for 30 min. The obtain solid was filtered and washed with ethyl acetate ( 50 ml) to get a pure (5S)2-[3-(3-Fluoro-4morpholin-4-yl-phenyl)-2-oxo-oxazolidin-isoindole-l,3-dione. Yield: 70 g (85% yields on theoretical)

Example-4:

A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (50 g, 0.196 moles) in Dimethyl formamide (75 ml) ,2-[(2S)-oxiran-2-ylmethyl]-lH-isoindole-l,3(2H)-dione (50 g,0.246 moles) and Lithium tertiary but oxide (5.0 gm, 0.0624 moles) were heated to 70-75°C and maintained at the same temperature for about 4-6 hrs. The reaction mixture was allowed to cool at 26°C, added methanol (250 ml) and stir the slurry for 30 min at 25-30°C. The resultant solid was filtered and washed with methanol (50 ml). The obtained crude solid was recrystallized with ethyl acetate to get the pure (5S) 2-[317

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PCT/IB2016/053003 (3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-isoindole-l,3-dione Yield: 65 g (77.7%)

Example- 5:

A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (100 g, 0.392moles), in Dimethyl formamide (200ml) , 2-[(2S)-oxiran-2-ylmethyl]-lH-isoindole-l,3 (2H)dione (100 g,0.492 moles) , and Lithium tertiary but oxide (5.0 gm,0.0625 moles) were added in one lot at 25 to 30°C, and heated to 80-85°C and maintained at the same temperature for about 4-6 hrs. The reaction mixture was cooled to ambient temperature, followed by addition of purified water (500 ml) and stir for 30 min at 25-30°C. The resultant solid was filtered and washed with purified water (100 ml). The obtained crude solid was recrystallized with ethyl acetate to get pure (5S)2-[3-(3-Fluoro-4-morpholin4-yl-phenyl)-2-oxo-oxazolidin-isoindole-l,3-dione.

Yield: 140 g (85%)

Example- 6:

Preparation of (S) 2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5ylmethyl] -isoindole-1,3-dione

A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (20 g, 0.0784moles),2[(2S)-oxiran-2-ylmethyl]-lH-isoindole-l,3(2H)-dione (20 g,0.0984 moles) ,Dimethyl formamide ( 80 ml) and sodium iodide ( 4.0 g) were added in one lot at 25 to 30°C, and the temperature was slowly raised to 110-115°C. The reaction mixture was maintained at 110-115°C for about 6 to 8 hrs. The reaction mixture was cooled to ambient temperature, added water (200 ml), stir for 30 min at 25-30°C and filtered the solid .The obtain crude solid was recrystallized with methanol (20 ml) to get a pure (5 S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-isoindole-l, 3-dione. Yield: 25 g (75%)

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Example- 7:

A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (25 g, 0.098 moles) in Tetrahydrofuran (50 ml), 2-[(2S)-oxiran-2-ylmethyl]-lH-isoindole-l,3(2H)-dione (25 g,0.123 moles) were added and stirred for 10 min at 25 to 30°C; followed by lot wise addition of sodium hydride (1.2 gm,0.05 moles ) at 25 to 30°C. The reaction mixture temperature was slowly raised to 50-60°C and maintained at the same temperature for about 2-3 hrs. The reaction mass was cooled to below 20°C, quenched with 25 ml of methanol to decompose the excess sodium hydride, distilled out solvent and added methanol (125 ml). The resulting slurry was stir for 30 min at 25-30° C and filtered. The obtain solid was taken into ethyl acetate (125 ml) and heated to70-75°C, stirred for 15-20 min, cooled the slurry to 25-30°C, filtered and washed with ethyl acetate ( 25 ml) to get the pure (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxooxazolidin-isoindole-l,3-dione. Yield: 34 g (77%)

Example- 8:

A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (25 g, 0.098 moles) in N,N Dimethyl formamide (50 ml), 2-[(2S)-oxiran-2-ylmethyl]-lH-isoindole-l,3(2H)dione (25 g,0.123 moles) were added and stirred for 10 min at 25 to 30°C; followed by lot wise addition of sodium hydride (1.2 gm,0.05 moles ) at 25 to 30°C. The reaction mixture temperature was slowly raised to 50-60°C and maintained at the same temperature for about 2-3 hrs. The reaction mass was cooled to below 20°C, quenched with 25 ml of methanol to decompose the excess sodium hydride, further added methanol (125 ml) and the resulting slurry was stir for 30 min at 25-30° C and filtered. The obtain solid was taken into ethyl acetate (125 ml) and heated to70-75°C, stirred for 15-20 min, cooled the slurry to 25-30°C, filtered and washed with ethyl acetate ( 25 ml) to get the pure (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxooxazolidin-isoindole-l,3-dione. Yield: 32 g (75%)

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Example-9:

Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-2-oxo-l, 3oxazolidin-5-yl} methyl) acetamide (Linezolid)

To the mixture of Methanol (100 ml) ,DM water (400 ml) and (S) 2-[3-(3-Fluoro-4morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl] -isoindole-1, 3-Dione (100 g 0.212 moles ) were added Methyl amine solution (47 g) to the reaction mixture at 2530°C, stirred and the temperature was slowly raised to 80-85°C and stirred for 2-3 hours at 80-85°C. The reaction mixture was cooled to 25-30°C and dichloromethane (500 ml) was added to it and stirred the reaction mixture for 15 min and separated the two layers. MDC was distilled out by atmospheric pressure completely to get the residual product (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at 25-30°C over a period of 60 min. After completion, 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with DM Water (200 ml). The dichloromethane layer was filtered through hyflo and distilled out dichloromethane completely under vacuum below 40°C. Cyclohexane (500 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, filtered the solid, washed with cyclohexane (200 ml) and dried the solid at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) (53 g 75%).

Example-10:

To the mixture of Methanol (100 ml) ,DM water (400 ml) &(S) 2-[3-(3-Fluoro-4morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl] -isoindole-1, 3-Dione (100 g 0.212 moles ) Hydrazine hydrate (50 g) was added to the reaction mixture at 25-30°C, stirred and the temperature was slowly raised to 70-75°C and stirred for 2-3 hours at 70-75°C. The reaction mixture was cooled to 25-30°C and dichloromethane (250 ml) was added to it and stirred the reaction mixture for 15 min and separated the two layers. MDC was distilled out by atmospheric pressure completely to get the residual product

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PCT/IB2016/053003 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (200 ml) was added to the residue and acetic anhydride (13 g) was slowly added at 25-30°C over a period of 60 min. The reaction mixture was stirred for 60 min at 25-30°C. After completion of the reaction, 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with water (100 ml). The dichloromethane layer was filtered through hyflow and distilled out dichloromethane completely under vacuum below 40°C. Cyclohexane (250 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, filtered the solid, washed with cyclohexane (100 ml) and dried the solid at 45-55°C to furnish pure crystalline 55 g of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2oxo-1,3 -oxazoli din-5 -yl} methyl)acetamide (Linezolid).

Example 11:

Methyl amine solution (50 g) was added to a mixture of methanol (100 ml), DM water (400 ml) and (5S) 2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5ylmethyl]-isoindole-l,3-dione (100 g 0.235 moles ) at 25-30°C. The reaction mixture was stirred, slowly raised to 80-85°C and stirred for 2-3 hours at 80-85°C. The reaction mixture was allowed to cool at 25-30°C; followed by addition of dichloromethane (500 ml) and stirred for 15 min to separate the layers. Purified water (500 ml) was added to the MDC layer and mixture was acidified to pH 2.0-3.0 with dilute hydrochloric acid and stirred for 10-15 min and two layers were separated and again basified with aqueous ammonia pH 10.0-11.0. to separate the MDC layer, and it was distilled out by atmospheric pressure completely to get the residual product of (5S)-5-(amino methyl)3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at 25-30°C over a period of 60 min. The reaction mixture was stirred for 60 min at 25-30°C.After completion of reaction, 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The di chloromethane layer was washed with D M Water (200 ml). The di chloromethane

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PCT/IB2016/053003 layer was filtered through hi-flow and di chloromethane was distilled out completely under vacuum below 40°C. Cyclohexane (500 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25°C, stirred for 60 min, the solid obtained was filtered, washed with cyclohexane (200 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3oxazolidin-5-yl}methyl)acetamide (Linezolid) (53 g 75% ).

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Claims

CLAIMS:

1. An improved process for the preparation of compound of formula (I) comprising the steps of;

a) reacting the compound of formula(III) with (S)-Glycidylphthalimide of formula(IX) in presence of alkali metal iodides (or ) metal hydrides to give a compound of formula(VI),

b) subjecting the compound of formula(VI) with aqueous methyl amine (or) hydrazine hydrate,

c) acylating the product of step b), and

d) Isolating the compound of formula (I).
2. An improved process for the preparation of (S)- N- [[3 - [3 -fluoro-4- [4morpholinyljphenyl] -2-oxo-5-oxazolidinyl] methyljPhthalimide of formula (VI)

Which comprises reacting carbamate compound of formula (III)

R represents hydrogen, C1-C5 alkyl, aryl, aralkyl;

With (S)-glycidyl phthalimide of formula (IX)

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In the presence of alkali metal iodides (or) metal hydrides 5 (Or)

In the presence of lithium tertiary butoxide used in the range 0.2-0.4 Mole equivalents based on carbamate compound of formula (III)
3. An improved process for the preparation of 2-[(25)-oxiran-2-ylmethyl]-l/7 10 -isoindole-1,3(2JY)-dione of formula IX, comprising the steps of:

a) l//-isoindole-l,3(2JY)-dione or phthalimide reacted with (5)-epichlorohydrin in presence of organic base in an organic solvent to obtain (5)-1-chioro-3phthalimido-2-propanol.

NH + ^υ (S)-(+)-Epichlorohydrin Phthalimide

Organic base / Organic solvent

-► (S)-l-Chloro-3-phthalimido 2-propanol

Wherein, the organic base is primary or secondary alkyl amines having C1-C5 carbon atoms.

b) (5)-1-chi oro-3-phthalimido-2-propanol is cyclized in presence of alkali metal alkoxide to obtain 2-[(25)-oxiran-2-ylmethyl]-l//-isoindole-l,3(2JY)-dione (A)-l-Chloro-3-phthalimido2-propanol

Cyclization

2-[(2.$')-Oxiran-2-ylmcthyl|-lH-isoindolcl,3(2H)-dione (IX)

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4. The process as claimed in claims 1 and 2, wherein the said alkali metal iodides is selected from lithium iodide, sodium iodide or potassium iodide; metal hydrides is selected from lithium hydride, sodium hydride or magnesium hydride; acylating reagents are selected from acetic anhydride or acetyl chloride.
5. The process as claimed in claims 1, 2 and 3, wherein the solvent is selected from alcohols, ketones, halogenated solvents, esters, hydrocarbon solvents, ethers, amides or dimethyl sulfoxide
6. The process as claimed in claim 3, wherein primary or secondary amines are selected from the group comprising of C1-C5 carbon atoms such as methylamine, ethylamine, ethyl methylamine, diethyl amine, dipropylamine, dibutylamine. Preferably diethyl amine; alkali metal alkoxides is selected from sodium methoxide, sodium ethoxide.
7. According to the preceded claims 2 and 3 processes are also used in the preparation of Linezolid.