FORM2
THE PATENTS ACT, 1970(39 of 1970)&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PROCESS FOR PREPARING AZITHROMYCIN
MONOHYDRATE
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY An Indian Company.
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates to process of preparing stable Azithromycin monohydrate of formula (I), by carrying out drying in air under humid conditions. This invention also discloses improved process for preparing Azithromycin monohydrate of formula (I) from Erythromycin A oxime of formula (II). It also discloses the process for preparing amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV), which is useful intermediate for the synthesis of Azithromycin monohydrate of formula (I).

>VCH3 H3CX /CH3
Y^o

H,C

CH3 y OH
Formula (II) CH3

H"sC^ ^CHo
H3C^y \.-,CH3 ^N^
H3C"-. j/^OH \I.-"CHa ,/-OH

J °

H3C,
CH,

''/,

Opv CH3 ^CH3 "CH3
"OH

Formula (IV) CH3
BACKGROUND OF THE INVENTION AND PRIOR ART:
Azithromycin also known as 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A belongs to macrolide class of compounds. It shows activity towards gram-positive and gram-negative bacteria. It is the only marketed 15-membered broad-spectrum semi-synthetic macrolide antibiotic from the group of azalides.
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Several process for preparing Azithromycin monohydrate have been disclosed in prior art for e.g. US Patent No. 4,517, 359 and US Patent No. 4,474, 768. Azithromycin monohydrate produced by these methods is found to be unstable, hygroscopic and thus difficult to handle during formulation.
Thus it is required to have an improved process for preparing stable Azithromycin monohydrate of formula (I), which is simple, cost-effective and easy to handle at commercial scale.
The process for preparing 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin of Formula (IV), as disclosed in US Patent No. 4,328,334 involves reaction of Erythromycin A oxime (II) with sulfochlorides in presence of sodium bicarbonate as base in acetone-water mixtures. After the completion of reaction acetone was removed from the reaction mixture, the pH was adjusted to 5.5 using HCI and extracted repeatedly in methylene chloride. Finally methylene chloride was completely distilled off to obtain 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV). The compound obtained by this process lacks in purity and hence quality of final product i.e. Azithromycin is also affected.
Therefore it is required to have an improved process for preparing 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV), which results in improved yield and purity.
Inventors of following invention have surprisingly found that reaction of Erythromycin A oxime (II) with arene sulphonyl halide of formula (III), in presence of base and water immiscible solvent results in amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV), which has high purity and stability.
OBJECT OF THE INVENTION:
Accordingly the object of the present invention is to provide an improved process for preparing Azithromycin monohydrate of formula (I), by carrying out drying in air under humid conditions.
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Another object of the invention is to provide process for preparing 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV) having high purity and stability.
Also the object of the invention is to provide amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula {N).
Yet another object of the invention is to provide an improved process for preparing Azithromycin monohydrate of formula (I), with high purity by making use of amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV).
Thus it is the object of the present invention to provide simple, cost-effective and easy to handle process for preparing stable Azithromycin monohydrate of formula (I) and its intermediates.
BRIEF DESCRIPTION OF THE DRAWINGS:
Fig. 1 is XRD graph of amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV).
SUMMARY OF THE INVENTION:
According to the object of the present invention, there is provided an improved process for preparation of stable Azithromycin monohydrate of formula (I) comprising of drying Azithromycin monohydrate wet cake in air under humid conditions.
According to another embodiment there is provided process for preparing Azithromycin monohydrate of formula (I) comprising,
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H,C

H3C
HjCfc^V \..,„CH, Nq
HoC. ^CHo
Formula (I) CH3

(a) reacting Erythromycin A oxime of formula (II) or a salt thereof with arene sulphonyl halide of formula (III) R-C6H4-S02-X

./

OH

H3C,

,VCH3 H3C^ --CH3

'OH
HO, H3C°
t o r

"'0 0 CH3

CH3 "Ns1/^0H
Formula (II) CHa
CH3
wherein R is hydrogen, alkyl, halogen or acylamino and X is halogen, in presence of base and water immiscible solvent to give 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV),

'OH

H3C. ^-CH3
"CH3 >T
"OH

»0 CH3
,o-"N/3C"'.
CH,
H* • V<1;
CH3 >^ OH
Formula (IV) CH3
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(b) hydrogenating 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-
homoerythromycin A of Formula (IV), under aqueous acidic condition to give 9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V),

H,C

converting 9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V) to Azithromycin monohydrate of formula (I),
(d) isolating wet cake of Azithromycin monohydrate by conventional method,
(e) drying said isolated wet cake of Azithromycin monohydrate under humid conditions to obtain stable Azithromycin monohydrate of formula (I).
Yet another embodiment of the present invention provides method of preparation of amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of formula (IV) comprising, reacting Erythromycin A oxime (II) or a salt thereof with arene sulphonyl halide of formula (III) R-C6H4-S02-X, wherein R is hydrogen, alkyl halogen or acylamino and X is halogen, in presence of base and a water-immiscible solvent.
There is also provided amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV).
DETAILED DESCRIPTION OF THE INVENTION:
The process for preparing Azithromycin monohydrate of formula (I) comprises,
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H,C
\ N-
H3C»^/ H3C/,, ,l/^>
OH

H3C. CH3
y..u,CH3 ^hT OH \CH-s
,^n3
-OH

.H20

,0>
H,C

H3C,
'"'or N>-p ^CH3
CH3 CH3
OH
CH3 >r^ >
Formula (I) CH3

(a) reacting Erythromycin A oxime of formula (II) or a salt thereof with arene sulphonyl halide of formula (III) R-C6H4-S02-X
,OH
Formula (II)
ACH3 H3C^ ^CH3
wherein R is hydrogen, alkyl, halogen or acylamino and X is halogen, in presence of base and water immiscible solvent to give 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV),

H3C^/

OH

Pl'ibv J*^'*'V..11CH3 .\CH3
-OH

f 0
H,C

CH,

''//

'o' N0g CH3
XCH3
CH3 "OH

Formula (IV) CH3
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(b) hydrogenating 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-
homoerythromycin A of Formula (IV), under aqueous acidic condition to give 9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V),

H
,N \ H3C CH3H3C*V \ CH3 Nl^
"^■..p^OH^"'^
,.--\"'c'Y '"''O^^O^XH,
H3C y ^/\/ CH3
O^N^ 'O" "CH3
1 °\ /k
CH3 y^ OH
1Formula (V) CH3
(c) converting 9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V) to Azithromycin monohydrate of formula (I),
(d) isolating wet cake of Azithromycin monohydrate by conventional method,
(e) drying said isolated wet cake of Azithromycin monohydrate under humid conditions to obtain stable Azithromycin monohydrate of formula (I).
In accordance with step (a) of the present invention, Erythromycin A oxime of formula (II) or a salt thereof is reacted with arene sulphonyl halide of formula (III) R-C6H4-S02-X, wherein R is hydrogen, alkyl, halogen or acylamino and X is halogen, in presence of base and water immiscible solvent. The most preferred example of compound of formula (III) is para-toluene sulphonyl chloride. The base used is selected from group comprising of inorganic bases like alkali earth metal and alkaline earth metal hydroxides or carbonates, or organic base the preferred examples of base include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, ammonia, triethyl amine, pyridine and the like the most preferred being sodium bicarbonate. The water-immiscible solvent is selected from group of methylene chloride, chloroform, carbon tetrachloride and like.
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The reaction is carried out in temperature range of about 0°C to about 10°C. The reaction gets completed in about 4 to about 10 hours. After completion of the reaction the pH of the reaction mixture is adjusted in range of 5 to 6 by using acetic acid and layers are separated. The pH of aqueous layer is adjusted in range of 10 to 12.5 with sodium hydroxide solution. The aqueous layer is further chilled to temperature between 0°C to 15°C when the product precipitates out. The product 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV) is isolated and dried by conventional methods. It is found that the product has amorphous nature. This method avoids use of double solvents for the reaction as required by the process given in prior art.
In accordance with step (b) of the present invention, 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin of Formula A (IV) is hydrogentated under aqueous acidic conditions. The preferred acid used for hydrogenation reaction is selected from group of acetic acid, phosphoric acid, sulphuric acid and like. The hydrogenating agent can be selected from platinum oxide, palladium-carbon, platinum-carbon, rhodium-carbon and like, the most preferred being platinum oxide. The reaction can be carried out at temperatures ranging from 0°C to ambient temperature. The hydrogen pressure can be kept in range of about 2 kg/cm2 to about 10 kg/cm2, more preferably about 4 kg/cm2 to about 6 kg/cm2. The reaction gets completed within 1-24 hours. After the completion of the reaction the catalyst is removed from the reaction mixture by filtration and the pH is adjusted to 10 to 12 using sodium hydroxide solution. The product 9a-deoxo-9a-aza-9a-homoerythrofnycin A of formula (V) gets precipitated out, which can be isolated and dried by conventional methods. The crude product thus obtained can be crystallized from acetone-water mixtures.
9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V) is converted to Azithromycin monohydrate by methylation in accordance with the Eschweiler-Clarke method or by any methods known to person skilled in art. The wet cake thus obtained by isolation of the compound by the conventional method is dried in air under humid conditions. The drying can be carried out in air preferably using air tray dryers.
The humidity in the dryer is maintained above 60%. This can be done either by keeping water trays in the dryer or by passing humid air in the dryer. The temperature is
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maintained below 35°C in order to prevent degradation of the product. The drying is continued till the required moisture content and OVI is obtained. Drying may take from about 5 hours to about 1 week.
The Azithromycin monohydrate of formula (I) obtained by above described process of drying comprises from 2.5% to 6.5% w/w of water. Also it is observed that the ethanol content is less than about 1.5%. The total OVI of the sample is not exceeding 1.5%.
The following examples illustrate the process of the invention, but they are not intended to limit the scope of invention.
Example 1: Preparation of 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A
150 ml of water is chilled to 0-3°C and 19 g of sodium bicarbonate is added to it. 15 g Erythromycin A oxime is added to an aqueous solution of sodium bicarbonate and the reaction mixture is cooled to 0-3° C under stirring. A solution of 75 g p-toluenesulfonyl chloride in 15 ml methylene chloride is then added at 0-3°C and the reaction mixture stirred for about 3 hours at 0 to 3°C. After the completion of the reaction, the pH of the reaction mixture is adjusted to 5 to 6 by the addition of acetic acid under stirring. The aqueous layer is separated and its pH adjusted to 10.0-12.5 with sodium hydroxide solution to precipitate 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A having amorphous nature, which is filtered, washed with water, dried.
Example 2: Preparation of 9a-deoxo-9a-aza-9a-homoerythromycin A
65 g of product obtained in Example 1 is added to 400 ml water and cooled to 0-10°C. Acetic acid is added to adjust the pH to 5-6. 1 g activated charcoal is added to the reaction mixture and it is filtered. The reaction mass is charged in reactor and slurry of 3 g of Pt02 in 50 ml water is added to it. Hydrogenation is carried out under a hydrogen pressure of 2.0 to 5.0 kg/cm2 at 10 to15°C. After the completion of the reaction, the catalyst is removed by the filtration and its pH adjusted to 10-12 with dilute sodium hydroxide solution. Precipitates of 9a-deoxo-9a-aza-9a-homoerythromycin A are filtered, washed with water and dried under vacuum. Crude product is recrystallized from acetone-water mixture.
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Example 3: Preparation of Azithromycin monohydrate (wet cake)
10 g product of Example 2 is added to 200 ml acetonitrile and heated to 40-45°C. 46 ml of (1:1) mixture of formic acid and formaldehyde is added dropwise to the reaction mixture and stirring continued for 20 hours. After completion of the reaction, reaction mixture was filtered and the pH was adjusted to 9-11 by adding sodium hydroxide solution at 40-45°C to obtain precipitates of Azithromycin monohydrate which are filtered and suck dried. The wet cake of Azithromycin monohydrate is dissolved in ethanol and the solution heated to 40-45°C and ethanol is distilled off to obtain thick slurry. Again ethanol is added to the slurry and heated to 40-45°C to obtain clear solution. Then it is cooled to 25-30°C and slowly water is added to obtain Azithromycin monohydrate crystals which are filtered and suck dried.
Example 4: Preparation of stable Azithromycin monohydrate
25 g of the wet cake obtained in Example 3 is spread over ss tray dryers. The humidity of dryer is maintained above 60% by keeping tray of water in the dryer. The temperature of dryer is maintained below 35°C for about 10 hours to obtain stable Azithromycin monohydrate.
M/C: Between 4.0-6.5% w/w
Ethanol content: between 0.75-1.3% w/w
OVI: between 0.75 to 1.5%
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We claim:
1. A process for the preparation of stable Azithromycin monohydrate of formula (I) comprising of drying Azithromycin monohydrate wet cake in air under humid conditions.
H3C

2. A process as claimed in claim 1, wherein the said drying in air is carried out preferably in air tray dryer.
3. A process as claimed in claim 1 and 2, wherein the said humidity is greater than about 60%.
4. A process as claimed in claim 1 and 2, wherein the said humid condition is maintained by keeping water trays in the dryer.
5. A process as claimed in claim 1 and 2, wherein the said humid condition is maintained by passing humid air in the dryer.
6. A process as claimed in claim 1 and 2, wherein the said drying takes place at temperature below 35°C.
7. A process for preparation of Azithromycin monohydrate of formula (I) comprising,
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H,C

H3C»^/

H3C- ^CH3 ...11CH3 ^N OH
'-OH

.H20

H,C
H,C

'"0
3^'/,,
CH,

CHg
XCH3 ~CH3
"OH

Formula (I) CH3
(a) reacting Erythromycin A oxime of formula (II) or a salt thereof with arene sulphonyl halide of formula (III) R-C6H4-S02-X


H3C,
HO, H3C°'
»»°
CH3

./
OH *CH3 BjC^.CHa
'OH H3C,
CH3 "CH3
CH3
'"OYYCH!

Formula (II) CH3
wherein R is hydrogen, alkyl, halogen or acylamino and X is halogen, in presence of base and water immiscible solvent to give 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV),

H3C»^/
H,C

CH3
Formula (IV) CH3

(b) hydrogenating 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-
homoerythromycin A of Formula (IV), under aqueous acidic condition to give 9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V),
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Formula (V) CH3
(c) converting 9a-deoxo-9a-aza-9a-homoerythromycin A of formula (V) to Azithromycin monohydrate of formula (I),
(d) isolating wet cake of Azithromycin monohydrate by conventional method,
(e) drying said isolated wet cake of Azithromycin monohydrate under humid conditions to obtain stable Azithromycin monohydrate of formula (I).

8. A process as claimed in claim 7, wherein the said arene sulphonyl halide of formula (III) R-C6H4-S02-X is p-toluene sulphonyl chloride.
9. A process as claimed in claim 7, wherein the said water-immiscible solvent in step (a) is selected from group of methylene chloride, chloroform, carbon tetrachloride and like, preferably methylene chloride.

10. A process as claimed in claim 7, wherein the said base in step (a) is selected from group comprising of inorganic bases like alkali earth metal and alkaline earth metal hydroxides or carbonates, or organic base selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, ammonia, triethyl amine, pyridine and the like.
11. A process as claimed in claim 7, wherein the said acid in step (b), is selected form acetic acid, phosphoric acid, sulphuric acid and like.
12. A process as claimed in claim 7, wherein the said hydrogenating agent in step (b), is selected from platinum oxide, palladium-carbon, platinum-carbon, rhodium-carbon and like, preferably platinum oxide.
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13. A process as claimed in claim 7, wherein the said drying is carried out in air-preferably using air tray dryers.
14. A process as claimed in claim 7, wherein the said humidity in step (e) is greater than about 60%.
15. A process as claimed in claim 7, wherein the said humid condition in step (e) is maintained by keeping water trays in the dryer.
16. A process as claimed in claim 7, wherein the said humid condition in step (e) is maintained by passing humid air in the dryer.
17. A process as claimed in claim 7, wherein the said drying in step (e) takes place at temperature below 35°C.
18. A process of preparation of amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin of Formula (IV) comprising, reacting Erythromycin A oxime (II) or a salt thereof with arene sulphonyl halide of formula (III) R-C6H4-S02-X, wherein R is hydrogen, alkyl halogen or acylamino and X is halogen, preferably p-toluene sulphonlyl chloride, in presence of base selected from group comprising of inorganic bases like alkali earth metal and alkaline earth metal hydroxides or carbonates, or organic base, selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, ammonia, triethyl amine, pyridine and the like and a water-immiscible selected from methylene chloride, chloroform, carbon tetrachloride and like, preferably methylene chloride.
19.Amorphous9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin of Formula (IV).
<^z
Dated this 29th day of August 2005
S. Majumdar Of S. Majumdar & Co. Applicant's Agent
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A B S T R A CT
Title: PROCESS FOR PREPARING AZITHROMYCIN MONOHYDRATE
The invention relates to process of preparing stable Azithromycin monohydrate of formula (I), by drying in air under humid conditions. It also discloses amorphous 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A of Formula (IV) and its process for preparation, which is an useful intermediate for preparing Azithromycin monohydrate.
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