WO2010122571A2

WO2010122571A2 - A process for the selective methylation of erythromycin a derivatives.

Info

Publication number: WO2010122571A2
Application number: PCT/IN2010/000226
Authority: WO
Inventors: Rajiv Sakhardande; Manmohan Nimbalkar; Rajan Ramalingam; Sunil Uttarwar; Gautam Wani; Subarao Patil; Sandip Khilari; Rohidas Mhaske; Baban Gharge
Original assignee: Elder Pharmaceuticals Ltd.
Priority date: 2009-04-23
Filing date: 2010-04-07
Publication date: 2010-10-28
Also published as: WO2010122571A3

Abstract

A process for selective methylation at 6 position of erythromycin A derivatives.

Description

TITLE OF THE INVENTION:

A process for the selective methylation of erythromycin A derivatives.

FIELD OF THE INVENTION: The invention relates to the cost-effective industrial process for the selective methylation of erythromycin A derivatives.

BACKGROUND OF THE INVENTION:

Erythromycin A derivatives are compounds of formula I.

(I)

Wherein:

Rl and R2 are independently hydrogen or a hydroxy protecting group for example silylating groups at position 2' and 4". Further erythromycin A derivatives includes erythromycin A 9 oximes derivatives 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. Clarithromycin, 6-O-methylerythromycin A, is a semi-synthetic macrolide antibiotic of formula (II) which exhibits strong antibacterial activity towards a wide range of bacteria, and because of its high stability in the acidic environment of the stomach, it can be orally administered to treat respiratory organ diseases.

(H)

Clarithromycin is mostly prepared by a common approach from erythromycin A that involves the steps of protecting the 9-oxo group with a substituted oxime group; protecting the 2' and 4" hydroxyl group with the suitable protecting group; methylating the 6-hydroxyl group to give protected clarithromycin oxime; and deprotecting group at the 2', 4" and 9 positions. The said process involves the critical step of selective methylation of hydroxyl group at 6-position of erythromycin A with methylating agent and base in the presence of solvent.

In general Clarithromycin is prepared from erythromycin A derivatives of formula-I.

6-O-methylation of various erythromycin derivatives has been reported in several patents and publications. Clarithromycin has been first disclosed in US4331803. The process involves selective methylation of OH group at 6-position of O, N-dibenzyloxycarbonyl-des- N-methyl erythromycin A with a methylating agent in the presence of base and a polar aprotic solvent which are N, N-dimethyl formamide, N ,N-dimethyl acetamide, dimethylsulfoxide or hexamethylphosphoric triamide, or their mixture with tetrahydrofuran. However, in this process, along with 6-OH group, other hydroxyl groups are also methylated and 11-O-methyl form is produced, as major byproduct, thus further purification is necessary to get the quality product.

US4672109 describes selective methylation of hydroxy group at 6-position using a polar aprotic solvent such as dimethylsulfoxide, N, N-dimethyl formamide and/or hexamethylphosphoric triamide and a mixture of one of these solvents and tetrahydrofuran or 1, 2-dimethoxy ethane. Example of this patent describes further quenching step after methylation and extraction with hexane. Commercially disclosed process is not beneficial as recovery of tetrahydrofuran from dimethylsulfoxide and hexane layer is difficult.

US4680386 patent describes the use of solvents like N, N-dimethyl formamide, dimethylsulfoxide, and/or hexamethylphosphoric triamide and a mixture of one of these solvent and an inert solvent e.g. tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or ethyl acetate in the methylation of hydroxy group at the position 6 of erythromycin A derivative, at 0°C to room temperature.

Watanabe,Yoshiaki et. Al, in the journal reference Heterocycles (1990), 31(12), 2121-4, describes selective O-methylation of the C-6 hydroxyl group of erythromycin A by using its 9-oxime derivative as starting material by reacting with excess of methyl iodide and potassium hydroxide in the presence of dimethylsulfoxide and tetrahydrofuran. WO 97/19096 discloses a process in which the 6-O-methylation is carried out using the mixture of solvents including N, N-dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2- dimethoxyethane, acetonitrile and ethyl acetate in the presence of strong alkali metal base and weak organic amine base at -5°C to 5°C.

WO97/36912 discloses a process for methylation of 2 '-protected oxime derivative of erythromycin A in the presence of methyl-tert-butyl ether with polar aprotic solvents.

WOO 1/64224 describes methylation of silylated erythromycin A oxime derivative in the presence of base and solvent comprising methyl-tert butyl ether.

US2003023053 describes silylation in dichloromethane and 6-O-methylation of erythromycin A derivative in the presence of dimethylsulfoxide and methylene chloride.

Another process for the preparation of clarithromycin from erythromycin A oxime, disclosed in US20040010128 describes the use of toluene and polar aprotic solvent mixture in the methylating step. The process eliminates the use of costly tetrahydrofuran, as recovery of tetrahydrofuran from the used solvent mixture of the methylation step is very difficult. The preferred reaction temperatures being, 5°C to 15°C because higher temperatures have been leading to formation of undesired products. Time required is about 2 hours.

WO2006/ 100691 discloses silylation in dichloromethane and selective methylation of erythromycin A derivative with a methylating agent in a mixture of acyclic or cyclic alkanes having C₆-Ci₀ carbon atoms, such as hexanes, heptanes, cyclohexanes and the like and a polar aprotic solvents in presence of base. The patent does not teach use of aromatic hydrocarbons as solvent. The preferred reaction temperatures being 15°C to 30°C and time required being up to 2 hours. Solvents used are highly inflammable and their use is discouraged.

WO2007/029265 describes process of selective 6-O methylation of erythromycin A derivative using ternary solvent system of chlorinated hydrocarbon, polar aprotic solvent and non-polar solvent at very low temperature i.e. -3°C to -9°C. Use of chlorinated hydrocarbon is essential feature of the invention.

Solvent and temperature plays critical role in the methylation of erythromycin A derivatives. Selection of solvent and temperature conditions controls the yield and purity of the product.

Thus, there is a requirement of a cost-effective industrial process for the selective methylation of erythromycin A.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide a process for the selective 6-0- methylation of erythromycin A derivatives.

Another object of the present invention is to provide a process of selective methylation of erythromycin A derivatives in the presence of polar aprotic solvent and xylene to yield high purity product.

SUMMARY OF THE INVENTION: The invention comprises a process for the preparation of erythromycin A derivatives of formula (T), comprising of reaction of silylated erythromycin A derivative of formula- Ill,

(I)

Wherein:

Rl and R2 are independently hydrogen or a hydroxy protecting group at position 2' and 4" such as silylating groups. Further erythromycin A derivatives includes erythromycin A 9 oximes derivatives 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, with methylating agent in the presence of polar aprotic solvent and xylene.

DETAILED DESCRIPTION OF THE INVENTION: Accordingly, the invention comprises of a process for the preparation of erythromycin A derivatives of formula (T).

(I)

Wherein:

Rl and R2 are independently hydrogen or a hydroxy protecting group at position 2' and 4" such as silylating groups. Further erythromycin A derivatives includes erythromycin A 9 oximes derivatives 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.

The present invention discloses a process for the selective methylation of erythromycin A derivatives.

The process for the preparation of erythromycin A derivatives of formula (I) comprises of silylation with silylating agent in dichloromethane and selective methylation of erythromycin A derivatives of formula (III) with methylating agent in the presence of polar aprotic solvent and xylene in presence of a base.

(III)

Wherein:

Rl and R2 are hydrogen, or hydroxy protecting group at position 2' and 4" such as silylating groups.

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.

The polar aprotic solvent is selected from dimethylsulfoxide (DMSO), N, N- dimethylforrnamide (DMF), N, N-dimethylacetamide, or any suitable polar aprotic solvent known in the art. Preferably, the polar aprotic solvent used is dimethylsulfoxide .

It was surprisingly found that when xylene is used as one of the solvent, it substantially reduces reaction time. It was also noticed that it eliminates the use of higher temperatures and further surprising is use of mixture of o-xylene, p-xylene, m-xylene, or only isomer of o-, p- and m-xylene does not affect the reaction providing flexibility to the reaction.

Methylation reaction is carried out in a mixture of solvents selected from dimethylsulfoxide: xylene (1:1), dimethylformamide: xylene (1:1), N, N- dimethylacetamide: xylene (1:1).

The methylating agent is selected from methyl halide such as methyl iodide or methyl bromide or methyl chloride. Dimethylsulfate is also used as methylating agent in one preferred embodiment.

The base is selected from metal hydroxides and metal hydrides such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like.

The present invention discloses methylation of erythromycin A derivatives in the presence of polar aprotic solvent and xylene which makes the process cost effective and industrially viable.

EXAMPLES:

Example - 1 : Preparation of Clarithromycin

To a solution of erythromycin oxime (100 gm) in dichloromethane (800 ml), charged pyridine hydrobromide (25 gm), distilled out dichloromethane partly and 2-methoxy propene (34.5 ml) was charged at 6 - 7°C and maintained for 2.5 to 3 hours at 20 - 25°C. Further hexamethyldisilazane (42.4 ml) was charged and maintained for 1.5 - 2 hour. After completion of reaction, charged aqueous sodium bicarbonate solution (20 gm in 160 ml) and the layers were separated and aqueous layer extracted with dichloromethane. Distilled out dichloromethane under vacuum. Charged xylene (234 ml). Distilled out xylene under vacuum to remove traces of dichloromethane. Charged xylene (1600 ml) to the residue and charged dimethylsulfoxide (1600 ml). Cooled the reaction mass to 12-13°C and charged methyl iodide (23.28 gm), potassium hydroxide (10 gm) and maintained the temperature for 30 min. at 12-13 °C. Then charged dimethylamine (39 gm) and water (672 ml) at 25-30°C. Stirred and settled the layers and aqueous layer extracted with xylene. Combined xylene layers and distilled under vacuum. Charged methanol (200 ml) to the residue and heated to 50 - 55°C and remove traces of xylene under vacuum. Charged methanol (672 ml), 85% formic acid (42.04 gm), water (370 ml), sodium bisulfite (277.6 gm) heated the reaction mass to 65-70°C, and maintained for 4 - 5 hours. Cooled the reaction mass to room temperature, stirred the reaction mass, adjusted the pH to 10 - 10.2 using aqueous sodium hydroxide solution and maintained for 1 hour. The product that precipitated out was filtered, washed with water, dried and then recrystallized from denatured absolute alcohol to obtain the clarithromycin.

Claims

We claim:

1. A process for selective methylation at 6-position of erythromycin A derivatives of formula III to prepare erythromycin A derivative of the formula (I) which comprises of: methylation at 6-position of silylated product of formula (III) in polar aprotic solvent and xylene in the ratio of 1 : 1 , in presence of a base selected from potassium hydroxide or sodium hydroxide using methyl halide or dimethylsulfate as methylating agent, preferred being methyl iodide.

(I)

wherein, Rl and R2 is hydroxy protecting group at position 2' and 4" such as silylating groups and 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.

(III)

2. A process for the preparation of clarithromycin which comprises of selective methylation at 6-position of a silylated erythromycin A derivative of formula III comprising of : a) methylation of silylated product of formula (III) in polar aprotic solvent and xylene in presence of a base selected from potassium hydroxide or sodium hydroxide, using methyl halide or dimethylsulfate as methylating agent, preferred being methyl iodide; and b) deoximation and desilylation of the methylated product to form clarithromycin.

3. The process as claimed in claim 1 and 2, wherein polar aprotic solvent is selected from N, N-dimethyl formamide, N, N-dimethylacetamide.

4. The process as claimed in claim 1 and 2, wherein xylene used is o-xylene or p- xylene or m-xylene, or mixture thereof.