Amorphous solid dispersion of orforglipron HEMI-calcium and process for preparation thereof

Abstract

The present application provides amorphous solid dispersions of Orforglipron hemi- calcium and pharmaceutical compositions thereof. The present application also relates to a process for preparation of Orforglipron and salts thereof.

Description

[0001] AMORPHOUS SOLID DISPERSION OF ORFORGLIPRON HEMI-

[0002] CALCIUM AND PROCESS FOR PREPARATION THEREOF

[0003] CROSS REFERENCE

[0004] This application claims the priority of our Indian provisional applications IN 202441066162 filed on 02ndSeptember 2024, IN 202441075168 filed on 04thOctober 2024, IN 202441088405 filed on 15thNovember 2024.

[0005] FIELD OF THE INVENTION

[0006] The present application provides amorphous solid dispersions of Orforglipron hemi-calcium and pharmaceutical compositions thereof. The present application also relates to a process for preparation of Orforglipron and salts thereof.

[0007] BACKGROUND OF THE INVENTION

[0008] Orforglipron is an investigational drug candidate originally developed by Chugai Pharmaceuticals Co. Ltd. for the treatment of type 2 diabetes. Orforglipron is a non-peptide agonist for the glucagon-like peptide- 1 (GLP-1) receptor, currently in Phase III for the treatment of obesity and diabetes mellitus. Orforglipron is chemically known as 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2- [(4S)-2-(4- fluoro-3 , 5 -dimethylphenyl)-3 - [3 -(4-fhroro-l-methylindazol-5 -yl)-2-oxoimidazol-l-yl] - 4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2-methyl- cyclopropyl] -4H-1, 2, 4-oxadiazol-5-one and has the following structure. (Orforglipron, II) Orforglipron may be prepared as a pharmaceutically acceptable salt. One salt of Orforglipron is a hemi-calcium salt, 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]- 2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxo imidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]ind ol-l- yl]-2-methyl cyclopropyl] -4H-1, 2, 4-oxadiazol-5-one, 0.5 Ca, and has structure are shown below.

[0009] Orforglipron Hemi Calcium (I)

[0010] Crystalline hydrate polymorph of Orforglipron hemi-calcium salt is disclosed in WO2018056453 (hereinafter referred as the WO’453 application). Both WO’453 application and WO2024137426 (hereinafter referred as the WO’426 application) disclose multi-step synthetic process for preparation of Orforglipron. However, the prior art processes are not suitable for commercial production of Orforglipron since the reported processes produce Orforglipron contaminated with impurities.

[0011] The inventors of the present application have developed an improved and cost-effective process for the commercial production of Orforglipron that avoids the formation of impurities.

[0012] W02023220109 (hereinafter referred as the WOT 09 application), WO2023220112 (hereinafter referred as the WOT 12 application) and WO2024129676 (hereinafter referred as the WO'676 application) disclose pharmaceutical composition comprising Orforglipron or pharmaceutically acceptable salts thereof, preferably hemi-calcium salt. WOT 12 application and WOT 09 application disclose composition comprising spray dried dispersion (SDD) of Orforglipron hemi-calcium with povidone or copovidone as polymer.

[0013] However, the new solid dispersions of a pharmaceutically useful compound or salt thereof can provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, and / or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Orforglipron hemi-calcium.

[0014] SUMMARY OF THE INVENTION

[0015] First aspect of the present application provides amorphous solid dispersion comprising Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients.

[0016] Second aspect of the present application provides a process for the preparation of Orforglipron of formula (II) comprising reaction of a compound of formula (III) with a compound of formula (IV) or salt thereof wherein, “X” is a halogen.

[0017] Third aspect of the present application provides a compound of formula (III) and / or compound of formula (Illa).

[0018]

[0019] Fourth aspect of the present application provides a process for the preparation of Orforglipron hemi-calcium (I) comprising reacting Orforglipron (II) with calcium hydroxide in presence of a suitable solvent.

[0020] Fifth aspect of the present application provides a process for the preparation of crystalline Orforglipron hemi-calcium (I), comprising: a) providing a solution or suspension of Orforglipron (II) in a first solvent b) adding calcium hydroxide; c) adding a second solvent; d) isolating crystalline Orforglipron hemi-calcium (I).

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 illustrates PXRD pattern of amorphous form of Orforglipron hemi-calcium prepared according to Example 9.

[0023] Figure 2 illustrates PXRD pattern of crystalline form of Orforglipron hemi-calcium prepared according to Example 10.

[0024] Figure 3 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 (1 :3) prepared according to Example 13.

[0025] Figure 4 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 (1 :5) prepared according to Example 14.

[0026] Figure 5 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPC (1 :3) prepared according to Example 15.

[0027] Figure 6 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPC (1 :5) prepared according to Example 16. Figure 7 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Soluplus (1:3) prepared according to Example 17.

[0028] Figure 8 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Soluplus (1:5) prepared according to Example 18.

[0029] Figure 9 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with methylcellulose (1:3) prepared according to Example 19.

[0030] Figure 10 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with methylcellulose (1:5) prepared according to Example 20.

[0031] Figure 11 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with ethyl cellulose (1:3) prepared according to Example 21.

[0032] Figure 12 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with ethyl cellulose (1:5) prepared according to Example 22.

[0033] Figure 13 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC-AS (1:3) prepared according to Example 23.

[0034] Figure 14 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC-AS (1:5) prepared according to Example 24.

[0035] Figure 15 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit L100 55 (1:3) prepared according to Example 25.

[0036] Figure 16 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit L100 55 (1:5) prepared according to Example 26.

[0037] Figure 17 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC-P (1:3) prepared according to Example 27.

[0038] Figure 18 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC-P (1:5) prepared according to Example 28.

[0039] Figure 19 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with cellulose acetate phthalate (CAP) (1:3) prepared according to Example 29. Figure 20 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with cellulose acetate phthalate (1 :5) prepared according to Example 30.

[0040] Figure 21 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Soluplus (1:3) prepared according to Example 31.

[0041] Figure 22 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with polyvinyl alcohol (1:3) prepared according to Example 32.

[0042] Figure 23 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Carbopol 71G (1:2) prepared according to Example 33.

[0043] Figure 24 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit E PO (1:2) prepared according to Example 34.

[0044] Figure 25 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and meglumine (1:2) prepared according to Example

[0045] 35 (HPMC E5: meglumine (95:05)).

[0046] Figure 26 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and meglumine (1:2) prepared according to Example

[0047] 36 (HPMC E5: meglumine (85: 15)).

[0048] Figure 27 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and poloxamer 188 (1:2) prepared according to Example 37 (HPMC E5: poloxamer 188 (95:05)).

[0049] Figure 28 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and poloxamer 188 (1:2) prepared according to Example 38 (HPMC E5: poloxamer 188 (85: 15)).

[0050] Figure 29 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and d-oc-tocopheryl polyethylene glycol succinate (hereinafter called as “TPGS”) (1:2) prepared according to Example 39 (HPMC E5:TPGS (95:05)). Figure 30 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and Tocopheryl polyethylene glycol succinate (TPGS) (1:2) prepared according to Example 40 (HPMC E5:TPGS (92.5:7.5)).

[0051] Figure 31 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and Tocopheryl polyethylene glycol succinate (TPGS) (1:2) prepared according to Example 41 (HPMC E5:TPGS (90:10)).

[0052] Figure 32 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 and Tween 80 (1:2) prepared according to Example 42 (HPMC E5: Tween 80 (99.5:0.5)).

[0053] Figure 33 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit E PO and meglumine (1:2) prepared according to Example 43 (Eudragit E PO: meglumine (95:5)).

[0054] Figure 34 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit E PO and poloxamer 188 (1:2) prepared according to Example 44 (Eudragit E PO: poloxamer 188 (95:5)).

[0055] Figure 35 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit E PO and TPGS (1:2) prepared according to Example 45 (Eudragit E PO:TPGS (95:5)).

[0056] Figure 36 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit E PO and TPGS (1:2) prepared according to Example 46 (Eudragit E PO:TPGS (90: 10)).

[0057] Figure 37 illustrates PXRD pattern of amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit E PO and SLS (1:2) prepared according to Example 47 (Eudragit E PO:SLS (90: 10)).

[0058] DETAILED DESCRTTPION OF THE INVENTION

[0059] The following definitions used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short-range molecular order similar to a crystalline solid.

[0060] As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.

[0061] All ranges recited herein include the endpoints, including those that recite a range "between" two values.

[0062] Terms such as "about," "generally," "substantially," “approximately,” and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

[0063] The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0064] All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

[0065] “Halogen” is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.

[0066] First aspect of the present application provides amorphous solid dispersion of Orforglipron hemi-calcium comprising Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients.

[0067] Suitable pharmaceutically acceptable excipients which can be used in step (a) include, but are not limited to: diluents such as starches, pre-gelatinized starches, lactose, powdered celluloses, methyl cellulose, ethyl cellulose, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, polyvinyl alcohols, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), HPMC- 15 CPS; pre-gelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pre-gelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates such as Eudragit L and Eudragit S, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

[0068] In a preferred embodiment, the pharmaceutically acceptable excipients are selected from a group of polymers like HPC, HPMC, HPMC-AS, HPMC-P, Soluplus, methylcellulose, ethyl cellulose, Eudragit, polyvinyl alcohol, CAP and mixture thereof.

[0069] If the amorphous solid dispersion is found to be hygroscopic or the formulation contains a hygroscopic ingredient, or to increase the stability of the amorphous solid dispersion comprising Orforglipron hemi-calcium, other carriers such as syloid, colloidal silicon dioxide, amorphous silica, micro crystalline cellulose, and the like, may be added in the amorphous solid dispersion.

[0070] In one embodiment, the amorphous solid dispersion optionally comprises one or more pharmaceutical excipients selected from a group of basic substance such as meglumine and the like; a solubilizer such as poloxamer, d-oc-tocopheryl polyethylene glycol succinate (TPGS), sodium lauryl sulphate (SLS), Tween 80 and the like.

[0071] One embodiment of the present application provides a process for preparation of amorphous solid dispersion comprising Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients, comprising; a) providing a solution comprising Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture of solvents, b) removing solvent from the solution obtained in step (a), and c) isolating amorphous solid dispersion comprising Orforglipron hemi- calcium and one or more pharmaceutically acceptable excipients.

[0072] Providing a solution in step (a) includes direct use of a reaction mixture containing Orforglipron hemi-calcium obtained during its synthesis or dissolving Orforglipron hemi-calcium and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.

[0073] Any physical form of Orforglipron-hemi-calcium may be utilized for providing the solution of step (a). Specifically, hydrate form of Orforglipron-hemi- calcium may be utilized for providing the solution of step (a).

[0074] Suitable solvent includes but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; alcohol solvent but not limited to methanol, ethanol, isopropanol and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof. Specifically, suitable solvent may be selected from an alcohol solvent such as methanol, ethanol, n-butanol, isopropanol. More preferably, the suitable solvent is methanol.

[0075] After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

[0076] Step (b) involves removing solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, spray-drying or any other technique known in the art. Step (c) involves isolation of amorphous solid dispersion comprising Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipient by any means known in the art.

[0077] The resulting amorphous solid dispersion obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

[0078] In embodiments, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with a pharmaceutically acceptable excipient, wherein the ratio of Orforglipron hemi-calcium and the pharmaceutically acceptable excipient is 1:0.1 to 1:10, w / w.

[0079] In other embodiments, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with the pharmaceutically acceptable excipient, wherein the ratio of Orforglipron hemi-calcium and the pharmaceutically acceptable carrier is 1 :1 to 1 :5, w / w.

[0080] In other embodiments, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with the pharmaceutically acceptable excipient, wherein the ratio of Orforglipron hemi-calcium and the pharmaceutically acceptable carrier is 1 :1 to 1 :3, w / w.

[0081] In a specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with the pharmaceutically acceptable excipient, wherein the ratio of Orforglipron hemi-calcium and the pharmaceutically acceptable carrier is 1 :2, w / w. In a specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with the pharmaceutically acceptable excipient, wherein the ratio of Orforglipron hemi-calcium and the pharmaceutically acceptable carrier is 1 :3, w / w.

[0082] In a specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with the pharmaceutically acceptable excipient, wherein the ratio of Orforglipron hemi-calcium and the pharmaceutically acceptable carrier is 1 :5, w / w.

[0083] In one specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with HPMC E5 (1:3, w / w).

[0084] In another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with HPC (1:3, w / w).

[0085] In yet another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with Soluplus (1:3, w / w).

[0086] In still another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with methylcellulose (1:3, w / w).

[0087] In another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with ethyl cellulose (1 :3, w / w).

[0088] In still another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with HPMC- AS (1:3, w / w).

[0089] In another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit (1 :3, w / w).

[0090] In yet another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with hydroxypropyl methylcellulose phthalate (HPMC-P) (1:3, w / w). In still another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with cellulose acetate phthalate (1:3, w / w).

[0091] In another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with polyvinyl alcohol (1 :3, w / w).

[0092] In another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with HPMC and a basic substance such as meglumine.

[0093] In still another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with HPMC and a solubilizer such as poloxamer, Tween 80, TPGS and the like.

[0094] In another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit and a basic substance such as meglumine.

[0095] In still another specific embodiment, the present application provides amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit and a solubilizer like poloxamer, Tween 80, TPGS and the like.

[0096] In other embodiment of the present invention provides the amorphous solid dispersion of the present application may be advantageously used in preparation of a pharmaceutical composition comprising Orforglipron hemi-calcium with one or more pharmaceutically acceptable excipients.

[0097] The amorphous solid dispersion of Orforglipron hemi-calcium of the present application is stable and has excellent physico-chemical properties. The amorphous solid dispersion of Orforglipron hemi-calcium of the present application may be easily formulated into a pharmaceutical composition comprising Orforglipron hemi- calcium.

[0098] Solid forms of Orforglipron hemi-calcium of the present application with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

[0099] Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pre-gelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pre-gelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pre-gelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

[0100] Second aspect of the present application provides a process for the preparation of Orforglipron of formula (II) or pharmaceutically acceptable salt thereof, comprising reaction of a compound of formula (III) with a compound of formula (IV) or salt thereof

[0101] Wherein, “X” is a halogen.

[0102] In one embodiment the present application provides a process for preparation of Orforglipron of formula (II) or pharmaceutically acceptable salts, comprising reaction of compound of formula (III) with compound of formula (IV) or salts thereof in presence of a base in a solvent.

[0103] In one embodiment, the base is selected from an inorganic base that includes but is not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; organic base that includes but not limited to triethylamine (TEA), diisopropyl ethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, N-methylpyrrolidine and the like. Preferably, the suitable base may be an organic base. More preferably, the suitable base is triethylamine. Solvent that includes but is not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl / -butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; and mixtures thereof. Preferably, the solvent may be a chlorinated solvent. More preferably, the solvent is dichloromethane. The reaction may be carried out at a temperature of about 0°C to about boiling point of the solvent used.

[0104] In one embodiment, the present application provides a process for the preparation of Orforglipron of formula (II) or pharmaceutically acceptable salt thereof, comprising reaction of a compound of formula (III) with a compound of formula (IV) or salt thereof

[0105] Wherein, “X” is a chloro.

[0106] In a preferred embodiment, the present invention provides a process for the preparation of Orforglipron of formula (II) or pharmaceutically acceptable salts, comprising reacting a compound of formula (Illa) with a compound of formula (IV) to in presence of a base and a suitable solvent.

[0107]

[0108] In another embodiment, a process for the preparation of compound of formula

[0109] (Ill), comprising reacting a compound of formula (V) with a suitable acid halide source in a suitable solvent to produce compound of formula (III);

[0110] In embodiments, the conversion of compound of formula (V) to its corresponding acid halide (III) by reacting compound of formula (V) with a suitable acid halide source in a suitable solvent. Suitable acid halide source that includes but is not limited to thionyl halides such as thionyl chloride and the like; oxalyl halides such as oxalyl chloride and the like; phosphorous halides such as PCh, PCI5, PBn and the like; phosphorous oxyhalides such as POCI3 and the like; cyanuric chloride and the like. Preferably, the suitable reagent is oxalyl chloride. In embodiments, compound of formula (V) may be converted to its corresponding acid halide (III) in presence of catalytic amount of DMF.

[0111] In embodiments, process for the preparation of Orforglipron by using compound of formula (III) and / or compound of formula (Illa) of the present invention significantly reduces time for formation of the product (about 2-3 hrs) to form Orforglipron, whereas the process reported in the WO ’426 application takes about 17 hours to 55 hours for formation of Orforglipron. Hence, the process of the present application is suitable for higher scale production of Orforglipron.

[0112] Third aspect of the present application provides a compound of formula (III). wherein, “X” is a halogen.

[0113] In one specific embodiment, the halogen is chloro.

[0114] In another embodiment, the present application provides a compound of formula (Illa).

[0115] In one embodiment, the compound of formula (III) may be used for preparation of Orforglipron and salt thereof. In another embodiment, the compound of formula (Illa) may be used for preparation of Orforglipron and salt thereof.

[0116] The prior arts, WO’453 and WO’426 applications, disclose a process for preparation of Orforglipron by coupling of 5-((S)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)-l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclo-propyl)- lH-indole-2-carboxylic acid (compound of formula (V) with (S)-l-(4-fluoro-l- methyl-lH-indazol- 5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c] pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one

[0117] (compound of formula (IV) using coupling agents such as such as 1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4, 5-b] pyridinium-3 -oxide hexafluoropphosphate (HATU) or (l-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), in presence of a base (i.e. DIPEA) and after stirring for prolonged time (17-55 hours) to get the Orforglipron. However, the said reported synthetic step for Orforglipron induces formation of many impurities. Since these impurities are formed at the last step of the synthesis, removal of these impurities necessitates additional purification steps which substantially increase production costs. Moreover, coupling agents like HATU, COMU and alternative coupling agents like EDC.HC1 are significantly expensive. These coupling agents also tend to generate unwanted byproducts (such as 1,1, 3, 3 -tetramethylurea - a known teratogen - from HATU), further complicating purification and contributing to higher manufacturing expenses. In addition, when Orforglipron and salt thereof contaminated with a significant amount of impurities, it may raise safety concerns. Regulatory agencies such as the USFDA or EMA may consider such contamination as non-compliant with quality standards.

[0118] Fourth aspect of the present application provides a process for the preparation of Orforglipron hemi-calcium (I) comprising reacting Orforglipron (II) with calcium hydroxide in presence of a suitable solvent.

[0119] The suitable solvent includes but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; alcohol solvent such as methanol, ethanol, propanol and the like; ether solvents such as diethyl ether, methyl / -butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof.

[0120] Fifth aspect of the present application provides a process for preparation of crystalline Orforglipron hemi-calcium (I), comprising: a) providing a solution or suspension of Orforglipron (II) in a first solvent b) adding calcium hydroxide; c) adding a second solvent; d) isolating crystalline Orforglipron hemi-calcium (I); The first solvent of step a) includes but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; alcohol solvent such as methanol, ethanol, propanol and the like; ether solvents such as diethyl ether, methyl / -butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; ; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof. Preferably, the solvent may be selected from mixture of alcohol solvent and water. More preferably, the solvent is mixture of ethanol and water.

[0121] The suitable second solvent of step b) including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl / -butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; water; and mixtures thereof. Preferably, the solvent is water.

[0122] Suitable techniques that may be used for the isolation of Orforglipron hemicalcium of the present invention include but not limited to filtration, decantation, solvent evaporation using flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, freeze- drying or any other technique known in the art.

[0123] In one embodiment, the present application provides a process for the preparation of Orforglipron hemi-calcium (I) comprising:

[0124] (a) reacting a compound of formula (V) with a suitable reagent in a suitable solvent to produce compound of formula (III)

[0125] wherein X is halogen;

[0126] (b) reacting compound of formula compound of formula (III) with a compound of formula (IV) or salt thereof to produce Orforglipron

[0127] (c) reacting Orforglipron (II) with calcium hydroxide in presence of a suitable solvent.

[0128] In an embodiment, pharmaceutically acceptable salts of the compounds of the invention include the acid addition and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include the zz aluminium, arginine, benzathine, calcium, choline, diethylamine, di-olamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tro- methamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemi-calcium salts.

[0129] Pharmaceutically acceptable salts of compounds of the invention, may be prepared, respectively, by one or more of three methods: (i) by reacting the compound with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring- opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention, to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

[0130] Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

[0131] Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

[0132] EXAMPLES:

[0133] Reference Example-1: Process for the preparation of Orforglipron (II) using EDC.HC1: To a mixture of l-(4-fluoro-l-methyl-lH-indazol-5-yl)-3-((45)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin- 3-yl)-l,3-dihydro-2H-imidazol-2-one hydrochloride (IV) (0.28 g, 0.532 mmol) in DCM (3 mL) was added DIPEA (0.25 g, 1.93 mmol) at 25-35 °C under nitrogen atmosphere. The obtained mixture was stirred for 5-10 min at 25-35 °C. 5-((5)-2,2- dimethyltetrahydro-2H-pyran-4-yl)-l-((1 ,25)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)cyclopropyl)-lH-indole-2-carboxylic acid (V) (0.2 g, 0.486 mmol), followed by EDC.HC1 (0.112 g, 0.584 mmol), was then added into the mixture at 25- 35 °C. The obtained reaction mixture was stirred at 25-35 °C for 18-20 h before being analyzed by LC-MS.

[0134] Results: LC-MS of the crude reaction mixture shows the following %AUCs - Orforglipron (II) (65.62%); unreacted acid (V) (18.17%); intramolecular cyclized impurity with m / z = 394 [M+H]+(16.21%); dimethylamide impurity with m / z = 439 [M+H]+(not detected).

[0135] Reference Example-2: Process for the preparation of Orforglipron (II) using HATU: To a mixture of 5-((5)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((1 ,25)-2- methyl- 1 -(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)cyclopropyl)- lH-indole-2- carboxylic acid (V) (0.20 g, 0.486 mmol) and HATU (0.203 g, 0.534 mmol) in THF (0.8 mL) and DMAc (0.5 mL), maintained at 25-35 °C, was added DIPEA (0.25 mL, 1.44 mmol) at 25-35 °C under nitrogen atmosphere. The obtained mixture was stirred at 25-35 °C for 1.5 h. Thereafter, l-(4-fluoro-l-methyl-lH-indazol-5-yl)-3-((45)-2-(4- fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin- 3-yl)-l,3-dihydro-2H-imidazol-2-one hydrochloride (TV) (0.255 g, 0.485 mmol) was added. The obtained reaction mixture was stirred at 25-35 °C for 18-20 h before being diluted with EtOAc (4.0 mL) and quenched saturated aqueous NH4CI (2.0 mL). The obtained mixture was stirred at 25-35 °C for 10 min. Layers were allowed to settle. The organic layer was separated, washed with brine (2.0 mL), dried over anhydrous NaiSCL (0.2 g) and concentrated under reduced pressure below 45 °C to obtain the crude residue, which was analyzed by LC-MS.

[0136] Results: LC-MS of the crude residue shows the following AUCs - Orforglipron (II) (41.57%); unreacted acid (V) (30.73%); intramolecular cyclized impurity with m / z = 394 [M+H]+(not detected); dimethylamide impurity m / z = 439 [M+H]+(26.22%)

[0137] Example: Process for the preparation of Orforglipron of the present invention using compound of formula (Illa)

[0138] Step-A [Preparation of 5-((5)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((15,25)- 2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2- carbonyl chloride (Illa)]: To a mixture of 5-((5)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)-l-((15,25)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)- lH-indole-2-carboxylic acid (V) (20.0 g, 0.0486 moles) in DCM (400 mL), at 0-5°C under nitrogen atmosphere, was added DMF (0.1 mL), followed by oxalyl chloride (6.78 g, 0.0534 moles) over a period of 15-20 min. The reaction mixture warmed to 10-20°C and stirred at the same temperature for 1 -2 h. Thereafter, an additional lot of oxalyl chloride (3.08 g, 0.0243 moles) was added over a period of 5-10 min into the reaction mixture maintained at 0-5 °C. The reaction mixture warmed to 10-20°C and stirred at the same temperature for 1-2 h. Thereafter the reaction mixture was concentrated under reduced pressure below 45°C. The obtained acid chloride was dried for 1-2 h under reduced pressure below 45 °C to obtain a pale yellow solid, which dissolved in DCM (200 mL) and taken forward to the next step. Step-B [Preparation of Orforglipron (II)]: To a solution of l-(4-fluoro-l-methyl- lH-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetra- hydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one hydrochloride (IV) (25.56 g, 0.0486 moles) in DCM (200 mL) was slowly added triethylamine (17.21 g, 0.170 moles) at 0-10 °C under nitrogen atmosphere. The reaction mixture was stirred for 5-10 min at 0-10 °C and then treated slowly over a period of 20-30 min at 0-10 °C with the acid chloride solution (Illa), prepared in Step-A. The reaction mixture thus obtained stirred at 10-20 °C for 1-2 h and then quenched at the same temperature with saturated aqueous NH4CI solution (200 mL). The organic layer separated from the aqueous layer, which then extracted with DCM (100 mL). The organic layers combined, washed with aq. NaHCCL (100 mL), brine (200 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure at 40-45 °C to obtain the crude residue, which was analyzed by LC-MS.

[0139] Results: LC-MS of the crude residue shows the following %AUCs - Orforglipron (II) (97.06%); unreacted acid (V) (0.96%); intramolecular cyclized impurity with m / z = 394 [M+H]+(1.79%); dimethylamide impurity with m / z = 439 [M+H]+(not detected)

[0140] Example-1: Preparation of (A)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-lH- indole-2-carboxylic acid: To a solution of ethyl (5)-5-(2,2-dimethyltetrahydro-2H- pyran-4-yl)-lH-indole-2-carboxylate (100 g, 0.3318 moles) in methanol (1500 mL) was added a solution of sodium hydroxide (29.20 g) in water (350 mL) over a period of 15-30 min at 25-35 °C. The obtained reaction mixture was heated to 60-70°C and maintained at the same temperature for 2-3 h. The reaction mixture was cooled to 25- 35°C and acidified with 3M aqueous HC1 solution (350 mL), followed by concentrated hydrochloric acid (30 mL) in order to attain a pH of 1-2. Water (800 mL) was added in to the resulting suspension, which was then stirred at 25-35 °C for 30-45 min and filtered. The obtained wet cake was washed with water (300 mL) and dried under reduced pressure below 45 °C for 2-3 h to obtain the title compound [83.5 g, purity by HPLC: 98.99%].

[0141] Example-2: Preparation of (5)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N- methyl-N-phenyl-lH-indole-2-carboxamide: To a solution of (S)-5-(2,2- dimethyltetrahydro-2H-pyran-4-yl)-lH-indole-2-carboxylic acid (80 g, 0.2927 moles) in dimethyl acetate (DMAc) (640 mL) was added thionyl chloride (62.68 g) over a period of 15-30 min at 10-15 °C under nitrogen atmosphere. The obtained reaction mixture stirred at 25-35°C for 2-3 h and then cooled to 0-5 °C. The reaction mixture was treated first with / V-methyl aniline (37.63 g, 0.3512 moles) over a period of 15-20 min and then with TEA (106.62 g, 1.054 moles) over a period of 30-45 min at 0-5°C. Thereafter the reaction mixture warmed to 25-35°C, stirred at the same temperature for 1-2 h and then cooled to 10-15°C. Cold water (640 mL) added over a period of for 15-30 min in to reaction mixture maintained at 10-15 °C. The reaction mixture then warmed to 25-35 °C and stirred at the same temperature for 30-45 min. The resulting suspension filtered. The obtained wet cake was washed with water (640 mL) and dried at 45-50 °C in a hot air oven for 18-20 h to obtain the title compound [102 g, purity by HPLC: 99.80%].

[0142] Example-3: Preparation of (A)- 1-( cyano methyl )-?-( 2.2-diinethyltet rahydro-2I I- pyran-4-yl)-N-methyl-N-phenyl-lH-indole-2-carboxamide: To a stirred solution of (6')-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl- l H-indole-2- carboxamide (180 g, 0.4966 moles) in l,3-dimethyl-2-imidazolidinone (DMI, 1800 mL) at 10-15°C was added a solution of potassium hydroxide (111.45 g, 1.986 moles) in water (180 mL) over a period of 15-30 min, followed by chloro acetonitrile (75.03 g, 0.9932 moles) over a period of 30-45 min. The obtained reaction mixture stirred at 10-20°C for 1-2 h and then added to cold water (0-5 °C, 18 L). The obtained suspension stirred for 30-60 min and allowed to room temperature. The reaction mixture filtered and obtained wet cake washed with water (1.8 L). The resulting solid was dissolved in ethyl acetate (2.7 L) and washed with water (2 X900 mL), followed by brine (900 mL). The resulting solution was stirred with activated charcoal (9 g) for 15-30 min at 25-35 °C and filtered through a Celite bed, which was then washed with ethyl acetate (90 mL). The filtrate and washings were combined, dried over anhydrous sodium sulfate and finally concentrated under reduced pressure below 45 °C. The crude product thus obtained was purified by column chromatography using 60-120 mesh silica gel and 40% EtO Ac- hexane to obtain the title compound [170 g, purity by HPLC: 98.27%].

[0143] Example-4: Preparation of l-((15,25)-l-cyano-2-methylcyclopropyl)-5-((A)-2,2- dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-lH-indole-2- carboxamide: A solution of (5)- l -(cyanomethyl )-5-(2, 2-dimethyltetrahydro-2H- pyran-4-yl)-N-methyl-N-phenyl-lH-indole-2-carboxamide (85.0 g, 0.2117 moles) and ( / )-4-methyl- l , 3, 2-di oxathiolane 2,2-dioxide (87.90 g, 0.6351 moles) in dry toluene (850 mL) was slowly added to lithium bis(trimethylsilyl)amide (LHMDS) (IM in THF, 846.80 mL), maintained at 0-5 °C. The reaction mixture warmed to 25- 35 °C and allowed to stir at the same temperature for 4-6 h. The reaction mixture then cooled to 10-15 °C, quenched with saturated NH4CI solution (1275.0 mL) and extracted with ethyl acetate (1700 mL). The ethyl acetate layer washed successively with water (850 mL) and brine (850 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure at 40-45 °C to obtain a pale brown solid (90.0 g). This crude compound was purified by column chromatography using 100- 200 silica gel mesh and 30% EtOAc-hexane to obtain the title compound (major isomer only) [66.0 g, purity by HPLC: -92%].

[0144] Example-5: Preparation of 5-((A)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N- methyl-l-((lA,2A)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)cyclopropyl)-N-phenyl-lH-indole-2-carboxamide: To a solution of 1-((1 ,25)-1- cyano-2-methylcyclopropyl)-5-((5)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N- methyl-N-phenyl-lH-indole-2-carboxamide (119.0 g, 0.0149 moles) in dichloromethane (DCM) (1190.0 mL) was added hydroxylamine hydrochloride (187.27 g, 2.694 moles) at 10-12 °C. Triethylamine (272.71 g, 2.6949 moles) added to the above reaction mixture over a period of 45 min at 10-12 °C. The reaction mixture stirred at the same temperature for 16-20 h. The reaction mixture quenched with saturated aqueous NH4CI solution (1190.0 mL) and stirred for 10-15 min. The organic layer separated, washed with brine (595 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure at 40-45 °C. The off-white solid thus obtained stirred with MTBE (595 mL) at 40-50 °C for 60 min. The resulting suspension cooled to 25-35 °C and filtered to obtain an off-white solid, which dried under suction for 15-20 min. The preceding steps of MTBE trituration, filtration and drying was repeated twice on the obtained solid to obtain the purified N'-hydroxyacetimidamide intermediate which was finally dried under reduced pressure at 40-45 °C for 2 h. The N'-hydroxyacetimidamide intermediate was then dissolveed in DCM (1190.0 mL) at 25-35 °C. The obtained solution was cooled to 10-15 °C and treated with CDI (87.39 g, 0.5389 moles), followed by DBU (102.57 g, 0.6737 moles) under nitrogen atmosphere. The reaction mixture thus obtained warmed to 25-35 °C and stirred at the same temperature for 3-4 h. The reaction mixture was washed successively with IN HC1 (3 X 595 mL), water (1190 mL) and brine (1190 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40-45 °C. The obtained off-white solid was stirred with hexane (1190 mL) at 25-35 °C for 2-3 h, filtered and dried under reduced pressure at 40-45 °C for 2 h to obtain the title compound as a white solid [105.5 g, purity by HPLC: 98.40%].

[0145] Example-6: Preparation of 5-((N)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l- ((15,2N)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH- indole-2-carboxylic acid: A solution of NaOH (83.48 g, 2.087 moles) in water (157 mL) added to a suspension of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N- methyl-l-((15,25)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)- N-phenyl-lH-indole-2-carboxamide (104.5 g, 0.2087 moles) in dimethylsulfoxide (DMSO) (522.5 mL) at 25-30 °C. The reaction mixture heated to 90-95°C and stirred at the same temperature for 16-20 h. The reaction mixture cooled to 25-35°C, stirred for 10 min at the same temperature, diluted with cold water (836 mL) and then washed with di chloromethane (4X 522.5 mL). The aqueous layer thus obtained cooled to 10-15 °C, slowly acidified with 3M HC1 solution (-784 mL) and then extracted with ethyl acetate (2X 1567.5 mL). The ethyl acetate extracts combined, washed successively with water (-522 mL) and brine (-522 mL), dried over sodium sulfate and finally concentrated under reduced pressure at 40-45 °C. The obtained solid was dried funder reduced pressure at 40-45 °C for 2 h followed by hot air oven at 55-60 °C for 16-20 h to obtain the title compound [82.0 g, purity by HPLC: 99.69%].

[0146] Example-7: Preparation of Orforglipron (II):

[0147] Step-A [Preparation of 5-((5)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((15,25)- 2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2- carbonyl chloride (Illa)]: To a suspension of 5-((5)-2,2-dimethyltetrahydro-2H- pyran-4-yl)-l-((15,25)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)cyclopropyl)-lH-indole-2-carboxylic acid (V) (32.0 g, 0.0777 moles) in DCM (640 mL), at 0-5°C under nitrogen atmosphere, was added DMF (1-2 drops), followed by oxalyl chloride (10.85 g, 0.0855 moles) over a period of 20-25 min. The reaction mixture warmed to 10-20°C and stirred at the same temperature for 2-3 h. The reaction mixture then cooled to 0-5°C and treated with a second lot of oxalyl chloride (4.93 g, 0.0388 moles). The reaction mixture warmed again to 10-20°C, stirred at the same temperature for 1-2 h and then concentrated under reduced pressure below 45 °C. The obtained acid chloride was dried for 1-2 h under reduced pressure below 45 °C to obtain a pale yellow solid, which dissolved in DCM (320 mL) and taken forward to the next step.

[0148] 'H NMR (400 MHz, CDC13): 8 9.28 (s, 1H), 7.68 (s, 1H), 7.54-7.52 (m, 2H), 7.42- 7.37 (m, 1H), 3.85-3.76 (m, 2H), 3.03-2.88 (m, 1H), 1.93-1.90 (m, 1H), 1.82-1.65 (m, 4H), 1.65-1.56 (m, 1H), 1.52-1.48 (m, 1H), 1.32 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H), 1.24 (s, 3H).

[0149] 13C NMR (100 MHz, CDCh): 8 161.75, 159.15, 156.54, 140.97, 140.78, 130.39, 129.07, 125.83, 121.80, 121.10, 112.31, 72.00, 61.59, 44.49, 37.35, 35.53, 33.54, 31.59, 25.63, 21.73, 20.78, 13.59.

[0150] Step-B [Preparation of Orforglipron (II)]: To a solution of l-(4-fluoro-l-methyl- lH-indazol-5-yl)-3-((4S)-2-(4-fhioro-3,5-dimethylphenyl)-4-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one hydrochloride (IV) (42.09 g, 0.08 moles) in DCM (320 mL) was slowly added triethylamine (27.51 g, 0.2719 moles) at 0-10 °C under nitrogen atmosphere. The reaction mixture was stirred for 5-10 min at 0-10 °C and then treated slowly over a period of 30-40 min at 0-10 °C with the acid chloride solution (Illa), prepared in Step- A. The reaction mixture thus obtained stirred at 10-20 °C for 1-2 h and then quenched at the same temperature with saturated aqueous NH4CI solution (320.0 mL). The organic layer separated from the aqueous layer, which then extracted with DCM (160 mL). The organic layers combined, washed with brine (320.0 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure at 40- 45 °C to obtain the crude product as a pale yellow solid (78 g). This combined with another lot (22 g) of the crude product prepared separately on a 10 g scale by following the same procedure described above. The combined crude product was purified by column chromatography using 100-200 silica gel mesh and 1% MeOH- DCM followed by trituration with MTBE (5 vol.) at 50-60 °C for 50-60 min and then at 25-35°C for 50-60 min to obtain title compound (75 g, Purity by HPLC: 98.4- 99.5%).

[0151] Example 8: Preparation of Orforglipron hemi-calcium (I): A solution of sodium hydroxide (0.4248 g, 0.0106 moles) in water (5.36 mL) was added to a suspension of Orforglipron (II) (8.0 g, 0.009 moles) in ethanol (40 mL) at 25-35 °C and stirred for 5-10 min at the same temperature. The reaction mixture was treated with an aqueous solution of calcium acetate [prepared by dissolving calcium acetate (0.965 g, 0.0061 moles) in water (4.8 mL)], followed by water (4.8 mL). The obtained reaction mixture was stirred for 3 h at 25-35 °C. Water (8.56 mL) was added in to the resulting suspension which was then stirred for 1 h at 25-35 °C. Water (16.4 mL) was added and stirring was continued for one more hour at 25-35 °C. The obtained solids were filtered, washed with water (8.0 mL) and dried under suction. The resulting wet cake was dried under reduced pressure below 50 °C for 1-2 h to obtain the title compound as an off-white solid [7.0 g, purity by HPLC: 98.95%].

[0152] Example 9: Preparation of amorphous Orforglipron hemi-calcium (I): Orforglipron hemi-calcium salt (I) (30 mg) was dissolved in di chloromethane (2 mL) at 25-30 °C. The obtained solution was filtered to render it particle free. It was then concentrated to dryness under reduced pressure below 45 °C to afford the title compound [25 mg, purity by HPLC: 99.74%]. PXRD pattern is shown in Figure 1.

[0153] Example 10: Preparation of crystalline form of Orforglipron hemi-calcium: To a suspension of Orforglipron (1.0 g, 1.13 mmol) in ethanol (5 mL) was added water (0.7 mL), followed by a suspension of calcium hydroxide (0.058 g, 0.79 mmol) in water (0.6 mL) at 25-35 °C. The obtained reaction mixture was stirred at 25-35 °C for 5 min and then treated with another lot of water (0.6 mL). The reaction mixture was further treated with another three lots of water (3.6 mL in total) at intervals of 10 min. The resulting suspension was warmed to 40-45 °C, stirred at the same temperature for 3-5 h, cooled to 25-35 °C and filtered. The obtained wet cake was washed with water (2.0 mL) and dried in a hot air oven below 60 °C for 18-20 h to obtain the title compound as crystalline solid [0.85 g, purity by HPLC: 99.91%]. PXRD pattern is shown in Figure 2.

[0154] Example 11: Converting the amorphous Orforglipron hemi-calcium to crystalline Orforglipron hemi-calcium: To a solution of amorphous Orforglipron hemi-calcium (0.75 g) in ethanol (5.25 mL) was added water (0.75 mL) at 25-35 °C and stirred at the same temperature. Additional water (4.5 mL in total) was added the above reaction mixture at 25-35 °C in five lots at intervals of 10 min. The resulting suspension was stirred at 25-35 °C for 10-20 min. Water (1.5 mL) was added to the above reaction mixture and then stirred for 1-2 h more at 25-35 °C. The obtained solids were filtered, washed with water (1.5 mL) and dried in hot air oven below 60 °C for 18-20 h to obtain crystalline Orforglipron hemi-calcium salt [0.55 g, purity by HPLC: 99.90%].

[0155] Example 12: Preparation of amorphous form of Orforglipron hemi-calcium: To a solution of Orforglipron (1.0 g, 1.13 mmol) in DCM (10 mL) was added calcium hydroxide (0.05 g, 0.67 mmol) at 25-35°C. The obtained reaction mixture stirred at 25-35°C for 18-20 h and filtered. The filtrate was concentrated under reduced pressure below 45 °C and dried for 1 h to obtain the title compound as amorphous solid [0.95 g, purity by HPLC: 99.73%].

[0156] Example-13: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC E5 (1:3)

[0157] A mixture of Orforglipron hemi-calcium (40 mg) and HPMC E5 (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast centrifugal evaporation at 80°C, under pressure to obtain the title compound. PXRD pattern shown in Figure 3.

[0158] Example-13a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC E5 (1:3)

[0159] Amorphous solid dispersion of Orforglipron hemi-calcium and HPMC E5 (1:3), as prepared in example 13, was kept at 25°C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months.

[0160] Example-14: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with HPMC E5 (1:5)

[0161] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and HPMC E5 (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 4.

[0162] Example-15: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPC (1:3)

[0163] A mixture of Orforglipron hemi-calcium (40 mg) and HPC (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 5.

[0164] Example-15a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with HPC (1:3)

[0165] Amorphous solid dispersion of Orforglipron hemi-calcium and HPC (1:3), as prepared in example 15, was kept at 25°C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months.

[0166] Example-16: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with HPC (1:5)

[0167] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and HPC (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 6.

[0168] Example-17: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Soluplus (1:3)

[0169] A mixture of Orforglipron hemi-calcium (40 mg) and Soluplus (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 7.

[0170] Example-17a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with Soluplus (1:3)

[0171] Amorphous solid dispersion of Orforglipron hemi-calcium and soluplus (1 :3), as prepared in example 17, was kept at 25°C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months.

[0172] Example-18: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Soluplus (1:5)

[0173] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and Soluplus (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 8.

[0174] Example-19: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with methylcellulose (1:3)

[0175] A mixture of Orforglipron hemi-calcium (40 mg) and methyl cellulose (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 9.

[0176] Example-19a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with methylcellulose (1:3)

[0177] Amorphous solid dispersion of Orforglipron hemi-calcium and methyl cellulose (1:3), as prepared in example 19, was kept at 25°C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months.

[0178] Example-20: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with methylcellulose (1:5)

[0179] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and methyl cellulose (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 10.

[0180] Example-21: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with ethyl cellulose (1:3) A mixture of Orforglipron hemi-calcium (40 mg) and ethyl cellulose (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 11.

[0181] Example-21a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with ethyl cellulose (1:3)

[0182] Amorphous solid dispersion of Orforglipron hemi-calcium with ethyl cellulose (1:3), as prepared in example 21, was kept at 25°C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months.

[0183] Example-22: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with ethyl cellulose (1:5)

[0184] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and ethyl cellulose (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 12.

[0185] Example-23: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-AS (1:3)

[0186] A mixture of Orforglipron hemi-calcium (40 mg) and HPM-AS (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 13. Example-23a: Stability of amorphous solid dispersion of Orforglipron hemicalcium with HPMC-AS (1:3)

[0187] Amorphous solid dispersion of Orforglipron hemi-calcium with HPMC-AS (1:3), as prepared in example 25, was kept at 25°C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months

[0188] Example-24: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-AS (1:5)

[0189] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and HPMC-AS (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 14.

[0190] Example-25: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Eudragit L10055 (1:3)

[0191] A mixture of Orforglipron hemi-calcium (40 mg) and Eudragit L100 55 (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 15.

[0192] Example-25a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with Eudragit L100 (1:3)

[0193] Amorphous solid dispersion of Orforglipron hemi-calcium with Eudragit LI 00 (1:3), as prepared in example 27, was kept at 25 °C / 60% RH for 3 months under closed conditions and found to be physically and chemically stable. Similarly, under closed conditions, found to be stable at 40°C / 75% RH for 3 months.

[0194] Example-26: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with Eudragit L10055 (1:5)

[0195] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and Eudragit LI 00 55 (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 16.

[0196] Example-27: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with hydroxypropyl methylcellulose phthalate (HPMC-P) (1:3)

[0197] A mixture of Orforglipron hemi-calcium (40 mg) and Hydroxypropyl methylcellulose phthalate (HPMC-P) (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 17.

[0198] Example-27a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-P (1:3)

[0199] Amorphous solid dispersion of Orforglipron hemi-calcium with HPMC-P (1:3), as prepared in example 29, was kept at 25°C / 60% RH and 40°C / 75% RH under closed conditions for 3 months and found to be physically stable for 3 months.

[0200] Example-28: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with hydroxypropyl methylcellulose phthalate (HPMC-P) (1:5)

[0201] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and Hydroxypropyl methylcellulose phthalate (HPMC-P) (200 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 18.

[0202] Example-29: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with cellulose acetate phthalate (1:3)

[0203] A mixture of Orforglipron hemi-calcium (40 mg) and cellulose acetate phthalate (120 mg) in methanol (2 mL) was stirred for 30 min at 50 °C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80 °C, under pressure to obtain the title compound. PXRD pattern shown in Figure 19.

[0204] Example-30: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with cellulose acetate phthalate (1:5)

[0205] A mixture of Orforglipron hemi-calcium hydrate (40 mg) and cellulose acetate phthalate (200 mg) in methanol (2 mL) was stirred for 30 min at 50°C. The resulting clear solution was evaporated under fast Centrifugal Evaporation at 80°C, under pressure to obtain the title compound. PXRD pattern shown in Figure 20.

[0206] Example-31: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with soluplus (1:3)

[0207] A mixture of Orforglipron hemi-calcium (60 mg) and soluplus (180 mg) were trichurated together using mortar and pestle to form uniform physical mixture. This mixture was then loaded into Vaccum Compression molding (VCM) die. The mixture heated to 200°C and maintained at set temperature for 30 minutes under vacuum. The mixture was then rapidly cooled to 25°C to obtain the title compound. PXRD pattern shown in Figure 21.

[0208] Example-32: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with polyvinyl alcohol (1:3)

[0209] A solution of Orforglipron hemi-calcium hydrate (200 mg) and Polyvinyl alcohol (600 mg) in methanol (30 mL) was stirred for 30 min at 60°C. Water (15 mL) was added dropwise to the above solution. The resulting clear solution was subjected to fast solvent evaporation using rotavapor at 80°C. PXRD pattern shown in Figure 22.

[0210] Example-32a: Stability of amorphous solid dispersion of Orforglipron hemi- calcium with Polyvinyl alcohol (1:3)

[0211] Amorphous solid dispersion of Orforglipron hemi-calcium with Polyvinyl alcohol (1:3), as prepared in example 32, was kept at 25°C / 60% RH under open conditions for 1 week and found to be physically stable.

[0212] Example-33: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Carbopol 71G (1:2)

[0213] A mixture of Orforglipron hemi-calcium hydrate (50 mg) and Carbopol 71 G (100 mg) in methanol (2 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 23.

[0214] Example-34: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Eudragit E PO (1:2)

[0215] A mixture of Orforglipron hemi-calcium hydrate (50 mg) and Eudragit E PO (100 mg) in methanol (2 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 24.

[0216] Example-35: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with HPMC-E5 and meglumine (1:2)

[0217] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (95 mg) and meglumine (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 25.

[0218] Example-36: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-E5 and meglumine (1:2)

[0219] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (85 mg) and meglumine (15 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 26.

[0220] Example-37: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-E5 and Poloxamer 188 (1:2)

[0221] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (95 mg) and Poloxamer 188 (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 27.

[0222] Example-38: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-E5 and Poloxamer 188 (1:2)

[0223] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (85 mg) and Poloxamer 188 (15 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 28. Example-39: Preparation of amorphous solid dispersion of Orforglipron hemicalcium with HPMC-E5 and Tocopheryl polyethylene glycol succinate (TPGS) (1:2)

[0224] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (95 mg) and TPGS (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 29.

[0225] Example-40: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-E5 and Tocopheryl polyethylene glycol succinate (1:2)

[0226] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (92.5 mg) and TPGS (7.55 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 30.

[0227] Example-41: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-E5 and Tocopheryl polyethylene glycol succinate (1:2)

[0228] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (90 mg) and TPGS (10 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 31.

[0229] Example-42: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMC-E5 and Tween 80 (1:2)

[0230] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMC E5 (99.5 mg) and Tween 80 (0.5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 32.

[0231] Example-43: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Eudragit E PO and meglumine (1:2) A mixture of Orforglipron hemi-calcium hydrate (50 mg), Eudragit E PO (95 mg) and meglumine (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 33.

[0232] Example-44: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Eudragit E PO and Poloxamer 188 (1:2)

[0233] A mixture of Orforglipron hemi-calcium hydrate (50 mg), Eudragit E PO (95 mg) and Poloxamer (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 34.

[0234] Example-45: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with Eudragit E PO and TPGS (1:2)

[0235] A mixture of Orforglipron hemi-calcium hydrate (50 mg), Eudragit E PO (95 mg) and TPGS (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 35.

[0236] Example-46: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMCAS and TPGS (1:2)

[0237] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMCAS (90 mg) and TPGS (10 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 36.

[0238] Example-47: Preparation of amorphous solid dispersion of Orforglipron hemi- calcium with HPMCE5 and SLS (1:2)

[0239] A mixture of Orforglipron hemi-calcium hydrate (50 mg), HPMCE5 (95 mg) and SLS (5 mg) in methanol (2.5 mL) was stirred for 30 min at 60°C. The resulting clear solution was subjected to Fast Centrifugal Evaporation at 80°C. PXRD pattern shown in Figure 37.

Claims

Claims:

1. A process for the preparation of Orforglipron of formula (II) or pharmaceutically acceptable salt thereof, comprising reaction of a compound of formula (III) with a compound of formula (IV) or salt thereofwherein X is a halogen.

2. The process of claim 1 , wherein X is chloro.

3. The process of claim 1 , further comprises a process for preparation of compound of formula (III) comprising reacting a compound of formula (V) with a suitable reagent in a suitable solvent to produce compound of formula (III);wherein X is halogen.

4. The process of claim 3, wherein the suitable reagent is selected from a group of thionyl chloride and oxalyl chloride.

5. A process for the preparation of Orforglipron hemi-calcium (I) comprising reacting Orforglipron (II) with calcium hydroxide in presence of a suitable solvent.

6. A process for the preparation of Orforglipron hemi-calcium (I) comprising: a) reacting a compound of formula (V) with a suitable acid halide in a suitable solvent to produce compound of formula (III)wherein X is halogen; b) reacting compound of formula compound of formula (III) with a compound of formula (TV) or salt thereof to produce Orforglipron (II)c) reacting Orforglipron (II) with calcium hydroxide in presence of a suitable solvent.

7. An amorphous solid dispersion of Orforglipron hemi-calcium comprising Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipient is selected from a group of HPC, HPMC, HPMC-AS, HPMC-P, Soluplus, methylcellulose, ethyl cellulose, Eudragit, polyvinyl alcohol, carbopol, and cellulose acetate phthalate or mixtures thereof.

8. The amorphous solid dispersion of claim 7, wherein the amorphous solid dispersion optionally comprises a solubilizer.

9. The amorphous solid dispersion of claim 8, wherein the solubilizer selected from a group of poloxamer, d-oc-tocopheryl polyethylene glycol succinate (TPGS), sodium lauryl sulphate (SLS) and Tween 80.

10. The amorphous solid dispersion of claim 7, wherein the amorphous solid dispersion comprises Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipient is HPMC.

11. The amorphous solid dispersion of claim 10, wherein the amorphous solid dispersion further comprises a solubilizer.

12. The amorphous solid dispersion of claim 7, wherein the amorphous solid dispersion comprises Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipient is polyvinyl alcohol.

13. The amorphous solid dispersion of claim 12, wherein the amorphous solid dispersion further comprises a solubilizer.

14. The amorphous solid dispersion of claim 7, wherein the amorphous solid dispersion comprises Orforglipron hemi-calcium and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipient is Eudragit.

15. The amorphous solid dispersion of claim 14, wherein the amorphous solid dispersion further comprises a solubilizer.

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