FORM 2 THE PATENTS ACT, 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
Title: “Novel process for the preparation of Formula
(II) and Preparation of Retapamulin therefrom”.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of
compound of formula (II). More particularly, the present invention
relates to economically and commercially viable process for the
preparation of compound of formula (II) from Pleuromutilin of formula
(I). Compound of formula (II), also known as halopleuromutilin, is
further used as a starting material in preparation of Retapamulin of
formula (III). Retapamulin of formula (III) is a class of pleuromutilin
derivative and used in the treatment of secondarily infected traumatic
lesion (SITL).


Halopleuromutilin-Compound of formula (II) is claimed as a product in US3979423 dated November 15, 1973. In US ‘423, the patent has disclosed a general formula (A) which has also covered Halopleuromutilin of formula (II). Accrodingly, US’423 patent has disclosed preparation of Chloropleuromutilin and Bromopleuromutilin of formula (II).
Further, the Patent has disclosed a process for the preparation of Halopleuromutilin of formula (II) from Pleuromutilin of formula (I) via tosyloxy derivative of Pleuromutilin. Example-1 of US’423 has described a process for the preparation of tosyloxy derivative of pleuromutilin (P).

Example-2 of US ‘423 has described a process for the preparation of
Halopleuromutilin.
According to Example-2(a), tosyloxy derivative of formula (P) of
Example-1 is further converted into chloropleuromutilin of formula (II)
(wherein R1 is Cl) using metal chloride (lithium chloride) in presence of
acetone as solvent. In a similar manner Example-2(c) has described a
process for the preparation of Bromopleuromutilin of formula (II),
wherein R1 is Br.
Thus the process for the preparation of Halopleuromutilin of formula
(II) is a 2 step process.
There are number of patent and non-patent references available for the preparation of Retapamulin of formula (III). Retapamulin of formula (III) is claimed as a product in its product Patent US6281226 (Equivalent USRE43390) having priority date of October 29, 1997 filed by Smith Kline Beecham (GB).

Another Patent US 7875630, having priority date September 3, 2003 filed by Glaxo Group Limited, has disclosed a process for the preparation of Retapamulin of formula (III).
None of the prior art reference has disclosed a single step process for the preparation of Halopleuromutilin of formula (II).
No prior art reference has disclosed a process for the preparation of Retapamulin of formula (III) from pleuromutilin of formula (I) via using Halopleuromutilin of formula (II).
There is a demand of providing process which is of single step, simple, easy to operate, economically viable process for the preparation of Halopleuromutilin of formula (II).
It is also demanded to provide simple, robust, easy to operate and commercially viable process for the preparation of Retapamulin of formula (III) from pleuromutilin of formula (I).
Further observations on prior art references and comparative data shall be provided at the time of filing complete application.
OBJECTS OF THE INVENTION
Accordingly, the main object of the present invention is to overcome
the problems faced by the prior art processes in the preparation of compound of formula (II).
It is also an object of the present invention to overcome the problems faced by the prior art processes in the preparation of Retapamulin of formula (III).
The other object of the present invention is to provide a simple, robust, easy to operate, economically viable process for the preparation of compound of formula (II).

Yet another object of the present invention is to provide a simple, robust, easy to operate, economically viable process for the preparation of Retapamulin of formula (III).
It is also an object to provide a process for the preparation of compound of formula (II) from Pleuromutilin of formula (I).
Yet there is an object to provide a process for the preparation of Retapamulin of formula (III) from Pleuromutilin of formula (I).
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows IR Spectra of 14-chloropleuromutilin of formula (II-A).
FIG. 2 shows MASS Spectra of 14-chloropleuromutilin of formula
(II-A).
FIG. 3 shows IR Spectra of 14-bromopleuromutilin of formula (II-B).
FIG. 4 shows MASS Spectra of 14-bromopleuromutilin of formula
(II-B).
FIG. 5 shows DSC of Retapamulin of formula (III).
FIG. 6 shows 1H NMR Spectra of Retapamulin of formula (III).
FIG. 7 shows MASS Spectra of Retapamulin of formula (III).
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of
Halopleuromutilin compound of formula (II). More particularly, the present invention relates to economically and commercially viable process for the preparation of compound of formula (II) from Pleuromutilin of formula (I).
Compound of formula (II), also known as Halopleuromutilin, is further used as a starting material in preparation of Retapamulin of formula (III).


The present innovators have comprehensively and successfully developed a new process for the preparation of Halopleuromutilin of formula (II) from Pleuromutilin of formula (I). Halopleuromutilin of formula (II) is further used in preparing Retapamulin of formula (III).
Halopleuromutilin of formula (II) refers to 14-choropleuromutilin of formula (II-A) and 14-bromopleuromutilin of formula (II-B).


Route of synthesis for the preparation of Halopleuromutilin of formula (II) and Retapamulin of formula (III) is shown as follows:



According to the first embodiment (scheme-2) of the present invention, there is provided a single step process for the preparation of Halopleuromutilin of formula (II) from pleuromutilin of formula (I), the process for the preparation of Halopleuromutilin of formula (II) comprises:
(i) Reacting pleuromutilin of formula (I) with triphenyl phosphine (TPP) and tetrahalo methane in an organic solvent;
(ii) removing the excess of organic solvent from reaction mixture to give Halopleuromutilin of formula (II);
There is a possibility that the said halogenation may takes place at –OH or at Double bond of formula (I) instead of 14th position i.e. –OH group of –CO-CH2-OH of the pleuromutilin of formula (I) which may lead to the product (also known as impurity) other than Halopleuromutilin of formula (II).
Inventors have surprisingly found that Triphenyl Phosphene (TPP) when reacted with pleuromutilin of formula (I) in presence of selective organic solvent, it gives Halopleuromutilin of formula (II). Thus, halogenation takes place at 14th position i.e. –OH of –CO-CH2-OH

group of pleuromutilin of formula (I) and not at –OH or double bond group.
While conducting halogenation reaction, for each 100 gms of
pleuromutilin of formula (I): (i) Triphenyl phosphine (TPP) is taken 100 gms to 300 gms,
preferably 100-200 gms, (ii) Tetrahalo methane is taken between 1 volume to 5 volumes, (iii) Organic solvent is consumed between 2 to 20 volumes.
Organic solvent used in the process may be selected from Acetonitrile, tetrahydrofuran (THF) or dichloro metane (MDC). The selection of organic solvent plays an important role in the halogenation reaction. The other solvents such as Dimethyl formamide, benzene if used in the reaction, may lead to impurity formation which again fails in converting pleuromutilin of formula (I) to Halopleuromutilin of formula (II) in good yields. Organic solvent used in the halogenation reaction is consumed between 2 to 20 volume compared to pleuromutilin of formula (I) w/w, preferably 2 to 10 volume compared to pleuromutilin of formula (I).
Tetrahalo methane used in the process is selected from Carbon tetrachloride (CCl4) or Carbon tetrabromide (CBr4).
Reaction temperature also plays a vital role in the halogenation reaction. The said halogenation reaction may be carried out at a temperature between 300C to 750C. The ideal reaction temperature is between 250C to 500C, more preferably 250C to 400C.
Halopleuromutilin of formula (II) may be obtained in yield greater than 50% when the reaction time is kept between 1 hrs to 20 hrs, more preferably 2 to 10 hrs.
Thus the said halogenation is a critical selective halogenation in which selection of organic solvent, temperature range and time for reaction

play an important role and avoid formation of impurities during the reaction.
The success of the present method depends critically on the initial presence of an alcohol to trap the intermediate phosphonium species. If the alcohol is added last, the Ph3P-CX4 reaction may go to completion, in which case little or no alkyl halide is formed. Since the reaction displays several characteristics of an SN2 process.
The reaction mechanism along with the possible impurity formation mechanism is illustrated as follows.


From the above it is clear that the selective halogenation of pleuromutilin of formula (I) with tetrahalo methane in presence of triphenyl phosphine (TPP) may give Halopleuromutilin of formula (II) with a yield greater than 50% w/w if the critical parameters like selection of organic solvent, temperature range and time for reaction are controlled appropriately.
After completion of the reaction, excess organic solvent is removed by distillation under vacuum at a temperature between 300C to 600C.
Thus in case if Carbon tetrachloride (CCL4) is used as tetrahalo methane then Chloropleuromutilin (R1 is Cl) of formula (II) may be obtained. In case if Carbon Tetrabromide (CBr4) is used as tetrahalo methane then Bromopleuromutilin (R1 is Br) of formula (II) is obtained.
The reaction takes place at selective 14-position of formula-I and thus 14-chloropleuromutilin of formula (II-A) or 14-bromopleuromutilin of formula (II-B) is obtained.
The Halopleuromutilin of formula (II) thus obtained is taken further for column purification and crystallization, if needed. Column purification is carried out using fractional column using silica gel column chromatography using hexanes or mixture of solvents such as ethylacetate:hexane, methanol:hexane, ethanol:hexane, toluene:hexanes. It is also possible to use n-heptane or n-hexane instead of hexanes in column chromatography.
Halopleuromutilin of formula (II) may also be taken for crystallization, if needed. General process for crystallization may be briefly described as follows:
Halopleuromutilin of formula (II) is dissolved in an organic solvent at a temperature between 500C to 1000C; activated charcoal is added into it and stirred for half an hour; Taken it for hot filtration over hyflo bed; anti-organic solvent is added after removing excess of organic

solvent; cooled the reaction mass to -50C to 100C and stirred till Halopleuromutilin of formula (II) precipitated out; filtered it and washed with organic solvent to give pure Halopleuromutilin of formula (II).
Crystallization process may be carried out using organic solvents selected from methanol, ethanol, isopropanol, ethyl acetate, toluene.
Anti-organic solvents may be selected from hexanes, n-hexane, n-heptane.
According to the second embodiment (Scheme-1), there is provided a process for the preparation of pure Retapamulin of formula (III) from Pleuromutilin of formula (I), the process for the preparation of pure Retapamulin of formula (III) comprises:
i. Reacting pleuromutilin of formula (I) with triphenyl phosphine (TPP) and tetrahalo methane in an organic solvent at a temperature between 250C to 400C for 2 to 10 hrs to give Halopleuromutilin of formula (II);
ii. Reacting Halopleuromutilin of formula (II) with Tropine thiol. HCl of formula (IV) in presence of organic solvent and an aqueous inorganic Base at a temperature between 400C to 600C to give crude Retapamulin of formula (III);
iii. Crystallizing crude Retapamulin to give pure Retapamulin of formula (III).
In step (i):
There is a possibility that the said halogenation may takes place at –OH or at Double bond of formula (I) instead of 14th position i.e. –OH group of –CO-CH2-OH of the pleuromutilin of formula (I) which may lead to the product (also known as impurity) other than Halopleuromutilin of formula (II).

Inventors have surprisingly found that Triphenyl Phosphene (TPP) when reacted with pleuromutilin of formula (I) in presence of selective organic solvent, it gives Halopleuromutilin of formula (II). Thus, halogenation takes place at 14th position i.e. –OH of –CO-CH2-OH group of pleuromutilin of formula (I) and not at –OH or double bond group.
While conducting halogenation reaction, for each 100 gms of
pleuromutilin of formula (I): (i) Triphenyl phosphine (TPP) is taken 100 gms to 300 gms,
preferably 100-200 gms, (ii) Tetrahalo methane is taken between 1 volume to 5 volumes, (iii) Organic solvent is consumed between 2 to 20 volumes.
Organic solvent used in the process may be selected from Acetonitrile, tetrahydrofuran (THF) or dichloro metane (MDC). The selection of organic solvent plays an important role in the halogenation reaction. The other solvents such as Dimethyl formamide, benzene if used in the reaction, may lead to impurity formation which again fails in converting pleuromutilin of formula (I) to Halopleuromutilin of formula (II) in good yields. Organic solvent used in the halogenation reaction is consumed between 2 to 20 volume compared to pleuromutilin of formula (I) w/w, preferably 2 to 10 volume compared to pleuromutilin of formula (I).
Tetrahalo methane used in the process is selected from Carbon tetrachloride (CCl4) or Carbon tetrabromide (CBr4).
Reaction temperature also plays a vital role in the halogenation reaction. The said halogenation reaction may be carried out at a temperature between 300C to 750C. The ideal reaction temperature is between 250C to 500C, more preferably 250C to 400C.

Halopleuromutilin of formula (II) may be obtained in yield greater than 50% when the reaction time is kept between 1 hrs to 20 hrs, more preferably 2 to 10 hrs.
Thus the said halogenation is a critical selective halogenation in which selection of organic solvent, temperature range and time for reaction play an important role and avoid formation of impurities during the reaction.
The success of the present method depends critically on the initial presence of an alcohol to trap the intermediate phosphonium species. If the alcohol is added last, the Ph3P-CX4 reaction may go to completion, in which case little or no alkyl halide is formed. Since the reaction displays several characteristics of an SN2 process.
The reaction mechanism for preparation of Halopleuromutilin of formula (II) along with the possible impurity formation mechanism is already illustrated in the above paragraphs.
From the above it is clear that the selective halogenation of pleuromutilin of formula (I) with tetrahalo methane in presence of triphenyl phosphine (TPP) may give Halopleuromutilin of formula (II) with a yield greater than 50% w/w if the critical parameters like selection of organic solvent, temperature range and time for reaction are controlled appropriately.
After completion of the reaction, excess organic solvent is removed by distillation under vacuum at a temperature between 300C to 600C.
Thus in case if Carbon tetrachloride (CCL4) is used as tetrahalo methane then Chloropleuromutilin (R1 is Cl) of formula (II) may be obtained. In case if Carbon Tetrabromide (CBr4) is used as tetrahalo methane then Bromopleuromutilin (R1 is Br) of formula (II) is obtained.

The reaction takes place at selective 14-position of formula-I and thus 14-chloropleuromutilin of formula (II-A) or 14-bromopleuromutilin of formula (II-B) is obtained.
The Halopleuromutilin of formula (II) thus obtained is taken further for column purification and crystallization, if needed. Column purification is carried out using fractional column using silica gel column chromatography using hexanes or mixture of solvents such as ethylacetate:hexane, methanol:hexane, ethanol:hexane, toluene:hexanes. It is also possible to use n-heptane or n-hexane instead of hexanes in column chromatography.
Halopleuromutilin of formula (II) may also be taken for crystallization, if needed. General process for crystallization may be briefly described as follows:
Halopleuromutilin of formula (II) is dissolved in an organic solvent at a temperature between 500C to 1000C; activated charcoal is added into it and stirred for half an hour; Taken it for hot filtration over hyflo bed; anti-organic solvent is added after removing excess of organic solvent; cooled the reaction mass to -50C to 100C and stirred till Halopleuromutilin of formula (II) precipitated out; filtered it and washed with organic solvent to give pure Halopleuromutilin of formula (II).
Crystallization process may be carried out using organic solvents selected from methanol, ethanol, isopropanol, ethyl acetate, toluene.
Anti-organic solvents may be selected from hexanes, n-hexane, n-heptane.
In step (ii):
Tropine-3-thiol hydrochloride of formula (IV) is readily available in the market which is taken between 80 gms to 150 gms in the reaction.

Organic solvent used in the process may be selected from Acetonitrile, ethanol, methanol or Isopropanol. Compared to Tropine-3-thiol hydrochloride, organic solvent is taken between 5 to 50 volumes as to achieve appropriate liquefied mixture during the reaction and to make the reaction mixture homogeneous which will ultimately helps in complete conversion from formula (II) to formula (III).
Inorganic base selected from NaOH, NH4OH, Na2CO3, NaHCO3 is used to prepare aqueous base. Inorganic base is consumed between 0.3 mole to 0.7 moles compared to tropine-3-thiol hydrochloride while water is taken between 10 to 50 volumes compared to inorganic base (w/w).
Temperature is kept between 400C to 600C during the reaction. The reaction is completed in 1 to 10 hrs with a yield greater than 55% w/w of Retapamulin of formula (III).
After completion of the reaction, the reaction mixture is extracted with ethyl acetate, organic layer is collected & distilled out completely at below 500C (with or without vacuum) to obtain crude Retapamulin of formula (III).
In step (iii):
Crude Retapamulin of formula (III) obtained from step (ii) is taken for crystallization. General process for crystallization may be briefly described as follows:
Retapamulin of formula (III) is dissolved in an organic solvent at a temperature between 500C to 1000C; Added activated charcoal into it and stirred for half an hour; Taken it for hot filtration over hyflo bed; Remove the excess organic solvent and add anti-solvent; cooled the reaction mass till Retapamulin of formula (III) precipitated out; filtered it and washed with organic solvent to give pure Retapamulin of formula (III).

Crystallization process may be carried out using solvents selected from water, methanol, ethanol, isopropanol (IPA), ethyl acetate, toluene.
Though use of anti-solvents is optional, it may be selected from water, hexanes, n-hexane, n-heptane. Crystallization process may be carried out at a temperature between -50C to 1000C.
Below combination (in Table-1) are the best options to give pure Retapamulin of formula (III) with ≤ 95% purity.
Table-1:

Solvent Anti-solvent Yield (w/w) Purity (By HPLC)
Isopropyl alcohol (IPA) Not required 90% Not less than 99%
IPA water 73% 97%
Water Not required 95% 95%
The present invention demonstrated examples cited below, which are provided as illustration only and therefore should not be construed as limitation of the possible and future invention.
EXAMPLES Materials and methods:
All reagents were of analytical reagent grade and were used without further purification. Solvents employed were purified by standard procedure before use.
For the purpose of preparation of the compounds of formula (II) and (III), the starting material of formula (I), reactants, catalyst, solvents are commercially available in the market. Starting materials may also be prepared using any process which is reported in the prior art.

To monitor the reactions, as well as, to establish the identity and purity of reactants and products, thin layer chromatography was performed on microscopic glass slides (2x7.5 cm) coated with silica gel-G, using ethyl acetate : hexane or ethyl acetate : heptane, as the solvent systems and spots were visualized under UV radiation.
Melting Point (M.P.), FTIR, purity by HPLC, DSC, 1H NMR, MASS has been determined as per the process known in prior art.
Example-1: Preparation of 14-chloropleuromutilin of formula (II-A) from pleuromutilin of formula (I):
In RBF, Charge Carbon tetrachloride (100ml, 1V) and Triphenyl phosphine (150gm, 0.57mole) to it at 25-30°C and heat the reaction mass at 35-45°C to get clear solution. Add solution of Pleuromutiline (100gm, 0.26mole) in acetonitrile (500ml, 5Vol) to the reaction mass and allow to stir for 2 to 3hrs., check progress of reaction using TLC & if reaction complies than distilled out solvent to get an oily mass or semisolid. Purification done by column chromatography method using silica gel and mobile phase combination of heptane and ethyl acetate 20%, 40% & 60% to get pure fractions and choose pure fraction to get 14-chloroPleuromutilin of formula (II-A). Appearance: White to off white solid powder Yield: 0.90 w/w. M.P.: 120-1250C
FTIR (KBr): -Cl at 786cm-1 (disappear of –OH peak) (Fig-1) Mol. Wt.: 396.95g/mol MASS: 303 m/z (Fig-2)
Example-2: Preparation of 14-bromopleuromutilin of formula (II-B) from pleuromutilin of formula (I):
In RBF, Charge Carbon tetrabromide (100ml, 1V) and Triphenyl phosphine (150gm, 0.57mole) to it at 25-30°C and heat the reaction mass at 35-45°C to get clear solution. Add solution of Pleuromutiline (100gm, 0.26mole) in acetonitrile (500ml, 5Vol) to the reaction mass

and allow to stir for 2 to 3hrs., check progress of reaction using TLC & if reaction complies than distilled out solvent to get an oily mass or semisolid. Purification done by column chromatography method using silica gel and mobile phase combination of heptane and ethyl acetate 20%, 40% & 60% to get pure fractions and choose pure fraction to get 14-bromo Pleuromutiline of formula (II-B). Appearance: White to off white solid powder Appearance: White to off white solid powder Yield: 0.92 w/w. M.P.: 90-950C
FTIR (KBr): -Br at 720 cm-1 (disappear of –OH peak) (Fig-3) Mol. Wt.: 441.40 g/mol MASS: 303 m/z (Fig-4)
In a similar manner the below compounds (Table-2; example 3 to 10) were also prepared by controlling critical parameters such as selection of organic solvent, time required for reaction.
Remarks show the effect of the critical parameters on the reaction as well as on yield of Halopleuromutilin of formula (II).
Table-2:

Example No. Tetrahalo methane Organic Solvent Time
for
reaction Remarks (Yield (w/w)
1 CCl4 Acetonitrile 3hr clean reaction 0.90
2 CBr4 Acetonitrile 3hr clean reaction 0.92
3 CCl4 Dichlromethane (MDC) 12hr impurity formed 0.52
4 CCl4 Acetonitrile-dichloromethane 20hr impurity formed 0.45
5 CCl4 Dimethyl formamide-Benzene 24hr impurity formed 0.25
6 CCl4 Tetrahydro furan (THF) 4hr impurity formed 0.55
7 CBr4 MDC 14hr impurity formed 0.56
8 CBr4 Acetonitrile-MDC 20hr impurity formed 0.48
9 CBr4 Dimethyl formamide-Benzene 24hr impurity formed 0.32
10 CBr4 THF 4hr impurity formed 0.49

Example-11: Preparation of crude Retapamulin of formula (III):
In RBF, charge Tropine-3-thiol hydrochloride (100gm, 0.51mole) and Water (400ml, 4V) at room temperature and stir to get homogeneous solution. Add solution of sodium hydroxide (20gm, 0.5mole) in water (100ml, 1V) to the reaction mass. Charge solution of 14-chloropleuromutilin (0.56mole) of formula (II-A) in Ethanol (1125ml, 5V) to the reaction mass and heat to get dissolved at 50-55°C. allow to stir for 2hr. after completion of the reaction charge Ethyl acetate (2250, 10V) to the reaction mass and do layer separation, collect organic layer & distilled off to get solid material as crude Retapamulin as white to yellowish solid. Yield: 0.98w/w
Example-12: Preparation of crude Retapamulin of formula (III):
In RBF, charge Tropine-3-thiol hydrochloride (100gm, 0.51mole) and Water (400ml, 4V) at room temperature and stir to get homogeneous solution. Add solution of sodium hydroxide (20gm, 0.5mole) in water (100ml, 1V) to the reaction mass. Charge solution of 14-bromopleuromutilin (0.56mole) of formula (II-B) in Ethanol (1125ml, 5V) to the reaction mass and heat to get dissolved at 50-55°C. allow to stir for 2hr. after completion of the reaction charge Ethyl acetate (2250, 10V) to the reaction mass and do layer separation, collect organic layer & distilled off to get solid material as crude Retapamulin as white to yellowish solid. Yield: 0.98w/w
Example-13: Preparation of crude Retapamulin of formula (III):
In RBF, charge Tropine-3-thiol hydrochloride (100gm, 0.51mole) and Water (400ml, 4V) at room temperature and stir to get homogeneous solution. Add solution of sodium hydroxide (20gm, 0.5mole) in water (100ml, 1V) to the reaction mass. Charge solution of 14-chloropleuromutilin (0.56mole) of formula (II-A) in IPA (1125ml, 5V) to the reaction mass and heat to get dissolved at 50-55°C. allow to stir for 2hr. after completion of the reaction charge Ethyl acetate (2250,

10V) to the reaction mass and do layer separation, collect organic layer & distilled off to get solid material as crude Retapamulin as white to yellowish solid. Yield: 0.79
Example-14: Preparation of crude Retapamulin of formula (III):
In RBF, charge Tropine-3-thiol hydrochloride (100gm, 0.51mole) and Water (400ml, 4V) at room temperature and stir to get homogeneous solution. Add solution of sodium hydroxide (20gm, 0.5mole) in water (100ml, 1V) to the reaction mass. Charge solution of halo-pleuromutilin (0.56mole) of formula (II) [selected from either Formula (II-A) or (II-B)] in Ethyl acetate (1125ml, 5V) to the reaction mass and heat to get dissolved at 50-55°C. allow to stir for 2hr. after completion of the reaction charge Ethyl acetate (2250ml, 10V) to the reaction mass and do layer separation, collect organic layer & distilled off to get solid material as crude Retapamulin as white to yellowish solid. Yield: 0.71w/w
Example-15: Purification of crude Retapamulin of formula (III):
In RBF, crude Retapamulin (100gm) dissolved in Iso propyl alcohol (400ml) and heat to get clear solution, micron filter and collect filter ml. charge and cool to 0-5°C for 2hr to get white crystalline solid material. Filter it and give wash of IPA, suck dry to get solid material. Dry at 40-45°C to get solid material Retapamulin as white solid. Yield: 0.90w/w.
M.P.: (by DSC): 1290C (Range: 127-1320C) (Fig-5) Purity by HPLC: Not less than 99% 1H NMR: OH (4.59), CH=CH (5.031-5.097, 6.109-6.182), S-H (5.54-5.56) (Fig-6) Mol. Wt.: 517.77 g/mol MASS: M+1= 518.9 m/z (Fig-7)

ADVANTAGES OF THE INVENTION
The present invention provides a robust, easy to operate, economically & commercially viable process for the preparation of Halopleuromutilin of formula (II) and Retapamulin of formula (III) with greater yield and purity.
Further, the process for the preparation of Halopleuromutilin of formula (II) is a single step process and obviates the problems faced by the prior art.
The present invention avoids the use of hazardous chemicals and reagents and tedious, complex and lengthy reaction stages & work-up thus the present invention provides an environment friendly, non-hazardous, safe and cost-effective process for the preparation of Halopleuromutilin of formula (II) and process for the preparation of Retapamulin of formula (III) therefrom.
It will be readily apparent to a person skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.
All patents and publications mentioned in the specification are indicative of the levels of those of ordinary skill in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations, which are not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and

described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. Other embodiments are set forth within the following claims.

We claim:
1. A process for the preparation of Halopleuromutilin of formula
(II), the steps comprises:
(i) Reacting pleuromutilin of formula (I) with triphenyl phosphine (TPP) and tetrahalo methane in an organic solvent at a temperature between 250C to 400C for 2 to 10 hrs;
(ii) removing the excess of organic solvent from reaction mixture to give Halopleuromutilin of formula (II);
(iii) optionally, carrying out purification to obtain pure Halopleuromutilin of formula (II).
2. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-1 wherein tetrahalomethane is selected from tetrachloromethane (CCl4) or tetrabromomethane (CBr4).
3. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-1 wherein organic solvent is selected from Acetonitrile, tetrahydrofuran (THF) or dichloro metane (MDC).
4. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-1 wherein purification is carried out using crystallization process or column chromatography.
5. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-4 wherein crystallization is carried out by dissolving halopleuromutilin of formula (II) in organic solvent selected from methanol, ethanol, isopropanol, ethyl acetate, toluene and precipitating out it using anti-solvent selected from hexanes, n-hexane, n-heptane.
6. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-4 wherein column

chromatography is carried out using fractional column process using mixture of ethyl acetate:heptane with a ratio selected from 80:20 , 60:40 or 40:60.
7. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-1 wherein Halopleuromutilin of formula (II) is 14-Chloropleuromutilin of formula (II-A) or 14-bromopleuromutilin of formula (II-B).
8. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-1 further comprises a process for the preparation of Retapamulin of formula (III), a process for the preparation of Retapamulin of formula (III) comprises:
(i) Reacting Halopleuromutilin of formula (II) with Tropine thiol. HCl of formula (IV) in presence of organic solvent and an aqueous inorganic Base at a temperature between 400C to 600C to give crude Retapamulin of formula (III);
(ii) Crystalizing crude Retapamulin to give pure Retapamulin of formula (III).
9. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-8 wherein Halopleuromutilin of formula (II) is selected from 14-Chloropleuromutilin of formula (II-A) or 14-bromopleuromutilin of formula (II-B).
10. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-8 wherein organic solvent is selected from Acetonitrile, ethanol, methanol or Isopropanol.
11. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-8 wherein inorganic base is selected from NaOH, NH4OH, Na2CO3 or NaHCO3.
12. The process for the preparation of Halopleuromutilin of formula (II) as claimed in claim-8 wherein crystallization is carried out by dissolving Retapamulin of formula (III) in

organic solvent selected from water, methanol, ethanol, isopropanol, ethyl acetate, toluene and optionally precipitating out it using anti-solvent selected from water, hexanes, n-hexane, n-heptane.