BACKGROUND OF THE INVENTION 6-0-Methylerythromycin A (Clarithromycin) of Formula 1, 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.

Furthermore, it has greater stability at physiological pH, which renders it as a

superior alternative to its parent compound, erythromycin. Clarithromycin is a useful therapy for infections of the upper and lower respiratory tract, for infections due to chlamydia, mycoplasma and legionella, for infections of soft tissue, and for the eradication of H. Pylori (when used in combination with acid suppressing agents).

The critical step in the synthesis of clarithromycin is the selective methylation of 6-hydroxy position of erythromycin A of Formula il, FORMULA II since erythromycin A has many hydroxy groups. In U. S. Patent No.

4,331,803, there is described a method for methylating the hydroxy group at the 6-position of erythromycin A derivatives, with a methylating agent in the presence of a base in a polar solvent. By following this method one gets compounds which are methylated at hydroxy groups other than the 6-position along with the 6-0-methyl form and therefore, requires a good purification

technique to get the intended 6-0-methyl form which reduces the yield drastically.

Another method described in U. S. Patent No. 4,672,109 for carrying out the selective methylation recommends use of a polar aprotic solvent such as dimethyl sulphoxide (DMSO), N, N-dimethylformamide (DMF), hexamethylphosphoric triamide, a mixture consisting of two or more of these solvents, or a mixture consisting of one of these solvents and tetrahydrofuran.

The most preferred example of the solvents in the prior art is the mixture of DMSO and tetrahydrofuran for affecting the desired methylation followed by quenching with aqueous dimethylamine solution and extraction with hexanes.

A major limitation of the above procedure from a commercial view point, is that recovery of tetrahydrofuran which becomes extremely difficult to accomplish as it distributes almost equally, among both the aqueous dimethylsulphoxide and hexane layers and forms a constant boiling azeotrope with hexanes. Tetrahydrofuran is an expensive solvent and adds a significant cost factor in the overall cost of production of clarithromycin. Hence, non- accomplishment of the recovery of tetrahydrofuran makes the said process costly and renders it unattractive on a commercial scale. Moreover, the use of solvent tetrahydrofuran is burdened with the risk of fire and explosion.

SUMMARY OF THE INVENTION It is an object of the present invention to develop an alternate commercially viable solvent system, which does not use tetrahydrofuran for carrying out selective methylation of erythromycin A derivatives and would be easy to separate and recover at commercial scale.

The present invention relates to a process for carrying out selective methylation at 6-position of erythromycin A derivatives in which the term "erythromycin A derivative"means erythromycin A having no substituent group or having conventional substituent groups in organic synthesis, in place of a hydrogen atom of the 2'and 4"hydroxy groups and/or a methyl group of the 3'-dimethyl amino group which is prepared according to the conventional manner. Erythromycin A derivatives also include 2', 4"-bis trimethyl silyl or as 2'-carbobenzyloxy or as 3'-dicarbobenzyloxy) erythromycin A derivatives.

Further the term erythromycin A derivatives also include"erythromycin A 9 oximes"having at the 9-position the general formula, wherein R is a hydrogen atom or a 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.

More particularly, the present invention relates to a process, which comprises dissolving erythromycin, A derivative in a mixture of toluene and a polar aprotic solvent and reacting it with a methylating agent in the presence of a base.

The above reaction of methylation is affected in a mixture of toluene and a dipolar aprotic solvent, preferred examples of the polar aprotic solvents used are dimethyl sulphoxide, N, N-dimethylformamide, hexamethyl

phosphoric triamide and the like. The ratio of toluene and dipolar aprotic solvent varies from 1: 1 to 1: 5, preferably 1: 1.

Examples of the methylating agents are methyl halides such as methyl iodide, methyl bromide and the like ; dimethyl sulphate, methyl p-tolune sulphonate, methyl methane sulphonate and the like.

The suitable base is selected from the group consisting of potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride and the like.

Generally the reaction can be carried out at a temperature upto 100°C, preferably at 5-25°C, more preferably at 5-15°C. However, carrying out the methylation reaction at higher temperature leads to the formation of undesired products and therefore, requires extra purification to get the pure 6-0-methyl form which reduces the yield.

The above reaction is efficiently accomplished in 1-2 hours. However, the length of time required will vary depending upon such factors as temperature of reaction, concentration and presence or absence of efficient stirring.

After the reaction is over the reaction mixture is quenched in aqueous dimethylamine solution and more water is added. Toluene layer is separated and subjected to vacuum distillation to recover pure toluene as a recovered solvent and desired methylated compound.

In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, this is not intended in any way to limit the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Preparation of 6-O-Methyl-2'-O-benzyloxy-carbonyl erythromycin A 9- [O- (1-methoxy-1-methylethyl) oxime.

2'-O-Benzyloxycarbonyl erythromycin A 9-[O- (1-methoxy-1- methylethyl) oxime] (125g, 0.131 moles) was dissolved into a mixture of toluene (1875moi) and dimethylsulphoxide (1875ml) at 20-25°C under stirring.

Cooled the reaction mixture to about 10°C, added dimethylsulphate (24.7gm, 0.196moles) and potassium hydroxide (12.96gm, 0.196moles) at this temperature under stirring. Stirred at this temperature for about 2 hours.

After the completion of the reaction, the reaction mixture was diluted with water and layers were separated. Aqueous layer was again extracted with toluene (2 x 250moi) and the combined toluene layer was washed with water.

The solvent was recovered from the toluene layer through distillation under reduce pressure to give 121gm of crude 6-0-methyl-2'-benzyloxy carbonyl erythromycin A9- [O- (1-methoxy-methylethyl) oxime] which on crystallization gave 84 gm (yield 65% of theory) of pure product. Recovery of toluene was 2257ml, (95% v/v) and purity by GC, 99.5%.

EXAMPLE 2 Preparation of 6-O-Methyl-2'-O, 3'-N-bis (benzyloxycarbonyl)-N- demethyl erythromycin A 9- [0- (1-methoxy-1-methylethyl) oxime] Dissolved 2'-O, 3'-N-bis (benzyloxycarbonyl)-N-demethylerythromycin A 9- [O- (1-methoxy-1-methylethyl) oxime] (5gm, 0.0051 mole) in a mixture of

toluene (75mi) and DMSO (75moi) at 20-25°C under stirring. Cooled it to 10°C, added methyl iodide (0.79gm, 0.0055moles) and potassium hydroxide (0.37gm, 0.0055moles). Stirred the reaction mixture for about 1 hr. After the reaction was over, the reaction mixture was quenched with aqueous dimethylamine solution (40% w/v), added water to it, stirred and layers were separated. Extracted the aqueous layer with toluene (2x10ml) and toluene was recovered (87ml, 92% v/v purity by GC >99%) from the combined toluene layer under vacuum to give 4.29gm of crude 6-O-methyl-2'-0, 3'-N- bis (benzyloxycarbonyl)-N-demethyl erythromycin A9-[O- (1-methoxy-1- methylethyl) oxime] which on crystallization gave 3.56gm (yield 70%).

EXAMPLE 3 Preparation of 2', 4"-O-Bis (trimethylsilyl)-6-O-methylerythromycin A 9-[O- (1-methoxy-1-methylethyl) oxime].

2', 4"-O- (trimethylsilyl) A9- [O- (1-methoxy-1-methylethyl) oxime] (50gm, 0.052moles) was dissolved in toluene (750ml) at 25-30°C. To it was added dimethyl sulphoxide (750mol) and the resulting reaction mixture was cooled to 5-8°C. Added dimethyl sulphate (7.19gm, 0.057moles) and potassium hydroxide (3.76gm, 0.057 moles) at 5-8°C. Stirred the reaction mixture for about 2 hours at 5-8°C and added excess of dimethylamine aqueous solution (40% w/v). Water (500ml) was added to the reaction mixture, separated the toluene layer and extracted the aqueous layer with toluene (2 x 250mi). The combined toluene layer was washed with water (2 x 100mi) and concentrated to give the desired methylated crude product (48. 2gm) which on crystallization

gave 35.5gm of pure product. Toluene recovery was (1180ml 94.5% v/v ; purity by GC. 99.5%).

EXAMPLE 4 Preparation of 2', 4"-0-Bis (trimethylsilyl)-6-O-methylerythromycin A 9-[O- (1-methoxy-1-methylethyl) oxime] 2', 4"-O-Bis (trimethylsilyl) erythromycin A9- [0- (1-methoxy-1- methylethyl) oxime] (50gm, 0.052 moles) was dissolved in toluene (750mi) at 25-30°C and added DMSO (750moi) to it. The reaction mixture was then cooled to 8-12°C. To it was added methyl iodide (8.08gm, 0.057moles) and potassium hydroxide (3.76gm, 0.057moles) at 8-12°C. Stirred the resulting reaction mixture for about 2 hours at the same temperature. After the reaction was over, added excess of aqueous dimethylamine solution (40% w/v) and water (500ml) keeping the temperature at 8-12°C. The aqueous layer was further extracted with toluene (2 x 250ml). The combined toluene layer was subjected to vacuum distillation to recover toluene completely to give the crude methylated product (48.4gm) which after crystallization gave 35.7gm (70% yield) of pure product. Toluene recovery was (1137ml, 91% v/v) purity by GC (>99%).

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.