FIELD OF INVENTION
The present invention generally relates to the preparation of isoxazolyl penicillins and more specifically relates to an in-situ preparation of acid chloride of 3-phenyl-5-methyl-isoxazole derivatives formed as an intermediate during the preparation of isoxazolyl penicillin derivatives.
BACKGROUND OF INVENTION
Isoxazolyl penicillins are active against infections caused by susceptible gram-positive bacteria. They are narrow spectrum beta-lactam antibiotics belonging to the penicillin family and are used extensively for anti-bacterial formulations.
Pharmaceutical industry is often posed by a major challenge to develop a process of preparation of chemical compounds which balances the efficiency and cost-effectiveness at industrial scale. Thus, preparationof a pharmaceutical compound having considerable purity and yield particularly for Isoxazolyl penicillins is often a technically challenging task.
Many processes in the prior art have been probed for the production of isoxazolyl penicillin derivatives such as oxacillin, cloxacillin, dicloxacillin or flucloxacillin. Generally, the preparation methods for isoxazolyl penicillins is a multi step process which involves the preparationof an intermediate i.e. carbonyl chloride of 3-phenyl-5-methyl-4-isoxazole-carboxylic acid derivative in the first reaction step which is subsequently followed by a second step for condensation of the intermediate. Theintermediate formed in the first step is isolated from the reaction mixture and crystallized in the presence of an organic solvent.This crystallized compound is further dissolved in an ester and reacted with 6-amino penicillanic acid.
The major challenge faced during this process isitscost-effectiveness.The industrial scale production of these compounds entails greater investment attributable to a multi-step chemical process. This multi step process involves production of an intermediate followed by its addition of an organic solvent to commence the purification and crystallization procedure. Filtration and crystallization procedure is an extensive and a time consuming process. The intermediate compound is isolated from the reaction mixture and crystallized. The pure crystals of this intermediate are dissolved in an organic solvent to initiate the final step of the isoxazolyl penicillin synthesis. This multi step process demands an increased cost of production primarily due to isolation and complex purification methods employed for the intermediate.
As a further disadvantage of this multistep process, the intermediate i.e. carbonyl chloride of 3-phenyl-5-methyl-4-isoxazole-carboxylic acid derivativeis a highly corrosive compoundand tends to react with the moisture present in the atmosphere. Consequently, the yield of the intermediate is lowered during itspurification and crystallization since it converts to its corresponding acid upon contact with the moisture present in the atmosphere.Moreover, the solubility of the intermediate in the solvents used for purification methods further lower the yield, as some of the intermediate stays dissolved in the mother liquor and cannot be recovered upon multiple extractions also. Thus, the purification and crystallization proceduresrequire optimum reaction conditions which should reduce any contact with moisture and also maintain a temperature and pressure regulated environment.
Another drawback of this traditional method of preparation of isoxazolyl penicillin derivatives is the use of hexane as an organic solventfor the crystallization of the intermediate. As known in the literature, hexane is a flammable compound and is a potential environmental hazard. The use of hexane for the purification of the intermediate poses difficulty in handling due to its flammable nature.
The traditional industrial scale methods of production of isoxazolyl penicillins incur high capital costs as they generally require the use of machinery/equipment namely but not limited to sparkler filter, centrifuge/ agitated nutch filter, dryer and solvent distillation system. It is further mentioned that if the processes vide the prior art were to be used, all or most of the above machinery/equipment will need to be used thereby increasing running expenditure on the bulk production of the named products. It is classified here, that the improvements are not limited to just the factors as mentioned herein.
Therefore, there remains a need for improvements in the art for an efficient and cost effective process for the preparation of isoxazolyl penicillin derivatives.
OBJECT OF INVENTION
It is an object of the invention to provide an improved process for the preparation of isoxazolyl penicillin derivatives having formula (I).

Formula (I)

wherein X1 and X2 can be independently selected from the group comprising but not limited to hydrogen, chlorine or fluorine, and its pharmaceutically suitable salts.
It is still another object of the invention to provide a cost-effective method of preparation of isoxazolyl penicillin derivatives having formula (I).
SUMMARY
The invention relates to an improved process for the preparation of isoxazolyl penicillin derivatives which involves an in-situ preparation of an intermediate, i.e an acid chloride of 3-phenyl-5-methyl-isoxazole derivative having formula (III)

Formula (III)
wherein X1 and X2 can be independently selected from the group comprising but not limited to hydrogen, chlorine or fluorine, further adding ethylacetate and condensing with 6-aminopenicillanic acid in the presence of a base followed by treatment with a saturated salt solution and crystallisation; filtering the resulting reaction mixture; anddrying in a temperature regulated environment.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 illustrates a flow chart for the filtration procedure according to one embodiment of the present invention
FIG. 2 illustrates a flow chart for the drying procedure according to another embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The various aspects of the present invention leading to an improved process for the preparation of isoxazolyl penicillin derivatives are detailed below.
The present invention relates to an improved process for preparation of isoxazolyl penicillins having formula (I), which involves an in-situ preparation of an intermediate, i.e an acid chloride of 3-phenyl-5-methyl-isoxazole derivative having formula (III). The term "in situ" is defined herein as performing two or more reaction sequences without isolating any of the intermediate that is produced during the reactionsequence. One aspect of the invention involves a method for producing the compound having formula (I) in situ, comprising
a) preparing an acid chloride of formula (III) and dissolving it in an ester,
b) adding acid chloride solution from step (a) to abasic solution of 6-aminopenicillanic acid, followed by addition ofa saturated salt solution,
c) crystallization with sodium-2-ethyl hexanoate,
d) filteringfollowed by washing; and
e) drying the wet material in a temperature controlled environment.
In an embodiment of the invention, the ester used in step (a) is selected from but not limited to ethylacetate, methylacetate or mixtures thereof or any acetate immiscible with water.
As used herein and if not otherwise stated the term a salt of isoxazolyl penicillin derivatives specifically comprising from the group oxacillin, cloxacillin, dicloxacillin or flucloxacillin includes a salt of oxacillin, cloxacillin, dicloxacillin or flucloxacillin with different cations, for example alkali or earth alkali cations, such as sodium, potassium or magnesium, preferably sodium. Such salts may be obtained using salifying compounds such as but not limited to sodium-2-ethylhexanoate.
In a preferredembodiment of the invention, sodium salt of derivatives of isoxazolyl penicillins selected from the group comprising oxacillin, cloxacillin, dicloxacillin or flucloxacillin are prepared in-situ from benzaldehyde derivatives as the starting material to result into corresponding acid chloride of 3-phenyl-5-methyl-isoxazole derivatives having a formula (III). This compound of formula (III) is directly dissolved in an ester, preferably ethylacetate without its isolation, purification or crystallization. The acid chloride intermediate is condensed with a basic solution of 6APA. Alternatively, compound of formula (III) can also be isolated from the reaction mixture and then transferred to a reaction vessel where dissolution in an ester preferably ethylacetate is followed by condensation with 6APA.The organic layer is separated from the reaction mixture. The combined extracts are then washed with brine and sodium-2-ethyl hexanoate is added to yield sodium salt of the isoxazolyl penicillin which is followed by filtration and drying procedures to obtain sterile and oral, purified isoxazolyl penicillin derivative.
Condensation of the intermediate i.e. acid chloride of 3-phenyl-5-methyl-isoxazole derivatives having formula (III) with 6APA is done in the presence of an ester, wherein step (a)is performed in situ. In this aspect of the invention, compound of formula (III) is not purified and isolated as a white crystalline compound. In comparison to an in-situ process, the traditional methodsfor preparation of compound (I) have notyielded the expected results due to the drawbacks associated with the solvents used and low yield of the intermediate. In addition, there is an economic advantage to combining multiple reaction steps without having to isolate each of compounds that is produced.
The improvement of the present process over the traditional methodsisin that the reaction can be carried out without isolating the intermediate at any stage i.e. reaction can be carried out in an in-situ manner, which is very useful on commercial scales. It incurs less capital costs since the cost of equipments / machinery used otherwise for purification of the intermediate iscompletely eliminated.
The intermediate consists of a highly reactive acid chloride functional group which is highly susceptible to conversion to an acid upon contact with water present in the atmosphere. Such a reactive intermediate when isolated and purified renders greater disadvantage of getting converted to an acid, thereby affecting the yield and purity of the final product. One of ordinary skill in the art would readily appreciate that there is considerable merit in the process wherein this intermediate is not isolated and the reaction is taken forward by directly proceeding with the next reaction step.
Furthermore, as described in the embodiment, the intermediate doesnot entail any purification procedure which involves the use of toxic and highly flammable organic solvents such as hexane. In the widely used processes for the production isoxazolyl penicillins, hexane is found to be the most appropriate solvent for the purification of the said intermediate. In comparison, the in-situ process which embodies the present invention completely eliminates the use of hexane since the purification step is discarded and the reaction is directly advanced by immediately proceeding with the subsequent reaction step i.e. dissolution in an ester prior to condensing with 6-APA.Consequently, the process is less polluting and hence eco-friendly.
In the detailed description of the invention, numerous specific details are described to provide a thorough understanding of the various embodiments of the invention. However, one skilled in the relevant art will recognize that an embodiment of the invention can be practiced without one or more of the specific details, or with other apparatus, systems, assemblies, methods, components, materials, parts, and/or the like.
The compounds of Formula (I) of this invention may be prepared by methods that include processes known in the prior arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of Formula I of this invention are illustrated by the following reaction scheme. Other processes are described in the experimental section. Some of the starting compounds for the reactions described in the schemes and Examples are prepared as illustrated herein.
Scheme I

In another embodiment of the invention, the filtration and drying methods as illustrated by flow charts in FIG.1 and FIG.2, used for the preparation of isoxazolyl penicillin derivatives provide considerable enhancement in the output efficacy. Filtration and drying method used hereinis a temperature sensitive procedure since it may result indecomposition of the final productat high temperature.In accordance with invention, sterile filters are used to maintain the sterility of the pharmaceutical compound, where sterile product is required.Filtration of the final product is carried out under vacuum in an agitated nutch filter. The solution as obtained after solvent extraction is subject to an inert environment.Vacuumis applied to the chamber which results into separation of the mother liquor leaving behind a precipitate. The precipitateis washed with solvent to expel any further impurities. This wet precipitate corresponds to crude compound which is further subject to drying in a temperature regulated environment.
Thewet precipitate isexposed to mechanical stress by using a constant stirring mechanism at anelevated temperature under reduced pressure, thereby allowing the residual solventto evaporate from the reaction mediumand resulting into a substantially pure isoxazolyl penicillin derivative. Also, the solvent recovered from the system can be recycled and hence, this procedure is an environment friendly method.Furthermore, since drying is carried out under reduced pressure wherein the drying temperature and agitated nutch filtration time are kept low, the final product is improvedin quality characteristics such as purity. Alternatively, the wet precipitate obtained after filtration from an agitated nutch filter can be isolated and processes such as vacuum drying, tray drying etc can be employed for drying purposes. Such filtration and drying procedures are efficient since these can be appliedfororal grade of medicines.
The filtration and drying procedures employed for the preparation of isoxazolyl penicillin derivatives as explained in the present invention can be better understood in connection with the following flow charts. FIG. 1 illustrates theflow chart for filtration procedure, while FIG. 2 shows a flow chart about the drying techniquein accordance with the present invention.
Isoxazolyl penicillin derivatives obtained from the above process have also shown to have lower concentration of solvents present as an impurity in the final product.
The method for preparation of isoxazolyl penicillins as described in various embodiments of the present invention is achieved byan in-situ preparation of an intermediate, i.e an acid chloride of 3-phenyl-5-methyl-isoxazole derivative having formula (II), conferring high purity without the loss of the intermediate during its isolation, purification and crystallization procedure. As a consequence, there is a considerable improvement in the process efficacy in contrast to the preparation methods already available in the prior art.Also, the industrial applicability of the process as described herein is enhanced significantly since it can be easily set up at an industrial scale without the use of complex purification methods or equipments, which thereby increase the efficiency and substantially reducethe cost of industrial production.
While the present invention has been described in terms of their specific embodiments, certain modifications in the process of the subject compound including specially designed equipments used are intended to be included within the scope of the present invention.
The foregoing technique has been found to be markedly efficient and efficacious, both from commercial point ofview, as well as from manufacturing point ofview, and affords good quality of isoxazolyl penicillin derivatives of the formula (I). Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention within the scope of disclosure.
Several variations in the processes and the methods herein disclosed will suggest themselves to those skilled in the art. However, it is to be understood that the present disclosure relates to the preferred embodiment of the invention which is for purposes of illustration only and not to be construed as limiting the scope of the invention.
EXAMPLES:
Example 1
Preparation of Cloxacillin sodium
O-chlorobenzaldehyde(850g) is dissolved in methanol(2.5-2.6L) at room temperature.Hydroxylamine salt(516g) was added and the reaction mixture was heated to 38-40ºC for 1 hour followed byaddition of sodium carbonate (460-470g). The pH is maintained at around 9.5 and the reactionmixture is cooled to room temperature. Triethylamine (4g) is added and chlorine gas (510-520g) is passed for 24hrsby maintaining a temperature of 0-5ºC. Nitrogen gas is purged for 4-5 hrs. After the completion of the chlorination reaction, methanol (575L) is added followed by addition of sodium carbonate (750-780g) to reach a pH of around 7-7.5. Methylacetoacetate (686g) and soda ash (50-100g) is added to the reaction mixture till an exothermic reaction is achieved. The solution thus obtained was hydrolysed by the addition of caustic flakes (460g). Sulphuric acid was added and the pH was adjusted to around 8.6-8.8. Organic impurities are extracted in solvent , acid is isolated dried , added in Toluene (about 3.5), its Phosphorous pentachloride (540g app.) was added with constant stirring.After reaction is over , organic layer is washed with water, Toluene recovered under reduced pressure .To this resulting solution of 3-(2-chlorophenyl)-5-methyl-4-isoxazole-carbonyl chloride, ethyl acetatewas added. 6-aminopenicillanic acid (300g) was dissolved in ammonium hydroxide (260-270mL) and pH was adjusted to 7.0-9.0.This solution was then added to the reaction solution containing 3-(2-chlorophenyl)-5-methyl-4-isoxazole-carbonyl chloride (377g) and the pH was maintained to be around 2.0-2.3. Common salt (100g) was added with constant stirring and the layers were allowed to settle. Organic layers were separatedand the combined extracts were then washed with brinefollowed by addition of sodium-2-ethyl hexanoate (590-630g) while maintaining the pH at7.8-8.1. The solution was then subject to filtration and washed with organic solvent under reduced pressure and nitrogen gas atmosphere.The wet precipitate was then subject to vacuum drying to yield sodium salt of 6-[[3-(2-chlorophenyl)-5-methyl-1,2-oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (cloxacillin sodium).
Example 2
Preparation of Dicloxacillin sodium
2,6-dichlorobenzaldehyde (850g) is dissolved in methanol (2.5-2.6L) at room temperature. Hydroxylamine salt (400-425g) was added and the reaction mixture was heated to 38-40ºC for 1 hour followed by addition of sodium carbonate (350-460g). The pH is maintained at around 9.5 and the reaction mixture is cooled to room temperature. Triethylamine (4g) is added and chlorine gas (approx. 400g) is passed for 24hrs by maintaining a temperature of 0-5ºC. Nitrogen gas is purged for 4-5 hrs. After the completion of the chlorination reaction, methanol (approx. 1000ml) is added followed by addition of sodium carbonate (700gm app.) to reach a pH of around 7-7.5. Methylacetoacetate (approx. 550g) and soda ash (25-50g) is added to the reaction mixture till an exothermic reaction is achieved. The solution thus obtained was saponified by the addition of caustic flakes (340-375g). Sulphuric acid was added and the pH was adjusted to around 8.6-8.8. Organic impurities are extracted in solvent , acid is isolated dried, added in Toluene(about 3.5mL) lts Phosphorous pentachloride (540gm app) was added with constant stirring. After reaction is over, organic layer is washed with water, Toluene recovered under reduced pressure To this resulting solution of 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazole-carbonyl chloride, ethyl acetate was added. 6-aminopenicillanic acid (300g) was dissolved in ammonium hydroxide (260-270mL) and pH was adjusted to 7.0-8.0. This solution was then added to the reaction solution containing 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazole-carbonyl chloride (411g)and the pH was maintained to be around 2.0-3.0. Common salt (100g) was added with constant stirring and the layers were allowed to settle. Organic layers were separated and the combined extracts were then washed with brine followed by addition of sodium-2-ethyl hexanoate (590-630g) while maintaining the pH at 7.0-9.0. The solution was then agitatedand cooled to 0 to 5ºC. The resulting precipitate was filteredand washed with organic solvent under reduced pressure, and nitrogen gas atmosphere. The wet precipitate was then subject to vacuum drying to yield sodium salt of 6-[[3-(2,6-chlorophenyl)-5-methyl-1,2-oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (dicloxacillin sodium).
Example 3
Preparation of Flucloxcillin sodium
2-chloro-6-fluorobenzaldehyde (850g) is dissolved in methanol (2.5-2.6L) at room temperature. Hydroxylamine salt (475-500 g) was added and the reaction mixture was heated to 38-40ºC for 1 hour followed by addition of sodium carbonate (460-500g). The pH is maintained at around 9.5 and the reaction mixture is cooled to room temperature. Triethylamine (4g) is added and chlorine gas (400-500g) is passed for about 24hrs by maintaining a temperature of 0-5ºC. Nitrogen gas is purged for 4-5 hrs. After the completion of the chlorination reaction, methanol (approx 1000L) is added followed by addition of sodium carbonate (about 600g) to reach a pH of around 7-7.5. Methylacetoacetate (500-550g) and soda ash (25-50g) is added to the reaction mixture till an exothermic reaction is achieved. The solution thus obtained was saponified by the addition of caustic flakes (about 460g). Sulphuric acid was added and the pH was adjusted to around 8.6-8.8. Organic impurities are extracted in solvent , acid is isolated dried , added in Toluene(about 3.5) then Phosphorous pentachloride (about 540g) was added with constant stirring. After reaction is over , organic layer is washed with water , Toluene recovered under reduced pressure.To this resulting solution of 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole-carbonyl chloride, ethyl acetate was added. 6-aminopenicillanic acid (300g) was dissolved in ammonium hydroxide (260-270mL) and pH was adjusted to 7.0-9.0. This solution was then added to the reaction solution containing 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole-carbonyl chloride (399g) and the pH was maintained to be around 2.0-2.3. Common salt (100g) was added with constant stirring and the layers were allowed to settle. Organic layers were separated and the combined extracts were then washed with brine followed by addition of sodium-2-ethyl hexanoate (590-630g) while maintaining the pH at 7.8-8.1. The solution was then agitated and cooled to 0 to 5ºC. The resulting precipitate was filtered under reduced pressure and nitrogen gas atmosphere. The wet precipitate was then subject to vacuum drying to yield sodium salt of 6-[[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (flucloxacillin sodium).
Example 4
Preparation of Oxacillin sodium
Benzaldehyde (850g) is dissolved in methanol (4-5 L) at room temperature. Hydroxylamine salt (516-550 g) was added and the reaction mixture was heated to 38-40ºC for 1 hour followed by addition of sodium carbonate (approx450-500g). The pH is maintained at around 9.5 and the reaction mixture is cooled to room temperature. Triethylamine (4g) is added and chlorine gas (510-520g) is passed for 24hrs by maintaining a temperature of 0-5ºC. Nitrogen gas is purged for 4-5 hrs. After the completion of the chlorination reaction, methanol (approx. 1000mL) is added followed by addition of sodium carbonate (425-450g) to reach a pH of around 7-7.5. Methylacetoacetate (686gapp) and soda ash (25-50g) is added to the reaction mixture till an exothermic reaction is achieved. The solution thus obtained was saponified by the addition of caustic flakes (approx. 460g). Sulphuric acid was added and the pH was adjusted to around 8.6-8.8. Organic impurities are extracted in solvent , acid is isolated dried , added in Toluene(about 3.5 lts) Phosphorous pentachloride (approx540g) was added with constant stirring. After reaction is over, organic layer is washed with water , Toluene recovered under reduced pressure.To this resulting solution of 3-phenyl-5-methyl-4-isoxazole-carbonyl chloride, ethyl acetate was added. 6-aminopenicillanic acid (300g) was dissolved in ammonium hydroxide (260-270mL) and pH was adjusted to 7.0-9.0. This solution was then added to the reaction solution containing 3-(2-chlorophenyl)-5-methyl-4-isoxazole-carbonyl chloride (336g) and the pH was maintained to be around 2.0-2.3. Common salt (100g) was added with constant stirring and the layers were allowed to settle. Organic layers were separated and the combined extracts were then washed with brine followed by addition of sodium-2-ethyl hexanoate (590-630g) while maintaining the pH at 7.8-8.1. The solution was then agitated and cooled to 0 to 5ºC. The resulting precipitate was filtered under reduced pressure , washed with organic solvent and nitrogen gas atmosphere. The wet precipitate was then subject to vacuum drying to yield sodium salt of 6-[[3-phenyl-5-methyl-1,2-oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (oxacillin sodium).
CLAIMS
We Claim:
1. A process for the preparation of a compound selected from the group consisting of isoxazolyl penicillins having formula (I),

Formula (I)
and its pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from hydrogen and halogens, wherein said process comprises;
a) in-situ preparation ofintermediate of formula (III) followed by dissolution in an ester,

Formula (III)
b) condensation of acid chloride solution from step (a) with a basic solution of 6-aminopenicillanic acid, followed by addition of a saturated salt solution,
c) crystallization with sodium salt of ethyl hexanoic acid,
d) filtration at a reduced pressure and inert atmosphere,
e) drying under mechanical stress and reduced pressure and temperature.
2. The process according to claim 1, wherein saidintermediate obtained in step (a) isnotisolated from the reaction mixture.
3. The process according to claim 1, wherein said ester in step (a) is selected from the group comprising of methyl acetate, ethyl acetate, propyl acetate, iso-butyl acetate, n-butyl acetate, t-butyl acetate, methyl formate, ethyl formate, propyl formate or mixtures thereof.
4. The process according to claim 1, wherein said inert atmosphere during filtration in step d) is generated using nitrogen or a member form the inert gas family.
5. A process for the preparation of a compound selected from the group consisting of isoxazolyl penicillins having formula (I),

Formula (I)
and its pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from hydrogen and halogens, wherein the process comprises,
a) preparingan intermediate, wherein the preparation of the said intermediate is in-situ and is characterized in the steps comprising,
i. reacting corresponding benzaldehyde derivative with hydroxylamine salt, followed by addition of chlorine in the presence of triethylamine,
ii. adding an esterin the presence of sodium methoxide followed by reaction with phosphorous pentachloride or any chlorinating agent.

b) dissolving the said intermediate directly in an ester,without isolating said intermediate from the reaction mixture,
f) reaction with basic solution of 6-aminopenicillanic acid followed by addition of a saturated salt solution,
g) crystallization with sodium salt of ethyl hexanoic acid,
h) filtration at a reduced pressure and inert atmosphere,
i) drying under mechanical stress and reduced pressure and temperature.
6. The process according to claim 5, wherein said ester is selected from the group comprising of methyl acetate, ethyl acetate, propyl acetate, iso-butyl acetate, n-butyl acetate, t-butyl acetate, methyl formate, ethyl formate, propyl formate or mixtures thereof.
7. The process according to claim 5, wherein said chlorinating agent is selected from the group comprising of thionyl chloride, phosphoryl chloride or oxalyl chloride-etc
8. The process according to claim 5, wherein said inert atmosphere during filtration in step (h) is generated using nitrogen or a member form the inert gas family.
9. A process for the preparation of cloxacillin and its pharmaceutically acceptable salt thereof, wherein the process comprises
a) preparing intermediate of formula (III), where X1 is hydrogen and X2 is chlorine,

Formula (III)
wherein the preparation of the said intermediate is in-situ and is characterized in the steps comprising,
i. reacting o-chlorobenzaldehyde with hydroxylamine salt at a pH range of 9 to 10,
ii. passing chlorine gas in the presence of triethylamine in an inert atmosphere at a temperature range of from about -10 ºC to 10 ºC, preferably 0 ºC to 5 ºC,
iii. adding methylacetoacetate in the presence of sodium methoxide,
iv. adding phosphorous pentachloride and thionyl chloride under vacuum
b) dissolving the said intermediate directly in an ester, without isolating said intermediate from the reaction mixture,
c) reaction with basic solution of 6-aminopenicillanic acid followed by addition of a saturated salt solution,
d) crystallization with sodium salt of ethyl hexanoic acid,
e) filtration at a reduced pressure and inert atmosphere,
f) drying under mechanical stress and reduced pressure and temperature.

10. The process according to claim 8, wherein said ester is selected from the group comprising of methyl acetate, ethyl acetate, propyl acetate, iso-butyl acetate, n-butyl acetate, t-butyl acetate, methyl formate, ethyl formate, propyl formate or mixtures thereof.
11. The process according to claim 8, wherein reaction of o-chlorobenzaldehyde with hydroxylamine salt in step (i) is carried out and at a temperature range of from about 30 ºC to 50 ºC, preferably 35 ºC to 45 ºC.
12. The process according to claim 8, wherein said inert atmosphere is generated using nitrogen or a member from the inert gas family.