FIELD OF THE INVENTION: I
The present invention relates to an industrially scalable process for the preparation of 2',4"-di-O-benzoyl-1 l-N-(4-Azidobutyl)-6-0-methylerythromycin and its impuriy
BACKGROUND OF THE INVENTION:
2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin of formula-I is used in preparation of macrolide compounds which are used as medicaments for the treatments or prevention of inflammatory and allergic diseases such as chronic obstructive pulmonary disease (COPD), asthama, rheumatoid arthritis, atopic dermatitis or inflammatory bowel disease or proliferative diseases such as cancer.
2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin is also used to prepare
ketotides. Ketolides represent a newer class of macrolide antibiotics which are 14 membered
ring macrolide derivatives.
WO 2009/055557A1 discloses process for preparing intermediate comprising reaction of
10,11 -anhydro-2' ,4"-di-0-benzoy I-12-O-imidazolyIcarbony 1-6-O-methylerythromycin A
with 4-azidobutylamine and DBU in presence of DtvlF to get 2',4"-di-0-benzoyl-l l-N-(4-
Azidobutyl)-6-0-methylerythromycin.
Prior art describes only process for preparing 25,4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-
methylerythromycin while the present invention discloses recovery of ene impurity obtained
during reaction and prepare intermediate from that impurity. Recovery of impurity and its
conversation to final product results higher yield and purity of 2',4"-di-0-benzoyl-l l-N-(4-
Azidobutyl)-6-0-methylerythromycin which makes the process economical, eco friendly and fl

SUMMARY OF THE INVENTION:
The present invention relates to the process for preparation of 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin of formula-I.
In one aspect, the present invention relates to the process for preparation of 2\4"-di-0-benzoyl-1 l-N-(4-Azidobutyl)-6-0-methylerythromycin of formula-I comprising the steps of;
(a) Reacting 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0-
methylerythromycin with 4-Azido butyl amine in presence of base and solvent at warm
temperature
(b) Obtaining crude 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin
In another embodiment, the process for recovery of ene impurity 2',4"-di-0-benzoyl-10,11-
didehydro-6-O-methylerythromycin from 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-
methylerythromycin mother liquor comprises;
(a) Stirring solution of DM water and 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-
methylerythromycin mother liquor at ambient temperature
(b) Obtaining ene impurity 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-methylerythromycin
In another embodiment the 'insitu' process for preparing 2',4"-di-0-benzoyl-U-N-(4-
Azidobutyl)-6-0-methylerythromycin from 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-
methylerythromycin comprises;
(a) Reacting 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-methylerythromycin with carbonyldiimidazole in presence of solvent and base
(b) Reacting with 4-Azido butyl amine in presence of base and solvent at warm temperature


DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to an advantageous process for the preparation of 2',4"-di-0-benzoyl-U-N-(4-A2idobutyl)-6-0-methylerythromycin of formula-I and its impurity.
Formula-I
In one embodiment, the present invention relates to the process for preparation of 2',4"-di-0-benzoyl-1 l-N-(4-AzidobutyI)-6-0-methylerythromycin of formula-I comprising the steps of;
(a) Reacting 10,1 l-anhydro-2,,4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0-methylerythromycin with 4-Azido butyl amine in presence of base and solvent at warm temperature
(b) Stirring reaction mixture with solvent at ambient temperature
(c) Obtaining crude 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin
(d) Crystallizing 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin with solvent
The process for preparing 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin depicted in the following reaction scheme-I

The suitable solvent used in step (a) is selected from the group consisting of non-polar solvent, polar solvents, halogenated solvents, acetate solvents or mixture of two or more solvents. The non-polar solvent is selected from toluene, xylene or mixture of two or more solvents. The polar solvent is selected from dimethylacetamide, dimethylformamide or mixture of two or more solvents. The halogenated solvent is selected from dichloromethane, chloroform or mixture of two or more solvents. The acetate solvent is selected from ethylacetate, isopropylacetate or mixture of two or more solvents.
The base used in step (a) is organic base. The organic base is selected from the group
consisting of l,8-Diazabicyclo[5.4.0]undec-7-ene, l,5-Diazabicyclo(4.3.0)non-5-ene ,
Triethylamine, 4-DimethyIaminopyridine, N,N-Diisopropylethylamine, 1,1,3,3-
Tetramethylguanidinej Hexamethyldisilazane, 2,6-lutidine.
The above said process includes an ene impurity 2',4"-di-O-benzoyl-10,ll-didehydro-6-O-methylerythromycin of 10-16 %.
In another embodiment, the process for recovery of ene impurity 2',4"-di-O-benzoyl-10,ll-didehydro-6-O-methylerythromycin of formula-3 from 2',4"-di-0-benzoyI-l l-N-(4-Azidobutyl)-6-0-methylerythromycin mother liquor comprises;
Formula-3
(a) Stirring solution of DM water and 2\4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin mother liquor at ambient temperature
(b) Dissolving wet cake into solvent
(c) Obtaining ene impurity 2',4"-di-0-benzoyl-10,1 l-didehydro-6-O-methylerythromycin
The solvent used in step (b) is selected from the group consisting of halogenated solvents.
non-polar solvents or mixture of two or more solvents. The halogenated solvent is selected
from dichloromethane, chloroform, dichloroethane. The non-polar solvent is selected from
The HPLC purity of 2',4"-di-0-ben2oyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin is
99-99.9%.
In another embodiment, the process for preparing 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-
imidazolylcarbonyl-6-O-metoylerythromycin from ene impurity 2',4"-di-0-benzoyl-10,11-
didehydro-6-O-methyIerythromycin comprises;
(a) Reacting 2,}4"-di-O-ben2oyl-10,ll-didehydro-6-O-methylerythromycin with carbonyldi imidazole in presence of solvent and base
(b) Obtaining 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0-methylerythromycin
The process for preparing 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0-methylerythromycin depicted in the following reaction scheme-II
The suitable solvent used in step (a) is selected from the group consisting of non-polar
solvent. The non-polar solvent is selected from toluene, xylene, mixture of xylene or mixture
of two or more solvents.
The base used in step (a) is inorganic base. The inorganic base is selected from sodium
hydride, n-butyl lithium.
The reaction temperature for the above said process is 20-35°C.
The obtained 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0-
methylerythromycin is 99-99.9% pure.
In another embodiment the 'insitu' process for preparing 2',4"-di-0-benzoyl-l l-N-(4-
Azidobuty!)-6-0-methylerythromycin from 2',4"-di-O-benzoyl-10,l l-didehydro-6-0-
methylerythromycin comprises;

(a) Reacting 2',4"-di-O-benzoyl-10,ll-didehydro-6-O-methylerythromycin with carbonyldiimidazole in presence of solvent and base
(b) Reacting with 4-Azido butyl amine in presence of base and solvent at warm temperature
(c) Obtaining crude 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin
The suitable solvent used in step (a) is selected from the group consisting of non-polar
solvent. The non-polar solvent is selected from toluene, xylene, mixture of xylene or mixture
of two or more solvents. The suitable solvent used in step (b) is selected from the group
consisting of non-polar solvent, polar solvents, halogenated solvents, acetate solvents or
mixture of two or more solvents. The non-polar solvent is selected from toluene, xylene or
mixture of two or more solvents. The polar solvent is selected from dimethylacetamide,
dimethylformamide or mixture of two or more solvents. The halogenated solvent is selected
from dichloromethane, chloroform or mixture of two or more solvents. The acetate solvent is
selected from ethylacetate, isopropylacetate or mixture of two or more solvents.
The base used in step (a) is inorganic base. The inorganic base is selected from sodium
hydride; n-butyl lithium.The base used in step (b) is organic base. The organic base is
selected from the group consisting of I,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-
Diazabicyclo(4.3.0)non-5-ene,Triethylamine,4-Dimethylaminopyridine,N,N-
Diisopropylethylamine, 1,1,3,3-Tetramethylguanidine, Hexamethyldisilazane, 2,6-lutidine.
The reaction temperature for step (a) is 20-35°C. The reaction temperature for step (b) is 10-
15°C.
The HPLC purity of 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin is
99-99.9%.
The main object of present invention is isolating ene impurity 2',4"-di-0-benzoyl-10,11-
didehydro-6-O-methylerythromycin and preparing 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-
imidazolytcarbonyl-6-O-memylerythromycin from ene impurity which further converted into
2'!4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin. Moreover the present
invention also describes insitu process for preparing 2',4"-di-0-benzoyl-l l-N-(4-
Azidobutyl)-6-0-methylerythromycin from ene impurity 2',4"-di-O-benzoyl-10,l 1-
didehydro-6-O-methylerythromycin without isolating 10,1 l-anhydro-2',4"-di-0-benZoyl-12-
O-imidazolylcarbonyl-6-O-methylerythromycin avoids multistep of isolation and
purification. The present invention is cost-effective process results in higher yield and higher

The present invention provides economical, robust, and industrially compatible and safe process for preparing 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin.

The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of 10,ll-anhydro-2\4"-di-O-benZoyl-12-O-
imidazolylcarbonyI-6-O-methyIerythromycin
To the 2',4"-di-O-benzoyl-10)ll-didehydro-6-O-methylerythromycin (200 g) added toluene (1400 mL) at room temperature and stirred for 15 min. Washed with water (600 mL). The organic layer approximately (400 mL) distilled out under vacuum at 65 - 70 °C. Added CDI (72 g) into reaction mixture and stirred for 15 min at room temperature. Cooled the reaction mixture and added sodium hydride (5 g x 3) under nitrogen atmosphere and stirred for 2 h at room temperature. The excess of sodium hydride was quenched with slowly addition of water (1200 mL) and separate the layer. The organic layer was washed with brine solution (20%; 400 mL) and distilled out under vacuum to give 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolyIcarbonyl-6-O-methylerythromycin.
HPLC purity: 99.93 %
Example-2: Preparation of 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0- |
methylerythromycin
To the 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0-
methylerythromycin added DMF (300 mL) and stirred for 10 min at room temperature. Cooled to 10 - 15 °C. Added 4-Azido butyl amine (15 g, 0.1314 mol) into reaction mixture and stirred for 30 min at 10 - 15 °C. Added l,8-Diazabicyclo[5.4.0]undec-7-ene (15 g, 0.0985) to reaction mixture and warmed and stirred to 40 - 45 °C for 8 - 10 h. DM water (1500 mL) was added and stirred for 15 min. Dichloromethane (800 mL) was charged into reaction mixture and stirred at RT for 30 min. Separated the layer. Organic layer washed with water (400 mL) and distilled off u/vacuum at 50 - 60 °C to get crude 2',4"-di-0-benzoyl-l 1-N-(4-Azidobutyl)-6-0-methylerythromycin. The crude products crystallize from IPA.
HPLC purity: 99.91 %
Examp!e-3: Preparation of 2\4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-
methylerythromycin (insitu)
To the 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-methylerythromycin (200 g) added toluene
_^_Xl400^mtVatr-rpom-tem peratiif e-, aod-sti reed^-forr-J^-m i n.^Washed-wi thTwater-(600-m L)=—T-he

organic layer approximately (400 mL) distilled out under vacuum at 65 - 70 °C. Added CDI (72 g) into reaction mixture and stirred for 15 min at room temperature. Cooled the reaction mixture and added sodium hydride (5 g x 3) under nitrogen atmosphere and stirred for 2 h at room temperature. The excess of sodium hydride was quenched with slowly addition of water (1200 mL) and separate the layer. The organic layer was washed with brine solution (20%; 400 mL) and added DMF (300 mL) and stirred for 10 min at room temperature. Cooled to 10 - 15 °C. Added 4-Azido butyl amine (15 g, 0.1314 mol) into reaction mixture and stirred for 30 min at 10 - 15 °C. Added l,8-Diazabicydo[5.4.0]undec-7-ene (15 g, 0.0985) to reaction mixture and warmed and stirred to 40 - 45 °C for 8 - 10 h. DM water (1500 mL) was added and stirred for 15 min. Dichloromethane (800 mL) was charged into reaction mixture and stirred at RT for 30 min. Separated the layer. Organic layer washed with water (400 mL) and distilled off u/vacuum at 50 - 60 °C to get crude 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-O-methylerythromycin. The crude products crystallize from IPA. HPLC purity: 99.92%

Claims:
1. A process for preparing 2\4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-
methylerythroraycin (Formula-I) comprising
Formula-I
(a) Reacting 10,11 -anhydro-2'J4"-di-0-benZoyl-12-O-imidazolylcarbonyI-6-O-methylerythromycin with 4-Azido butyl amine in presence of 1,8-Diazabicyclo[5.4,0]undec-7-ene and dimethylformamide at warm temperature
(b) Obtaining crude 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-methylerythromycin
(c) Crystallizing 2'J4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin with isopropylalcohol
2. A process for recovery of ene impurity 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-
methylerythromycin (formula-3) comprising
Formula-3
(a) Stirring solution of DM water and 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin mother liquor at ambient temperature
(b) Obtaining ene impurity 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-methylerythromycin

3. A process for preparing 10,ll-anhydro-2',4"-di-O-benZoyl-12-O-imidazolylcarbonyl-
6-O-methylerythromycin from ene impurity 2',4"-di-O-benzoyl-10,ll-didehydro-6-O-
methylerythromycin comprising
Formula-2
(a) Reacting 2',4"-di-O-benzoyl-10,ll-didehydro-6-O-methyIerythromycin with carbonyldiimidazole in presence of toluene and sodium hydride
(b) Obtaining 10,1 l-anhydro-2',4"-di-0-benZoyl-12-0-imidazolylcarbonyl-6-0- . methyl erythromyci n
4. An insitu process for preparing 2',4"-di-0-benzoyl-l l-N-(4-Azidobutyl)-6-0-
methylerythromycin (formula-1) from ene impurity 2',4"-di-O-benzoyI-10,l 1-
didehydro-6-O-methylerythromycin (formula-3) comprising
(a) Reacting 2',4"-di-O-benzoyl-10,l l-didehydro-6-O-rnethylerythromycin with carbonyldiimidazole in presence of solvent and base
(b) Reacting with 4-Azido butyl amine in presence of base and solvent at warm temperature
(c) Obtaining crude 2',4"-di-0-benzoyl-ll-N-(4-Azidobutyl)-6-0-methylerythromycin

5. The process according to claim 4, wherein the solvent for step (a) is non-polar solvent selected from the group consisting of toluene, xylene, mixture of xylene or mixture of two or more solvents.
6. The process according to claim 4, wherein the base for step (a) is inorganic base selected from sodium hydride, n-butyl lithium.
7. The process according to claim 4, wherein the solvent for step (b) is selected from the group consisting of polar solvents like dimethylacetamide, dimethylformamide, halogenated solvents like dichloromethane. chloroform, acetate solvents like ethylacetate, i so propyl acetate or mixture of two or more solvents.
8. The process according to any of the preceding claims wherein the purity of 2',4"-di-