TITLE OF THE INVENTION

A Process for preparing Clarithromycin and Clarithromycin intermediate

Technical filed:

The present invention relates to a process for preparing Clarithromycin.

The present invention also relates to a process for preparing Clarithromycin Intermediate.

Background and Prior Art:

Clarithromycin is a semi-synthetic derivative of erythromycin. Clarithromycin differs from erythromycin in it's methyl substitution at the number six position of the macrolide ring. The chemical structure of Clarithromycin i.e. 6-O-methyl erythromycin A is :

Formula (III)

It exhibits excellent antibacterial activity against gram positive bacteria, some gram negative bacteria, anaerobic bacteria, mycoplasmas and chlamydias. It is not only having bactericidal activity against some organisms by virtue of its synergism with its microbiologically active 14 OH metabolite but also by its Post Antibiotic Effect (PAE). It is stable under acidic conditions. The above attributes render it a superior alternative to erythromycin. Clarithromycin is useful in the therapy for infections of the upper and lower respiratory tract in human and children.

A commonly used method of preparing Clarithromycin i.e. 6-O-methyl eythromycin A from erythromycin A comprises the following steps:

1. Protecting the 9-oxo group with a substituted oxime group,

2. Protecting the hydroxyl group in position 2' and 4" with the suitable protecting group like silyl,

3. Methylating the hydroxyl in position 6 to give protected silylated Clarithromycin oxime, and

4. Deprotecting group i.e. substituted oxime and silyl at the 2', 4" and 9' position.

The critical step in the synthesis is the selective methylation of hydroxy group at 6 position of erythromycin A of formula (IV),

Formula (IV)

The selective methylation at 6-position of erythromycin A comprises methylating erythromycin A or erythromycin A derivatives with methylating agent and base in the presence of solvent. The 6- O methylation of erythromycin derivatives in converting erythromycin A to Clarithromycin has been reported in US 4,331,803 (here after referred as '803); US 4,672,109 (here after referred as '109); US 4,680,386 (here after referred as '386); US 4,990,602 ((here after referred as '602); International publication WO 97 /19096; International publication WO 01/87807(Equivalent US publication no. US 2004010128); International publication WO01/64224.

Erythromycin derivatives used in the preparation of Clarithromycin by selective methylation is disclosed in several patents or published applications like US 4,496,717; US 4,670,549; US 4,672,109; EP 260,938; US 4,990,602; etc.

'803 patent describes the process of 6-O-methylation which has been carried out in the presence of polar aprotic solvents which are N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO) or hexamethylphosphoric triamide, preferably N,N-dimethyl formamide, dimethyl sulfoxide or their mixture with tetrahydrofuran. But this reported method yielded an undesired side product due to methylation at hydroxy group other than the 6-position

along with 6-O-methylation and thus the process needs further purification to get pure 6-0- methylerythromycin A (Clarithomycin).

'109 patent describes the process for carrying out selective methylation by using a polar aprotic solvent such as DMSO, DMF, hexamethylphosphoric triamide, a mixture consisting two or more of this solvents or a mixture consisting one of these solvents and tetrahydrofuran, 1,2- dimethoxyethane and the like. The preferred examples of '109 use the mixture of DMSO and tetrahydrofuran for selective methylation and further quenching with triethyl amine and extraction with hexane.

WO 97/19096 discloses a mixture of solvents including DMF, DMSO, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile and ethyl acetate for use in the 6-O-methylation step.

The recovery of tetrahydrofuran from the used solvent mixture of the methylation step is very difficult. Further tetrahydrofuran is an expensive solvent and thus increases the cost of production. Thereby, WO 01/87807 discloses 6-O-methylation of an erythromycin A derivative by using toluene and polar aprotic solvent mixture to reduce the cost of methylation by eliminating the use of costly tretrahydrofuran. In this international publication, the selective methylation is carried out at temperature upto 100° C, preferably at 5-15° C.

Further US 5,892,008; US 5,864,023; US 5,837,829; and US 5,719,272 report 6-O-methylation of erythromycin A derivatives using solvent mixture of DMSO and tetrahydrofuran at temperature 5 to 10° C; 1-5° C, 5° C, 0 to 5° C respectively.

'386 patent describes the use of solvents like DMF, DMSO, hexamethylphosphoric triamide in the methylation of hydroxy group at the position 6 of erythromycin A derivative at a temperature between 0° C to RT.

WOO 1/64224 describes 6-O-methylation of a protected silyl erythromycin A oxime by using solvent methyl tertbutyl ether and a polar aprotic solvent at temperature in the range of 9 to 15° C

Patent application US 2003/0023053 describes 6-O-methylation of Erythromycin A derivative in the presence of dimethyl sulfoxide and methylene chloride at temperature range 0 to 5° C.

However, carrying out the reaction at higher temperature (i.e. above 0° C) leads to the formation of undesired side products and therefore requires extra purification to reduce the undesired impurities, which further reduces the yield. Further the freezing temperature of mixture consisting of DMSO and tetrahydrofuran in 1:1 ratio is 2 to 1° C and the freezing temperature of mixture consisting of DMSO and toluene in 1 : 1 ratio is 5 to 4° C, so it is difficult to carry out the 6-0- methylation below 0° C.

Objects:

The main object of the invention is to provide a process of highly selective 6-O-methylation of erythromycin A derivative comprising ternary solvent system at low temperature, as low as - 9 ⁰ C.

Another object of the invention is to provide a process of highly selective 6-O-methylation of erythromycin A derivative comprising ternary solvent system, which consist of a chlorinated hydrocarbon, a polar aprotic solvent and a non polar solvent, at temperature in the range of -3 to - 9° C.

Yet another object of the invention is to provide a process of 6-O-methylation, which enhances selective methylation of erythromycin A derivative and reduces the impurity, Clarithromycin A.

Yet another object of the invention is to provide a process for preparing Clarithromycin by highly selective 6-O-methylation of erythromycin A derivative comprising ternary solvent system at low temperature, as low as - 9 ⁰ C and further deprotection by method known in the art.

Yet another object of the invention is to provide a process of preparing Clarithromycin by highly selective 6-O-methylation of erythromycin A derivative comprising ternary solvent system, which consist of a chlorinated hydrocarbon, a polar aprotic solvent and a non polar solvent, at temperature in the range of -3 to -9° C and further deprotection by method known in the art.

Yet another object of the invention is to provide a process of preparing highly pure Clarithromycin without affecting the yield.

Detailed Description

The present invention discloses a process for preparing Clarithromycin of formula (III)

Formula III with high purity comprising selectively methylating a 2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy-l-methylethyl)oxime] of formula (II)

Formula II with methylating agent while stirring in the presence of a base and a ternary solvent system comprising a chlorinated hydrocarbon, a polar aprotic solvent and a non polar solvent, at temperature in the range of -3 to -9° C to obtain 6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] of formula (I)

Formula I

deprotecting the 6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy-l- methyl ethyl) oxime] of formula (I)

Formula I with acid such as formic acid, deoximating agent such as sodium bisulfite and denatured spirit, adding aqueous sodium hydroxide solution to the reaction mixture to adjust the pH to 10.5, filtering out the Clarithromycin of formula (III)

Formula III and washing the Clarithromycin with water.

Clarithromycin obtained by the invention was further purified by conventional purification method.

The present invention also discloses a process of preparing a 6-O-methyl-2',4"-O- bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] of formula (I)

Formula I by selective methylation at 6 position of a 2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l- methoxy-l-methylethyl)oxime] of formula (II) comprising methylating a 2',4"-O- bis(trimethylsilyl) erythromycin A 9-[O-( 1 -methoxy-1 -methylethyl)oxime] of formula (II)

Formula II with methylating agent while stirring in the presence of a base and a ternary solvent system comprising a chlorinated hydrocarbon, a polar aprotic solvent and a non polar solvent, at temperature in the range of -3 to -9° C.

A protected silylated erythromycin A oxime (i.e. erythormycin A derivative) used in the present invention can be erythromycin A having conventional protecting groups in organic synthesis at the 2' and 4" hydroxyl groups and / or methyl group of 3'-dimethyl amino group which are prepared according to conventional manner.

The preferred protected silylated erythromycin A oxime (i.e. 2',4"-O-bis(trimethylsilyl) erythromycin A 9~[O-(l-methoxy -l-methylethyl)oxime]) of formula (II)

Formula (II)

used in the present invention was prepared by the known method.

The solvent system of the present invention was ternary solvent system comprising chlorinated hydrocarbon, a polar aprotic solvent and a non polar solvent.

The ternary solvent system comprising chlorinated hydrocarbon, a polar aprotic solvent and a non polar solvent in the ratio from 1:3:0.5 to 2.5:4:3.5.

The chlorinated hydrocarbon was selected from the group consisting of methylene chloride, ethylene dichloride, chloroform or carbon tetrachloride.

The polar aprotic solvent was selected from the group consisting of DMSO; DMF; N,N- dimethylacetamide or any suitable polar aprotic solvent known in the art. The preferred polar aprotic solvent was DMSO. The non polar solvent was toluene.

The ternary solvent system comprises methylene chloride, DMSO and toluene. The ternary solvent system comprising methylene chloride, DMSO and toluene in the ratio of 2:3:1 or 2.5:3:0.5 or 1:3.7:2.7 or 1:3.7:3.17.

The ternary solvent system comprises ethylene dichloride, DMSO and toluene. The ternary solvent system comprising ethylene dichloride, DMSO and toluene in the ratio of 2:3:1.

The ternary solvent system comprises chloroform, DMSO and toluene.

The ternary solvent system comprising chloroform, DMSO and toluene in the ratio of 2:3:1.

The ratio of three solvents of the present solvent system was selected in order to carry out the highly selective 6-O-methylation reaction at lower temperature, preferably below 0° C, more preferably as low as -9° C.

The process of 6-O-methylation was carried out at -3 to -9° C, preferably at temperature in the range pf-7 to -9° C.

The methylating agent was selected from the group consisting of methyl iodide, methyl bromide, or any suitable methylating agent known in the art. The preferred methylating agent was methyl iodide.

The base was selected from the group consisting of potassium hydroxide, sodium hydroxide or any suitable base known in the art. The preferred base was potassium hydroxide.

While doing the experiments, we have found that the 6-O-methylation reaction using binary solvent system comprising DMSO and toluene or DMSO and tetrahydrofuran in the ratio of 1 : 1 was difficult to carry out below 0° C as dimethyl sulfoxide crystallizes out below 0° C.

Further if methylation reaction is carried out at 0° C or higher (more than 0° C) temperature then it gives impurity called Clarithromycin A due to methylation at H-O position with the desired product 6-O-methyl erythromycin. Thus affecting the selectivity of methylation at 6 position and needs- further extensive purification.

To reduce the Clarithromycin A impurity level associated with the process of prior art, in the present invention the 6-O-methylation of protected silylated erythromycin A oxime derivative was carried out below 0° C, even as low as -9° C by using the ternary solvent system which consist of the chlorinated hydrocarbon, the polar aprotic solvent and the non polar solvent. Thus, the 6-O- methylation of protected silylated erythromycin A oxime derivative of the present invention has reduced the level of impurities substantially and enhanced selectivity of methylation at 6 position.

The invention is further illustrated by the following examples, which should not construe the effective scope of the claims.

Example IA

Preparing Clarithromycin using ternary system

126.6 gm of 2\4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l-methoxy -1- methylethyl)oxime] which was prepared by known method, was added to the solvent system consisting of 1000 ml of methylene chloride, 1500 ml of DMSO and 500 ml of toluene in the ratio of 2:3:1 while stirring. The reaction mass was chilled to -5° C. 27.6 gm of methyl iodide and 11.72 gm potassium hydroxide were added with stirring. Stirring was continued while maintaining the temperature at -9° to - 8° C. The methylation reaction was monitored by HPLC. The time required for completion of reaction was about 55 minutes. The reaction mixture was further quenched by adding 40 % dimethyl amine with stirring. The stirring was stopped and the organic layer was separated from the reaction mixture. The remaining reaction mixture was washed with toluene. The combined toluene layer was then subjected to distillation to give 6-O- methyl-2',4"-O-bis(trimethylsilyi) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] which was mixed with 300 ml of denatured spirit and 300 gm of sodium bisulfite. 11.6 gm of formic acid was added to the mixture and the mixture was stirred at refluxed temperature to give Clarithromycin. Heating was continued and the suspension was stirred for 2 hours. The mixture was then cooled to about 20° C and sodium hydroxide solution was added at about this temperature until the pH reaches about 10.5. The solid Clarithromycin was filtered, washed with water and dried.

The % yield and purity of Clarithromycin was 90 and 85 respectively. The % of Clarithromycin A impurity was 0.25 %.

Example IB

Preparing Clarithromycin using binary system

126.6 gm of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l-methoxy -1- methylethyl)oxime] which was prepared by known method, was added to the solvent system consisting of DMSO and toluene in the ratio of 1:1 while stirring. The reaction mass was chilled to 5° C. 27.6 gm of methyl iodide and 11.72 gm potassium hydroxide were added with stirring.

Stirring was continued while maintaining the temperature at 5°-6° C. The methylation reaction was monitored by HPLC. The reaction was completed in an about 55 minutes. The reaction mixture was further quenched by adding 40 % dimethyl amine with stirring. The stirring was

stopped and the organic layer was separated from the reaction mixture. The remaining reaction mixture was washed with toluene. The combined toluene layer was then subjected to distillation to give 6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9- [O-(l -methoxy- 1-methylethyl) oxime] which was mixed with 300 ml of denatured spirit and 300 gm of sodium bisulfite. 11.6 gm of Formic acid was added to the mixture and the mixture was stirred at refluxed temperature to give Clarithromycin. Heating was continued and the suspension was stirred for 2 hours. The mixture was then cooled to about 20° C and sodium hydroxide solution was added at about this temperature until the pH reaches about 10.5. The solid Clarithromycin was filtered, washed with water and dried.

The % yield and purity of Clarithromycin was 48 and 65 respectively. The % of Clarithromycin A impurity was 15 %.

Example 2

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was prepared by 6-O-methylation of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l- methoxy -l-methylethyl)oxime] by using solvent system comprising methylene chloride, DMSO and toluene in the ratio of 2.5:3:0.5 at -9° to -8° C instead of 2:3:1 ratio as the procedure described in example IA. 6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was further deprotected as the procedure described in the example IA.

The % yield and purity of Clarithromycin was 90 and 85 respectively. The % of Clarithromycin A impurity was 0.26 %.

Example 3

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was prepared by 6-O-methylation of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l- methoxy -l-methylethyl)oxime] by using solvent system comprising methylene chloride, DMSO and toluene in the ratio of 1:3.7:2.7 at -7° to -6° C instead of 2:3:1 ratio at -9° to -8° C as the procedure described in example IA.

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9- [O-(l -methoxy -l-methylethyl)oxime] was further deprotected as the procedure described in the example IA.

The % yield and purity of Clarithromycin was 91 and 81. The % of Clarithromycin A impurity was 0.26 %.

Example 4

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was prepared by 6-O-methylation of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l- methoxy -l-methylethyl)oxime] by using solvent system comprising methylene chloride, DMSO and toluene in the ratio of 1:3.7:3.17 at -7° to -6° C instead of 2:3:1 ratio at -9° to -8° C as the procedure described in example IA. 6-O-methyl-2 ' ,4 " -O-bis(trimethylsilyl) erythromycin A 9-[O-( 1 -methoxy -1 -methylethyl)oxime] was further deprotected as the procedure described in the example IA.

The % yield and purity of Clarithromycin was 90 and 80. The % of Clarithromycin A impurity was 0.26 %.

Example 5

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9- [O-(l -methoxy -l-methylethyl)oxime] was prepared by 6-O-methylation of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l- methoxy -l-methylethyl)oxime] by using solvent system comprising chloroform, DMSO and toluene in the ratio of 2:3:1 at -7° to -6° C instead of methylene chloride, DMSO and toluene in the ratio of 2:3:1 at -9° to -8° C as the procedure described in example IA.

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9- [O-(l -methoxy -l-methylethyl)oxime] was further deprotected as the procedure described in the example IA.

The % yield and purity of Clarithromycin was 90 and 80 respectively. The % of Clarithromycin A impurity was 0.27 %.

Example 6

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l -methoxy -l-methylethyl)oxime] was prepared by 6-O-methylation of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l- methoxy -l-methylethyl)oxime] by using solvent system comprising ethylene dichloride, DMSO and toluene in the ratio of 2:3:1 at -7° to -6° C instead of methylene chloride, DMSO and toluene in the ratio 2:3:1 at -9° to -8° C as the procedure described in example IA.

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was further deprotected as the procedure described in the example IA.

The % yield and purity of Clarithromycin was 91 and 80 respectively. The % of Clarithromycin A impurity was 0.3 %.

Example 7

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was prepared by 6-O-methylation of 2',4"-O-bis(trimethylsilyl)- erythromycin A 9-[O-(l- methoxy -l-methylethyl)oxime] by using solvent system comprising methylene chloride, DMSO and toluene in the ratio of 1:3:2 at -9° to -8° C instead of 2:3:1 as the procedure described in example IA.

6-O-methyl-2',4"-O-bis(trimethylsilyl) erythromycin A 9-[O-(l-methoxy -l-methylethyl)oxime] was further deprotected as the procedure described in the example IA.

The % yield and purity of Clarithromycin was 90 and 78. The % of Clarithromycin A impurity was 5 %.