FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention - AN IMPROVED PROCESS FOR SYNTHESIS OF 10-
DIHYDRO-10-DEOXO-11 - AZAERYTHROMYCIN A
2. Applicant(s)
r
(a) NAME : LUPIN LIMITED
(b) NATIONALITY : AN INDIAN
(c) ADDRESS : 159, CST Road, Kalina, Santacruz (East), Mumbai 400 098, Maharashtra, 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 THE INVENTION
The present invention relates to an improved process for preparing 10-dihydro-10-deoxo-11-azaerythromycin A of the formula (I) from its precursor iminoether of formula (II) by catalytic hydrogenation at an ambient temperature and low pressure in presence of polyhalogenated alkanes, for example, chloroform.
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In the process of the present invention the hydrogenated product (I) is converted to azithromycin of formula (III) by conventional Eschweiler-Clarke procedure.


BACKGROUND OF THE INVENTION
10-Dihydro-l0-deoxo-l1-azaerythromycin A of the formula (I) (CAS registration number 76801-85-9) is the ultimate intermediate of the macrolide antibiotic azithromycin (N-methyl-11 -aza-10-deoxo-l0-dihydroerythromycin A) of the formula (III). The compound of formula (I) is converted to azithromycin of formula (III) by N-methylation (US 4,517,359).
Synthesis of 10-Dihydro-l0-deoxo-ll-azaerythromycin A of the formula (I) from 6,9-iminoether of formula (II) is well described in the art either (i) by reduction with sodium borohydride in methanol (J. Chem. Soc. Perkin Trans. 1, 1986, 1881; J. Org. Chem. 1997, 62, 7479-7481) or (ii) by catalytic.hydrogenation (J. Ghem. Soc.Perkin Trans. 1, 1986,1881).
Catalytic hydrogenation processes for the iminoether of the formula (II) described in J. Chem. Soc. Perkin Trans. 1, 1986, 1881 discloses the use of PtO2, at a pressure of 70atm (~1028psi) at room temperature. Since it is a high-pressure process, it requires high capital expenditure.
Various other catalytic processes reported in the prior art for the conversion of ,(II) to (I) are summarized below.
US 4,328,334 discloses the use of noble metal catalysts like Rh/C or PtO2 and aqueous acetic acid as medium for catalytic hydrogenation. This process requires high hydrogen gas pressure of 65-70atm (~955-1028psi) at ambient temperature.
US 5,869,629 describes a hydrogenation process using the catalyst Pt/C in a mixture of an aqueous acid, e.g. hydrochloric or acetic acid, and an alcohol, e.g. methanol. Though a lower pressure of 75psi was used to accomplish the reaction, this process has major
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drawbacks like the use of acidic condition, very high catalyst load (100% weight basis with respect to the iminoether), and high reaction completion time of 12hrs.
WO 94/26758 describes use of PtO2 as the catalyst and acetic acid as medium. But here also the rate of hydrogenation is slow requiring about 48hrs for completion of the reaction.
US 6,528,492 reports the use of Raney Nickel W6 containing 10-11% aluminum as catalyst but no enabling disclosure has been provided.
WO 02/44193 Al describes catalytic hydrogenation in alcohol-water mixture. Though the process uses relatively lower pressure (less than 5bar, i.e., 72.5psi) at 35°C but suffers from the drawback of adjusting specific pH of 5.7 or 5.8 with hydrochloric or perchloric acid. In addition, the catalyst loading is also relatively high, e.g., 19-20% weight basis, with respect to the iminoether of formula (II).
WO 2003/102009 describes and claims the process of hydrogenation with Pt/C in aqueous phosphoric acid at pH 4-4.5, but again suffers from the disadvantage of using acidic condition, high hydrogen pressure of l0-40bar (~145-580psi) and longer reaction time of 12-24hrs.
Thus it is obvious from the prior art that all the methods suffer from one or other following disadvantages:
(a) High hydrogen pressure,
(b) High catalyst load vis-a-vis the substrate (II),
(c) Use of strong acids leading to impurity formation in higher proportions since the compounds (II) and (I) are vulnerable to acidic conditions because of the presence of large number of secondary and tertiary alcoholic functions iand sugar-linkages in the macrolide structure, and
(d) Acidic condition would call for special material of construction of the reactor, thereby increasing the capital expenditure.
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Moreover the impurities thus formed are difficult to remove from the final product azithromycin (III) to attain pharmaceutically acceptable quality.
Hence there is a need to provide a process which eliminates the shortcomings of the prior art mentioned hereinbefore, thus providing a process for the manufacture of azithromycin (III) in the most cost-effective manner.
OBJECTS OF THE INVENTION
Thus the basic object of the present invention is to provide a process not only free from the shortcomings mentioned hereinbefore but also to develop an easily operable process for catalytic hydrogenation of the iminoether of formula (II) for the preparation of 10-Dihydro-10-deoxo-11 -azaerythromycin A of the formula (I).
A further object is to provide a process which is cost effective, avoids additional unnecessary unit process like pH adjustment and also avoids the use of high hydrogen pressure, thereby resulting in lower capital cost, less hazards and consequently more amenable to large scale synthesis.
The present invention is thus specifically useful in developing an economically viable and technologically superior process for manufacture of azithromycin from compound of formula (I).
SUMMARY OF THE INVENTION
Thus according to the main aspect of the present invention there is provided an improved method of preparation of compound of formula (I) by catalytic hydrogenation of the iminoether of the formula (II) with relatively lesser quantity of catalyst with Tespect to iminoether in presence of a polyhalogenated alkane.
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10-Dihydro-l,0-deoxo-l1-azaerythromycin A of the formula (I), so prepared from the iminoether (II), is then converted to Azithromycin of formula (III) by conventional methods reported in the art.

DETAILED DESCRIPTION OF INVENTION
The catalytic hydrogenation process of converting the imnoether of formula (II) to the compound of formula (I) requires the presence of acid for faster and easier reduction.
Use of strongly acidic condition during hydrogenation leads to formation of appreciable quantity of impurities.
However, J, Org. Chem., Vol. 37, No. 2, 1972, pages 335-336 provides a method for the preparation of amine hydrochlorides from azides, nitriles, oximes and nitro compounds
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by catalytic hydrogenation of these compounds in a solvent containing a small amount of chloroform.
Presumably, upon hydrogenolysis, chloroform generates hydrogen chloride in situ necessary for the protonation.
However, this publication does not provide a process for reducing the iminoether of formula (II) for the preparation of 10-Dihydro-10-deoxo-11-azaerythromycin A, a highly acid sensitive substrate. It has to be emphasized here that there is a considerable difference between the compounds used as substrates in the prior art and that of the present invention. Most importantly, the substrate of the present invention is a macrolide having several secondary and tertiary alcoholic functionalities which are not affected in the catalytic hydrogenation mentioned herein. Nowhere in the prior art the catalytic hydrogenation on such type of macrolide moiety containing iminoether functionality is reported.

It has been stated that the reaction is facilitated by the presence of hydrogen ions in the reaction mass, but only to a desired concentration which is achieved by the addition of
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Accordingly, the present inventors have developed a process for the catalytic hydrogenation in presence of a polyhalogenated alkane of iminoether of formula (II) to prepare 10-Dihydro-10-deoxo-l 1-azaerythromycin A of the formula (I) without adding external acidic substances (SCHEME-1).

polyhalogenated alkanes like chloroform to the reaction mass. Correspondingly the hydrogen halide formed in situ combines with the amine of formula (I) once it is formed in the reaction.
The product of the formula (I) is then recovered from the reaction mass by removing the catalyst, concentrating the filtrate, dissolving the product in water and finally rendering the reaction mass alkaline, when the product precipitates.
The polyhalogenated alkanes employed in the present invention is selected from chloroform, bromoform, and a mixture thereof, the most preferable being chloroform.
The polyhalogenated alkane of the present invention is added to a solution of the 6,9-iminoether of formula (II) at an ambient temperature. The threshold ratio of the iminoether (II) to polyhalogenated alkane, when the reaction proceeds slowly, is at the mole proportion of 1:0.75. Below this threshold ratio the reaction is very sluggish. On the other hand, when the ratio of the iminoether (II) to polyhalogenated alkane is greater, for example, about 1:3, the specificity decreases leading to more impurity formation. However, the preferred mole proportion of the iminoether (II) to polyhalogented alkanes ranges from 1:1 to 1:1.2 as the impurity formation is very low as well as the rate is moderately faster to complete the reaction in 5-6hrs.
The solution is prepared by dissolving the said 6,9-iminoether in an organic solvent suitable for catalytic hydrogenation. Solvents preferred in the present invention are Cl-C6 straight or branched chain alcohols or a mixture thereof. Particularly, the solvents of interest are methanol, ethanol and isopropanol or mixtures, though this does not exclude the possibility of utilizing other organic solvents employed for conventional catalytic hydrogenation.
However, ethanol is the most preferred solvent for the present invention. When ethanol is used as a solvent, it may be either absolute ethanol or industrial alcohol. When isopropanol is the solvent, larger volume of isopropanol is required to dissolve the
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substrate as well as the reaction rate decreases slightly. On the other hand, when
methanol is used as the solvent, the formation of side products increases. '
As mentioned hereinbefore, use of the polyhalogenated alkanes affords the catalytic hydrogenation of iminoether of formula (II) with a relatively lower catalyst loading with respect to the iminoether. For example, 10-15% (dry weight basis) catalyst loading with respect to the iminoether effectively completes the reaction within 5-6hrs. A minor change in the reaction rate is noticed with respect to the catalyst loading. A commonly used catalyst like 5% Platinum on carbon is used herein. However, other conventional catalysts known in the art like Ni, Raney-Ni, Pt, Pd are not excluded.
As mentioned hereinbefore, the hydrogenation process of the present invention is carried out at low hydrogen pressure in comparison to that described in the art. In fact, catalytic' hydrogenation process of the present invention is accomplished at a hydrogen pressure ranging from about 50psi to about 250psi, more preferably from about 125psi to 200psi and most preferably from about 150psi to about 180psi. Interestingly the present inventors have found that the reaction rate increases with the hydrogen pressure.
Most conveniently, the catalytic hydrogenation of the present invention is effected at an ambient temperature of 25-40°C.

Furthermore, the said catalytic hydrogenation is effected without adding any external acidic substances and hence avoids harsh acidic conditions responsible for degradation of the unstable intermediates as mentioned earlier.
The compound of formula (I) is further converted to azithromycin of formula (III) by conventional methods like Eschweiler-Clarke methylation procedure, well known in the art.
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The invention is now described more explicitly in the following examples in which Example-1 is presented as a comparative or reference example to illustrate that the reaction does not progress in the absence of polyhalogenated alkanes.
EXAMPLES
Example-1 : Catalytic hydrogenation of 6,9-iminoether in absence of any polyhalogenated alkane
lOg (0.0137 mole) of the iminoether of the formula II was dissolved in 50ml ethanol. 2.2g of 5% Pt/C catalyst containing 50-60% moisture was added to it. The mixture was hydrogenated at 30-35°C under 150psi for about 6hrs. HPLC analysis of the reaction mass showed that there was no progress of the reaction. The reaction mass was filtered through celite and the filtrate was concentrated to recover 9g of the starting material.
Example-2: Preparation of 10-Dihydro-l0-deoxo-11-azaerythromycin A by catalytic hydrogenation of 6,9-iminoether in presence of chloroform, in ethanol
50g (0.0684 mole) of the iminoether of the formula II was dissolved in 250ml ethanol. llg of 5% Pt/C catalyst containing 50-60% moisture and lOg (0.084 mole) of chloroform were added to it. The mixture was hydrogenated at 30-35°C under 150psi. The reaction was monitored by HPLC and completed in 5-6hrs. The catalyst was filtered and the filtrate was evaporated to yield a semisolid residue. The residue was dissolved in water. Liquor ammonia was added to the solution at 25-35°C to adjust the pH between 9 and 10. The slurry was stirred for 30min. The white solid was then filtered and vacuum dried (500-600 mm/Hg vacuum) at 50-5 5 °C to furnish 40g of the title compound 10-dihydro-10-deoxo-l 1-azaerythromycin A. Yield: 79.6%, purity by HPLC 85%.
Example-3: Preparation of 10-Dihydro-10-deoxo-l 1-azaerythromycin A by catalytic hydrogenation of 6,9-iminoether in presence of higher quantity of chloroform (1:3 mole equivalent): impurity formation
15g (0.0205 mole) of the iminoether of the formula II was dissolved in 75ml industrial ethanol. 3.3g of 5% Pt/C catalyst containing 50-60% moisture and 7.3g (0.0612 mole) of
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chloroform were added to it. The mixture was hydrogenated at 30-35°C under 160-170psi. The reaction was monitored by HPLC and completed in 5-6hrs. The catalyst was filtered and the filtrate was evaporated to yield a semisolid residue. The residue was dissolved in water. Liquor ammonia was added to the solution at 25-35°C to adjust the pH between 9 and 10. The slurry was stirred for 30min. The white solid was then filtered and vacuum dried (500-600 mm/Hg vacuum) at 50-55°C to yield 9.75g of 10-dihydro-10-deoxo-11-azaerythromycin A. Yield: 65%, purity by HPLC 85%, new unknown impurity 1%.
Examplc-4: Preparation of 10-Dihydro-10-deoxo-l 1-azaerythromycin A by catalytic hydrogenation of 6,9-iminoether in presence of 0.75 mole equivalent of chloroform
15g (0.0204 mole) of the iminoether of the formula II was dissolved in 75ml ethanol. To this, 3.3g of 5% Pt/C catalyst containing 50-60% moisture and 1.83g (0.00153mole) of chloroform were added. The mixture was hydrogenated at 30-35°C under 150psi. The reaction was monitored by HPLC and completed in 6-7hrs. The catalyst was filtered and the filtrate was evaporated to yield a semisolid residue. The residue was dissolved in water. Liquor ammonia was added to the solution at 25-35°C to adjust the pH between 9 and 10. The slurry was stirred for 30min. The white solid was then filtered and after vacuum drying (500-600 mm/Hg vacuum) at 50-55°C it furnished 12.6g of mixture of products comprising 36% unreacted starting material and 38.5% of 10-dihydro-10-deoxo-11 -azaerythromycin A.
Example-5: Preparation of 10-Dihydro-l0-deoxo-l 1-azaerythromycin A by catalytic hydrogenation of 6,9-iminoether in presence of chloroform, in methanol
lOg (0.0136 mole) of the iminoether of the formula II was dissolved in 50ml commercial methanol. 0.5g of 5% Pt/C catalyst containing 50-60% moisture and 1.96g (0.0164 mole) of chloroform were added to it. The mixture was hydrogenated at 30-35°C under 150psi. The reaction was monitored by HPLC and completed in 5-6hrs. The catalyst was filtered and the filtrate was evaporated to yield a semisolid residue. The residue was dissolved in water. Liquor ammonia was added to the solution at 25-35°C to adjust the pH between 9 and 10. The slurry was stirred for 30min. The white solid was then filtered and vacuum
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dried (500-600 mm/Hg vacuum) at 50-55°C to furnish 7.9g of the title compound 10-dihydro-10-deoxo-l 1-azaerythromycin A. Yield: 79%, purity by HPLC 70%.
Example-6: Preparation of 10-Dihydro-10~deoxo-l 1-azaerythromycin A by catalytic hydrogenation of 6,9-iminoether in presence of chloroform, in isopropyl alcohol
lOg (0.0136 mole) of the iminoether of the formula II was dissolved in 100ml isopropyl alcohol and 2.2g of 5% Pt/C catalyst containing 50-60% moisture and 1.96g (0.0164 mole) of chloroform were added to it. The mixture was hydrogenated at 30-35°C under 150psi. The reaction was monitored by HPLC and completed in ll-12hrs. The catalyst was filtered and the filtrate was evaporated to yield a semisolid residue. The residue was dissolved in water. Liquor ammonia was added to the solution at 25-35°C to adjust the pH between 9 and 10. The slurry was stirred for 30min. The white solid was then filtered and vacuum dried (500-600 mm/Hg vacuum) at 50-55°C to furnish 7.5g of 10-dihydro-10-deoxo-l 1-azaerythromycin A. Yield: 74.7%, purity by HPLC 83%.
Example-7: Preparation of azithromycin of formula (III) from 10-Dihydro-10-deoxo-11-azaerythromycin A of formula (I)
80g of 10-Dihydro-10-deoxo-l 1-azaerythromycin A of formula (I), prepared in the Example 2, was dissolved in 560ml acetone at 25-30°C. To this solution 16ml of formaline solution and 20ml of 85% formic acid was added. The reaction mixture was then refluxed for 120-18 Omin. After the completion of the reaction, acetone was distilled out under vacuum below 50°C till viscous oily mass resulted. To this 800ml DM water was added and cooled to 25-30°C. The pH of the solution was then adjusted to 5.5 with liquor ammonia and the aqueous layer was extracted with DCM for several times to remove impurities. The aqueous layer was then basified to pH 10 with about 120ml of liquor ammonia at 25-3 0°C in presence of 400ml DCM. After extraction, the DCM layer was separated and the aqueous layer was extracted with DCM for several more times. Finally, all the DCM extracts were pooled and evaporated under vacuum at below 50°C temperature. To the residue, 80ml ethanol was added and then stripped off. Finally charged 200ml ethanol to the oily residue to dissolve it completely at 25-35°C and added this solution to 480ml of water at the same temperature. The precipitated product was
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We claim
1. A process for the preparation of the compound of formula (I) comprising of catalytic hydrogenation of the iminoether of formula (II) with relatively low load of catalyst with respect to the iminoether in presence of

a polyhalogenated alkane.
2. A process as claimed in claim 1 wherein the polyhalogenated alkane is selected from chloroform, bromoform and a mixture thereof.
3. A process as claimed in claim 1 wherein the polyhalogenated alkane is chloroform.
4. A process as claimed in claim 1 wherein the polyhalogenated alkane is used in 0.5 to 3 molar equivalent with respect to the iminoether of formula (II), preferably in 1 to 1.5 molar equivalent with respect to the iminoether of formula (II).
5. A process as claimed in any of the preceding claims wherein the catalyst is Pt/ C in amount of 10-15% by weight, with respect to iminoether.
6. A process as claimed in any of the preceding claims wherein the catalytic hydrogenation is carried out in an organic solvent selected from C1-C6 straight or branched chain alcohol and a mixture thereof.
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7. A process as claimed in claim 6 wherein the catalytic hydrogenation is carried out in ethanol.
8. A process as claimed in any of the preceding claims wherein the catalytic hydrogenation is carried out at a temperature of 25-40°C.
9. A process as claimed in any of the preceding claims wherein the catalytic hydrogenation is carried out under a hydrogen pressure of 50psi to 300psi, preferably from 125psi to 200psi, and most preferably from 150psi to 180psi
10. A process for the preparation of azithromycin comprising of
(i) converting a compound of formula (II) to a compound of formula (I) by
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a process claimed in claim 1 or claim 3, and


(ii) N-methylating the compound of formula (I) using aqueous
formaldehyde and formic acid in molar proportions of 1:1.8 and 1:3.4, respectively with respect to the compound of formula (I).
Dated this 7th day of February, 2006.
Dr. Sanchita Ganguli of S. Majumdar & Co. Applicant's agent
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