FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Chlorzoxazone (1) having purity greater than 99.0%. Also, the present invention provides process for the purification of 5-chlorobenzo[d]oxazol-2(3H)-one (1).
BACKGROUND OF THE INVENTION
Chlorzoxazone is a muscle relaxant which acts at central level and is used in the treatment of muscle spasms and the resulting pain. It is chemically known as 5-chlorobenzo[d]oxazol-2(3H)-one marketed under the brand name paraflex by Ortho Mcneil Pharmaceutical Inc.
The following patents describes the synthesis of Chlorzoxazone (1), the contents of which are hereby incorporated as reference in their entirety.
US3812138 discloses, process for the preparation of Chlorzoxazone (1) by heating a mixture of 4-chloro-2-aminophenol (3) and urea in the presence of concentrated hydrochloric acid in an autoclave at 125 °C. On completion of the reaction, the reaction mass was cooled to room temperature and the crystalline precipitate was suspended in 1500 parts of water. The product was isolated at pH 5-6 and dried to result 5-chlorobenzo[d]oxazol-2(3H)-one (1). The process did not report the purity of the product. It is not industrially efficient due to high temperature and tedious workup.
EP0477819 discloses process for the preparation of Chlorzoxazone (1) by treating 4-chloro-2-aminophenol (3) with phosgene in the presence of triethylamine. The process suffers in terms of yield and does not report the purity of the compound obtained.
To overcome the above-mentioned disadvantages coupled with prior art the present inventors herby report an improved process for the preparation of Chlorzoxazone (1) with simple reaction conditions and greater purity.

OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide an improved process for the preparation of Chlorzoxazone (1).
Another objective of the present invention is to provide a process for the purification of Chlorzoxazone (1).
Yet, another objective of the present invention is to provide Chlorzoxazone (1) with purity greater than 99.0 % by High-performance liquid chromatography (HPLC).
SUMMARY OF THE INVENTION
Accordingly, in one embodiment the present invention provides an improved process for the preparation of Chlorzoxazone (1) with purity greater than 99.0% by (HPLC).
In another embodiment, the steps involved in the preparation of Chlorzoxazone (1) as shown in scheme-1 are as follows:
a) reduction of 4-chloro-2-nitrophenol (4) with sodium dithionite to form 4-chloro-2-aminophenol (3)
b) cyclisation of 4-chloro-2-aminophenol (3) with triphosgene (2) to form 5-chlorobenzo [d] oxazol-2(3H)-one (1).
c) purifying 5-chloro benzo[d]oxazol-2(3H)-one (1).
In another embodiment the present invention provides process for the purification of Chlorzoxazone (1) comprising of.
a) providing a solution of Chlorzoxazone (1) in a suitable protic solvent;
b) treating with neutral charcoal;
c) isolating solid Chlorzoxazone (1);
d) dissolving the solid in a protic solvent;
e) cooling the reaction mixture; and
f) isolating pure Chlorzoxazone (1)

In another embodiment the present invention also provides a process for removing the impurities 4-chloro-2-nitrophenol (impurity A), 4-chloro-2-aminophenol (impurity B), 2-amino phenol (impurity C) and benzo[d]oxazol-2(3H)-one (impurity D).
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates the X-Ray powder diffraction pattern (XRPD) of Chlorzoxazone (1).
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the present invention provides an improved process for the synthesis of Chlorzoxazone (1) with purity greater than 99.0% by HPLC as illustrated in scheme 1.
Step a) proceeds with reacting 4-chloro-2-nitrophenol (4) with sodium dithionite in a suitable protic solvent to form 4-chloro-2-aminophenol (3). The reaction may be carried out at a temperature of 20-40 °C preferably 25-40 °C and more preferably 25-35 °C. Though many methods are existed in the prior art for the conversion of nitro functionality to amino functionality, they have significant drawbacks in terms of toxicity and requirement of inert medium. In the present invention, innovators have used sodium dithionite which is nontoxic and doesn't require any strict anhydrous conditions which means the reaction can take place in water.
Step b) proceeds with reacting 4-chloro-2-aminophenol (3) with triphosgene (2) in a suitable aprotic solvent in the presence of suitable base to form 5-chloro benzo[d]oxazol-2(3H)-one (1). The reaction may be carried out at a temperature of

-5 to 10 °C preferably -5 to 5 °C and more preferably -5 to 0 °C. On completion of the reaction, the pH was adjusted to 7-8 by using a suitable acid. In the present invention, the innovators have used triphosgene which is a safer substitute for phosgene to handle on large scale. And the present innovators also provided the compound 5-chloro benzo[d]oxazol-2(3H)-one (1) with purity greater than 99.0%. Further, the present invention discloses purification method for the removal of impurity which is advantageous over prior art, as the formation of 2-chloro aminophenol (impurity C) may carry forward to next stages which eventually convert into benzo[d]oxazol-2(3H)-one (impurity D). This may affect the quality of the final compound Chlorzoxazone (1).
In another embodiment, the present invention provides a purification of crude Chlorzoxazone (1) comprising:
a. providing a solution of Chlorzoxazone (1) in a suitable protic solvent;
b. treating with neutral charcoal;
c. isolating solid Chlorzoxazone (1);
d. dissolving the solid in a protic solvent;
e. cooling the reaction mixture; and
f. isolating pure Chlorzoxazone (1).
The said purification can be carried out at a temperature of 40-60 °C preferably 40-50 °C and more preferably 40-45 °C.
The suitable protic solvents used in the present invention can be selected from the group comprising of methanol, ethanol, isopropanol, water or the like preferably methanol, water were used in the present invention.
The suitable aprotic solvents used in the present invention can be selected from the group comprising of tetrahydrofuran, dichloromethane, ethyl acetate, dichloro ethane or the like preferably dichloromethane was used in the present invention.
The suitable bases used in the present invention can be selected from the group comprising of sodium hydride, triethylamine, N,N-diisopropylethyl amine, 4-

dimethylamino pyridine or the like preferably triethylamine was used in the present invention.
The suitable acid used in the present invention can be selected from the group comprising of hydrochloric acid, hydrobromic acid, methane sulfonic acid, toluene sulfonic acid, trifluoro acetic acid preferably hydrochloric acid was used in the present invention.
The Chlorzoxazone (1) obtained after purification is having purity greater than 99.0 % by HPLC. In one embodiment, Chlorzoxazone (1) obtained after purification is having total impurities less than 1.0% (w/w) and each individual impurity less than 0.15% (w/w). which are represented as 4-chloro-2-nitrophenol (impurity A), 4-chloro-2-aminophenol (impurity B), 2-amino phenol (impurity C) and benzo[d]oxazol-2(3H)-one (impurity D).

The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.
EXAMPLES EXAMPLE 1 Preparation of 2-amino-4-chlorophenol (3)
4-chloro-2-nitrophenol (4) (100 g) was added to water (1300 mL) at 20-25 °C. Sodium dithionite (400 g) was added to the reaction mass at 20-25 °C and allowed to stir for 5-6 h at 25-35 °C. Methanol (500 mL) and sodium dithionite (103 g, 0.591 mol) were added and stirred for 1-1.5 h at 25-35 °C. Methanol was distilled off completely under vacuum at 45-50 °C. The reaction mass was cooled to 20-25 °C, stirred for 35-40 min and filtered. The obtained solid was dried to afford 2-amino-4-chlorophenol (3).
Yield: 54.0 %; Purity :96.0%.

EXAMPLE 2
Preparation of 5-chlorobenzo[d]oxazol-2(3H)-one (1)
4-chloro-2-aminophenol (3) (100 g, 0.696) was dissolved in dichloromethane (9O0 mL) at 20-25 °C. The reaction mass was cooled to 0-5 °C and triphosgene (2) (82.6 g, 0.278 mol) in dichloromethane (750 mL) was added slowly for 20-30 min at 0 °C, stirred for 30 min. The reaction mixture was further cooled to 0 to -5 °C and triethylamine (580 mL) was added slowly for 2-3 h at -5 to 0 °C. The reaction mass was heated to 20-25 °C and stirred for 1-1.5 h. On completion of the reaction, water was added and cooled to 0-5 °C. The pH was adjusted to 7.5-7.8 by using 50% of hydrochloric acid solution. The reaction mixture was stirred for 30-40 min at 5-10 °C and filtered. The obtained solid was washed with water and dried to afford 5-chlorobenzo[d]oxazol-2(3H)-one (1).
Yield: 89. %; Purity: 98.0%.
EXAMPLE 3
Purification of 5-chlorobenzo[d]oxazoI-2(3H)-one (1)
Crude 5-chlorobenzo[d]oxazol-2(3H)-one (1) (100 g) was dissolved in methanol (2500 mL) at 20-25 °C. Neutral carbon (10 g) was added and stirred for 30 minutes at 20-25 °C. The reaction mass was filtered through Hyflo and washed with methanol. The obtained filtrate was filtered through micron filter. The filtrate was distilled off under vacuum. The obtained compound was dissolved in 10 volumes of water and cooled to 25-30 °C for 30-60 min. The solid so obtained was filtered, washed with water and dried under vacuum to yield pure 5-chlorobenzo[d]oxazol-2(3H)-one (1) in crystalline form. Yield: 97.0 %; Purity: 99.9%.

EXAMPLE 4
Alternative process for the purification of 5-chlorobenzo[d]oxazol-2(3H)-one
(1)
Crude 5-chlorobenzo[d]oxazol-2(3H)-one (1) (100 g) was dissolved in methanol (2500 mL) at 20-25 °C. Neutral carbon (10 g) was added and stirred for 30 minutes at 20-25 °C. The reaction mass was filtered through Hyflo and washed with methanol and water mixture. The obtained filtrate was filtered through micron filter. The filtrate was distilled off under vacuum. The obtained compound was dissolved in 10 volumes of mixture of 9: 1 water and methanol and cooled to 25-30 °C. The solid so obtained was filtered, washed with water and dried under vacuum to yield pure 5-chlorobenzo[d]oxazol-2(3H)-one (1) in crystalline form. Yield: 97.0 %; Purity: 99.9%.

We claim:
1. A process for the preparation of Chlorzoxazone (1) having purity greater
than 99.0% comprising:
a) reducing chloro-2-nitrophenol (4) with sodium dithionite in a protic solvent to form 4-chloro-2-aminophenol (3); and
b) reacting 4-chloro-2-aminophenol (3) with triphosgene (2) in an aprotic solvent in the presence of a base to form 5-chloro benzo[d]oxazol-2(3H)-one (1).
c) purifying 5-chloro benzo[d]oxazol-2(3H)-one (1).

2. The process according to claim 1, wherein step a) the protic solvent is selected from methanol, ethanol, isopropanol, water and mixtures thereof.
3. The process according to claim 1, wherein step b) the aprotic solvent is selected from tetrahydrofuran, dichloromethane, ethylacetate, dichloroethane and the mixtures thereof.
4. The process according to claim 1, wherein step b) the base is selected from sodium hydride, triethylamine, N, N-diisopropylethyl amine, 4-dimethylamino pyridine.
5. A process for the purification of Chlorzoxazone (1), which comprises the steps of:
a. providing a solution of Chlorzoxazone (1) in a protic solvent;
b. treating with neutral charcoal;
c. isolating solid Chlorzoxazone (1);
d. dissolving the solid in a protic solvent;
e. cooling the reaction mixture; and
f. isolating pure Chlorzoxazone (1).
6. The process according to claim 5, wherein step a), step d) the protic solvent is selected from methanol, ethanol, isopropanol, water.
7. The process according to claim 5, Chlorzoxazone (1) obtained having purity greater than 99.0% and characterized by one or more of the following:
a. Less than 0.05% of 2-chloro aminophenol (impurity C); and

b. Less than 0.05% of benzo[d]oxazol-2(3H)-one (impurity D).