FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 6-0-methyl erythromycin A derivatives, intermediates of clarithromycin, by selective methylation of erythromycin A derivative in a mixture of acyclic or cyclic alkanes having C6- Cio carbon atoms, such as hexanes, heptanes, cyclohexane and a polar aprotic solvent using a methylating agent in the presence of a base under mild conditions
BACKGROUND OF THE INVENTION
6-O-methyl erythromycin (Clarithromycin) of formula I,

(Formula Removed)
is a semi-synthetic macrohde antibiotic related to erythromycin A It exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria etc Clarithromycin is efficacious when administered orally
Clarithromycin has been first disclosed in US Patent 4,331,803 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 the synthesis of clarithromycin is the third step (c), which involves the selective methylation of 6-hydroxy position of erythromycin A of formula II,
(Formula Removed)
wherein R is hydrogen atom or a substituent group such as a 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
US Patent 4,331,803 discloses a process for methylation of hydroxyl group at 6-position of erythromycin with a methylating agent in the presence of a base and a polar solvent However, using the specified reaction conditions, the other hydroxyl
groups are also methylated along with the 6-OH group and hence, extra purifications are required to get the product of required quality and therefore, yields are less US Patent 4,679,109 discloses selective methylation at 6-position using a polar aprotic solvent such as dimethyl sulphoxide, N,N-dimethylformamide, hexamethylphosphonc triamide or a mixture thereof and a mixture consisting of these solvents and tetrahydrofuran In the exemplified process after methylation quenching is effected using dimethylamine solution and extractions with hexane The major drawback of this process is from commercial point of view because recovery of tetrahydrofuran is very difficult as it distributes almost equally among both aqueous dimethyl sulphoxide and hexane layers
US Patent 5,719,272 discloses a process for methylation wherein presence of methyl-t-butyl ether is recommended alongwith polar aprotic solvents
Recently, a US application US 2004/0010128 A, 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 at 5-15°C
The common and major drawbacks of most of the processes described above are low yield and low purity The desired product is always contaminated with other methylated hydroxyl compounds and extra purifications are required to obtain the product of required quality
In view of the above, there is an urgent need to develop a simple, cost-effective and environmentally friendly process for the selective methylation of 6-hydroxy of erythromycin A, which is easy to operate on an industrial scale
Accordingly, a simple method for selective methylation is provided for the preparation of 6-Omethyl erythromycin A derivative and using the resulting derivative, clarithromycin is obtained in high yield and high purity
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of 6-O-methyl erythromycin A derivative which comprises the selective methylation of erythromycin A denvative with a methylating agent 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 in the presence of a base, under mild conditions
More particularly, the above 6-Omethylated erythromycin A oxime derivative is used in the preparation of clanthromycin of high purity and yield
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to preparation of 6-O-methyl erythromycin A derivative by selective methylation of 6-position of erythromycin A derivative Erythromycin A denvative means erythromycin A having no substituent group or having conventional substituent groups in place of hydrogen atoms at position 2' and 4" hydroxyl groups, including 2', 4" bistnmethylsilyl, 2'-carbobenzyloxy or 3'-dicarbobenzyloxy Further erythromycin A derivative include erythromycin A 9 oximes having at the 9-position the general formula,
(Formula Removed)
wherein R is 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
Erythromycin A derivatives are prepared by the methods known in prior art Specifically methylation of erythromycin A derivative is earned out 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 The polar aprotic solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,2-dimethoxyethane, hexamethylphosphonc triamide and the like
The methylating agent used is a common methylating agents known in art such as methyhodide, methyl bromide, methyl chloride dimethylsulfate, methyl />-toluene sulphonate, methyl methane sulphonate and the like
The base usually used is metal hydroxides and metal hydndes such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydnde and the like
It is advantageous to use acyclic or cyclic alkane, preferably cyclohexane with a polar aprotic solvent because using alkanes the reaction mixture is biphasic and most of the impunties remain in dimethyl sulphoxide layer leading to pure product The ratio of alkane and a polar aprotic solvent can be selected from 1 0 5 to 1 5 and preferably 1 1 is used The reaction is preferably carried out between 15° to 60°C and most preferably between 18-30°C It is advantageous to carry out the reaction at around ambient temperature as at higher temperature formation of undesired side-products are more and at low temperature, rate of reaction is slow and sometimes, reaction is incomplete and further putting burden of cooling on equipment
The reaction is generally carried out between Vi-2 hr under mild conditions and preferably completed within 1 hour The completion of reaction is monitored by high
performance liquid chromatography After completion of reaction, the reaction mixture is diluted with dimethylamine solution and water Thereafter organic layer is separated and the desired methylated compound is isolated by distillation of solvent Solvent is recovered quantitatively and recycled Further the 6-O-methylated derivative is deprotected and clarithromycin is prepared in high yield and high purity The major advantages realized in the present invention are
• Use of alkanes preferably cyclohexane leading to selective methylation of
erythromycin A derivative under mild conditions, therefore industrially and
environmentally friendly
• Clarithromycin obtained from this intermediate is in high yield and purity
• Easier separation of layers due to biphasic nature of reaction mixture, thus handing is easy
• Solvent is recovered almost quantitatively
Now the example will illustrate the process of this invention, which is not intended in anyway to limit the scope of the invention
Example I
Preparation of 2,,4"-O-(Trimethvlsilvl)ervthromycin A 9-[O-(l-methoxy-l-methylethyl)oximel
To a solution of erythromycin oxime of formula II (R and R1 = hydrogen, 100 g) in methylene chloride (350 ml), 2-methoxy propene (25 g) and pyridine hydrobromide (26 g) were added at 5°C and further stirred at 20-25°C for 3-½ h To this hexamethyldisilazane (26 g) was added at 15°C 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
Preparation of 2', 4"-O-Bis(trimethvlsilyl)-6-O-methvlervthromvcin A 9-[O-(1-methoxy-l-methylethyl)oxime
To the above residue, cyclohexane (1600 ml) was added to get a clear solution To this dimethylsulfoxide (1600 ml) was added at 20-25°C Methyl iodide (56 g) followed by powdered potassium hydroxide (36 g) were added and stirred for 30 mm to 60 mm To the reaction mixture dimethyl amine (39 6 g) and water (650 ml) were added and stirred for ½ h The organic layer was separated and the aqueous layer was further extracted with cyclohexane (650 ml) The organic layers were combined, washed with water (2x500 ml) and solvent was removed to get the title compound
Preparation of Clarithromycin
The methylated compound obtained in the above step was dissolved in 600 ml of ethanol/ water (1 1) To this solution 260 g of sodium hydrogen sulphite and 23 g of 98% formic acid were added and the reaction mixture was refluxed for three hours Thereafter the reaction mixture was diluted with 200 ml of water 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 recrystalhzed from ethanol to obtain 56g of title compound having purity 98 5%by HPLC.

We Claims ;-
1 A process for the preparation of 6-O-methylerythromycin A derivative which composes the selective methylation of erythromycin A derivative of formula II,
(Formula Removed)
wherein R is hydrogen atom or a substituent group such as a lower alkyl group, which is substituted or unsubstituted, an aryl substituted methyl group, a substituted oxyalkyl group, or a thwalkyl group, R1 is 2',4 "-bistrimethylsilyl, 2'- carbobenzyloxy, 3 '-dicarbobenzyloxy or other hydroxyl protecting group
with a methylating agent in a mixture of a acyclic or cyclic alkane having C6-C10 carbon atoms, and a polar aprotic solvent in the presence of a base, under mild conditions
2 The process according to claim 1, wherein the acyclic or cyclic alkane is selected from hexanes, heptanes and cyclohexane containing C6-C10 carbon atoms
3 The process according to claim 1, wherein acyclic or cyclic alkane is cyclohexane
4 The process according to claim 1, wherein the reaction is conducted at temperature between 12 to 60°C
5 The process according to claim 2, wherein the reaction is conducted at temperature between 15 to 30°C
6 The process according to claim 1, wherein the methylating agent is methyl iodide, methyl bromide, methyl chloride and dimethyl sulphate
7 The process according to claim 1, wherein the polar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide, dimethyl sulphoxide, 1,2-dimethoxyethane and hexamethyl phosphoric triamide
8 The process according to claim 7, wherein the polar aprotic solvent is dimethyl sulphoxide
9 The process according to claim 1, wherein the base is potassium hydroxide, sodium hydroxide, sodium hydride or potassium hydride
10 The process according to claim 9, wherein the base is potassium hydroxide
11 The process according to claim 1, wherein 6-O-methylerythromycin A derivative is converted to clarithromycin of formula I,
(Formula Removed)
by following conventional methods.