Title of Invention

A PROCESS FOR THE PREPARATION OF ERYTHROMYCIN 9-0-[SUBSTITUTED]-OXIME

Abstract

A process for the preparation of Erythromycin -9-0-[Substituted]-oxime of Formula III; wherein R = Substituted or unsubstituted alkyl Aryl group ; Comprises reacting Erythromycin A 9-Oxime with aryl alkyl halide using inorganic base in presence of polar aprotic solvents, preferably acetonitrile, wherein the amount of acetonitrile provided is in the ratio of 2:20 by volume of Erythromycin A-9-Oxime.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION 1. An improved process for the preparation of Erythromycin Derivative. A PROCESS FOR THE PREPRATION OF ERYTHROMYCIN 9-0-[SUBSTITUTED]-OXIME 2. Alembic Limited Alembic Road; Vadodara-390003 GUJARAT. INDIA The following specification particularly describes and ascertains the nature of the invention, and the manner in which it is to be performed. GRANTED 13-1-2005 i Field of the Invention: The present invention relates to erythromycin derivatives. More particularly; this invention relates to a process for the preparation of Erythromycin -9-0-[Substituted or un substituted aryl alkyl ]-oxime; which is a key intermediate for the preparation of 6-0-methyl erythromycin A (Clarithromycin). The present invention relates to a process for the preparation of [ Formula -I]. BACKGROUND OF THE INVENTION: Previously known methods for the preparation of Clarithromycin include example given in United States patent document no. US 4672109 (equivalent patent EP 0158467), which discloses the preparation of Erythromycin -9-0-[o-(chlorobenzyl)]- oxime from reaction of Erythromycin-9-Oxime and o -Chlorobenzyl chloride. The key intermediate (Formula - I) is prepared by reacting Erythromycin A -9-oxime with o-Chlorobenzyl chloride in the presence of potassium hydroxide and N.N-dimethylformamide which gives low yield of Erythromycin -9-0-[o-(chloro benzyl)]-oxime. [Scheme-1]. A comparative data of some reported methods is given in [table 1]. Erythromycln -9-Oxime Erythromycin-9-0[0-(chloro benzyl Oxime [SCHEME-1 ] US 4680386 (equivalent patent EP 0180415) describes the methods for the preparation of 6-O-Methylerythromycin A derivative and also discloses by reference, the preparation of Erythromycin -9-0-[o-(chloro benzyl)]-oxime. This key intermediate (I) is prepared by the same method as explained above i.e. Reacting Erythromycin-9-oxime with o-Chlorobenzyl chloride in the presence of potassium hydroxide and N,N-dimethylformamide as solvent; which results in 'ow yield. Further it can be understood and demonstrated that owing to the high soiling point of dimethylformamide (151-154), it takes a long time to dry the wet mass isolated from any of the examples above. Further more the above mentioned examples invariably require the product to be purified in order to achieve optimum purity of the substance. This results in higher consumption of energy and engages prolonged process time. We have now evolved a synthetic route for the preparation of Erythromycin -9-0-[substituted or unsubstituted aryl alky! ] -oxime which starts from easily available materials, and employs mild reaction conditions, thus making it suitable for large-scale production. The product thus isolated does not require any purifications neither does it involve prolonged drying time, rendering the claimed process efficient in cost and energy. Table 1: Summary of the Invention The present invention also provides a process for the preparation of the compound of [Formula -I], in which Erythromycin A -9- Oxime of structural [Formula -II] is subjected to treatment with a protecting agent such as substituted or unsubstituted alkyl, so as to yield the Erythromycin -9-0-[substituted or unsubstituted aryl alkyl]-oxime. This explained in Scheme-ll. In Formula-I R is Substituted or unsubstituted Apyl Alkyl. [Formula -II] [Formula-1] [Scheme- II] The present invention also provides a method for preparation of other 9-O-protected derivatives of Erythromycin-9-oxime by using the same method. Other objects and the advantages of the present invention will be apparent from the following descriptions. Detailed Description of the Invention The present invention relates to a method for the preparation of Erythromycin -9-0-[o-(chlorobenzyl)]-oxime and other 9-O-substituted erythromycin 9-oxime derivatives which comprises reacting Erythromycin A - 9 - Oxime with a suitable substituted or unsubstituted aryl alkyl halide in presence of acetonitrile as solvent and alkali metal base such as powdered potassium hydroxide; Sodium Hydride which gives high purity and better yields. The present invention is illustrated in more detail as follows: Erythromycin A-9-Oxime dissolves in a solvent such as acetonitrile; together with substituted or unsubstituted aryl alkyl halide such as o-Chlorobenzyl benzyl chloride and powdered potassium hydroxide; agitated at a temperature between 30°C and boiling point of the solvent to give a compound of Formula I. The amount of acetonitrile as solvent is kept 2 to 20 volumes of the Erythromycin-A-9-Oxime. The process of the present invention is described by the following examples, which are illustrative only and should not be construed as to limit the scope of the reaction in any manner. Example 1 To an agitated slurry of 100 g of Erythromycin A-9-oxime in 500 ml of acetonitrile was added 11.2 gm of solid Potassium hydroxide powder at a temperature of 40°C followed by the addition of 18.56 ml of o-Chlorobenzyl chloride. The reaction was continued for 120 min and reaction progress was followed by thin layer chromatography for determination of reaction completion. The reaction mass was then cooled to RT and 600 ml water was added to the reaction mass under slow agitation. The crystals were filtered and washed with 360 ml of water. The wet mass was dried under reduced orobenzyl pressure to give high yield 109 g (Assay 98% w/w, yields 98%) of Erythromycin -9-0-[o- (chlorobenzyl)]-oxime. Example 2 To an agitated slurry of 10 g of Erythromycin A-9-oxime in 20 ml of acetonitrile was added 1.12 gm of solid Potassium hydroxide powder at a temperature of 40°C to the reaction mass followed by the addition of 2.51 g of benzyl bromide. The reaction was continued for 300 min and reaction progress was followed by thin layer chromatography for determination of reaction completion. The reaction mass was then cooled to RT and 25 ml water was added to the reaction mass under slow agitation. The crystals were filtered and washed with 50 ml of water. The wet mass was dried under reduced pressure to give high yield 10.84 g (Assay 98% w/w, yields 99.4%) of Erythromycin -9-O-benzyl oxime. Example 3 To an agitated solution of 10 g of Erythromycin A-9-oxime in 200 ml of acetonitrile was added 1.12 gm of solid Potassium hydroxide powder at a temperature of 40°C to the reaction mass followed by the addition of 2.36 g of p-chlorobenzyl chloride. The reaction was continued for 240 min and reaction progress was followed by thin layer chromatography for determination of reaction completion. The reaction mass was then cooled to RT and 240 ml water was added to the reaction mass under slow agitation. The crystals were filtered and washed with 100 ml of water. The wet mass was dried under reduced pressure to give high yield 10.95 g (Assay 98% w/w, yields 99.5%) of Erythromycin -9-0-[p-(chlorobenzyl )]-oxime. Example 4 To an agitated slurry of 10 g of Erythromycin A-9-oxime in 50 ml of Acetonitrile was added 0.48 gm of NaH suspension at a temperature of 40°C followed by the addition of 18.56 ml of o-Chlorobenzyl chloride. The reaction was continued for 60 min and reaction progress was followed by thin layer chromatography for determination of reaction completion. The reaction mass was then cooled to RT and 10 ml of methanol was added, contents were agitated for 30 min and 70 ml water was added to the reaction mass under slow agitation. The crystals were filtered and washed with 50 ml of water. The wet mass was dried under reduced pressure to give high yield 10.75 g (Assay 98% w/w, yields 98.58%) of Erythromycin -9-0-[o-(chlorobenzyl )]-oxime. We Claim: 1. A process for the preparation of Erythromycin -9-0-[Substituted]-oxime of Formula III; wherein R = Substituted or unsubstituted alkyl Aryl group ; Comprises reacting Erythromycin A 9-Oxime with aryl alkyl halide using inorganic base in presence of polar aprotic solvents, preferably acetonitrile, wherein the amount of acetonitrile provided is in the ratio of 2:20 by volume of Erythromycin A-9-Oxime. [Formula - III] A process as claimed in claim 1 wherein R is substituted or unsubstituted aryl alkyl. A process as claimed in claim 1 and 2 wherein substituted or unsubstituted aryl alkyl is substituted benzyl. A process as claimed in claim 1, 2 and 3 wherein substituted benzyl is o chloro benzyl chloride. 5. A process as claimed in claim 1 wherein inorganic bases are sodium hydride and potassium hydroxide. 6. A process as claimed in claim 5 wherein inorganic base is preferably potassium hydroxide. Dated this 3rd day of October 2002

Documents:

862-mum-2002-cancelled pages(13-1-2005).pdf

862-mum-2002-claims(granted)-(13-1-2005).doc

862-mum-2002-claims(granted)-(13-1-2005).pdf

862-mum-2002-correspondence 1(15-4-2005).pdf

862-mum-2002-correspondence 2(29-10-2003).pdf

862-mum-2002-correspondence(ipo)-(20-7-2004).pdf

862-mum-2002-form 1(3-10-2002).pdf

862-mum-2002-form 13(13-1-2005).pdf

862-mum-2002-form 19(3-11-2003).pdf

862-mum-2002-form 2(granted)-(13-1-2005).doc

862-mum-2002-form 2(granted)-(13-1-2005).pdf

862-mum-2002-form 3(3-10-2002).pdf

862-mum-2002-power of attorney(6-5-2004).pdf