Claims:1. A crystalline form of Sulfonamide Di-demethyl Azithromycin compound of formula-II

Formula-II
characterized by at least one of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1,
ii. a powder X-ray diffraction pattern having peaks at about 7.74, 11.05, 12.64, 15.40, 15.92 and 16.58 ? 0.2?.

2. The compound of claim 1, wherein crystalline form of Sulfonamide Di-demethyl Azithromycin has purity more than 99%, when measured by HPLC.

3. The compound of claim 1, wherein crystalline form of Sulfonamide Di-demethyl Azithromycin is used as reference markers and/or reference standards during the synthesis of Azithromycin.

4. A process for the preparation of Sulfonamide Di-demethyl Azithromycin compound of formula-II

Formula-II
the process comprises step of
a) treating 10,11-anhydro-2',4"-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methyl erythromycin A compound of formula III

Formula-III
with suitable base in a ether solvent to obtain 2’,4"-di-O-benzoyl-(10E)-10,11-di-dehydro-11-deoxy-6-O-methyl erythromycin A, compound of formula IV,
b) isolating Sulfonamide Di-demethyl Azithromycin from the reaction mixture of step (b).

5. The process of claim 4, wherein the halogenated solvent is selected from the group comprising one or more of chloroform, dichloromethane and carbon tetrachloride.

6. The process of claim 5, wherein the halogenated solvent is carbon tetrachloride.

7. The process of claim 4, wherein crystalline form of Sulfonamide Di-demethyl Azithromycin y has purity more than 90%, when measured by HPLC.

8. The compound of claim 4, wherein crystalline form of Sulfonamide Di-demethyl Azithromycin y is used as reference markers and/or reference standards during the synthesis of Azithromycin.
, Description:Field of Invention

The present invention provides a process For the Preparation of Sulfonamide Di-demethyl Azithromycin. In particular aspect of present invention provides crystalline form of Sulfonamide Di-demethyl Azithromycin. In further aspect of present provides the use of a crystalline form of Sulfonamide Di-demethyl Azithromycin Impurity as reference markers and/or reference standards during the synthesis of Azithromycin.

Background of the invention

Azithromycin is an antibiotic useful for the treatment of bacterial infections. It is an azalide, a subclass of macrolide antibiotic. It is derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered and is structurally represented by Formula (I):

Formula I
U.S. patent No. US 4,517,359 describe Azithromycin and process for the preparation thereof. The process for the preparation of Azithromycin described in several patents, U.S. patent Nos. 4,886,792; 5,518,703; 5,686,587; 6,013,778; 7,205,395; 7,435,805 U.S. 7,235,646; 7,414,114; 6,420,537 and 6,703,372. There are several pending patent applications which also describe the process for the preparation of Azithromycin US 20050222052 US 20090093420 and WO00215842.

The object of present invention is to provide an improved process for the preparation of 3’-N-([4-(Acetyl amino) phenyl] sulfonyl) -3’,3’-di-demethylazithromycin (referred herein after “Sulfonamide Di-demethyl Azithromycin”). The process of preparation Sulfonamide Di-demethyl azithromycin is very simple cost effective and may be employed at commercial scale. The product obtained by using instant process provides better yield and purity.

Summary of the invention

The present invention provides a crystalline form of Sulfonamide Di-demethyl Azithromycin compound of formula-II

Formula-II
The present invention also provides a use of crystalline form of Sulfonamide Di-demethyl Azithromycin, as reference standards in a qualitative analysis of Azithromycin.

The present invention also provides a process for the preparation of Sulfonamide Di-demethyl Azithromycin thereof compound of formula-II

Formula-II

The present invention also provides a Sulfonamide Di-demethyl Azithromycin, has purity more than 90 % when measured by HPLC.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of crystalline form of Sulfonamide Di-demethyl Azithromycin

Detailed description of the invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Ka radiation, having the wavelength 1.54 Å.

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. A reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

The present invention provides a crystalline form of Sulfonamide Di-demethyl Azithromycin, compound of formula-II

Formula-II
In another aspect, the present invention provides a crystalline form of Sulfonamide Di-demethyl Azithromycin is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1.

In another aspect, the present invention provides a crystalline solid form of Sulfonamide Di-demethyl Azithromycin, having an X-ray diffraction pattern according to Figure 1, which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K a-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 7.74, 11.05, 12.64, 15.40, 15.92 and 16.58 ? 0.2?.

The XRPD characteristic peaks of the crystalline form of Sulfonamide Di-demethyl Azithromycin, having purity more than 99 %, further defined from the Table 1:

2 Theta peaks d-spacing [Aº] Relative Intensity [%]
7.74 11.41 42.03
8.25 10.71 35.71
11.05 8.00 100
12.64 7.00 52.93
15.40 5.75 82.12
15.92 5.56 32.02
16.58 5.34 47.01
18.47 4.80 34.97
18.91 4.69 38.34
19.30 4.59 36.09

The crystalline form of Sulfonamide Di-demethyl Azithromycin obtained as per Example 2 to the present invention was stored at 25°C for a period of 3 months and no conversion in the polymorphic form was observed.

Yet in one another aspect of the present invention provides the use of crystalline form of Sulfonamide Di-demethyl Azithromycin, as reference standards in a qualitative analysis of Azithromycin.

Yet in one another aspect of the present invention provides Sulfonamide Di-demethyl Azithromycin has purity more than 90% determined by HPLC.

The present invention provides a process for the preparation of Sulfonamide Di-demethyl Azithromycin compound of formula-II

Formula-II
the process includes step of;
a) treating 3’-(N,N-di-demethyl)azithromycin compound of formula III

Formula-III
with 4-acetamide benzene sulfonyl chloride in a halogenated solvent to obtain Sulfonamide Di-demethyl Azithromycin,
b) isolating 3’-N-([4-(Acetyl amino) phenyl] sulfonyl) -3’,3’-di-demethyl azithromycin from the reaction mixture of step (a).

The present invention process involves dissolving 3’-(N,N-di-demethyl)azithromycin in halogenated solvent, followed by slowly portion wise addition of 4-Acetamide benzene sulfonyl chloride at temperature in between range of -8?C to -12 ?C, wherein the halogenated solvent is selected from the group comprising one or more of chloroform, dichloromethane and carbon tetrachloride. The reaction mixture was stirred for the period of 4 hours to 6 hours. After completion of reaction quench the reaction mass by addition of water and separate the layer. Organic layer is washed with 2% to 4% aqueous solution sodium hydroxide, followed by washing brine solution. The solvent is distilled out to get crude product. The crude product is suspended in diethyl ether to get 3’-N-([4-(Acetyl amino) phenyl] sulfonyl) -3’,3’-di-demethylazithromycin.

The process of the present invention is depicted in the following scheme 1:

Scheme 1

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES:

Example-1: Preparation of 3’-N-([4-(Acetyl amino) phenyl] sulfonyl) -3’,3’-di-demethylazithromycin

Dissolved 3’-(N,N-di-demethyl)azithromycin (0.2g) in dichloromethane (3.0ml), followed by slowly portion wise addition of 4-Acetamide benzene sulfonyl chloride (0.071g) into the reaction mixture at temperature of about -8?C to -120C. The reaction mixture was stirred for the period of 4 hours. After completion of reaction, the reaction mixture was quenched with water (10ml). Organic layer was washed with 2% aqueous solution of sodium hydroxide, followed by addition of 10ml water, then finely washed with 10ml brine solution. The solvent was distilled out to get crude product. The crude product was suspended in diethyl ether to get pure tiled compound.
Yield: 0.195g
HPLC purity: 92.0%
Moisture Content: 3.77%.
Mass: (M+1). : 918.5
1H NMR (400 MHz, CDCl3): 9.05, bs, 1H; 7.82, d, 2H; 7.67, d, 2H; 5.02 bs, 2H; 4.69, bs, 2H; 4.35 d, 1H; 4.16, m, 1H; 3.96, m, 1H; 3.64 m, 1H; 3.45- 3.50, m, 2H; 3.16, s, 3H; 3.01-3.07, m, 2H; 2.98, m, 1H; 2.71-2.74, m, 2H; 2.54, m, 2H; 2.31-2.34, m, 3H; 2.22, s, 3H; 1.86-2.12, m, 10H; 1.67, d, 2H; 1.30-1.57, m, 4H; 1.15-1.27, m, 18H; 1.14, s, 3H; 0.86-1.07, m, 7H.
13C NMR (400 MHz, CDCl3): 178.55; 169.41; 142.49; 134.15; 128.28; 119.37; 101.98; 94.80; 84.20; 78.00; 77.91; 74.24; 73.71; 73.59; 72.92; 69.71; 67.85; 65.83; 65.62; 62.74; 55.29; 49.28; 46.04; 45.21; 41.76; 39.15; 36.38; 34.63; 29.66; 27.26; 26.53; 25.58; 24.64; 21.93; 21.52; 21.21; 20.74; 18.07; 16.32; 15.24; 14.86; 11.15; 9.62; 7.48.