Description Title of Invention: A COST EFFECTIVE PROCESS FOR

PREPARING 6,9-IMINO ETHER

Field of the invention

[1]

[2] The present invention relates to an improved process for the preparation of 6,9-imino ether of formula (I) an intermediate used in preparation of Azithromycin. The present invention further provides a process for preparation of Azithromycin.

(I)

[4]

Background of the invention

[5]

[6] The chemical name of Azithromycin is

9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A and formula is C ₃₈ H ₇₂ N ₂ Oi ₂ and molecular weight is 748.98. [7] [8] Azithromycin is used as Antibacterial. It belongs to macrolide antibiotic class of drugs. It is Semi-synthetic macrolide and related to erythromycin A. It exists in mainly in two polymorphic form i.e Azithromycin monohydrate and Azithromycin dihydrate.

It is used in bacterial infection and malaria. [9] [10] US patent no. 4,517,359 discloses first time a process for the preparation of

Azithromycin. However it does not mention the preparation of intermediates.

[H]

[12] US patent no. 4,328,334 discloses a process for the preparation of 6,9-imino ether in example- 1. The process involves reacting erythromycin A oxime (II) with p- toluenesulfonyl chloride in the presence of a sodium carbonate and in the presence of acetone and water.

[13]

[14] US patent no. 6,528,492 discloses a process for the preparation of 6,9-imino ether in example 1. The process involves reacting erythromycin A with O-(mesitylenesulfonyl) hydroxylamine (MSH) in acetone in presence of sodium bicarbonate to give 6,9-imino ether. The yield obtained is 75%. [15] [16] WO2007015265 discloses a process for the preparation of 6,9-imino ether. 6,9-imino ether is prepared from Erythromycin thiocyanate without isolating Erythromycin base and Erythromycin oxime and Beckmann's rearrangement of erythromycin oxime is carried in the presence biphasic solvent system comprising methylene chloride and water in the presence of triethylamine along with sodium bicarbonate to obtain 87-96

% pure 6,9-imino ether. [17] [18] In all of the above process, there is no recycling and reuse of the reagent is mentioned. Hence, at industrial scale, at each production cycle new reagents are needed which add up to the overall cost. [19] [20] Therefore, there is a need to develop an easy to operate, industrially feasible, eco- friendly and yet cost effective process for preparing 6,9-imino ether. [21] [22] The research work was directed by the present inventors towards not only improving yield and purity, but also to reduce the overall cost of production of Azithromycin. The present inventors observed that recycling and reuse of reagents will substantially reduce the cost of production of 6,9-imino ether which will result into overall cost reduction for the production of Azithromycin. [23]

Summary of the invention [24] [25] It is therefore an object of the present invention to provide an cost effective process for preparing 6,9-imino ether. [26] [27] Another object of the present invention is to provide a process for preparing highly pure 6,9-imino ether. [28] [29] Another object of the present invention is to provide an improved process which is simple and easy to handle at an industrial scale. [30] [31] Another object of the present invention is to provide an improved process for

preparing Azithromycin.

[32] [33] Accordingly, in one aspect the present invention provides an improved process of preparation of 6,9-Imino ether (I)

(I)

[35] comprising steps of: [36] (i) reacting Erythromycin oxime base (II)

[38] with paratoluenesulfonyl chloroide in the presence of a base in a solvent to for time sufficient for the reaction to take place;

[39] (i) acidifying the reaction mixture and extracting it with organic solvent; [40] (ii) separating aqueous and organic phase; [41] (iii) basifying the aqueous phase obtained in step (ii) and isolating 6,9-Imino ether; [42] (iv) reusing the organic phase obtained hereinabove step (iii) in next production cycle of 6,9-Imino ether.

[43] [44] In another aspect, the present invention provides a process of preparation of Azithromycin (IV)

[45]

(IV)

[46] comprising steps of: [47] (i) reacting Erythromycin oxime base (II)

[49] with paratoluenesulfonyl chloroide in the presence of a base in a solvent to for time sufficient for the reaction to take place;

[50] (ii) acidifying the reaction mixture and extracting it with organic solvent; [51] (iii) separating aqueous and organic phase; [52] (iv) basifying the aqueous phase obtained in step (ii) and isolating 6,9-Imino ether

(I);

[54] (v) reusing the organic phase obtained hereinabove step (iii) in next production cycle of 6,9-Imino ether. [55]

Detailed description of the invention

[56] [57] The present invention provides an improved process of preparation of 6,9-Imino ether (I)

(I)

[59] comprising steps of:

[60] (i) reacting Erythromycin oxime base (II)

[62] with paratoluenesulfonyl chloroide in the presence of a base in a solvent to for time sufficient for the reaction to take place;

[63] (ii) acidifying the reaction mixture and extracting it with organic solvent; [64] (iii) separating aqueous and organic phase; [65] (iv) basifying the aqueous phase obtained in step (ii) and isolating 6,9-Imino ether; [66] (v) reusing the organic phase obtained hereinabove step (iii) in next production cycle of 6,9-Imino ether.

[67] [68] The synthetic reaction scheme of the present invention is as shown in scheme-I.

(IV) Azithromycin (Ill)

[70] Scheme-I [71] [72] In the process of present invention, erythromycin oxime base (II) is reacted with paratoluenesulfonyl chloroide in the presence of a base and in the presence of a solvent at O ⁰ C to 5 ⁰ C. The base is selected from the group of alkali and alkaline earth metal carbonate, bicarbonate and hydroxide. The example of base includes but not limited to NaHCO ₃ , KHCO ₃ , LiHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Li ₂ CO ₃ , CaCO ₃ , MgCO ₃ , NaOH, KOH, LiOH, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, potassium tert-butoxide and the like or mixtures thereof. Para toluenesulfonyl chloroide is dissolved in chlorinated solvent such as dichloromethane. Erythromycin oxime base (II) is added to a pre cooled aqueous solution of base sodium bicarbonate. The Para toluenesulfonyl chloroide solution is added to the reaction mixture at about O ⁰ C to about 5 ⁰ C. The reaction mixture is stirred for time sufficient at the same temperature for the Beckmann reaction to take place. It generally takes about 2 to about 3 hours. The pH of the reaction mixture is adjusted to about 5 to about 6 by using acid. The examples of acid includes but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and the like or mixtures thereof. Aqueous phase and organic phase of the reaction mixture is separated. The aqueous phase is basified using 10% aqueous NaOH solution to pH about 11 to about 12. The solid precipitates are filtered and suck dried. The solid is dried in vacuum oven at about 5O ⁰ C to about 6O ⁰ C to give 6,9-Imino ether. The organic phase obtained is reused in next production

cycle of 6,9-Imino ether. After completion of second production cycle, again an organic phase containing para toluene sulfonyl chloride is obtained which is used for the third production cycle of 6,9-Imino ether. Thus the o rganic phase collected from above production cycles can be recycled and reused up to 8 to 10 production cycles.

[73]

[74] The present invention further provides a process for the preparation of Azithromycin.

The 6,9-Imino ether as obtained by the present invention is reduced with hydrogen gas catalytically in the presence of noble metal catalyst such as Pt, Pd or PtO ₂ to give 9-deoxo-9a-aza-9a-homoerythromycin A which is further methylated at nitrogen atom using formic acid/formaldehyde in the presence of solvent to give Azithromycin.

[75]

[76] The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

[77]

[78] Example-1

[79]

[80] (a) Preparation of 6,9-imino ether

[81]

[82] Para toluene sulfonyl chloride solution was prepared by dissolving Para toluene sulfonyl chloride (49.88 g) in dichloromethane (100 ml). Erythromycin oxime base (100.0 g) was added to a pre cooled aqueous solution of Sodium bicarbonate (13.0 g sodium bicarbonate in 1000 ml water) at O ⁰ C to 5 ⁰ C. Para toluene sulfonyl chloride solution as prepared above was added to the reaction mixture at O ⁰ C to 5 ⁰ C. The reaction mixture was stirred for 2 to 3 hrs at the same temperature. The pH of the reaction mixture was adjusted to 5 to 6 by using hydrochloric acid. The organic phase and aqueous phase were sepearted. The pH of the aqueous phase was adjusted to 11 to 12 using 10% aqueous sodium hydroxide solution. The reaction mixture was stirred for about one hour. The resulting solid was filtered, suck dried and then dried in vacuum oven at 50° to 6O ⁰ C to give the title product (87.0 g)

[83]

[84] The organic phase collected from above reaction is used for next production cycle of

6,9-imino ether.

[85]

[86] (b) Preparation of 6,9-imino ether using recycled para toluene sulfonyl chloride

[87]

[88] Para Toluene sulfonyl Chloride (25.45 g) and dichloromethane (20 ml) was added to the above collected organic phase and stirred well to get clear solution. Erythromycin

Oxime Base (100.0 g) was added to a pre cooled aqueous solution of Sodium bicarbonate (13.0 g sodium bicarbonate in 1000 ml water) at O ⁰ C to 5 ⁰ C. Para toluene sulfonyl chloride solution as prepared above was added to the reaction mixture at O ⁰ C to 5 ⁰ C. The reaction mixture was stirred for 2 to 3 hrs at the same temperature. The pH of the reaction mixture was adjusted to 5 to 6 by using hydrochloric acid. The organic phase and aqueous phase were separated. The pH of the aqueous phase was adjusted to 11 to 12 using 10% aqueous sodium hydroxide solution. The reaction mixture was stirred for about one hour. The resulting solid was filtered, suck dried and then dried in vacuum oven at 50° to 6O ⁰ C to give the title product (88.0 g)

[89]

[90] The organic phase collected from above reaction is used for next production cycle of

6,9-imino ether.

[91]

[92] Example-2

[93]

[94] Preparation of 9-deoxo-9a-aza-9a-homoerythromycin A

[95]

[96] To a mixture of 6,9-imino ether (II) (70.Og) in methanol (700ml) was added acetic acid till pH 5 to 6 is obtained. PtO ₂ (7.Og) in water was added to the above mixture and reduced under hydrogenation condition at hydrogen pressure 8 to 9 kg at 4O ⁰ C to 45 ⁰ C for about 4 to 5 hours. After completion of the reaction the reaction mixture was filtered through hyflobed, washed with methanol. The combined filtrate was distilled under vacuum to evaporate methanol. D. M. water (700ml) was added to the remaining filtrate. The pH of the solution was adjusted to 11 to 12 using aq. Sodium hydroxide solution. The solid precipitated was filtered, suck dried and then dried in oven to give 9-deoxo-9a-aza-9a-homo erythromycin A (III) (55.0g).

[97] Yield: 85%

[98]

[99] Example-3

[100]

[101] Preparation of Azithromycin

[102]

[103] 9-Deoxo-9a-aza-9a-homoerythromycin A (III) (73.5g) was dissolved in acetone

(250ml). To this solution formic acid (19ml) followed by formaldehyde (37%, 20ml) were added and refluxed for 24 hrs. The pH of the reaction mixture was adjusted with alkali to 10.5 and filtered to remove particles. To the filtered acetone solution equal volume of water was added to precipitate azithromycin (IV). The crystals were filtered and dried under vacuum at 5O ⁰ C to give the title product (65g).