DESC:FORM 2
THE PATENT ACT, 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION
OF CLARITHROMYCIN BY SELECTIVE METHYLATION

IND-SWIFT LABORATORIES LIMITED
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160101

The following application particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a commercially viable and industrial advantageous process for preparation of clarithromycin of formula I,

via selective methylation of a hydroxy group at 6 position of erythromycin A derivative in the presence of at least one phase transfer catalyst.

BACKGROUND OF THE INVENTION
6-O-Methylerythromycin A (Clarithromycin) of Formula I, is a second-generation semi-synthetic macrolide antibiotic and exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, mycoplasma and chlamydia. Clarithromycin is efficacious when administrated orally.

Clarithromycin and its preparation has been first disclosed in US patent 4,331,803. The method for preparation of clarithromycin comprises of methylating O,N-dibenzyloxycarbonyl-des-N-methylerythromycin A with methyl iodide in a mixture of dry dimethylsulfoxide and tetrahydrofuran in the presence of alkyl metal hydride to give 6-O methyl, N-dibenzyloxycarbonyl-des-N-methylerythromycin A. The resulting compound is then purified by silica gel chromatography followed by debenzylation using palladium black followed by recrystallization from a mixture of chloroform and diethyl ether to give 6-O-methylerythromycin A. By following this method one gets compounds which are methylated at hydroxy group other than the 6 position along with 6-O methylation and therefore, requires a good purification technique to get the intended 6-O methylation which reduced the yield drastically.
US patent 4,672,109, discloses a method for the selective methylation of the 6-hydroxy group of erythromycin A via 9-oxime derivatives to give 6-O-methylerythromycin A 9-oximes. The preparation of 6-O-methylerythromycin A 9-oxime was also disclosed in US patent 4,670,549, The conversion of 6-O-methylerythromycin A 9-oximes to 6-O-methylerythromycin A was disclosed in Japanese Patent No. 95055958.
Thereafter, several other approaches for preparing 6-O-methyl erythromycin A have been published in literature. One of the most effective approaches involves the following steps: (a) protecting the 9-oxo group with a substituted oxime group; (b) protecting the hydroxyl group at positions 2' and 4'' (c) methylating the hydroxyl group at position 6 to give a protected clarithromycin oxime derivative and (d) removing the protecting group at 2', 4'' and 9 positions. The critical step in this synthesis of clarithromycin is the third step (c), which involves the selective methylation of 6-hydroxy position of erythromycin A of formula II,

wherein R is hydrogen atom or substituent group such as lower alkyl group, which is substituted or unsubstituted, an aryl substituted methyl group, a substituted oxyalkyl group, or a thioalkyl group; R1 is 2',4''-bistrimethylsilyl,2'-carbobenzyloxy-3'-dicarbobenzyloxy or other hydroxyl protecting group.

The 6-O-alkylation of various erythromycin derivatives in converting erythromycin A to clarithromycin has been reported in several US Patents including US4,680,386; US6,342,590; US6,617,436; US6,809,188 and US application US2009/0054634 and PCT publications including WO2005/ 090377A1; WO2006100691A2 and Indian application IN 376/CHE/2005. The said references describe methods of methylating the hydroxyl group at the 6 position by reacting the compound with a suitable methylating agent in the presence of a suitable base in a suitable solvent aprotic solvent or mixture of solvents or by changing solvent system and are incorporated herein by reference.

US Patent 4,680,386 herein referred as US '386 discloses the process for the preparation of 6-O methylerythromycin A 9-oxime comprises the conversion of erythromycin A 9-oxime into O,N-dibenzyloxycarbonyl-des-N-methyl erythromycin A 9-benzyl oxime derivative and followed by its 6-O methylation by reacting resulting compound with methyl iodide in dimethylsulfoxide and tetrahydrofuran in the presence of potassium hydroxide to give corresponding 6-O methyl derivative. Dissolving the resulting compound in a mixture of acetic acid, water and ethanol and then palladium black was added to the solution and precipitated the compound. The resulting compound was recrystallized with ethanol to give 6-O methyl-N-demethylerythromycin A 9-oxime and followed by converting it into 6-O-methylerythromycin A 9-oxime. Further, conversion of 6-O methyl-N-demethylerythromycin A 9-oxime into clarithromycin is not exemplified in US '386 patent.
However, US '386 patent exemplified few reference examples for conversion of 6-O methyl-N-demethylerythromycin A 9-oxime into clarithromycin and the resulting clarithromycin was recrystallized with ethanol. If 6-O methyl-N-demethylerythromycin A 9-oxime may be converted into clarithromycin and recrystallized with ethanol according to reference examples as given; then it will results in very poor yield of about 30% of clarithromycin (from erythromycin A 9-oxime).

US Patent 6,342,590 discloses a process for converting 9-allyl oxime silyl erythromycin derivative to 6-O-methyl derivative using a suitable methylating agent in the presence of base a mixture of dimethyl sulfoxide and tetrahydrofuran with and using erythromycin A 9-oxime as key intermediate. Finally, the resulting compound is converted into clarithromycin and recrystallized from ethanol to give clarithromycin having overall about 40 % yield from erythromycin A 9-oxime.

US Patent 6,617,436 herein referred as US '436 discloses a process for converting a 9-oxime silyl erythromycin derivative to 6-O-methyl derivative using a mixture of solvents like dimethyl sulfoxide/ methyl tert-butyl ether with methylating agent in the presence of base. Finally, the resulting compound was converted into clarithromycin and recrystallized from ethanol.
Clarithromycin obtained as per process of US '436 is silent about the yield and purity of clarithromycin after recrystallized from ethanol.
US Patent 6,809,188 herein referred as US '188 discloses a process for selective methylation at 6 position of erythromycin A N-oxide derivative in mixture of dimethyl sulfoxide and tetrahydrofuran with alkylating agent in the presence of base Finally, the resulting compound was converted into clarithromycin. But US '188 is silent about the purity of clarithromycin and does not involve recrystallization of clarithromycin.

US Patent 6,900,296, describes a process for selective methylation of hydroxy group at 6-poisition of erythromycin A derivative by methylating the erythromycin A derivative with a methylating agent in a mixture of toluene and a polar aprotic solvent in presence of a base. Invention focus on the use of toluene and its recovery and does not provide further details for conversion of corresponding oxime to clarithromycin.

US patent application 2009/0054634 A1 discloses a process for the preparation of clarithromycin through selective methylation at 6 position of 9-oxime silyl erythromycin derivative in methyl tert-butyl ether and with or without another aprotic solvent with alkylating agent in the presence of base. Finally, the resulting compound was converted into clarithromycin and recrystallized from ethanol to give clarithromycin having 54-56% yield (from 9-oxime silyl erythromycin derivative).

PCT publication WO2005/090377A1 discloses a process for the preparation of clarithromycin through selective methylation at 6 position of 9-oxime silyl erythromycin derivative in a mixture of isopropyl acetate and dimethyl sulfoxide with methylating agent in the presence of base. Finally, the resulting compound is converted into clarithromycin and recrystallized from ethanol to give clarithromycin. The disclosure is silent about the yield and purity of clarithromycin after recrystallized from ethanol.
PCT publication WO2006/100691A2 discloses a process for the preparation of clarithromycin with high purity by converting erythromycin A 9-oxime into 9-oxime silyl erythromycin derivative and followed by its selective methylation at 6 position in a mixture of acyclic or cyclic alkanes having C6-C10 carbon atoms, such as hexane, heptane, cyclohexane and the like and a polar aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, 1,2-dimethoxyethane, hexamethylphosphoric triamide with methylating agent in the presence of base. Finally, the resulting compound is converted into clarithromycin and recrystallized from ethanol to give clarithromycin having 56% yield (from erythromycin A 9-oxime).

An Indian application IN 376/CHE/2005 discloses a process for the preparation of clarithromycin by converting erythromycin A 9-oxime into 9-oxime silyl erythromycin derivative and followed by its selective methylation at 6 position of 9-oxime silyl erythromycin derivative in a mixture of toluene, polar aprotic solvent such as dimethylsulfoxide and non-polar solvent such as n-hexane, hexanes, n-heptane, pentane, benzene, cyclohexane, carbon tetrachloride with methylating agent in the presence of base. Finally, the resulting compound was converted into clarithromycin and recrystallized from ethanol to give clarithromycin having 55% yield (from erythromycin A 9-oxime).

By following the above mentioned process, the product obtained contains 6-O-methyl erythromycin along with very high content of 6,11-dimethylated and 6,12-dimethylated and other mono and dimethylated derivatives because of further methylation at other hydroxy groups. It requires repeated purifications to get the intended 6-O-methyl erythromycin (clarithromycin) of reasonable purity which reduces the yield.
It is generally observed that the yield of clarithromycin before recrystallization with ethanol is 90-95% and after recrystallization the yield is reduced to 35-60 %.
Also, several of the above-described solvents are expensive, do not enable selective methylation, produce significant unwanted side products and/or cause complications during later phase separation steps. Many of the solvent systems mentioned in the above mentioned prior-art references are not recoverable either.

In view of the above, most of the disclosures try to reduce the impurities 6,11-dimethylated and 6,12-dimethylated and other mono and dimethylated derivatives by selective methylation at 6 position of erythromycin A derivative and modifying the solvent system or involving different oxime derivative of erythromycin A for reduce the said impurities. The common and major drawbacks of most of the processes described above are low yield and low purity, these disclosures either do not mention regarding the yield or if mention it is maximum up to 60%, which is less on commercial scale hence eventually increases the cost. The desired product is always contaminated with other methylated hydroxyl compounds and extra purifications are required to obtain the product of required quality.
So, there is an urgent need to develop a cost effective, commercially viable and industrial advantageneous process for synthesis of clarithromycin.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a commercially viable and industrial advantageneous process for preparation of clarithromycin of formula I with high yield and high purity.

The another object of the present invention is to provide a commercially viable and industrial advantageneous process for preparation of clarithromycin of formula I via selective methylation of a hydroxy group at 6 position of erythromycin A derivative in the presence of a catalyst.

Yet another object of the present invention is to provide a commercially viable and industrial advantageneous process for preparation of clarithromycin of formula I having high yield and purity, comprises selective methylation of a hydroxy group at 6 position of erythromycin A derivative.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of clarithromycin of formula I, having high yield and purity comprises the steps of:
a) reacting erythromycin A derivative of formula II,

wherein R is hydrogen atom or substituent group such as lower alkyl group, which is substituted or unsubstituted, an aryl substituted methyl group, a substituted oxyalkyl group, or a thioalkyl group; R1 is 2',4''-bistrimethylsilyl,2'-carbobenzyloxy-3'-dicarbobenzyloxy or other hydroxyl protecting group
with a methylating agent in the presence of a base and at least one phase transfer catalyst in a mixture of acyclic or cyclic alkanes having C6- C10 carbon atoms, such as hexanes, heptanes, cyclohexane and the like and a polar aprotic solvent at suitable temperature for suitable time;
b) extracting 6-O-methylated erythromycin A oxime derivative from biphasic system;
c) deoximating to give clarithromycin of formula I;
d) optionally, purified crude clarithromycin with a suitable organic solvent to obtain clarithromycin with high yield and high purity.

DETAILED DESCRIPTION OF THE INVENTION
The present invention describes an alternative, commercially viable and industrial advantageous process for preparation of clarithromycin with high yield and high purity, comprises of selective methylation of hydroxyl group at 6 position of erythromycin A derivative of formula II in the presence of at least one phase transfer catalyst. In prior art, the processes for the preparation of pure clarithromycin can results in 30-60% over all yield of pure clarithromycin (from erythromycin A derivative of formula II).
The present invention describes an alternative, commercially viable and industrial advantageous process for preparation of pure clarithromycin with over all yield greater than 68% and preferably greater than 70% (from erythromycin A derivative of formula II).
The present invention provides a process for preparation of 6-O-methyl erythromycin A derivative by selective methylation of hydroxyl group at 6 position by reacting erythromycin A derivative of formula II with a methylating agent in the presence of a base and at least one phase transfer catalyst in a mixture of suitable solvent which are capable of generating biphasic system, at a suitable temperature for sufficient time.
Erythromycin A derivatives of formula II can be prepared by using the methods known in prior art.
The solvents, that result in biphasic system, used for selective methylation of hydroxyl group at 6 position of erythromycin A derivative of formula II, includes but not limited to acyclic or cyclic alkanes having C6-C10 carbon atoms, such as hexane, heptane, cyclohexane, benzene, toluene, xylene, n-pentane and the like and a polar aprotic solvent. The polar aprotic solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,2-dimethoxyethane, hexamethylphosphoric triamide and the like.
The methylating agent used for methylation can be selected from methyl halides such as methyl bromide, methyl iodide; dimethyl sulfate; and alkyl or aryl sulfonates such as methyl-p-toluene sulfonate, methyl methane sulfonate and the like.
The base used may be selected from any metal hydroxide and metal hydride such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like
The phase transfer catalyst used for selective methylation of hydroxyl group at 6 position of erythromycin A derivative of formula II includes but not limited to tetraalkylammonium salts such as tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, tetra-n-butylammonium hydroxide, benzyltriethylammonium bromide, benzyltriethyl ammonium chloride, tetra-n-butylammonium hydrogensulfate and the like.
A phase-transfer catalyst (PTC) is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic reactants are often soluble in an aqueous phase but insoluble in an organic phase in the absence of the phase-transfer catalyst. The catalyst functions like a detergent for solubilizing the salts into the organic phase. Phase-transfer catalysis refers to the acceleration of the reaction upon the addition of the phase-transfer catalyst.
Phase-transfer catalysis reactions often provide higher yield than non-PTC reactions due to several reasons which broadly fall into the categories of higher selectivity (minimizing side reactions) and easier workup. By using a PTC process, one can achieve faster reactions, obtain higher conversions or yields, make fewer byproducts.
The catalyst may be used in an amount of from catalytic amount to several equivalents based on erythromycin A derivative. The reaction can be easily proceeds at a temperature of from 5 °C to 40 °C.
Although the stirring efficiency contributes to the shortening of the reaction time and the improvement in the yield, the reaction can be carried out from 10 minutes to several hours and is usually completed within 10 minutes to 2 hours and preferably within one hour. The reaction can be preferably carried out below 20-25 °C for 10 minutes to 1 hour.
Further, the use of phase-transfer catalyst during methylation reaction is provided a rocket start for initiating and completion of the reaction. In the absence of phase-transfer catalyst, during methylation reaction, degradation of methylated product starts and during the passage of time it increases. In contrary, when phase-transfer catalyst is used during methylation reaction, degradation of the methylated product did not occur during the passage of time or extended hours upto 48 hours and hence it results a great jump in the yield of clarithromycin before and after its purification.
After completion of the methylation reaction, protected clarithromycin oxime derivative is extracted from biphasic system. The resulting protected clarithromycin oxime derivative is dissolved in solvent (s) and reacted with sodium hydrogen sulfite in the presence of formic acid at a suitable temperature. The desired product is crystallized from reaction mixture and then optionally, recrystallized with suitable organic solvent to give pure clarithromycin with high yield. The solvent (s) used in the reaction can be selected from water, alcohol such as ethanol, denaturated spirit, methanol, isopropanol and the like or mixture thereof. The reaction can be preferably carried out at room temperature to reflux temperature for 10 minutes to several hours. The suitable organic solvent used in the recrystallization can be alcohol such as ethanol, methanol, isopropanol and the like.
Pure clarithromycin compound of formula I prepared according to present invention has purity of greater than 99.0%, preferably greater than 99.5% by HPLC, yield greater than 68% and preferably yield greater than 70%.
The progress of reaction completion at any stage can be monitored by suitable techniques such as high performance liquid chromatography [HPLC], thin layer chromatography [TLC], gas chromatography [GC] or ultra pressure liquid chromatography [UPLC] and the like. After completion of the reaction, the desired product can be isolated from the reaction mixture using suitable conventional methods or can be converted in situ to the next step. The resulting compound can be isolated by aqueous or non-aqueous workup.
Major advantage realized in the present invention is the use of phase transfer catalyst which surprisingly results in selective methylation and enhancement of yield and hence process is cost-effective.
Although, following examples illustrate practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention.

EXEMPLES :
Example-1 Preparation of 6-O-methylerythromycin A (Clarithromycin)
Step 1: Preparation of 2',4"-O-bis(trimethylsilyl)erythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To a solution of erythromycin oxime of formula II ( R and R1 is H; 100g) in dichloromethane (366ml), 2-ethoxy propene (18.3g) and pyridine hydrobromide (26g) were added at a temperature of 5-7°C and then temperature of the reaction was raised to 17-21°C. The reaction mixture was stirred at 17-21°C for 3.5 hours. After completion of the reaction, hexamethyldisilazane (26g) was added at a temperature of 14-16°C and stirred at same temperature for 2 hours. After completion of reaction, aqueous sodium bicarbonate solution (10%, 193ml) was added and stirred to separate the layers. The aqueous layer was extracted with dichloromethane (1 x 100ml). The organic layers were combined and washed with water (1 x 266ml). The solvent was completely distilled off to obtain the title compound as residue.
Step 2: Preparation of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To 2',4"-O-bis(trimethylsilyl)erythromycin A 9-O-(1-ethoxy-1-methylethyl) oxime, obtained as above, cyclohexane (1500ml) and dimethylsulfoxide (1500ml) were added at a temperature of 20-30°C. Then, reaction mass was cooled to 15°C and tetrabutyl ammonium bromide (5g), methyl iodide (28g) and powdered potassium hydroxide (40g) were added at 15-20°C and stirred for further 40 minutes. After completion of reaction, dimethylamine solution (40%, 39.6g) and water (635ml) were added, then stirred for 30 minutes. The layer were separated, and aqueous layer was further extracted with cyclohexane (500ml). Organic layers were combined, washed with water (2 x 266ml) and then cyclohexane was distilled out to get the title compound.
Step 3: Preparation of 6-O-methylerythromycin A (Clarithromycin)
To 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime, obtained as above, a mixture of 300ml denaturated spirit and 300ml water were added, followed by addition of sodium hydrogen sulphite (186g) and formic acid (26.6g, 85%) and then reaction mixture was refluxed for 4 hours. After completion of reaction, reaction mixture was diluted with water (535ml) and the pH of the reaction mass was adjusted to 10-12 using aqueous sodium hydroxide and the reaction mixture was stirred at 30-40°C for 1 hour. The product thus crystallized, was filtered, washed with water and dried to give crude clarithromycin. The resulting crude was repeatedly crystallized from ethanol to obtain 70.5g (70.5%) of title compound having purity 99.6% by HPLC.

Example-2 Preparation of 6-O-methylerythromycin A (Clarithromycin)
Step 1: Preparation of 2',4"-O-bis(trimethylsilyl)erythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To a solution of erythromycin oxime of formula II ( R and R1 is H; 100g) was in dichloromethane (366ml), 2-ethoxy propene (18.3g) and pyridine hydrobromide (26g) were added at a temperature of 5-7°C and further the temperature of the reaction was raised to 17-21°C and stirred for 3.5 hours. After completion of reaction hexamethyldisilazane (26g) was added at 14-16 °C and stirred at same temperature for 2 hours. After completion of reaction, aqueous sodium bicarbonate solution (10%, 193ml) was added and stirred to separate the layers. The aqueous layer was extracted with dichloromethane (1 x 100ml). The organic layers were combined and washed with water (1 x 266ml) and then completely distilled off the solvent to obtain the residue.
Step 2: Preparation of 2', 4"-O-bis(trimethylsiIyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To the above resulting compound of one part, cyclohexane (1500ml) was added to get a clear solution and then dimethylsulfoxide (1500ml) was added at a temperature of 20-30°C. Then, the reaction mass was cooled to 15°C and then tetrabutyl ammonium hydroxide (5g), methyl iodide (28g) and powdered potassium hydroxide (40g) were added at 15-20°C. Then the reaction mixture was stirred for 40 minutes. After completion of reaction, dimethylamine solution (40% , 39.6g) and water (635ml) were added and then stirred for 30 minutes, organic layer was separated and aqueous layer was further extracted with cyclohexane (500ml). Organic layers were combined, washed with water (2 x 266ml) and then cyclohexane was distilled out to get the title compound.
Step 3: Preparation of 6-O-methylerythromycin A (Clarithromycin)
To a solution of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime in a mixture of 300ml denaturated spirit and 300ml water (1:1), sodium hydrogen sulphite (186g) and formic acid (85%, 26.6g) were added and then reaction mixture was refluxed for 4 hours. Thereafter, reaction mixture was diluted with water (535ml) and the pH was adjusted to 10-12 using aqueous sodium hydroxide and then the reaction mixture was stirred at 30-40° C for 1 hour. Product thus crystallized was filtered out, washed with water and dried. The resulting crude was repeatedly crystallized from ethanol to obtain 71.2g (71.2%) of title compound having purity 99.80% by HPLC.

Example-3 Preparation of 6-O-methylerythromycin A (Clarithromycin)
Step 1: Preparation of 2',4"-O-bis(trimethylsilyl)erythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To a solution of erythromycin oxime of formula II ( R and R1 is H; 200g) in dichloromethane (732ml), 2-ethoxy propene (36.6g) and pyridine hydrobromide (52g) were added at a temperature of 5-7°C and further the temperature of the reaction was raised to 17-21°C and stirred for 3.5 hours. After completion of reaction hexamethyldisilazane (52g) was added at 14-16°C and stirred at same temperature for 2 hours. After completion of reaction, aqueous sodium bicarbonate solution (10%, 386ml) was added, stirred and layers were separated. The aqueous layer was extracted with dichloromethane (1 x 200ml). The organic layers were combined and washed with water (1 x 532ml). Dichloromethane was divided into two equal halves and then solvent was completely distilled off, independently for each part to obtain the residue.
Method A
Step 2: Preparation of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To the above resulting residue of one part, hexane (1500ml) was added to get a clear solution and then dimethylsulfoxide (1500ml) was added temperature of 20-30°C. Reaction mass was cooled to 15°C and then tetrabutyl ammonium iodide (5g), methyl iodide (28g) and powdered potassium hydroxide (40g) were added, stirred for 40 minutes at 15-20°C. After completion of reaction dimethylamine solution (40%, 39.6g) and water (635ml) were added then stirred for 30 minutes, organic layer was separated and aqueous layer was further extracted with hexane (500ml). Organic layers were combined, washed with water (2 x 266ml) and then hexane was distilled out to get the title compound.
Step 3: Preparation of 6-O-methylerythromycin A (Clarithromycin)
To a solution of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime in a mixture of 300ml denaturated spirit and 300ml water (1:1), sodium hydrogen sulphite (186g) and formic acid (85%, 26.6g ) were added and then reaction mixture was refluxed for 4 hours. Thereafter, reaction mixture was diluted with water (535ml) and the pH was adjusted to 10-12 using aqueous sodium hydroxide and the reaction mixture was stirred at 30-40°C for 1 hour. Product thus crystallized was filtered out, washed with water and dried. The resulting crude was repeatedly crystallized from ethanol to give 70.1g (70.1%) of title compound having purity 99.70% by HPLC.

Method B
Step 2: Preparation of 2',4"-O-bis(trimethylsilyl)-6-O methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime
To the above resulting residue of second part, heptane (1500ml) was added to get a clear solution and then dimethylsulfoxide (1500ml) was added at a temperature of 20-30°C. Reaction mass was cooled to 15°C and then tetrabutyl ammonium hydroxide (5g), methyl iodide (28g) and powdered potassium hydroxide (40g) were added at 15-20°C, stirred for 40 minutes. After completion of reaction dimethylamine solution (40%, 39.6g) and water (635ml) were added then stirred for 30 minutes, organic layer was separated and aqueous layer was further extracted with heptane (500ml). Organic layers were combined, washed with water (2 x 266ml) and then heptane was distilled out to get the title compound.
Step 3: Preparation of 6-O-methylerythromycin A (Clarithromycin)
To a solution of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-O-(1-ethoxy-1-methylethyl)oxime in a mixture of 300ml denaturated spirit and 300ml water (1:1), sodium hydrogen sulphite (186g) and formic acid (85%, 26.6g) were added and then reaction mixture was refluxed for 4 hours. Thereafter, reaction mixture was diluted with water (535ml) and the pH was adjusted to 10-12 using aqueous sodium hydroxide and the reaction mixture was stirred at 30-40°C for 1 hour. Product thus crystallized was filtered out, washed with water and dried. The resulting crude was repeatedly crystallized from ethanol to get 70.5g (70.5%) of title compound having purity 99.6% by HPLC.

Comparative Example
Step 1: Preparation of 2’,4’’-O-(trimethylsilyl)erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime
To a solution of erythromycin oxime of formula II (R and R1 = hydrogen; 100 g) in methylene chloride (350ml), 2-methoxy propene (25g) and pyridine hydrobromide (26g) were added at a temperature of 5oC and further stirred at 20-25oC for 3.5 hours. To this hexamethyldisilazane (26g) was added at 15oC and stirred for 2 h after which 180 ml of 10% aqueous sodium bicarbonate solution was added and the layers were separated. The aqueous layer was extracted with methylene chloride (1x100 ml). The organic layers were combined and washed with water (2x200 ml). Methylene chloride was completely distilled off to obtain the residue.

Step 2: Preparation of 2’, 4’’-O-Bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime
To the above residue, cyclohexane (1600 ml) was added to get a clear solution. To this dimethylsulfoxide (1600 ml) was added at 20-25oC. Methyl iodide (56g) followed by powdered potassium hydroxide (36g) were added and stirred for 30 minutes to 60 minutes. To the reaction mixture dimethyl amine (39.6g) and water (650ml) were added and stirred for 30 minutes. The organic layer was separated and the aqueous layer was further extracted with cyclohexane (650ml). The organic layers were combined, washed with water (2x500 ml) and solvent was removed to get the title compound.

Step 3: Preparation of 6-O-methylerythromycin A (Clarithromycin)
The methylated compound obtained in the above step was dissolved in 600ml of ethanol/ water (1:1). To this solution, sodium hydrogen sulphite (260g ) and 98% formic acid (23 g )were added and the reaction mixture was refluxed for three hours. Thereafter the reaction mixture was diluted with water (200 ml) and the pH was adjusted to 10.2 using aqueous sodium hydroxide. The reaction mixture was stirred at 25-35°C for one hour. The product which precipitated out was filtered, washed with water and recrystallized from ethanol to obtain 56g (56%) of title compound having purity 98.5% by HPLC. ,CLAIMS:WE CLAIM:
1. A process for the preparation of clarithromycin of formula I, having high yield, high purity, comprising the steps of:
a) reacting erythromycin A derivative of formula II,

wherein R is hydrogen atom or substituent group such as lower alkyl group, which is substituted or unsubstituted, an aryl substituted methyl group, a substituted oxyalkyl group, or a thioalkyl group; R1 is 2',4''-bistrimethylsilyl,2'-carbobenzyloxy-3'-dicarbobenzyloxy or other hydroxyl protecting group
with a methylating agent in the presence of a base, at least one phase transfer catalyst, in a solvent mixture of an acyclic or cyclic alkane having C6-C10 carbon atoms with a polar aprotic solvent at a suitable temperature for sufficient time;
b) extracting 6-O-methylated erythromycin A oxime derivative from biphasic system;
c) deoximating to give clarithromycin of formula I;
d) optionally, purifying crude clarithromycin with a suitable organic solvent to obtain clarithromycin with high yield and high purity.
2. The process as claimed in claim 1, wherein in step a) methylating agent is methyl halides, which is selected from methyl bromide, methyl iodide; dimethyl sulfate and alkyl or aryl sulfonates, which is selected from methyl-p-toluene sulfonate, methyl methane sulfonate.
3. The process as claimed in claim 1, wherein in step a) base is metal hydroxide and metal hydride, which is selected from sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride.
4. The process as claimed in claim 1, wherein in step a) acyclic or cyclic alkanes solvent having C6-C10 carbon atoms is selected from hexanes, heptanes, cyclohexane.
5. The process as claimed in claim 1, wherein in step a) phase transfer catalyst is tetraalkylammonium salt.
6. The process as claimed in claim 5, wherein tetraalkylammonium salt is selected from tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium iodide, tetra-n-butylammonium hydroxide, benzyltriethyl ammonium bromide, benzyltriethyl ammonium chloride and tetra-n-butyl ammonium hydrogensulfate.
7. The process as claimed in claim 1, wherein in step a) polar aprotic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethyl acetamide, 1,2-dimethoxyethane and hexamethylphosphoric triamide.
8. The process as claimed in claim 1, wherein in step a) reaction is carried out at a temperature 20-25 °C for 10 minutes to 1 hour.
9. The process as claimed in claim 1, wherein in step c) deoximating is carried out using sodium hydrogen sulfite in the presence of formic acid at a suitable temperature
10. The process as claimed in claim 1, wherein in step d) organic solvent is selected from ethanol, methanol, isopropanol.

Dated this 12th day of March, 2014

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(Dr. Asha Aggarwal)
Head-IPM Department
Ind-Swift Laboratories Limited