WO2007029266A2

WO2007029266A2 - A process for preparing 9-deoxo-9a-aza-9a-homoerythromycin a

Info

Publication number: WO2007029266A2
Application number: PCT/IN2006/000179
Authority: WO
Inventors: Hire Chandrabhan Madav; Sabade Kishore Balaji; Ambre Rajesh Vishwanath
Original assignee: Kopran Research Laboratories Ltd
Priority date: 2005-05-24
Filing date: 2006-05-24
Publication date: 2007-03-15
Also published as: WO2007029266A3

Abstract

The invention relates to a process for preparing ϑ-Deoxo-ϑa-aza-ϑa-homoerythromycin A of formula (III), which is an intermediate in the preparation of Azithromycin dihydrate.

Description

TITLE OF THE INVENTION

A process for preparing 9-Deoxo-9a-aza-9a-homoerythromycin A

Field of the Invention

The invention relates to a process for preparing 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (III).

Formula (III) The invention also relates to a process for preparing Azithromycin dihydrate of formula (I).

Formula (I)

Background of the invention

Azithromycin is a semi-synthetic macrolide antibiotic chemically related to ' Erythromycin. Azithromycin is a broad-spectrum bactericide and effective against a wide variety of microorganisms, such as Hemophilus influenzae, Streptococcus pneumoniae, Mycoplasma pneumoniae, Staphylococcus aureus, and Mycobacterium avium, and many others.

The transformation of Erythromycin A into Azithromycin comprises the conversion of Erythromycin into its oxime; Beckmann's rearrangement of the Erythromycin oxime into 6,9-Imino ether; hydrogenation of the 6,9-Imino ether to 9-deoxo-9a-aza-9a-homoerythromycin A and further reductive methylation to obtain Azithromycin.

Oxime of Erythromycin base is prepared by treating it with hydroxylamine hydrochloride in methanol. Beckmann's rearrangement of Erythromycin Oxime with p-Toluene sulfonyl chloride in aqueous acetone producing 6,9-Imino ether is very well documented in WO 94/26758, EP 0,137,132 and US 4,328,334. The stable hydrate form of 6,9-Imino ether and its process of preparation are disclosed in WO 00/27856.

The hydrogenation of 6,9-Imino ether to a secondary amine, 9-Deoxo-9a-aza-9a-homoerythromycin A, is carried out by using sodium borohydride in Methanol which is disclosed in J. Chem. Soc. Perkin Trans. 1, 1986, 1881; J. Org. Chem. 1997, 62, 7479-7481; US 4,328,334; US 5,869,629; International publications WO 01/00640; WO 03/082889 and WO 03/102009; or by catalytic hydrogenation in the presence of platinum dioxide and acetic acid as solvent, which is disclosed in Tetrahedron lett. 1994, 35, 3025; International publications WO 94/26758 and WO 03/102009; or by catalytic hydrogenation in the presence of platinum over carbon (Pt /C) or rhodium over carbon (Rh /C) at 3-10 atm in solvent consisting of water-acetic acid-methanol mixture, which is disclosed in US 4,328,334; US 5,869,629; and EP 0,879,823. Particularly, US 5,869,629 describes the process for hydrogenation of 6,9-Imino ether at low pressure and low temperature in presence of equal quantity of platinum with respect to 6,9-Imino ether to obtain 9-Deoxo-9a-aza-9a- homoerythromycin A in 12 to 13 hours. International publication WO 03/102009 describes hydrogenation of 6,9-Imino ether with platinum / carbon in water as solvent to which acid is added to adjust the pH till 4 followed by crystallization to obtain 9-Deoxo-9a-aza-9a-homoerythromycin A in crystalline form. The acid used here can be chosen from hydrochloric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, formic acid, preferably Phosphoric acid. The amount of catalyst used in this international publication is 50 to 10 % on the weight of 6,9-Imino ether.

Reductive methylation of the secondary Amine, 9-Deoxo-9a-aza-9a-homoerythromycin A is carried out to obtain Azithromycin. This process is described in US 4,517,359 and J. chem. Res. 1998, 132, which consists basically of the Escheweiler-Clarke reaction and uses formaldehyde in acetic acid or formaldehyde, and formic acid in carbon tetrachloride or chloroform for methylation.

Further EP 0,879,823 discloses preparation of Azithromycin from 6,9-Imino ether by carrying out the hydrogenation and reductive methylation sequentially with the noble, catalyst and hydrogen in the presence of formaldehyde. In this patent, the preferred catalyst is 5 % rhodium over carbon but platinum, palladium or rhuthenium, can also be used.

Further the product isolated in the prior art is Azithromycin in either monohydrate form or Azithromycin crude which has to be converted into its dihydrate form by crystallization, which is pharmaceutically acceptable form.

Objects of the invention

An object of the invention is to provide a process for preparing 9-Deoxo-9a-aza-9a- homoerythromycin A, which is an intermediate of Azithromycin dihydrate, where hydrogenation of 6,9-Imino ether to 9~Deoxo-9a-aza~9a-homoerythromycin A is carried out with at least 85 % conversion within 2 to 3 hours.

Another object of the invention is to provide most efficient process for preparing 9-Deoxo-9a-aza- 9a-homoerythromycin A.

Yet another object of the invention is to provide the process for preparation of Azithromycin dihydrate from 9-Deoxo-9a-aza-9a-homoerythromycin A.

Detailed description of the invention

The present invention discloses a process for preparing 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (III),

Formula (III)

which is an intermediate in the preparation of Azithromycin dihydrate of formula (I)

Formula (I) comprising hydrogenating 6,9-Imino ether of formula (II)

Formula (II) in the presence of methanol as a solvent, to which 70 % perchloric acid is added to adjust the pH to 5.5 in presence of Pt/C catalyst at temperature in the range of 30-50° C and pressure in the range of 10-14 kg/cm² to achieve atleast 85 % conversion of 6,9-imino ether to 9-Deoxo-9a-aza-9a- homoerythromycin A within 2-3 hours.

20 % by wt of the Pt/C catalyst is used in hydrogenation of 6,9-Imino ether with respect to 6,9-Imino ether. The Pt/C catalyst used in the hydrogenation of 6,9-Imino ether is either fresh or reactivated Pt/C catalyst along with fresh catalyst in the ratio of 98:2. The reactivated catalyst is prepared by isolating spent Pt/C catalyst from the hydrogenation of 6,9-Imino ether by filtration; reactivating the wet spent Pt/C catalyst by treating the same with strong acid till pH 3-6 while stirring; washing the treated catalyst with aqueous sodium carbonate solution followed by washing with hot water (55° C) till the pH of washing is neutral. The hydrogenation of 6,9-Imino ether is preferably carried out at temperature in the range of 40-45° C and pressure in the range of 13 to 14 kg/cm².

The time required for hydrogenation of 6,9-Imino ether to 9-Deoxo-9a-aza-9a-homoerythromycin A with atleast 85 % conversion and 90 % purity is 2-3 hours.

The present invention also discloses a process for preparing Azithromycin dihydrate of formula (I)

Formula (I)

comprising a) methylating the 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (III)

Formula III obtained by hydrogenating 6,9-Imino ether as per the invention, with formaldehyde and formic acid in presence of acetone or lower chain alcohol comprising methanol, ethanol or isopropanol as a solvent to obtain Azithromycin dihydrate of formula (I)

Formula I b) isolating the Azithroimycin dihydrate of formula (I)

Formula I from methylation of 9-Deoxo-9a-aza-9a-homoerythromycin A mixture, and c) purifying the Azithromycin dihydrate.

Azithromycin dihydrate is isolated in step (b) by separating acetone/ alcohol layer from the methylation of 9-Deoxo-9a-aza-9a-homoerythromycin A mixture followed by adding water to the acetone / alcohol layer within 12 hour while stirring, further stirring the mixture at 20° C for 12 hours; filtering the Azithromycin dihydrate of formula (I); washing the Azithromycin dihydrate with water and drying Azithromycin dihydrate at 65° C.

The alcohol / acetone to water ratio used to isolate Azithromycin dihydrate is atleast 1:2.3 v/v.

Azithromycin dihydrate is purified in step (c) by dissolving Azithromycin dihydrate in a solvent like acetone or lower chain alcohol comprising methanol, ethanol or isopropanol with stirring, adding charcoal to the solution with stirring, filtering the solution to obtain filtrate, adding water to filtrate at 50°-55°C, cooling aqueous filtrate to room temperature, chilling the aqueous filtrate to 0 to 5° C, filtering Azithromycin dihydrate from the aqueous filtrate; washing Azithromycin dihydrate with chilled water and drying Azithromycin dihydrate at 65° C.

The alcohol / acetone to water ratio used to purify the Azithromycin dihydrate is at least 1:6 v/v.

Particularly, the process for preparing 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (III) comprising hydrogenating the 6,9-Imino ether of formula (II) comprising dissolving the 6,9-Imino ether in methanol, cooling the reaction mixture at temperature 5-6° C; adjusting the pH of the reaction mixture to 5.5 with 70 % perchloric acid; hydrogenating the reaction mixture with Pt/C catalyst at temperature 30-50° C and pressure 10-14 kg/cm²; filtering the reaction mass; distilling out the methanol from the reaction mass to obtain residue, adding water to the residue, adjusting the pH of the reaction mass by adding 5 % aqueous sodium hydroxide solution; and filtering out the 9- Deoxo-9a-aza-9a-homoerythromycin A, followed by washing 9-Deoxo-9a-aza-9a- homoerythromycin A with water and drying at 65° C;

Particularly, the process for preparing highly pure Azithromycin dihydrate of formula (I)

Formula I without formation of Azithromycin monohydrate comprises the following steps: a) methylating the 9-Deoxo-9a-aza-9a-homoerythromycin A of foπnula (III)

Formula III

comprising dissolving the 9-Deoxo-9a-aza-9a-homoerythromycin A in solvent as lower chain alcohol or acetone; adding formic acid and formaldehyde mixture at 40° C; adjusting the pH with sodium hydroxide solution to 11 to 11.5 to obtain Azithromycin dihydrate in methylation mixture of 9-Deoxo-9a-aza-9a-homoerythromycin A;

b) Isolating Azithromycin dihydrate comprising giving charcoal treatment to the methylation mixture of 9-Deoxo-9a-aza-9a-homoerythromycin A; separating the alcohol or acetone layer from the reaction mixture; adding water to the alcohol / acetone layer within 12 hours; stirring the reaction mixture for 12 hours at 20° C; and filtering Azithromycin dihydrate of formula (I)

Formula I washing Azithromycin dihydrate with water and drying Azithromycin dihydrate at 65° C; and c) Purifying the Azithromycin dihydrate comprising dissolving Azithromycin dihydrate in a solvent like acetone or lower chain alcohol with stirring, adding the charcoal to the solution with stirring, filtering the solution to obtain filtrate, adding water to filtrate at temperature in the range of 50°-55°C, cooling the mixture to room temperature, chilling the mixture to 0° to 5° C, filtering the mixture to obtain Azithromycin dihydrate; washing the Azithromycin dihydrate with chilled water and drying the product.

Thus the invention provides an efficient process of hydrogenation of 6,9-Imino ether to 9-Deoxo-9a- aza-9a-homoerythromycin A with 85 % conversion within 2-3 hour. Further the invention provides Azithromycin dihydrate of pharmaceutically acceptable quality by methylating 9-Deoxo-9a-aza-9a- homoerythromycin A without formation of Azithromycin monohydrate and the process for preparing the same.

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

Example IA

Preparation of 6,9-Imino ether

To 100 gm of Erythromycin thiocynate, 450 ml of methylene chloride was added at 25⁰C. To this, 100 ml of Liquid ammonia was added and reaction mixture was stirred till it gets cleared solution. Once the reaction mixture was cleared, the layers were separated and organic layer was collected. Methylene chloride of organic layer was completely distilled off to obtain residue. To the residue, 100 ml of methanol was added followed by addition of 32 ml of triethylamine and 43.7 gm of hydroxylamine hydrochloride. Reaction mixture was stirred at room temperature for 10 minutes and then the reaction mixture was refluxed for 25 hours. The reaction mixture was cooled to 55⁰C and the solvent was distilled off from the reaction mixture. Reaction mixture was further cooled to room temperature and 460 ml of methylene chloride was added to it. The pH of the reaction mixture was adjusted to 9.8 to 10.0 by adding ammonia. Organic layer was separated from the reaction mixture and washed the organic layer with water. The organic layer was cooled to 0° to 3⁰C. Chilled Sodium bicarbonate solution (1.24 % w/v) was added to the reaction mixture followed by addition of p- toluene sulfonyl chloride solution (50 gm of p-toluene sulfonyl chloride + 100 ml methylene chloride) at 0° to 3°C and then reaction mixture was stirred for 2 hours at the same temperature. The pH of the reaction mixture was adjusted to 5.4 to 5.5 by adding acetic acid. Organic layer was separated from the reaction mixture. pH of aqueous layer of the reaction mixture was adjusted to 12 to 13 by adding Sodium hydroxide solution at 30° C. 6,9-Imino ether was filtered from the reaction mixture. The 6,9-Imino ether was washed with water and dried at 50 to 60⁰C. The yield and purity of 6,9-imino ether was 90% w/w and 95 %.

Example IB(A)

Hydrogenation of 6,9-Imino ether to 9-Deoxo-9a-aza-9a-homoerythromycin A (Using Fresh catalyst)

To the 650 ml of methanol, 100 gm of 6,9-Imino ether (prepared according to example IA) was added. The methanolic solution of 6,9-Imino ether was filtered after Charcoal treatment. The filtrate was chilled to 5° to 6°C. To this mixture, 70% perchloric acid solution was added to adjust the pH of the reaction mixture to 5.5. 20 gm of Pt/C catalyst was added to the reaction mixture. The reaction mixture was flushed with N₂ and then with H₂. The hydrogenation was carried out at temperature of 42° C and pressure of 14 kg/cm² with stirring for 3 hours. The reaction was monitored by HPLC. The spent catalyst was filtered from the reaction mixture. Methanol was distilled out from the reaction mixture to obtain residue. 700 ml of water was added to the residue. The pH of the residue was adjusted with 5 % aqueous sodium hydroxide solution to 12-12.5. The precipitated 9-Deoxo-9a-aza- 9a-homoerythromycin A was filtered and washed with water. The product thus obtained was dried at 65° C. The yield and purity of 9-Deoχo-9a-aza-9a-homoerythromycin A was 86.6 % and 91%.

Example IB(B) Hydrogenation of 6,9-Imino ether to 9-Deoxo-9a-aza-9a-homoerythromycin A

(Using Pt/c catalyst comprising reactivated Pt/C catalyst along with the fresh catalyst in the ratio of 98:2)

To the 650 ml of methanol, 100 gm of 6,9-Imino ether (prepared according to example IA) was added. The methanolic solution of 6,9-Imino ether was filtered after Charcoal treatment. The filtrate was chilled to 5° to 6°C. To this mixture, 70% perchloric acid solution was added to adjust the pH of the reaction mixture to 5.5. 20 gm of Pt/C catalyst comprising reactivated catalyst along with fresh catalyst in the ratio of 98:2 was added to the reaction mixture. The reaction mixture was flushed with N₂ and then with H₂. The hydrogenation was carried out at temperature of 42° C and pressure of 14 kg/cm² with stirring for 3 hours. The reaction was monitored by HPLC. The spent catalyst was filtered from the reaction mixture. Methanol was distilled out from the reaction mixture to obtain residue. 700 ml of water was added to the residue. The pH of the residue was adjusted with 5 % aqueous sodium hydroxide solution to 12-12.5. The precipitated 9-Deoxo-9a-aza-9a- homoerythromycin A was filtered and washed with water. The product thus obtained was dried at 65° C. The yield and purity of 9-Deoxo-9a-aza-9a-homoerythromycin A was 91.5 % and 91%.

9-Deoxo-9a-aza-9a-homoerythromycin A was characterized by IR (Refer Figure 1 of the Accompanying drawing).

Example 1C

Preparation of Azithromycin dihydrate

To the 300 ml of acetone, 100 gm 9-Deoxo-9a-aza-9a-homoerythromycin A (prepared according to Example IB) was added. The mixture of 17.49 ml of formic acid and 17.49 ml of formaldehyde was prepared. This mixture was added to 9-Deoxo-9a-aza-9a-homoerythromycin A solution within 5 to 6 hours at 40° C. The reaction was monitored for 2 hours at 40° to 45° C. The pH of the reaction mixture was adjusted to 11 to 11.5 by adding sodium hydroxide solution. The charcoal treatment was given to reaction mixture. The acetone layer was separated from the reaction mixture. To the acetone layer, 650 ml water was added within 12 hour while stirring. The mixture was stirred at 20° C for 12 hours. After the completion of reaction, Azithromycin dihydrate was filtered and washed with water. Azithromycin dihydrate was dried at 65° C. The yield and purity of the Azithromycin dihydrate was 87 % and 98 %. Example 1 D

Purification of Azithromycin dihydrate

To 10 gm of Azithromycin dihydrate, 30 ml acetone was added for 30 minutes with stirring till the clear solution obtained. 0.3 gm charcoal was added to this solution and the mixture was stirred for 30 minutes and subsequently filtered. To the filtrate, 180 ml of water was added at 50° to 55° C within 12 hour. The aqueous filtrate was cooled to room temperature and then chilled to 0° to 5° C. Azithromycin dihydrate was filtered from the aqueous filtrate and washed with chilled water (0° to 5° C). Azithromycin dihydrate was dried at 65° C. The yield and purity of Azithromycin dihydrate was 95 % and 100 %.

Azithromycin dihydrate was characterized by IR (Refer Figure 2 of the Accompanying drawing).

Claims

1. A process for preparing 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (III),

Formula (III) which is an intermediate in the preparation of Azithromycin dihydrate of formula (I)

Formula (I) comprising hydrogenating 6,9-Imino ether of formula (II)

Formula II in the presence of methanol as a solvent, to which 70 % perchloric acid is added to adjust the pH to 5.5 in presence of Pt/C catalyst at temperature in the range of 30°-50° C and pressure in the range of 10-14 kg/cm² to achieve atleast 85 % conversion of 6,9-Imino ether to 9-Deoxo- 9a-aza-9a-homoerythromycin A within 2-3 hours.

2. The process as claimed in claim 1, wherein 20 % by wt of the Pt/C catalyst is used in the hydrogenation of 6,9-Imino ether with respect to 6,9-Imino ether.

3. The process as claimed in claims 1 to 2, wherein the Pt/C catalyst is either fresh catalyst or Pt/C catalyst comprising reactivated catalyst along with the fresh catalyst in the ratio of 98:2.

4. The process as claimed in claim 1, wherein the hydrogenation of 6,9-Imino ether is carried out preferably at temperature in the range of 40°-45° C and pressure in the range of 13 to 14 kg/cm².

5. A process for preparing Azithromycin dihydrate of formula (I)

Formula (I) comprising a) methylating the 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (III)

Formula III obtained according to any one of claim 1 to 4, with formaldehyde and foπnic acid in presence of acetone or lower chain alcohol comprising methanol, ethanol or isopropanol as a solvent to obtain Azithromycin dihydrate of formula (I)

Formula I b) isolating the Azithromycin dihydrate of formula (I)

Formula I by separating acetone/ lower chain alcohol layer from the methylation of 9-Deoxo-9a- aza-9a-homoerythromycin A mixture, followed by adding water to the acetone / alcohol layer within 12 hour while stirring, further stirring the mixture at 20° C for 12 hours; filtering the Azithromycin dihydrate of formula (I)

Formula I washing the Azithromycin dihydrate with water and drying the Azithromycin dihydrate at 65° C, and c) purifying the Azithromycin dihydrate by dissolving it in a solvent like acetone or lower chain alcohol comprising methanol, ethanol or isopropanol with stirring, adding charcoal to the solution with stirring, filtering the solution to obtain filtrate, adding water to filtrate at 50°-55°C, cooling aqueous filtrate to room temperature, chilling the aqueous filtrate to 0° to 5° C, filtering Azithromycin dihydrate from the aqueous filtrate; washing the Azithromycin dihydrate with chilled water and drying Azithromycin dihydrate at 65° C.

6. The process as claimed in claim 5, wherein the lower chain alcohol / acetone to water ratio used to isolate Azithromycin dihydrate is atleast 1:2.3 v/v.

7. The process as claimed in claim 5, wherein the lower chain alcohol / acetone to water ratio used to purify the Azithromycin dihydrate is at least 1:6 v/v.

8. 9-Deoxo-9a-aza-9a-homoerythromycin A of formula III

Formula III prepared by the process as claimed in any one of claim 1 to 4.

9. Azithromycin dihydrate of formula I

Formula I prepared by the process as claimed in any one of claim 1 to 7.