MX2007011562A

MX2007011562A - A process for the preparation of 6-o-methyl erythromycin a derivative.

Info

Publication number: MX2007011562A
Application number: MX2007011562A
Authority: MX
Inventors: Chidambaram Venkateswaran Srinivasan; Rahul Saxena; Pranav Gupta
Original assignee: Ind Swift Lab Ltd
Priority date: 2005-03-23
Filing date: 2006-03-20
Publication date: 2008-03-11
Also published as: WO2006100691A3; WO2006100691A2; IL186185A0; CN101146815A; IL186174A0

Abstract

The present invention relates to an improved process for the preparation of 6-O-methylerythromycin A derivatives, intermediates of clarithromycin, by selective methylation of erythromycin A derivative in a mixture of a acyclic or cyclic alkanes having C<sub>6</sub>-C<sub>10</sub> carbon atoms, and a polar aprotic solvent using a methylating agent in the presence of a base under mild conditions.

Description

A PROCESS FOR THE PREPARATION OF DERIVATIVES OF THE 6-0-METHYL ERYTHROMYCIN A Description FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of derivatives of 6-O-methyl erythromycin A, intermediates of clarithromycin, by selective methylation of the derivative of erythromycin A in a mixture of acyclic or cyclic alkanes having C6. - Cio carbon atoms, such as hexanes, heptanes, cyclohexane and an aprotic polar solvent using a methylating agent in the presence of a base under moderate conditions.

BACKGROUND OF THE INVENTION 6-O-methyl erythromycin (Clarithromycin) of formula I, Formula I is a semi-synthetic macrolide antibiotic related to erythromycin A. It exhibits excellent anti-bacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, etc. Clarithromycin is effective when administered orally.

Clarithromycin has been first described in US Pat. No. 4,331,803. After that several other approaches to prepare 6-O-methyl erythromycin A have been published in the 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 the 2 'and 4"positions (c) methylating the hydroxyl group at position 6 to give a protected derivative of oxime clarithromycin and (d) removing the protecting group at the 2', 4 positions "and 9. The critical step in the synthesis of clarithromycin is the third step (c), which involves the selective methylation of the 6-hydroxy position of erythromycin A of formula II, Formula II wherein R is the hydrogen atom or a substituent group such as a lower alkyl group, which is substituted or unsubstituted, a methyl group substituted with aryl, a substituted oxyalkyl group, or a thioalkyl group; Rj is 2 \ 4"-bistrimethylsilyl, 2'-carbobenzylloxy, 3'-dicarbobenzylloxy or another hydroxyl protecting group.

US Pat. No. 4,331,803 describes a process for the methylation of the hydroxyl group in the 6- position of erythromycin with a methylating agent in the presence of a base and a polar solvent. However, using the specified conditions of the reaction, the other hydroxyl groups are also methylated together with the 6-OH group and therefore, extra purifications are required to achieve the product of the required quality and therefore, the yields are inferiors U.S. Patent 4,679,109 describes selective methylation at the 6-position using a polar aprotic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide or a mixture thereof and a mixture consisting of these solvents and tetrahydrofuran. In the exemplified process after methylation, rapid cooling is carried out using the dimethylamine solution and extractions with hexane. The main disadvantage of this process is from the commercial point of view because the recovery of tetrahydrofuran is very difficult since it is distributed almost equally between the aqueous layers of dimethyl sulfoxide and hexane.

US patent 5,719,272 describes a process for methylation where the presence of methyl t-butyl ether is recommended in conjunction with polar aprotic solvents.

Recently, a US application, US 2004/0010128 A, describes a process for the selective methylation of the hydroxy group at position 6 of the erythromycin A derivative by methylation of the erythromycin A derivative with an agent of methylation in a mixture of toluene and a polar aprotic solvent in the presence of a base at 5-15 ° C.

The common and major disadvantages 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 the 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 the 6-O-methyl 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 the 6-O-methyl erythromycin A derivative comprising the selective methylation of the erythromycin A derivative with a methylating agent in a mixture of acyclic or cyclic alkanes having Cio carbon atoms, such as hexanes, heptanes, cyclohexane and the like and a polar aprotic solvent in the presence of a base, under moderate conditions.

More particularly, the oxime derivative of the above-mentioned 6-O-methylated erythromycin A is used in the preparation of clarithromycin of high yield and purity.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the preparation of the 6-O-methyl erythromycin A derivative by selective methylation of the 6-position of the erythromycin A derivative. Derivative of erythromycin A means erythromycin A which has no substituent group or which it has conventional substituent groups in the place of the hydrogen atoms at the position of the 2 'and 4"hydroxyl groups, including 21,4" bistrimethylsilyl, 2'-carbobenzyloxy or 3'-dicarbobenzyloxy. Additionally, the derivative of erythromycin A includes the oximes of erythromycin A 9 which have the general formula in position 9, RON = C \ where R is the hydrogen atom or a substituent group such as the lower alkyl group, which is substituted or unsubstituted, a methyl group substituted with aryl, a substituted oxyalkyl group, or a thioalkyl group.

Derivatives of erythromycin A are prepared by methods known in the prior art. The methylation of the erythromycin A derivative is specifically carried out in a mixture of acyclic or cyclic alkanes having C6-C ?0 carbon atoms, such as hexane, heptane, cyclohexane and the like and a polar aprotic solvent. The aprotic polar solvent can be selected from N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, 1,2-dimethoxyethane, hexamethylphosphoric triamide and the like.

The methylation agent used is a common mutilation agent known in the art such as methyl iodide, methyl bromide, methyl chloride dimethyl sulfate, methyl p-toluene sulfonate, methyl methane sulfonate and the like.

The base used generally are metal hydroxides and metal hydrides such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like.

It is advantageous to use acyclic or cyclic alkane, preferably cyclohexane with a polar aprotic solvent because using the alkanes the reaction mixture is biphasic and most of the impurities remain in the dimethyl sulfoxide layer which leads to a pure product. The ratio of the alkane and an aprotic polar 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 preferably between 18-30 ° C. It is advantageous to carry out the reaction at approximately room temperature since at higher temperatures there is greater formation of unwanted side products and at low temperature, the speed of the reaction is slow and sometimes, the reaction is incomplete and additionally imposes the cooling load on the equipment .

The reaction is generally carried out between 1 / 2-2 hours under moderate conditions and is preferably completed within 1 hour. The completion of the reaction is monitored by high performance liquid chromatography. After the completion of the reaction, the reaction mixture is diluted with water and dimethylamine solution. After this the organic layer is separated and the desired methylated compound is isolated by distillation of the solvent. The solvent is recovered from the quantitative tide and recycled. Additionally, the 6-0-methylated derivative is deprotected and clarithromycin is prepared with high yield and high purity. The main advantages observed in the current invention are: • Use of alkanes preferably of cyclohexane leading to selective methylation of the erythromycin A derivative under moderate conditions, therefore under industrial and environmentally friendly conditions. • Clarithromycin obtained from these intermediates is of high yield and purity. • Easier separation of the layers due to the biphasic nature of the reaction mixture, in this way handling is easier. • The solvent is recovered almost quantitatively.

Now the example will illustrate the process of this invention, which is not intended in any way to limit the scope of the invention.

Example 1 Preparation of 2 ', 4"-0- (Trimethylsilyl) erythromycin A 9- [0- (1-methoxy-1-methylethyl) oxime] To a solution of erythromycin oxime of formula II (R and Ri = hydrogen, 100 g) in methylene chloride (350 ml), 2-methoxy propane (25 g) and pyridine hydrobromide (26 g) were added at 5 ° C. and subsequently stirred at 20-25 ° C for 3-1 / 2 h. To this was added hexamethyldisilazane (26 g) at 15 ° C and stirred for 2 h after which 180 ml of 10% aqueous sodium bicarbonate solution were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1 x 100 ml). The organic layers were combined and washed with water (2 x 200 ml). The methylene chloride was completely distilled to obtain the residue.

Preparation of 2 ', 4"-O-Bis (trimethylsilyl) -6-O-methylerythromycin A 9 [O- (1-methoxy-1-methylethyl) oxime] To the previous residue, cyclohexane (1600 ml) was added to achieve a clear solution. To this dimethyl sulfoxide (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 min at 60 min. To the reaction mixture (39.6 g) dimethyl amine and water (650 ml) were added and stirred for ^ h. The organic layer was separated and the aqueous layer was subsequently extracted with cyclohexane (650 ml). The organic layers were combined, washed with water (2 x 500 ml) and the solvent was removed to get the title compound.

Preparation of Clarithromycin The methylated compound obtained in the previous step was dissolved in 600 ml of water / ethanol (1: 1). To this solution 260 g of sodium hydrogen sulfite and 23 g of 98% formic acid were added and the reaction mixture was refluxed for three hours. The reaction mixture was then diluted with 200 ml of water and the pH adjusted to 10.2 using aqueous sodium hydroxide. The reaction mixture was stirred at 25-35 ° C for one hour. The product that was precipitated was filtered, washed with water and recrystallized from ethanol to obtain 56 g of the title compound having 98.5% purity by HPLC,

Claims

1. A process for the preparation of the 6-O-methylerythromycin A dative comprising the selective methylation of the erythromycin A dative of formula II, Formula II where R is the hydrogen atom or a substituent group such as a lower alkyl group, which is substituted or unsubstituted, a methyl group substituted with aryl, a substituted oxyalkyl group, or a thioalkyl group; Ri is 2 A 4"-bistrimethylsilyl, 2'-carbobenzyloxy, 3'-dicarbobenzyloxy or another hydroxyl protecting group. with a methylating agent in a mixture of an acyclic or cyclic alkane having? - Cio carbon atoms, and a polar aprotic solvent in the presence of a base, under moderate conditions.

2. The process according to claim 1, wherein the acyclic or cyclic alkane is selected from hexanes, heptanes and cyclohexane containing C6-Cio carbon atoms.

3. The process according to claim 1, wherein the acyclic or cyclic alkane is cyclohexane.

4. The process according to claim 1, wherein the reaction is conducted at a temperature between 12 to 60 ° C.

5. The process according to claim 2, wherein the reaction is conducted at a 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 sulfate.

7. The process according to claim 1, wherein the aprotic polar solvent is selected from the group consisting of N, N-dimethylformamide, W, N-dimethylacetamide, dimethyl sulfoxide, 1,2-dimethoxyethane and hexamethylphosphoric triamide.

8. The process according to claim 7, wherein the aprotic polar solvent is dimethyl sulfoxide.

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. The process according to claim 1, wherein the dative of 6-0-methylerythromycin A is converted to clarithromycin of formula I, Formula I following the conventional methods.