FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION (See section 10)
NOVEL PROCESS FOR THE PREPARATION OF
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERf-KURLA ROAD, ANDHERI (E), MUMBAI-400059.
MAHARASHTRA, INDIA
The following specificaf>on particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.


reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamirie, compound of formula 2, or its salt with a compound of formula 3,

wherein Y is selected from X, CCI3CO, 1-imidazolyl or substituted imidazolyl,; and Z is selected
from CCIjCO, 1-imidazolyl or substituted imidazolyl, and OR wherein X is a halo radical, and R
is selected from a substituted or unsubstituted linear, branched or cyclic alkyl radical, and aryl or
heteroar} I radical
Claims 17-25 are deleted
The word further is deleted from claim 11 for clarity
Claim 26 is presented as claim 17.
Enclosed please And amended claim pages 16,17 and 18
DE 1163328 , US 3062827 (Dl)
Dl discloses three methods for the preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, viz.
(a) reacting 3-(3,5-dimethylphenoxy)-l,2-propanediol with urea; or
(b) reacting 3-(3,5-dimethylphenoxy)-l-chloro-2-propanol with urea; or
(c) reacting 3-(3,5-dimethyIphenoxy)-2-hydroxy-l -propyl-carbamate with urea.
Thus the present invention is novel over Dl as Dl does not disclose process for preparing metaxalone by reacting l-amino-3-aryloxy -2-propanols with compound of formula 3.
The process of Dl is energy consuming requires elevated temperatures and yields 79% product.. This patent does not disclose the purity. We have disclosed on page 2 of specification that when we carried out the patented process the purity of the crude product obtained was only about 51% and unreacted 3-(3,5-dimethylphenoxy)-l,2-propanediol was found to be the major impurity. In contrast the novel process of the present invention gives metaxalone in 90% yield, See example I© on page 14 of specification and a purity > 99% as determined by HPLC. Thus the

present invention involves a technical advance as substantially all the starting material is converted tp the intended product. The process of the present invention is more efficient and gives high purity metaxalone and is thus inventive over Dl.
J.Am.Chem.Soc. 1959, vol 82,1166-71 (D2)
D2 discloses 2 methods for preparing compound of formula 1 and its analogues.

compound of formula I
D2 discloses that for compound of formula 1 when nitrogen of oxazolidinone ring is unsubstituted then it is prepared by reaction of alpha aryl ethers of glycerol and urea. D2 discloses that when nitrogen of oxazolidinone ring is substituted then it is prepared by reaction of l-amino-3-aryloxy -2-propanols with ethyl carbonate or phosgene.
D2 does not disclose preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (metaxalone in which nitrogen of oxazolidinone is unsubstituted) by reacting l-amino-3-aryIoxy -2-propanols with compound of formula 3 as disclosed in the present invention. Also in the present invention the compound of formula 3 are different compounds and do not include ethyl carbonate or phosgene. Thus the present invention is novel over D2 as D2 does not disclose process for preparing metaxalone by reacting I-amino-3-aryIoxy -2-propanols with compound of formula 3.
D2 discloses in Table 1 that metaxalone is prepared in 79% yield (purity unknown) by following the first method. In contrast the novel process of the present invention gives metaxalone in 90% yield, See example 1© on page 14 of specification and a purity > 99% as determined by HPLC. Thus the present invention involves a technical advance as substantially all the starting material is ' converted to the intended product. The process of the present invention is more efficient and gives high purity metaxalone and is thus inventive over D2.
Current Science, 1961, vol 30, No. 3, 99-100 (D3)
In view of D3 we have deleted claims 17-25.

Para3 of FER
Form 3 and 5 are corrected.
Para 4
Form 3 details for foreign filing is filed with petition.
Para 5
We are submitting US 2005/0075505 which is the US publication of the instant invention and notice of allowance form the USPTO wherein claims 28-37 as filed in US are allowed.
As instructed by the examiner the title is deleted from page 2.Amendments have been made on page 4,5. 7,12 so that the substitutions Y and Z are same as presented in amended claim I. Abstract page 20 is also amended to delete last paragraph. No new matter is added and amendments are made so that the description is in conformity with the claims.
Enclosed please find amended pages 2,4,5,7, 12 and 20 in duplicate.
The application is now in condition of allowance and we request that a patent may be granted to us for the instant invention.
If in examiner's view any issue still remains to be resolved, the applicants request a meeting with the examiner to put the application in condition for grant before the due date.
with kind regards
For SUN PHARMACEUTICAL INDUSTRIES LTD

Dr. Varsha Sacfekar
Manager, Intellectual Property Cell
#66455645. Ext 623
Fax:56455685
E-mail: Varsha.Sadekarffisunpharma.coin


3) Fresh page nos. 2,4,5 7 12 16 I8 20 in duplicate
4) Form 3 with petition
5) Cheque No.000359 drawn on rCICI bank for 4000/-

reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, or its salt with a compound of formula 3,


Y-C—Z
Formula 2 Formula 3
wherein Y is selected from X, CCl3CO, 1-imidazolyl or substituted imidazolyl,; and Z is selected from CCI3CO, 1-imidazolyl or substituted imidazolyl, and OR wherein X is a halo radical, and R is selected from a substituted or unsubstituted linear, branched or cyclic alkyl radical, and aryl or heteroaryl radical Claims 17-25 are deleted
The word further is deleted from claim 11 for clarity Claim 26 is presented as claim 17.
Enclosed please find amended claim pages 16,17 and 18
DE 1163328 , US 3062827 (Dl)
Dl discloses three methods for the preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, viz.
(a) reacting 3-(3,5-dimethylphenoxy)-l,2-propanediol with urea; or
(b) reacting 3-(3,5-dimethylphenoxy)-l-chloro-2-propanol with urea; or
(c) reacting 3-(3,5-dimethylphenoxy)-2-hydroxy-l-propyl-carbamate with urea.
Thus the present invention is novel over Dl as Dl does not disclose process for preparing metaxalone by reacting l-amino-3-aryIoxy -2-propanols with compound of formula 3.
The process of Dl is energy consuming requires elevated temperatures and yields 79% product.. This patent does not disclose the purity. We have disclosed on page 2 of specification that when we carried out the patented process the purity of the crude product obtained was only about 51% and unreacted 3-(3,5-dimethylphenoxy)-l,2-propanedioI was found to be the major impurity. In contrast the novel process of the present invention gives metaxalone in 90% yield, See example 1© on page 14 of specification and a purity > 99% as determined by HPLC. Thus the

present invention involves a technical advance as substantially all the starting material is converted to the intended product. The process of the present invention is more efficient and gives high purity metaxalone and is thus inventive over Dl,
J.Am.Chem.Soc. 1959, vol 82,1166-71 (D2)
D2 discloses 2 methods for preparing compound of formula 1 and its analogues.


H,C

compound of formula I
D2 discloses that for compound of formula 1 when nitrogen of oxazolidinone ring is unsubstituted then it is prepared by reaction of alpha aryl ethers of glycerol and urea. D2 discloses that when nitrogen of oxazolidinone ring is substituted then it is prepared by reaction of l-amino-3-aryloxy -2-propanols with ethyl carbonate or phosgene.
D2 does not disclose preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (metaxalone in which nitrogen of oxazolidinone is unsubstituted) by reacting l-amino-3-aryloxy -2-propanols with compound of formula 3 as disclosed in the present invention. Also in the present invention the compound of formula 3 are different compounds and do not include ethyl carbonate or phosgene. Thus the present invention is novel over D2 as D2 does not disclose process for preparing metaxalone by reacting l-amino-3-aryloxy -2-propanols with compound of formula 3.
D2 discloses in Table 1 that metaxalone is prepared in 79% yield (purity unknown) by following the first method. In contrast the novel process of the present invention gives metaxalone in 90% yield, See example 1© on page 14 of specification and a purity > 99% as determined by HPLC. Thus the present invention involves a technical advance as substantially all the starting material is converted to the intended product. The process of the present invention is more efficient and gives high purity metaxalone and is thus inventive over D2.
Current Science, 1961, vol 30, No. 3,99-100 (D3)
In view of D3 we have deleted claims 17-25.

Para3ofFER
Qrm 3 and 5 are corrected.
Para 4
Form 3 details for foreign filing is filed with petition.
Para 5
We are submitting US 2005/0075505 which is the US publication of the instant invention and notice of allowance form the USPTO wherein claims 28-37 as filed in US are allowed.
As instructed by the examiner the title is deleted from page 2,Amendments have been made on page 4,5, 7,12 so that the substitutions Y and Z are same as presented in amended claim 1. Abstract page 20 is also amended to delete last paragraph. No new matter is added and amendments are made so that the description is in conformity with the claims.
Enclosed please find amended pages 2,4,5,7, 12 and 20 in duplicate.
The application is now in condition of allowance and we request that a patent may be granted to us for the instant invention.
If in examiner's view any issue still remains to be resolved, the applicants request a meeting with the examiner to put the application in condition for grant before the due date.
with kind regards
For SUN PHARMACEUTICAL INDUSTRIES LTD
Dr. Varsha Saclekar
Manager, Intellectual Property Cell
#66455645, Ext 623
Fax: 56455685
E-mail: Varsha.Sadekar@siinpharma.com

I
enclosures: 1) Original Form 1,3 and 5
2) Original complete specification (Form 2) including cancelled page nos. 2,4,5,7, 12,
& 16-20
3) Fresh page nos. 2,4,5,7, 12,16-18, 20 in duplicate
4) Form 3 with petition
5) Cheque No.000359 drawn on ICICI bank for 4000/-6j


The present invention relates to a novel process of preparing 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, commonly known as metaxalone (INN Name), a compound of formula 1. 5-(3,5-Dimethylphenoxy)methyl-2-oxazolidinone is indicated as an adjunct to rest, physical therapy and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.

Formula 1
PRIOR ART
United States Patent No. 3062827 generically claims 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone. This patent also discloses three methods for the preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, viz.
(a) reacting 3-(3,5-dimethylphenoxy)-l,2-propanediol with urea; or
(b) reacting 3-(3,5-dimethylphenoxy)-l-chloro-2-propanol with urea; or
(c) reacting 3-(3,5-dimethylphenoxy)-2-hydroxy-l -propyl-carbamate with urea.
The patent exemplifies the process at elevated temperature i.e. 195-200°C and also involves distillation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone under high vacuum and temperature. This patent does not disclose the purity of the prepared 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone; the process described is energy consuming and yields 79% product. When we carried out the patented process the purity of the crude product obtained was only about 51% and unreacted 3-(3,5-dimethylphenoxy)-l,2-propanediol was found to be the major impurity. There is thus a need for a process wherein

the starting material is efficiently converted to 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone.
United States Patent No. 3446814 claims a method of preparing 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone by reacting triglycidyl isocyanurate with rn-xylenol The patent exemplifies reacting the raw materials with pulverized sodium hydroxide in chlorobenzene at its reflux temperature which is 131-132°C for 13 hours in presence of benzyltrimethylammonium chloride, followed by recrystallization of the product from chlorobenzene. This patent does not disclose the purity of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone. The process is also energy consuming and yields 76% product.
A novel process has been found for the preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone from 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine. None of the methods disclosed in prior art prepare 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone by the process of the present invention. The novel process converts the starting material to the intended product in an efficient manner such that substantially all of the starting material is converted to the intended product.
OBJECTS OF THE INVENTION:
An object of the present invention is to provide a novel process to prepare 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone.
A more particular object of the present invention is to provide a novel process that provides 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone in high yields in a substantially pure form.

) SUMMARY OF INVENTION :
The present invention provides a novel process for the preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) comprising


H,C

Formula 1 reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, or its acid addition salt with a compound of formula 3,

Y-C—Z
Formula 2 Formula 3
wherein Y is selected from X, CCI3CO, 1-imidazolyl or substituted imidazolyl,; and Z is selected from CCI3CO, 1-imidazolyl or substituted imidazolyl, and OR wherein X is a halo radical, and R is selected from a substituted or unsubstituted linear, branched or cyclic alkyl radical, and aryl or heteroaryl radical.
The novel process of the present invention has been found to be advantageous in that the reactions involved can be carried out without substantial expenditure of energy, and the desired product, viz. 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) can be obtained in high yields in a substantially pure form.
DETAILED DESCRIPTION OF THE INVENTION:
A novel method of preparation was conceived and developed by us so as to obtain substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1).

As referred to herein substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone is 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone with purity greater than 99%.
Preferably the substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone has purity greater than 99.5%, more preferably greater than 99.9% by HPLC.
Most preferably, substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) has a purity greater than 99.5% by HPLC and has no individual impurity that is more than 0.05% by HPLC.
The process of the present invention adopts a novel methodology to prepare 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone which comprises reacting, 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, a compound of formula 2, or its acid addition salt with compound of formula 3,
OH
,NH„
Y-C—Z
Formula 2 Formula 3
wherein Y is selected from X, CCl3CO, 1-imidazolyl or substituted imidazolyl,; and Z is selected from CCI3CO, 1-imidazolyl or substituted imidazolyl, and OR wherein X is a halo radical, and R is selected from a substituted or unsubstituted linear, branched or cyclic alkyl radical, and aryl or heteroaryl radical.
The substitutions on linear, branched or cyclic alkyl radical comprise of cyano, nitro, alkoxy, aryloxy, mercaptoalkyl, mercaptoaryl, alkyl or aryl sulphonyl. The preferred substitutions are the electron withdrawing substituents like cyano or nitro.
method for the preparation of the compound of formula 2, which comprises treating compound of formula 5 with a source of ammonia to yield compound of formula 2, and

The substitutions on aryl, heteroaryl or imidazolyl radical comprise of halo, cyano, nitro, -alkoxy, aryloxy, mercaptoalkyl, mercaptoaryl, alkyl or arylsulphonyl. .The preferred ; substitutions are the electron withdrawing substituents like halo, cyanp orftijtrQ, _ * %^
'.:«;■,
In preferred embodiments, the compound of formula 3 is preferably a carbonate or a haloformate, most preferably ethylchloroformate.
The present invention also discloses a method for the preparation of the compound of formula 2, which comprises treating compound of formula 5 with a source of ammonia to yield compound of formula 2, and optionally converting compound of formula 2 to its acid addition salt in order to isolate pure form of formula 2.
,0

Formula 5 The acid addition salt of compound of formula 2 may be selected from its hydrochloride, sulfate or hydrobromide salt, preferably its hydrochloride salt, in order to isolate pure form of formula 2.
Details of each step are as given below:
Preparation of 5-(3£-dimethylphenoxy)methyl-2-oxazolidinone
According to the process of the present invention, preparation of 5-(3,5-dimethylphenoxy)methyl-2~oxazoIidinone is carried out by reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine or its acid addition salt of formula 2, in an organic solvent in the presence of a base, with a compound of formula 3,


Y-C—Z
Formula 3 wherein Y is selected from X, CCI3CO, 1-imidazolyl or substituted imidazolyl,; and Z is selected from CCI3CO, 1-imidazolyl or substituted imidazolyl, and OR wherein X is a halo radical, and R is selected from a substituted or unsubstituted linear, branched or cyclic alkyl radical, and aryl or heteroaryl radical.
In preferred embodiments of the invention the compound of formula 3 is a carbonate or a haloformate, preferably a haloformate compound of formula 2 wherein Y is a halo radical and Z is OR wherein R is linear Ci to C4 alkyl radical, most preferably ethyl chloroformate.
The organic solvent is selected from polar and non-polar solvents comprising of aliphatic, cyclic or aromatic substituted or unsubstituted hydrocarbons such as benzene, toluene, xylene, cyclohexane, dichloromethane, dichloroethane, monochlorobenzene and the like; ketones such as acetone, methlyisobutylketone, methylethylketone, cyclohexanone and the like; cyclic and acyclic ethers such as ether, tetrahydrofuran, dioxan, dimethoxyethane, diglyme and the like; polyethers such as poly(alkylene glycol)s and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethylacetamide and the like. The preferred solvent is an aliphatic, cyclic or aromatic substituted or unsubstituted hydrocarbon, most preferably toluene.
The base for the reaction is selected from a group of organic or inorganic bases. The organic base may be selected from tertiary amines or aromatic bases, and the inorganic base may be selected from bicarbonates, carbonates, hydrides, hydroxides and oxides of alkali or alkaline earth metals. In preferred embodiments the base is an inorganic base, which is a carbonate of an alkali metal, the most preferred base being potassium carbonate. In the process of the present invention, when the reaction is carried out using an inorgainc base, addition of a facilitator has been found to be very advantageous. The facilitator is a

substance that has the property to complex or solvate metal cations, for example, a polyether. Alternatively, the facilitator may be a substance that can
• exchange the metal cations with hydrophobic cations, for example, a quaternary..,, ammonium salt or a quaternary ammonium hydroxide where substituents oh fife nitrogen are selected from alkyl or aralkyl groups, for example, benzyltrialkylammonium halide; or
• act in a fashion similar to phase transfer catalyst.
The facilitator may be selected from cyclic and acyclic polyethers. Cyclic ethers such as crown ethers and acyclic ethers such as poly(alkylene glycol) may be used. Poly(alkylene glycol) which may be used is poly(ethylene glycol) (PEG) with an average molecular weight in the range between 200 to 10,000, the most preferred facilitator for the reaction being PEG-400.
The reaction can be performed at temperatures ranging from 0 to 150°C for about 1 to 10 hours, preferably at 50 to 150°C for about 2 to 8 hours, the most preferred being about 100 to 110°C for about 5 hours.
For instance, the reaction is carried out by heating gradually to reflux a mixture of compound of formula 2, PEG-400 and an alkali metal carbonate in an organic solvent, cooled to ambient temperature and then ethyl chloroformate is added to it. The mixture is then heated for completion, to furnish the desired oxazolidinone (formula 1). The reaction mixture is worked up by standard methods known to those skilled in the art. The product is isolated with a yield of about 90%, and is greater than 99% pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone.
Optional Further Purification of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone
In another embodiment of the process of the present invention 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is purified to greater than 99% purity to yield substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone

V (formula 1) by recrystallization from an organic solvent, optionally by addition of a second organic solvent.
The solvent system which may be used in the purification step may comprise a mixture of solvents selected from a polar and non-polar organic solvent comprising aliphatic, cyclic or aromatic substituted or unsubstituted hydrocarbons such as benzene, toluene, xylene, cyclohexane, dichloromethane, dichloroethane, monochlorobenzene and the like; alcohols such as Ci-Ce alcohols like methanol, ethanol, propanols, butanols and the like; diols, polyols selected from ethylene glycol, propylene glycol and the like; esters such as ethyl acetate, butyl acetate and the like; ketones such as acetone, methlyisobutylketone, methylethylketone, cyclohexanone and the like; cyclic and acyclic ethers such as ether, tetrahydrofuran, dioxan, dimethoxyethane, diglyme and the like; polyethers such as poly(alkylene glycol) and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethylacetamide and the like, sulfoxides such as dimethyl sulfoxide and the like. The preferred organic solvent system for purification to achieve substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone is a mixture comprising acetone and toluene, in the ratio ranging from 0.5 : 1.0 to 1 : 10, most preferably in the ratio 1:1.
Preferably, for recrystallization, the dissolution is carried out at about ambient to 110°C, more preferably about 50 to 80°C.
Optionally, to the clear solution may be added another solvent and cooled gradually or spontaneously to about 0 to 30°C, preferably to 15 to 25°C.
The crystallized product is filtered, washed with a solvent and dried using conventional techniques known to those skilled in the art to yield substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone with purity greater than 99.9% by HPLC.
The substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone has purity greater than 99.5% and has no individual impurity that is more than 0.05% by HPLC.

In the preferred process of the present invention crystallization is allowed to occur by chilling or seeding or scratching the glass of the reaction vessel or cooling and other such common techniques, preferably cooling.
The product may be dried using different techniques of drying like fluid bed drying, tray drying and rotatory drying techniques with or without application of vacuum and / or under inert conditions.
Preparation of 3-(3,5-dimethyIphenoxy)-2-hydroxypropylamine (formula 2):
Step (a) -Preparation of 3-[(3,5-dimethylphenoxy)methyl]oxirane (formula 5):
According to the process of the present invention step (a) is carried out by reacting 3,5-dimethylphenol with epichlorohydrin and a base in a solvent, optionally in the presence of a facilitator.
The facilitator may be selected from quaternary ammonium salts such as benzyltrimethylammonium chloride and the like, or from cyclic and acyclic polyethers. Cyclic ethers such as crown ethers and acyclic ethers such as poly(alkylene glycol) may be used. Poly(alkylene glycol) which may be used is poly(ethylene glycol) (PEG) with an average molecular weight in the range between 200 to 10,000, preferably 200 to 1000, the most preferred being 400.
The solvent for the reaction could be an aliphatic, cyclic or aromatic substituted or unsubstituted hydrocarbons such as benzene, toluene, xylene, cyclohexane, dichloromethane, dichloroethane, monochlorobenzene and the like. In preferred embodiment, the solvent is a polar solvent comprising of cyclic and acyclic ethers such as ether, tetrahydrofuran, dioxan, dimethoxyethane, diglyme and the like; polyethers such as poly(alkylene glycol)s (PEG) such as PEG-200, PEG-400 and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide,

dimethylacetamide and the like, sulfoxides such as dimethyl sulfoxide and the like. In the present invention the preferred solvent is a water soluble ether, most preferably PEG-400, wherein no additional facilitator is required.
The base used could be selected from an organic or inorganic base, preferably an inorganic base selected from bicarbonates, carbonates, hydrides, hydroxides and oxides of alkali or alkaline earth metals. Most preferably the base is potassium hydroxide.
Further, the reaction may be carried out at about 20 to 80°C, The preferred temperature of step (a) may be 25 to 60°C, the most preferred being 35 to 45°C
The reaction may be carried out in poly(ethylene glycol)-400 in the presence of a base.
The reaction may be .carried out in poly(ethylene glycol)-400 in the presence of potassium hydroxide at 35 to 45°C.
The reaction mixture is worked up by standard methods known to those skilled in the art.
Step (b) -Preparation of 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine (formula 2):
According to the process of the present invention the preparation of compound of formula 2 is carried out by reacting 2-[(3,5-dimethylphenoxy)methyl]oxirane with ammonia, preferably in a solvent. Ammonia could be used in the form of liquor ammonia, liquid ammonia or ammonia gas.
According to one embodiment of the present invention the organic solvent is selected from polar solvents like; alcohols such as Cj-C6 alcohols like methanol, ethanol, propanols, butanols and the like; diols, polyols selected from ethylene glycol, propylene glycol and the like; ketones such as acetone, methlyisobutylketone, methylethylketone, cyclohexanone and the like; cyclic and acyclic ethers such as ether, tetrahydrofuran, dioxan, dimethoxyethane, diglyme and the like; polyethers such as poly(alkylene glycol)s and the

^p like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethylacetamide and the like, sulfoxides such as dimethyl sulfoxide and the like. When liquor ammonia is used polar water soluble solvents are preferred.
In a preferred embodiment of the present invention organic solvent is an alkanol selected from Ci to C4 alkanol or its admixture with water. More preferably the alkanol is methanol. Preferably, step (a) is carried out by adding a solution of 2-[(3,5-dimethylphenoxy)methyl]oxirane in methanol to a stirred solution containing large molar excess of liquor ammonia and methanol slowly over a period of about 9 hours while maintaining the temperature of about 25 to 30°C.
The reaction mixture is worked up by standard methods known to those skilled in this art. For instance, in a specific embodiment after completion of reaction methanol was distilled out below 60°C under vacuum. The product was extracted into methylene dichloride and the organic extract was acidified with cone. HCl added till about pH 2 to precipitate the product selectively as a hydrochloride salt devoid of impurities, which could be easily filtered to get 99% pure 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine hydrochloride.
The invention is illustrated but not restricted by the description in the following example.

EXAMPLES
Example -1
(a) Preparation of 2-[(3,5-Dimethylphenoxy)methyl]oxirane (formula 5)
To a stirred solution of 3,5-dimethylphenol (lOOg, 0.818 mol.), PEG-400 (300ml), epichlorohydrin (128.01ml, 1.63mol) at 25-30° C is added one part of potassium hydroxide (18.37 g, 0.32mol.). Two more lots of potassium hydroxide (18.37 g each, 0.64mol.) are charged, each after an hour's interval after cooling the mixture to 25-30° C. The mixture was then stirred further for an hour of at 35-45° C. Water (400ml) is slowly added and the product is extracted into hexane (2 x 200ml) and (IxlOOml). The combined hexane extract is concentrated at 60-65° C under vacuum. Any excess epichlorohydrin in the residue is finally stripped off by adding toluene (50.0ml) and degassing at 60-65°C under vacuum. Yield of the product is 142.0g.
(b) Preparation of 3-(3,5-Dimethylphenoxy)-2-hydroxypropylamine hydrochloride
(formula 2)
A solution of 2-[(3,5-dimethylphenoxy)methyl]oxirane (100.0 g, 0.561mol) in methanol (300.0ml) is added slowly during about 9hrs, to a stirred solution containing liquor ammonia (1150ml) and methanol (700ml) while maintaining the temperature between 25-30°C. After completion of addition, the mixture is stirred for a further 1 hr and the methanol was distilled out under reduced pressure at below 60° C. The product is then extracted into methylene dichloride (lx 300ml. & 1 x 200ml.). Pooled extracts are washed with water (2x 250ml). The organic layer is dried over anhydrous sodium sulfate, cooled to 5-10°C and cone. HC1 is added until the pH is about 2.0. The precipitated hydrochloride salt is filtered, washed successively with methylene dichloride (100.0ml) and hexane (50.0ml). Product is finally dried in air oven at 75-80° C to yield 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine hydrochloride, 62.0g (purity > 99.0%)

(c) Preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinahe (formula 1)
v ■.-■"■
v ■ A mixture of PEG-400 (50ml), toluene (500ml), potassium carboifate ppwder-(89.6g,
0.648mol), and 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine hydrochlonde-99% by HPLC).
(d) Purification of 5-(3,5-dimethylphenoxy)methy!-2-oxazolidinone (formula 1):
5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1), (5g) obtained in example 1(c) is dissolved in acetone (15ml) by heating to 60-65° C. To the clear solution is added toluene (15ml), cooled gradually to 20-25° C and stirred for 2 hrs. at this temperature. The crystallized product is filtered, washed with toluene (5 ml) and dried to get 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) with purity of 99.93% (having a maximum single impurity of 0.02%).
Example 2 : Method for analysis of purity by HPLC Buffer:
Dissolve 1.36g potassium dihydrogenorthophosphate in 1000ml of water. Take 650ml of
buffer add 2ml of triethylamine. Adjust pH to 2.5 by orthophosphoric acid.
Mobile phase:
Mix buffer solution and acetonitrile in the ratio of 650 : 350. Filter and degas prior to use.

Sample preparation: f. .... - *'.'•■ ■ ■■
Transfer about lOOmg accurately weighed sample into a 100ml volumetric flask. Dissolve
in and dilute upto mark with mobile phase. ^ ''
System suitability solution:
Transfer about lOmg of metaxalone into a 100ml volumetric flask. Dissolve in and dilute
upto mark with mobile phase.
Chromatographic system:
The liquid chromatograph is equipped with a 225nm UV detector and 25 cm x 4.6 mm,
5micron column that contains Hypersil BDS C8. The flow rate is about 1.0 ml/min.
Procedure:
Inject 10 ml of system suitability solution into the system and record the chromatograms
upto 25 min. Calculate the tailing factor of metaxalone peak. It should not be more than 1.5
and number of theoretical plates should not be less than 5000.
Inject 10 ml of sample preparation into the system and record the chromatograms upto 25
min. The retention time of metaxalone is 13min. Calculate the amount of related substances
by area normalization method, while disregarding any peak with an area percentage less
than 0.025.

We claim:
1. A novel process for the preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) comprising


H,C

Formula 1 reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, or its salt with a compound of formula 3,

Y-C—Z
Formula 2 Formula 3
wherein Y is selected from X, CCI3CO, 1-imidazolyl or substituted imidazolyl,; and Z is selected from CCI3CO, 1-imidazolyl or substituted imidazolyl, and OR wherein X is a halo radical, and R is selected from a substituted or unsubstituted linear, branched or cyclic alkyl radical, and aryl or heteroaryl radical.
2. A process as claimed in claim 1 wherein the reaction is carried out in the presence of a base.
3. A process as claimed in claim 2 wherein the base is potassium carbonate.
4. A process as claimed in claim 1 wherein in the compound of formula 3 Y is a halo radical and Z is OR wherein R is a linear Ci to C4 alkyl radical.
5. A process as claimed in claim 4 wherein the compound of formula 3 is ethyl chloroformate.
6. A process as claimed in claim 1 wherein the reaction is carried out in the presence of a facilitator.

7. A process as claimed in claim 6 wherein the facilitator is selected from cyclic and acyclic polyethers.
8. A process as claimed in claim 7 wherein the facilitator is poly(ethylene glycol) with an average molecular weight in the range between 200 to 10,000.
9. A process as claimed in claim 1 wherein the molar ratio of compound of formula 2 to compound of formula 3 is in the range of about 1:0.8 to 1:1.5.
10. A process as claimed in claim 1 wherein the 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained in a substantially pure form and has a purity greater than 99% by HPLC.
11. A process as claimed in claim 1 comprising additionally purifying 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) by crystallizing 5-(3,5-dimethylphenoxy)methyl~2-oxazolidinone (formula 1) from an organic solvent system.
12. A process as claimed in claim 11 wherein the 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained in a substantially pure form and has a purity greater than 99.5%.
13. A process as claimed in claim 11 wherein the 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained in a substantially pure form and has a purity greater than 99.9%.
14. A process as claimed in claim 11 wherein the 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained in a substantially pure form and has a purity greater than 99.5% and no individual impurity that is more than 0.05%.
15. A process as claimed in claim 11 wherein the organic solvent system is a mixture of acetone and toluene.
16. A process as claimed in claim 15 wherein the volume ratio of acetone : toluene is about 0.5 : 1.0 to 1 : 10.

'A
17. A process as claimed in claims 1 to 16 substantially as herein described and illustrated by examples 1 and analyzed as per example 2.
Dated this 10th day of January, 2003.

DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LIMITED