CLIAMS:1. The crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A 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 9.58, 10.03, 10.42, 12.19, 13.17, 15.64, 17.50, and 17.94 ± 0.2° ± 0.2°.

2. The compound of claim 1, wherein crystalline form of (10E)- 10,11-didehydro-11-deoxy-6-O-methylerythromycin A has purity more than 99%, when measured by HPLC.

3. A process for the preparation of (10E)-10,11-didehydro-11-deoxy-6-O-methyl erythromycin A 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-didehydro-11-deoxy-6-O-methyl erythromycin A, compound of formula IV,

Formula-IV
b) converting the obtain compound in step (a) to (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A in the alcoholic solvent,
c) isolating (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A from the reaction mixture of step (b).

4. The process of claim 3, wherein ether solvent is selected from the group comprising one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane and diisopropyl ether.

5. The process of claim 3, wherein alcoholic solvent is selected from the group comprising one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol and propylene glycol.

6. The process of claim 3, wherein base is selected from the group comprising one or more of organic base and Inorganic base.

7. The process of claim 6, wherein organic base is selected from the group comprising one or more of dimethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine and ammonia.

8. The process of claim 6, wherein inorganic base is selected from the group comprising one or more of sodium hydroxide, potassium hydroxide and potassium t-butoxide.

9. The process of claim 8, wherein base is sodium hydroxide.
,TagSPECI:Field of Invention

The present invention provides a process for the preparation of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A. In particular aspect of present invention provides crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A. In further aspect of present invention provides the use of a crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A as reference markers and/or reference standards during the synthesis of Clarithromycin.

Background of the invention

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-O-methyl erythromycin and is structurally represented by Formula (I):

Formula I
Clarithromycin approved indication for the treatment of mild to moderate infections caused by susceptible isolates of the bacteria and is available in the market under the trade name Biaxin®.

U.S. Patent No. 4331803 describes Clarithromycin and process for the preparation thereof. The process for the preparation of Clarithromycin described in several patents, U.S. patent Nos. 4,672,109; 5,844,105; 5,858,986; 5,945,405.

The object of present invention is to provide an improved process for the preparation of (10E)--10,11-didehydro-11-deoxy-6-O-methylerythromycin A (referred herein after “Clarithromycin Impurity N”). The process of preparation Clarithromycin Impurity N 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 (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A compound of formula-II

Formula-II

The present invention provides a use of crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A, as reference standards in a qualitative analysis of Clarithromycin.

The present invention provides a process for the preparation of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A thereof compound of formula-II

Formula-II

The present invention also provides a (10E)-10,11-didehydro-11-deoxy-6-O-methyl erythromycin A has a purity more than 99 % 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 Clarithromycin Impurity N.

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 (10E)- 10,11-didehydro-11-deoxy-6-O-methylerythromycin A, compound of formula-II

Formula-II

In another aspect, the present invention provides a crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A 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 (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A 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 9.58, 10.03, 10.42, 12.19, 13.17, 15.64, 17.50, and 17.94 ? 0.2?.

The XRPD characteristic peaks of the crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A, having purity more than 99 %, further defined from the Table 1:

2 Theta peaks d-spacing [Aº] Relative Intensity [%]
6.10 14.47 7.24
7.11 12.42 9.32
8.05 10.97 13.42
8.65 10.21 39.12
9.58 9.22 75.60
10.03 8.81 64.98
10.42 8.48 36.14
11.38 7.77 23.85
12.19 7.25 45.49
13.17 6.71 41.11
14.71 6.02 35.08
15.64 5.66 41.31
16.09 5.50 24.67
17.50 5.06 100
17.94 4.94 47.79
19.46 4.56 35.80
20.08 4.42 36.21
21.56 4.12 15.61
22.35 3.97 38.11
23.09 3.85 19.15
25.14 3.54 8.16
26.75 3.33 8.87
27.89 3.19 3.26

The crystalline form of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A 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 (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A, as reference standards in a qualitative analysis of Clarithromycin.

Yet in one another aspect of the present invention provides (10E)- 10,11-didehydro-11-deoxy-6-O-methylerythromycin A has purity more than 99% determined by HPLC.

The present invention provides a process for the preparation of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A compound of formula-II

Formula-II
the process includes 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-didehydro-11-deoxy-6-O-methyl erythromycin A, compound of formula IV;

Formula-IV
b) converting the obtain compound in step (a) to (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A in the alcoholic solvent;
c) isolating (10EE)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A from the reaction mixture of step (b).

The step (a) of the present invention involves the dissolving 10,11-anhydro-2',4"-di-O-benzoyl-12-O-imidazolyl carbonyl-6-O-methyl erythromycin A in solvent, followed by drop wise addition of 3N aqueous solution of base at temperature in between range of at 0-5°C, wherein base is selected from the group comprising one or more of organic base and inorganic base; organic base is selected from the group comprising one or more of dimethylamine, diethylamine, triethylamine and ammonia; inorganic base is selected from the group comprising one or more of sodium hydroxide, potassium hydroxide and potassium t-butoxide and ether solvent is selected from the group comprising one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane and diisopropyl ether.

After addition, the reaction mass stirred for the period of 3 hours at temperature in between range of 45?C to 50°C. After competition of reaction, concentrate the reaction mass to get residue. Ethyl acetate and water was added to the residue and stirred for the period of 15 minutes. Separate organic layer and washed with water and brine solution. Organic layer is concentrated to get 2’,4"-di-O-benzoyl-(10E)-10,11-didehydro-11-deoxy-6-O-methyl erythromycin A.

The step (b) of the present invention involves the dissolving 2’,4"-di-O-benzoyl-(10E)- 10,11-didehydro-11-deoxy-6-O-methyl erythromycin A in solvent, followed by drop wise addition of 10N aqueous solution of base at temperature in between range of at 20?C to 25°C, wherein base is selected from the group comprising one or more of sodium hydroxide or potassium hydroxide and potassium t-butoxide and alcoholic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol and propylene glycol.

After addition, the reaction mixture is heated to temperature in between range of 60?C to 65°C and stirrer for the period of 36 hours. After completion of reaction, concentrate the reaction mass under vacuum at temperature 40?C to get residue. Then ethyl acetate and water was added to the residue. Separate organic layer washed with water and again with brine solution. Concentrate the organic layer under vacuum to get crude product. The crude product is purified in ethanol and water mixture to obtain pure (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A.

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 2’,4"-di-O-benzoyl-(10E)-10,11-didehydro-11-deoxy-6-O-methyl erythromycin A

10,11-anhydro-2',4"-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycin A (50.0 gm) was dissolve in tetrahydrofuran (200mL), followed by drop wise addition of 3N solution of aqueous sodium hydroxide (60 mL) at temperature 0-5°C. After addition, the reaction mixture was stirred for 3 hours at temperature 45-50°C. After competition of reaction, concentrate the reaction mass to get residue. Ethyl acetate (250 mL) & water (100 mL) was added to the residue and stirred for the period of 15 minutes. Separate the layer and collected organic layer, washed with water (100 mL) & brine solution (100mL).Concentrated the organic layer to get titled compound (IV) as white crystalline powder.
Yield: 47.6 gm
Mass (M+1): 939

Example-2: Preparation of (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A (II)

2’,4"-di-O-benzoyl-(10E)-10,11-didehydro-11-deoxy-6-O-methyl erythromycin A (47.6 gm) was dissolve in methanol (250mL), followed by drop wise addition of 10N solution of aqueous sodium hydroxide (10 mL) at temperature 20-250C. After addition, the reaction was heated at temperature 60°C -65°C and stirred for 36 hours. After completion of reaction, concentrate the reaction mass under vacuum at temperature 400C to get residue. Then ethyl acetate (250 mL) and water (150 mL) was added to the residue. Layer were separated and collected organic layer, washed organic layer with water and again with brine solution (100mL). Organic layer was concentrated under vacuum to get crude product (38.1gm). The crude product was purified with ethanol and water to get pure (10E)-10,11-didehydro-11-deoxy-6-O-methylerythromycin A as white crystalline powder
Yield: 21.4gm
HPLC purity: 96.62%
1H NMR (400 MHz, CDCl3): 6.62, s,1H; 4.98-5.01, dd, 1H; 4.84,d,1H; 4.35, d, 1H; 3.97-4.04, m, 2H; 3.65-3.73, m, 2H; 3.45, m,1H; 3.37, bs, 1H; 3.30, s,3H; 3.21, s, 3H; 3.18, d, 1H; 3.0, t,1H; 2.87, t,1H; 2.38, bs, 1H; 2.34, bs, 1H; 2.26, s,6H; 2.21, d, 2H; 2.18, d, 1H; 2.02, d,1H; 2.0, s 3H; 1.89-1.93, m, 2H; 1.54-1.64, m, 4H; 1.40, s,3H; 1.38,s, 3H; 1.28, d, 3H; 1.20-1.25, m, 10H; 1.15, d, 3H; 1.08, d, 3H; 0.89, t, 3H.
13C NMR (400 MHz, CDCl3): 207.4; 175.1; 142.5; 138.6; 103.0; 96.41; 79.9; 79.8; 79.1; 78.4; 77.8; 73.1; 72.4; 70.8; 68.7; 65.5; 65.2; 58.2; 50.62; 49.3; 45.0; 40.2; 37.1; 34.9; 28.7; 22.34; 21.9; 21.4; 21.3; 20.6; 18.4; 18.2; 15.5; 13.1; 10.5; 9.5.
Mass: (M+1). : 730