Field of the Invention:
The present invention relates to novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, represented by the following structural formula:
Background of the Invention:
5-[[[(2S)-2-Amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-
(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid known as
Eluxadoline and is approved in US under the brand name VIBERZI for the treatment of
irritable bowel syndrome with diarrhea. Irritable bowel syndrome is a long-term disorder of
the gut with pain or discomfort in the abdomen (belly), bloating and altered bowel habit.
European Commission granted a marketing authorization for Eluxadoline (Truberzi) on 19th
September 2016.
5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and process for its preparation was first disclosed in US7741356 B2 herein after referred as US’356 B2.
US8691860 B2 discloses crystalline form-α of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1.
US7994206 B2 discloses crystalline form-β of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1.

US8609865 B2 discloses process for the preparation of crystalline form-α and form-β of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1.
Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of
amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1.
The second aspect of the present invention is to provide a novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 herein after designated as form-N and process for its preparation.
The third aspect of the present invention is to provide a novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 herein after designated as form-M1 and process for its preparation.
The fourth aspect of the present invention is to provide a novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 herein after designated as form-M2 and process for its preparation.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-N of 5-[[[(2S)-2-amino-3-[4-
(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1.
Figure 2: Illustrates the PXRD pattern of crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-
(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1.
Figure 3: Illustrates the PXRD pattern of crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-
(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1.

Detailed description of the Invention:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, l, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, diethylene glycol mono ethyl ether, cyclohexanol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The first aspect of the present invention provides a process for the preparation of
amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1, comprising of following steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a suitable solvent,
b) heating the reaction mixture,
c) adding the above reaction mixture to a pre-cooled suitable solvent,
d) stirring the reaction mixture,
e) filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.

Wherein,
In step-a) and c) the suitable solvent is selected from alcohol solvents, ketone solvents, ester
solvents, hydrocarbon solvents, polar aprotic solvents, ether solvents, nitrile solvents, chloro
solvents and polar solvents like water or mixture thereof;
in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the
solvent used in the reaction;
in step-c) the suitable temperature is ranging from -50°C to 0°C.
The preferred embodiment of the present invention provides a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of following steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a mixture of acetonitrile and water,
b) heating the reaction mixture to 40-45°C,
c) adding the above reaction mixture to a pre-cooled acetonitrile at 0-5°C,
d) stirring the reaction mixture, filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
The preferred embodiment of the present invention provides a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of following steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a mixture of acetonitrile and water,
b) heating the reaction mixture to 40-45°C,
c) adding the above reaction mixture to a pre-cooled acetone (or) heptane at 0-5°C,

d) stirring the reaction mixture, filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
The another preferred embodiment of the present invention provides a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of following steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a mixture of acetonitrile, methanol and water,
b) adding the above reaction mixture to a precooled water at 0°C to 5°C,
c) stirring the reaction mixture, filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
The second aspect of the present invention provides a novel crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 characterized by its powder X-Ray diffractogram having peaks at 6.3, 7.0, 7.5, 9.0, 10.1, 10.9, 11.3, 11.8, 13.1, 14.5, 15.3, 15.9, 16.3, 18.3, 18.5, 19.2, 19.6, 20.2, 21.4, 21.9, 23.5 and 24.0 ± 0.2 degrees of two-theta and the P-XRD pattern was depicted in figure-1.
In another embodiment of the present invention provides a process for the preparation of crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:

a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is same as defined in step-a) of the first aspect of the present invention;
in step-b) the suitable temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding methanol to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture at 40-45°C,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
The crystalline form-N of compound of formula-1 obtained according to the present invention is useful in the preparation of pure 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.

The third aspect of the present invention provide a novel crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 characterized by its powder X-Ray diffractogram having peaks at 6.2, 7.3, 7.9, 8.9, 9.7, 10.3, 10.7, 11.0, 11.1, 11.7, 12.7, 13.5, 13.9, 14.1, 14.5, 15.0, 15.6, 16.7, 17.0, 17.6, 18.1, 18.6, 18.9, 19.2, 20.1, 20.3, 21.0, 21.4, 22.0, 23.2, 23.6, 24.2, 24.8, 25.7, 26.9, 28.2, 29.6 and 32.3 ± 0.2 degrees of two-theta and the P-XRD pattern was depicted in figure-2.
In another embodiment of the present invention provides a process for the preparation of crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid,
b) heating and stirring the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is same as defined in step-a) of the first aspect of the present invention;
in step-b) the suitable temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:

a) Adding propylene glycol to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture to 60-65°C,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
The fourth aspect of the present invention provide a novel crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 characterized by its powder X-Ray diffractogram having peaks at 6.3, 7.1, 8.8, 9.8, 10.5, 11.0, 11.7, 12.0, 12.8, 13.9, 14.4, 15.1, 15.4, 15.7, 16.1, 17.2, 18.0, 18.6, 18.9, 19.2, 19.6, 20.2, 21.1, 21.3, 21.5, 22.2, 23.0, 23.4, 23.7, 24.3, 25.5, 26.0, 27.4, 27.8, 28.2, 28.9, 30.3 and 33.4 ± 0.2 degrees of two-theta and the P-XRD pattern was depicted in figure-3.
In another embodiment of the present invention provides a process for the preparation of crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is same as defined in step-a) of the first aspect of the present invention;

in step-b) the suitable temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding anisole to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture at 40-45°C,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The invention also encompasses pharmaceutical compositions comprising compound of formula-1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis:

PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1:
Preparation of Amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy
benzoic acid:
A mixture of 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid butanol solvate (100 gms), acetonitrile (150 ml) and water (150 ml) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with a mixture of acetonitrile and water. The reaction mixture was added to pre-cooled water at 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled water and dried to get the title compound.
Yield: 70.0 gms; M.R: 180-186°C; Purity by HPLC: 99.95%.
The P-XRD of the obtained compound was matching the P-XRD pattern of amorphous form disclosed in our co-pending Indian patent application 201641007801.
Example-2:
Preparation of Amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy
benzoic acid:
A mixture of 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (5.0 gms), acetonitrile (5.0 ml) and water (5.0 ml) was stirred for 10 minutes at 25-30°C. The reaction mixture was slowly added to pre-cooled water (50 ml) at 0-5°C and stirred

for 2 hours minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 2.9 gms; Purity by HPLC: 99.92%.
Example-3:
Preparation of Amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid:
A mixture of 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (2.0 gms), acetonitrile (2 ml) and water (2 ml) was heated to 40-45°C. The reaction mixture was slowly added to pre-cooled acetone (40 ml) at -40°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 1.3 gms.
Example-4:
Preparation of Amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid:
A mixture of 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (2 gms), acetonitrile (3 ml) and water (3 ml) was heated to 40-45°C. The reaction mixture was slowly added to pre-cooled acetonitrile (20 ml) at 0-5°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 1.23 gms.
Example-5:
Preparation of Amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid:
A mixture of 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol

solvate (5.0 gms), acetonitrile (3.5 ml), methanol (3.5 ml) and water (3.5 ml) was stirred for 10 minutes at 25-30°C. The reaction mixture was slowly added to pre-cooled water (3.5 ml) at 0-5°C and stirred for 2 hours minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 3.1 gms.
Example-6:
Preparation of crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-di methylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid:
Methanol (250 ml) was added to 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethyl phenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (50 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45°c and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 45.0 gms. The P-XRD pattern of the obtained compound was depicted in figure-1.
Example-7:
Preparation of crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-di methylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid:
Propylene glycol (2.0 ml) was added to 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethyl phenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (0.5 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 60-65°c and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 0.46 gms. The P-XRD pattern of the obtained compound was depicted in figure-2.
Example-8:

Preparation of crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-di methylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid:
Anisole (7.0 ml) was added to 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethyl phenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (1.0 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45°c and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 0.6 gms. The P-XRD pattern of the obtained compound was depicted in figure-3.
Example-9:
Preparation of crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-di methylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid:
Benzyl alcohol (2.0 ml) was added to 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethyl phenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxy benzoic acid 2-butanol solvate (0.5 gms) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture. 2-butanol (1.5 ml) was added to the obtained filtrate at 25-30°C and stirred form 30 minutes at the same temperature. Filtered the precipitated solid, washed with 2-butanol and dried to get the title compound. Yield: 0.30 gms.
The P-XRD of the obtained compound was matching crystalline form-N3 disclosed in our co-pending Indian patent application 201641015345.

We Claim:
1. A process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of following
steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a suitable solvent,
b) heating the reaction mixture,
c) adding the above reaction mixture to a pre-cooled suitable solvent,
d) stirring the reaction mixture,
e) filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.

2. The process as claimed in claim 1, wherein, in step-a) the suitable solvent is selected from alcohol solvents, nitrile solvents and polar solvents like water or mixture thereof; in step-c) the suitable solvent is selected from ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents, ether solvents, nitrile solvents, chloro solvents and polar solvents like water or mixture thereof; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction; in step-c) the suitable temperature is ranging from -50°C to 0°C.
3. The process as claimed in claim 1, wherein a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl] amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of following steps;

a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a mixture of acetonitrile and water,
b) heating the reaction mixture to 40-45°C,

c) adding the above reaction mixture to a pre-cooled acetonitrile at 0-5°C,
d) stirring the reaction mixture, filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
4. The process as claimed in claim 1, wherein a process for the preparation of amorphous
form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-
1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of
formula-1, comprising of following steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a mixture of acetonitrile and water,
b) heating the reaction mixture to 40-45°C,
c) adding the above reaction mixture to a pre-cooled acetone (or) heptane at 0-5°C,
d) stirring the reaction mixture, filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
5. The process as claimed in claim 1, wherein a process for the preparation of amorphous
form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-
1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of
formula-1, comprising of following steps;
a) Adding 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid 2-butanol solvate compound of formula-1 in a mixture of acetonitrile, methanol and water,
b) adding the above reaction mixture to a precooled water at 0°C to 5°C,
c) stirring the reaction mixture, filtering the precipitated solid and drying to get amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-

oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1.
6. Crystalline forms of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1:
a) Crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1 characterized by its powder x-ray diffractogram having peaks at 6.3, 7.0, 7.5, 9.0, 10.1, 10.9, 11.3, 11.8, 13.1, 14.5, 15.3, 15.9, 16.3, 18.3, 18.5, 19.2, 19.6, 20.2, 21.4, 21.9, 23.5 and 24.0 ± 0.2 degrees of two-theta.
b) Crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1 characterized by its powder x-ray diffractogram having peaks at 6.2, 7.3, 7.9, 8.9, 9.7, 10.3, 10.7, 11.0, 11.1, 11.7, 12.7, 13.5, 13.9, 14.1, 14.5, 15.0, 15.6, 16.7, 17.0, 17.6, 18.1, 18.6, 18.9, 19.2, 20.1, 20.3, 21.0, 21.4, 22.0, 23.2, 23.6, 24.2, 24.8, 25.7, 26.9, 28.2, 29.6 and 32.3 ± 0.2 degrees of two-theta.
c) Crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1 characterized by its powder x-ray diffractogram having peaks at 6.3, 7.1, 8.8, 9.8, 10.5, 11.0, 11.7, 12.0, 12.8, 13.9, 14.4, 15.1, 15.4, 15.7, 16.1, 17.2, 18.0, 18.6, 18.9, 19.2, 19.6, 20.2, 21.1, 21.3, 21.5, 22.2, 23.0, 23.4, 23.7, 24.3, 25.5, 26.0, 27.4, 27.8, 28.2, 28.9, 30.3 and 33.4 ± 0.2 degrees of two-theta.
7. A process for the preparation of crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:
a) Adding a suitable alcohol solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino] methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture,

c) cooling the reaction mixture,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-N of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
8. A process for the preparation of crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding propylene glycol to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture to 60-65°C,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-M1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
9. A process for the preparation of crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]
amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding anisole to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo propyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxy benzoic acid 2-butanol solvate,
b) heating and stirring the reaction mixture at 40-45°C,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture, filtering the solid and drying to get the crystalline form-M2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl] [(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
10. Use of crystalline form-N, form-M1 and form-M2 of compound of formula-1 obtained
according to the present invention in the preparation of amorphous form of 5-[[[(2S)-2-

amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.