Process for the preparation of tirzepatide

Abstract

The present invention relates to an improved process for the preparation of Tirzepatide represented by the following structural formula-1. Formula-1 (Or) H-Tyr1-Aib2-Glu3-Gly4-Thr5-Phe6-Thr7-Ser8-Asp9-Tyr10-Ser11-Ile12-Aib13-Leu14-Asp15-Lys16-Ile17- Ala18-Gln19-Lys20(AEEA-AEEA-γ-Glu-Eicosanedioicacid)-Ala21-Phe22-Val23-Gln24-Trp25-Leu26- Ile27-Ala28-Gly29-Gly30-Pro31-Ser32-Ser33-Gly34-Ala35-Pro36-Pro37-Pro38-Ser39-NH2. The present invention also relates to novel intermediate compounds which are useful for the preparation of Tirzepatide. The present invention further relates to processes for the preparation of novel intermediate compounds of Tirzepatide.

Description

[0001] Process for the preparation of Tirzepatide Related Application: This application claims the benefit of priority of our Indian patent application IN202441006135 filed on January 30, 2024 which is incorporated herein by reference. Field of the Invention: The present invention provides a process for the preparation of Tirzepatide represented by the following structural formula-1. H-Tyr1- Lys16-I17 le - Ala18-Gln19-Lys20(AEEA-AEEA-γ-Glu-Eicosanedioicacid)-Ala21-Phe22-Val23-Gln24-Trp25-Leu26- Ile27-Ala28-Gly29-Gly30-Pro31-Ser32-Ser33-Gly34-Ala35-Pro36-Pro37-Pro38-Ser39-NH2. Background of the Invention: Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. Tirzepatide is also known as LY3298176. Tirzepatide is a 39 amino acid modified peptide based on the GIP sequence. Tirzepatide contains 2 non-coded amino acids (aminoisobutyric acid, Aib) in positions 2 and 13, a C- terminal amide, and Lys residue at position 20 that is attached to 1,20-eicosanedioic acid via a linker. The molecular weight is 4813.53 Dalton and the empirical formula is C225H348N48O68. Tirzepatide was approved by USFDA on May 13, 2022 and EMEA on September 19, 2022. It is indicated for the treatment as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. US9474780 B2 describes Tirzepatide and its process for preparation. The said process involves preparation of Tirzepatide trifluoroacetate salt by conventional solid phase peptide synthesis using standard Fmoc / t-Bu strategy and Rink Amide resin solid-phase peptide synthesis protocols in an automated peptide synthesizer. After finishing the elongation of the peptide-resin, Alloc protecting group present on Lys20 was removed by using Pd(PPh3)4in presence of PhSiH3 as a scavenger and further additional coupling / deprotection cycles using a Fmoc / t-Bu strategy to extend the Lys20 side-chain involved Fmoc-NH-PEG2-CH2COOH, Fmoc-Glu(OH)-OtBu and HOOC-(CH2)18-COOtBu. The resulting peptide sequence was deprotected and cleaved from the resin followed by precipitation of crude Tirzepatide with cold ether. The crude Tirzepatide was purified by reversed-phase HPLC followed by lyophilizing the pure fractions. Still there is a significant need to develop a cost effective, commercially viable, large scale and robust process for the preparation of pure Tirzepatide with good yield. The present invention describes a process for the preparation of Tirzepatide which involves the coupling of the resin bound protected peptide back bone with novel side chain compound of formula-2. the substituents wherever necessary can be independently selected from halogens such as F, CI, Br & I, ΝO2and the substitution can take place at single or multiple positions on aryl group or R1 is . inventors after numerous trails and earnest efforts developed an improved process for the preparation of Tirzepatide which involves less number of synthetic steps, simple operations and easy to carry out chemical conversions. Further, a purification method has been developed by the present inventors which results in high pure Tirzepatide in higher yield and can be useful on the industrial scale. The process described in the present invention is simple, safe, economic and suitable for the production of Tirzepatide and its side chain on an industrial scale in good yield and better quality. Brief description of the invention: The first embodiment of the present invention is to provide a process for the preparation of Tirzepatide. The second embodiment of the present invention is to provide a process for the preparation of compound of formula-2. The third embodiment of the present invention is to provide a novel compound of formula-2a. The fourth embodiment of the present invention is to provide a process for the preparation of compound of formula-6. The fifth embodiment of the present invention is to provide a novel compound of formula-16a. The sixth embodiment of the present invention is to provide a novel compound of formula-18. Detailed description of the Invention: The “solvent” used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE), 1,2- dimethoxyethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl THF), 2- methoxyethyl ether (Diglyme), 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate (EtOAc), n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; “polar-aprotic solvents” such as dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane (DCM), dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and the like; “nitrile solvents” such as acetonitrile (ACN), propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol or isopropyl alcohol (IPA), n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like; “polar solvents” such as water; formic acid, acetic acid (AcOH) and the like or mixture of any of the afore mentioned solvents. The “base” used in the present invention can be selected from but not limited to “inorganic bases” selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; ammonia; “organic bases” like “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine (DIPEA), diisobutylamine, trimethylamine, triethylamine (TEA), triisopropylamine, tributylamine, tert.butyl amine, pyridine, piperidine, 4- dimethylaminopyridine (DMAP), quinoline, imidazole, N-methylimidazole, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), dimethylaniline, N-methylmorpholine (NMM), 1,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; “organolithium bases” such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; “organosilicon bases” such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof. The “acid” used in the present invention can be selected from but not limited to “inorganic acids” selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid; “organic acids” selected from tartaric acid, acetic acid, maleic acid, citric acid, malic acid, oxalic acid, formic acid, trifluoroacetic acid and like or combination thereof. The “coupling agent” used in the present invention can be selected from but not limited to N,N'-dicyclohexylcarbodiimide (DCC), N,N‟-diisopropyl carbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), N,N’-carbonyl diimidazole (CDI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1H-benzotriazolium 1-[bis(dimethylamino)methylene]- 5-chloro-hexafluorophosphate(1)-3-oxide (HCTU), (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxy-7-azatriazole (HOAt), 1-hydroxy benzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N- hydroxysuccinamide (HOSu), Nhydroxysulfosuccinimide (Sulfo-NHS), N- Hydroxyphthalimide (NHPI), ethyl cyano hydroxyiminoacetate (Oxyma), 7-Azabenzotriazol- 1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), N,N,N′,N′-Tetramethyl- O-(N-succinimidyl)uronium tetrafluoro borate (TSTU) or mixtures thereof. The “deprotecting agent” in the present invention can be selected based on the protecting group employed. The “deprotecting agent” in the present invention can be selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq. Phosphoric acid, trifluoroacetic acid (TFA), methanesulfonic acid, p- toluenesulfonic acid, trifluoromethanesulfonic acid and the like; acetyl chloride in combination with alcohols, bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate / imidazole, alkali metal bicarbonates, ammonia, aqueous ammonia, ammonium cerium(IV) nitrate (CAN), organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like; hydrogenating agents such as Pd / C, Pd(OH)2 / C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh / C, Ru, Raney-Ni, Zn-acetic acid, tri(C1-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides, sodium borohydride, Na-liquid ammonia and the like or combination thereof. Fmoc deprotection in the present invention can be carried out by using bases such as piperidine, piperazine, DBU, Oxyma, formic acid optionally in presence of a solvent such as DMF, NMP, THF, 2-methyl THF and the like or mixtures thereof. In an aspect of the present invention Fmoc deprotection is carried out by using 5-20% piperidine in DMF. The Alloc deprotection in the present invention is carried out by using Alloc deprotecting agents like tetrakis(triphenylphosphine)palladium(0) [Pd(pph3)4] optionally in presence of a base such as morpholine, N-methylmorpholine (NMM), DBU, piperidine, N- methylaniline optionally in presence of a solvent. The Dde deprotection in the present invention is carried out by using Dde deprotecting agents like hydrazine hydrate, ammonia, hydroxylamine hydrochloride and imidazole optionally in presence of solvent. The solvent for Alloc deprotection and Dde deprotection in the present invention is selected from those as defined above. In an aspect of the present invention, the solvent for Alloc deprotection and Dde deprotection is selected from dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), dichloromethane (DCM), dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and the like or mixtures thereof. The “cocktail mixture / cleaving reagent” used in the present invention is selected from HF, TFA (trifluoroacetic acid), TIS or TIPS (triisopropylsilane), Acetic acid, Hydrochloric acid, Phosphoric acid, Perchloric acid, Phenol, Anisole, Thioanisole, EDT (Ethane-1,2- dithiol), 1-dodecanethiol (DDT), Dithiothreitol (DTT), 3,6-dioxa-1,8-octanedithiol (DODT), methanesulfonic acid, water or mixtures thereof. The “cocktail mixture / cleaving reagent” in the present invention is used for cleavage of the peptide chain from the Resin or for the deprotection of side chain protecting groups of the amino acids or for both of them simultaneously. In an aspect of the present invention, the “cocktail mixture / cleaving reagent” is TFA:TIS:Phenol:Water. In the present invention ‘Resin’ is selected from Rink Amide Resin, Rink Amide AM Resin, Rink Amide MBHA Resin, PAL Resin, Sieber Amide Resin and the like. Tirzepatide obtained by the process of the present invention can be purified by RP- HPLC to achieve high pure compound. The buffer which can be used in the present invention as mobile phase can be selected from but not limited to aqueous ammonium acetate, aqueous ammonium bicarbonate, aqueous ammonium carbonate, aqueous ammonium chloride, aqueous ammonium formate, aqueous ammonia (ammonia solution or ammonium hydroxide), aqueous ammonium phosphate, aqueous ammonium sulfate, aqueous sodium acetate, aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous sodium chloride, aqueous sodium sulfate, aqueous monosodium phosphate (NaH2PO4), aqueous disodium hydrogen phosphate (Na2HPO4), aqueous potassium acetate, aqueous potassium carbonate, aqueous potassium bicarbonate, aqueous potassium chloride, aqueous potassium sulfate, aqueous monopotassium phosphate (KH2PO4), aqueous dipotassium phosphate (K2HPO4), aqueous tris(hydroxymethyl) aminomethane (Tris buffer), aqueous formic acid, aqueous hydrobromic acid, aqueous hydrochloric acid, aqueous acetic acid, aqueous trifluoroacetic acid, aqueous citric acid, aqueous boric acid, aqueous sulfuric acid, aqueous fumaric acid, aqueous tartaric acid, aqueous perchloric acid and aqueous orthophosphoric acid, isopropyl methylphosphonic acid (IMPA) in water, O-phthalaldehyde (OPA) in water or mixtures thereof. The pH of the buffer in the present invention is about 1 to about 12. In an aspect, the pH is about 1.5 to about 11, or about 2 to about 10, or about 2.5 to about 9, or about 3 to about 8, or about 3.5 to about 7, or about 4 to about 6, or about 4.5 to about 5. The molar concentration of the buffer in the present invention is about 1.5M to 0.01M. In an aspect, the buffer concentration is about 1.2 M to about 0.05 M, or is about 1.0M to about 0.07 M, or is about 0.5 M to about 0.1 M. The mobile phase for the RP-HPLC purification can be selected from the buffers as listed above and can also be selected from ammonium acetate, ammonium formate, acetic acid, trifluoroacetic acid, acetonitrile, water, alcohols such as methanol, ethanol, isopropyl alcohol (isopropanol) and the like or combination thereof. In an aspect of the present invention, the mobile phase for RP-HPLC purification is Ammonium acetate having concentration about 0.001M to about 0.2M. In an aspect of the present invention, the mobile phase for RP-HPLC purification is 0.01%-0.5% Acetic acid. In an aspect of the present invention, the mobile phase for RP-HPLC purification is Ammonium formate having concentration about 0.001M to about 0.2M. The “diluent” in the present invention is selected from but not limited to water, acetonitrile, acetonitrile:water, methanol:water, ethanol:water, acetonitrile:water, isopropanol:water, ammonia in water and the like. In the present invention the purification of Tirzepatide backbone, Tirzepatide or its salts is carried out by using Reverse phase high performance liquid chromatography (RP- HPLC) preferably using HPLC gradient method. The mobile phase can be selected from buffer, solvent or mixtures thereof selected from those as defined herein above. The first embodiment of the present invention provides an improved process for the preparation of Tirzepatide, comprising; a) coupling Fmoc-Ser(tBu)-OH with Resin, b) capping the Resin, c) selectively deprotecting the Fmoc group, d) repeating steps-a) & c) to couple remaining amino acids which are optionally protected as per the desired peptide sequence of Tirzepatide to the compound obtained in step c) in presence of a coupling agent optionally in presence of a solvent to provide Resin bound Tirzepatide backbone, e) converting the compound obtained in step-d) to Tirzepatide or its salt, f) purifying Tirzepatide or its salt to provide pure Tirzepatide or its salt. Various amino acids of Tirzepatide backbone as described above are optionally protected with different protecting groups which include but not limited to alkyloxy carbonyl such as methoxy carbonyl, ethoxy carbonyl, tert.butoxycarbonyl (Boc), Dde, IVDde and the like; benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), allyloxy carbonyl (Alloc), tert.butyl (tBu), 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf), p-methoxy benzyloxy carbonyl (Moz), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), formyl (CHO), 2- (trimethylsilyl)ethoxycarbonyl (Teoc), 1-adamantyloxycarbonyl (Adoc), 2-(p-biphenyl) isopropyloxycarbonyl (Bpoc), triphenylmethyl (Trityl or Trt), methoxymethyl (MOM), allyl, N-benzyloxymethyl (Bom), Tosyl (Tos), monomethoxytrityl (Mmt), methyltrityl (Mtt), 2,4- dimethylpent-3-yloxycarbonyl (Doc), tert-butoxymethyl (Bum), 2-(4-nitrophenyl) ethoxycarbonyl (Npeoc), 2,2,2-trichloroethoxycarbonyl (Troc), N-dithiasuccinoyl (Dts), benzothiazol-2-sulfonyl (Betsyl), 1,1-dimethyl-2,2,2-trichloroethoxy carbonyl (TcBoc), N- (diphenyl-4-pyridyl)methyl (Dppm) and the like. In an aspect of the present invention the amino acid coupling is carried out in presence of a coupling agent optionally in presence of a solvent or mixtures thereof, which are selected from those as defined above. In an aspect of the present invention amino acids as per the desired sequence of Tirzepatide are used for the coupling in an amount of 0.1 molar equivalents to 5 molar equivalents, coupling agent 0.1 molar equivalents to 5 molar equivalents and solvent 1 volumes to 10 volumes wherever necessary all with respect to the resin used. In an aspect of the present invention in some specific stages of amino acid coupling, the amount of amino acids (AA), coupling agents and solvents may vary based on the requirement of the amino acid coupling wherever necessary. In an aspect of the present invention Tirzepatide is synthesized by solid phase peptide synthesis or combination of solid phase peptide synthesis and solution phase peptide synthesis (Hybrid approach). In an aspect of the present invention, the amino acids are coupled by linear approach or by fragment approach or a combination thereof to prepare Tirzepatide. As used herein fragment approach means smaller peptide fragments are prepared by coupling corresponding amino acids by solid phase or by solution phase or by hybrid approach and the resulting peptide fragments are coupled with corresponding amino acids or other peptide fragments to obtain Tirzepatide. In the present invention capping is carried out by using acetic anhydride optionally in presence of a base and solvent as defined above. In the present invention, various bases that can be used for capping step are selected from but not limited to organic bases such as diisopropylethyl amine (DIPEA), diisopropylamine, pyridine, triethylamine, N-methylmorpholine. The solvent for capping step can be selected from but not limited to DCM, DMF, THF, methanol, ethanol and the like or mixtures thereof. In the present invention, Fmoc deprotection can be carried out by using base in presence of a solvent selected from those as defined above. In an aspect of the present invention the base for Fmoc deprotection can be selected from piperidine, piperazine, DBU and the solvent selected from DMF, NMP, THF, 2-methyl THF and the like. In an aspect of the present invention, Fmoc deprotection can be carried out by using piperidine, piperazine, DBU, Oxyma, formic acid optionally in presence of a solvent such as DMF, NMP, THF, 2-methyl THF and the like or mixture thereof. In an aspect of the present invention Fmoc deprotection is carried out by using 5- 20% piperidine in DMF. In an aspect of the present invention, the conversion in step-e) can be carried out by cleavage of the peptide chain from the Resin and deprotection of all the amino acids wherever applicable by using “cocktail mixture / cleaving reagent” and reacting the obtained compound with compound of formula-2 in a solvent optionally in presence of a base and / or a coupling agent. In another aspect of the present invention, the conversion in step-e) is carried out by deprotection of Lysine (if applicable), coupling of compound of formula-2 to the backbone at Lysine followed by deprotection of the amino acids and cleavage of the peptide chain from the Resin by using “cocktail mixture / cleaving reagent”. In a further aspect of the present invention, the conversion in step-e) is carried out by deprotecting the Alloc side chain protecting group of Lysine by using Alloc deprotecting agent optionally in presence of a base and a solvent and coupling of compound of formula-2 to the back bone at Lysine in a solvent optionally in presence of a base and / or a coupling agent. The deprotection of the amino acids and cleavage of the peptide chain from the Resin by using “cocktail mixture / cleaving reagent” provides Tirzepatide. In an aspect of the present invention Tirzepatide obtained by the process of the present invention can be purified by RP-HPLC to achieve high pure compound. In an aspect of the present invention, the Reversed phase high performance liquid chromatography (RP-HPLC) involves gradient method, which uses buffer, solvent or mixtures thereof as a mobile phase and can be selected from those as defined herein above. In an aspect of the first embodiment of the present invention, the conversion in step-e) is carried out by deprotecting the Alloc side chain protecting group of Lysine followed by reacting the obtained compound with compound of formula-2 wherein 'R1' wherever necessary can be independently selected from halogens such as F, CI, Br & I, ΝO2and the substitution can take place at single or multiple positions on aryl group or R1 is An aspect of the first embodiment of the present invention provides a process for the preparation of Tirzepatide, comprising; a) coupling Fmoc-Ser(tBu)-OH with Resin optionally in presence of a coupling agent and a solvent to provide Fmoc-Ser(tBu)-Resin, b) capping the Resin, c) deprotection of Fmoc from Fmoc-Ser(tBu)-Resin by using a base optionally in presence of a solvent to provide H-Ser(tBu)-Resin, d) repeating the coupling and Fmoc deprotection steps with remaining amino acids Fmoc- Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)- OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala- OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc- Aib-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc- Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Aib-OH and Boc-Tyr(tBu)-OH to the compound obtained in step c) to provide Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin, e) deprotecting the Alloc protecting group by using Alloc deprotecting agent optionally in presence of a base and a solvent, f) coupling of compound of formula-2 with the compound obtained in step-e) in a solvent optionally in presence of a base and / or a coupling agent to provide Resin bound protected Tirzepatide, g) treating the obtained compound with cocktail mixture / cleaving reagent to provide Tirzepatide, h) subjecting Tirzepatide to purification to provide pure Tirzepatide. In the above process, coupling steps can be carried out in presence of a coupling agent and / or a base optionally in presence of a solvent which are selected from those as defined above. Capping can be carried out by using an acetic anhydride in presence of a base such as diisopropylethylamine, diisopropylamine, pyridine, triethylamine, N-methylmorpholine in presence of a solvent such as DCM, DMF, THF, methanol, ethanol and the like or mixtures thereof. In an aspect of the present invention, step-g) of the above process can be carried out in different ways which include (a) global deprotection by treating with cocktail mixture to remove all the protecting groups and cleavage of the peptide from the resin at a time or (b) cleavage of the peptide from the resin followed by removal of the protecting groups or (c) removal of the protecting groups followed by cleavage of the peptide from the resin. Another aspect of the first embodiment of the present invention provides a process for the preparation of Tirzepatide, comprising; a) coupling Fmoc-Ser(tBu)-OH with Resin optionally in presence of a coupling agent and a solvent to provide Fmoc-Ser(tBu)-Resin, b) capping the Resin, c) deprotection of Fmoc from Fmoc-Ser(tBu)-Resin by using a base optionally in presence of a solvent to provide H-Ser(tBu)-Resin, d) repeating the coupling and Fmoc deprotection steps with remaining amino acids Fmoc- Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)- OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala- OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc- Aib-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc- Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Aib-OH and Boc-Tyr(tBu)-OH to the compound obtained in step c) to provide Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin, e) deprotecting the Alloc protecting group from the Lysine by using Alloc deprotecting agent optionally in presence of a base and a solvent, f) coupling of compound of formula-2a with the compound obtained in step-e) in a solvent optionally in presence of a base to provide Resin bound protected Tirzepatide, g) treating the to provide Tirzepatide, h) subjecting Tirzepatide to purification to provide pure Tirzepatide. In the above process, coupling steps can be carried out optionally in presence of a coupling agent, base and a solvent which are selected from those as defined above. Fmoc deprotection can be carried out by using the process as described herein above. Capping can be carried out by using an acetic anhydride in presence of a base such as diisopropylethylamine, diisopropylamine, pyridine, triethylamine, N-methylmorpholine in presence of a solvent such as DCM, DMF, THF, methanol, ethanol and the like or mixtures thereof. Alloc deprotecting agent is herein as defined above. In an aspect of the present invention, step-g) of the above process can be carried out in different ways which include (a) global deprotection by treating with cocktail mixture to remove all the protecting groups and cleavage of the peptide from the resin at a time or (b) cleavage of the peptide from the resin followed by removal of the protecting groups or (c) removal of the protecting groups followed by cleavage of the peptide from the resin. Another aspect of the first embodiment of the present invention provides a process for the preparation of Tirzepatide, comprising; a) treating Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(Alloc)-Ala- Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-Resin with Alloc deprotecting agent optionally in presence of a base and a solvent, b) coupling compound of formula-2a with the compound obtained in step-a) in a solvent optionally in presence of a base to provide Resin bound protected Tirzepatide, c) treating the obtained compound with cocktail mixture / cleaving reagent to provide Tirzepatide, d) subjecting Tirzepatide to purification to provide pure Tirzepatide. The Alloc deprotecting agent, solvent, base, cocktail mixture / cleaving reagent and purification conditions as defined herein in the present invention. Another aspect of the first embodiment of the present invention provides a process for the preparation of Tirzepatide, comprising; a) reacting Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys- Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala- Pro-Pro-Pro-Ser(tBu)-Resin with compound of formula-2a in a solvent optionally in presence of a base to provide Resin bound protected Tirzepatide, b) treating the obtained compound with cocktail mixture / cleaving reagent to provide Tirzepatide, c) subjecting Tirzepatide to purification to provide pure Tirzepatide. In an aspect of the present invention, step-b) of the above process can be carried out in different ways which include (a) global deprotection by treating with cocktail mixture to remove all the protecting groups and cleavage of the peptide from the resin at a time or (b) cleavage of the peptide from the resin followed by removal of the protecting groups or (c) removal of the protecting groups followed by cleavage of the peptide from the resin. The solvent, base, cocktail mixture / cleaving reagent and purification conditions as defined herein in the present invention. An aspect of the first embodiment of the present invention provides a process for the preparation of Tirzepatide, comprising; a) coupling Fmoc-Ser(tBu)-OH with Resin optionally in presence of a coupling agent and a solvent to provide Fmoc-Ser(tBu)-Resin, b) capping the Resin, c) Fmoc deprotection of Fmoc-Ser(tBu)-Resin by using a base optionally in presence of a solvent to provide H-Ser(tBu)-Resin, d) repeating the coupling and Fmoc deprotection steps with remaining amino acids or peptide fragments Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Gly-Ala-OH, Fmoc-Ser(tBu)- OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile- OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc- Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Dde)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Ile- Aib-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc- Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH, Boc-Tyr(tBu)-Aib-OH to the compound obtained in step c) to provide Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(Dde)-Ala- Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-Resin, e) deprotecting the Dde protecting group, f) coupling compound of formula-7 with the compound obtained in step-e) in a solvent optionally in presence of a coupling agent to provide Resin bound protected Tirzepatide, wher g) treating the obtained compound with cocktail mixture / cleaving reagent to provide Tirzepatide, h) subjecting Tirzepatide to purification to provide pure Tirzepatide. In the above process coupling steps can be carried out in presence of a coupling agent, optionally in presence of a base and a solvent which are selected from those as defined above. Capping can be carried out by using an acetic anhydride in presence of a base such as diisopropylethylamine, diisopropylamine, pyridine, triethylamine, N-methylmorpholine in presence of a solvent such as DCM, DMF, THF, methanol, ethanol and the like or mixtures thereof. Fmoc deprotection is carried out according to the process described herein in the present invention. The Dde deprotection in the present invention is carried out by using Dde deprotecting agents like hydrazine hydrate, ammonia, hydroxylamine hydrochloride and imidazole optionally in presence of solvent. The solvent is selected from dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), dichloromethane (DCM), dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and the like or mixtures thereof. In an aspect of the present invention, step-g) of the above process can be carried out in different ways which include (a) global deprotection by treating with cocktail mixture to remove all the protecting groups and cleavage of the peptide from the resin at a time or (b) cleavage of the peptide from the resin followed by removal of the protecting groups or (c) removal of the protecting groups followed by cleavage of the peptide from the resin. An aspect of the first embodiment of the present invention provides a process for the purification of Tirzepatide, comprising one or more of the following steps; a) dissolving crude Tirzepatide in diluent, b) subjecting the solution to RP-HPLC purification by using buffer as mobile phase A and solvent as mobile phase B, c) subjecting the obtained fractions in step-b) to RP-HPLC by using buffer as mobile phase A; solvent or a mixture of solvent and buffer as mobile phase B. In an aspect of the present invention, Reverse phase high performance liquid chromatography (RP-HPLC) involves gradient method, which uses buffer, solvent or mixtures thereof as a mobile phase. The diluent, buffer and solvent are selected from those as defined above in the present invention. The solvent can be selected from organic solvents such as acetonitrile, alcohol solvents selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2- butanol, tert-butanol and the like, DMF, THF, acetone or mixtures thereof. In an aspect of the above process the buffer is selected from aqueous ammonia, aqueous ammonium acetate, aqueous acetic acid, aqueous ammonium formate, aqueous trifluoroacetic acid or mixtures thereof. The diluent is selected from 0.1%-5% ammonia in water. The solvent is selected from acetonitrile:methanol:isopropanol or acetonitrile:methanol or acetonitrile:methanol:water. In an aspect of the above process the solvent is selected from acetonitrile:methanol:isopropanol (8:1:1) or acetonitrile:methanol (9:1). In an aspect of the above process the buffer is selected from 0.025M ammonium acetate in water, 0.1% acetic acid in water, 0.05% acetic acid in water, 0.005M ammonium formate in water, trifluoroacetic acid in water. In an aspect of the present invention the buffer pH is adjusted with aqueous acid. The second embodiment of the present invention provides a process for the preparation of compound of formula-2, comprising; a) reacting compound of formula-3 with compound of formula-4 in presence of a coupling agent and / or a base in a solvent to provide compound of formula-5, wherein b) reacting compound of formula-5 with compound of formula-6 in a solvent optionally in presence of a coupling agent and / or a base to provide compound of formula-7, c) reacting compound of in presence of a coupling agent and / or a base to provide compound of formula-8, d) a solvent to provide compound of formula-2. Wherein 'R1' represents substituted or unsubstituted aryl and the substituents wherever necessary can be independently selected from halogens such as F, CI, Br & I, ΝO2and the substitution can take place at single or multiple positions on aryl group or R1 is The coupling agent, base, and the solvent in various stages of the above process can be selected from those as defined above. In an aspect of the second embodiment of the present invention, in step-a) reaction of compound of fomula-3 with a coupling agent and / or a base in a solvent results in a compound of formula-9 which is formed in situ depending on the coupling agent and / or a base in a solvent used in the reaction in step-a) which upon treatment with compound of formula-4 in presence of a solvent / or a base provides compound of formula-5. wherein ‘R’ is as defined herein the present invention; and . reaction of compound of fomula-5 with a coupling agent and / or a base in a solvent results in compound of formula-10 which is formed in situ depending on the coupling agent and / or a base in a solvent used in the reaction in step-b) which upon treatment with compound of formula-6 in presence of a solvent / or a base provides compound of formula-7. wherein ‘R’ is same as defined herein above and . may be same or different. An aspect of the second embodiment of the present invention provides a process for the preparation of compound of formula-2, comprising; a) reacting compound of formula-7 with R1-OH in a solvent optionally in presence of a coupling agent and / or a base to provide compound of formula-8, b) treating compound of formula-8 with a deprotecting agent in presence of a solvent to provide compound of formula-2. The coupling agent, base, deprotecting agent and the solvent of the above process can be selected from those as defined above. The third embodiment of the present invention provides a novel intermediate compound represented by the following structural formula-2a. The compound represented by the structural formula-2a for the preparation of Tirzepatide. The fourth embodiment of the present invention provides a process for the preparation of compound of formula-6, comprising; a) treating compound of formula-11 with compound of formula-12 in presence of a solvent and / or a base optionally in presence of an alkali metal halide to provide compound of formula-13, wherein, ‘X’ represents halogens such as Cl, Br and I; b) reacting compound of formula-13 with compound of formula-14 in a solvent optionally in presence of a base to provide compound of formula-15, c) treat lvent optionally in presence of a base to provide compound of formula-16, . d) in presence of a base to provide compound of formula-18, e) debenzylating presence of a solvent to provide compound of formula-6. f) optionally purifying compound of formula-6 with a solvent to provide pure compound of formula-6. The alkali metal halide in step-a) is selected from potassium fluoride, potassium chloride, potassium bromide, potassium iodide, sodium fluoride, sodium chloride, sodium bromide, sodium iodide, lithium fluoride, lithium chloride, lithium bromide, lithium iodide and the like. The solvent in step-a) to step-f) wherever necessary is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, water and the like or mixtures thereof. The base in step-a) and step-d) is selected from inorganic bases, organic bases or mixtures thereof. The coupling agent in step-c) is selected from those as defined above. The debenzylating agent in step-e) is selected from Pd / C, Raney-Ni, Pd(OH)2 / C, palladium acetate, platinum oxide, Rhodium and the like. In one aspect of the above described process, the debenzylation step can be carried out as a single step or two steps, i.e., compound of formula-18 can be treated with a debenzylating agent directly provides mono benzyl compound or passes through mono benzyl compound which further converts to compound of formula-6. An aspect of the fourth embodiment of the present invention provides a process for the preparation of compound of formula-6, comprising; a) treating compound of formula-15 with a coupling agent in a solvent optionally in presence of a base to provide compound of formula-16, b) reacting compound of formula-16 with compound of formula-17 in a solvent optionally in presence of a base to provide compound of formula-18, c) debenzylating compound of formula-18 with a debenzylating agent in presence of a solvent to provide compound of formula-6. d) optionally purifying the compound of formula-6 with a solvent to provide pure compound of formula-6. The solvent in step-a) to step-d) is selected from those as defined above. The base in step-a) and step-b) is selected from those as defined above. The coupling agent in step-a) is selected from those as defined above. The debenzylating agent in step-c) is selected from those as defined above. The compound of formula-17 used as an input for the preparation of compound of formula-6 can be prepared as per the any of the processes known in the art. The fifth embodiment of the present invention provides a novel intermediate compound represented by the following structural formula-16a. The compound of of compound of formula-2a and in turn for the preparation of Tirzepatide. An aspect of the fifth embodiment of the present invention provides the use of novel intermediate compound of formua-16a for the preparation of compound of formula-2a and / or for the preparation of Tirzepatide. The sixth embodiment of the present invention provides a novel intermediate compound represented by the following structural formula-18. The novel preparation of compound of formula-2a and in turn for the preparation of Tirzepatide. An aspect of the sixth embodiment of the present invention provides the use of novel intermediate compound of formua-18 for the preparation of compound of formula-2a and / or for the preparation of Tirzepatide. The pH of the buffer in the present invention is from about 1 to about 12. In an aspect, the pH is about 1.5 to about 11, or about 2 to about 10, or about 2.5 to about 9, or about 3 to about 8, or about 3.5 to about 7, or about 4 to about 6, or about 4.5 to about 5. The molar concentration of the buffer in the present invention is about 1.5M to 0.01M. In an aspect, the buffer concentration is about 1.2 M to about 0.05 M, or is about 1.0M to about 0.07 M, or is about 0.5 M to about 0.1 M. In an aspect, the buffer concentration is about 1.2 M to about 0.05 M, or is about 1.0M to about 0.07 M, or is about 0.5 M to about 0.1 M. The mobile phase for the HPLC purification can be selected from the buffers as listed above and can also be selected from water, TFA, acetonitrile, alcohols such as methanol, ethanol, isopropyl alcohol and the like or combination thereof. The “diluent” in the present invention is selected from but not limited to water, acetonitrile, acetonitrile:water, methanol:water, ethanol:water, acetonitrile:water, isopropanol:water and the like or combination thereof. Different grades of stationary phases which can be used in the purification processes of the present invention include but not limited to C18 columns, C16 columns, C14 columns, C12 columns, C10 columns, C8 columns, C6 columns, C4 columns, phenyl columns, polymeric adsorbent columns, RP-amide columns and the like. The flow rate in the HPLC purification processes of the present invention is about 0.1 mL / min to about 400 mL / min. The run time in the HPLC purification processes of the present invention is about 10 min to about 400 min. The wavelength in the HPLC purification processes of the present invention is about 200 nm to about 250 nm. Tirzepatide obtained by the process of the present invention is having purity of greater than about 90% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 95% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 96% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 97% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 98% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 98.5% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 98.8% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 99% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 99.2% by HPLC. In an aspect, Tirzepatide is having purity of greater than about 99.3% by HPLC. HPLC Method of Analysis: Tirzepatide: Column: C8 Column; Wavelength: 210 nm; Diluent: Acetonitrile:Water; Elution: Gradient; Buffer: Ammonium Sulphate and Ammonium Phosphate mono basic in Milli-Q-Water and Orthophosphoric acid; Mobile Phase-A: Buffer and Methanol; Mobile Phase-B: Acetonitrile:Methanol:Water. Formula-5a: Column: C8 Column; Wavelength: 220 nm; Diluent: Methanol; Elution: Gradient; Buffer: Water:Acetonitrile:Perchloric acid; Mobile Phase-A: 100% Buffer; Mobile Phase-B: Acetonitrile. Formula-7a: Column: C18 Column; Wavelength: 220 nm; Diluent: Isopropanol:Acetonitrile; Elution: Gradient; Buffer: Water:Acetonitrile:Perchloric acid; Mobile Phase-A: 100% Buffer; Mobile Phase-B: Acetonitrile:Methanol:Water. Formula-6: Column: C18 Column; Wavelength: 215 nm; Diluent: Methanol:Water; Elution: Gradient; Buffer: Perchloric acid:Milli-Q-Water; Mobile Phase-A: 100% Buffer; Mobile Phase-B: Acetonitrile:Milli-Q-Water:Methanol. Tirzepatide obtained as per the process of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used. The seventh embodiment of the present invention provides the use of Tirzepatide obtained as per the process of the present invention for the preparation of pharmaceutical formulations. The eighth embodiment of the present invention provides a pharmaceutical composition comprising Tirzepatide obtained by the process of the present invention and at least one pharmaceutically acceptable excipient. The ninth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the patient a therapeutically effective amount of Tirzepatide obtained by the process of the present invention. The present invention is schematically represented as follows; Scheme-1:

[0002] Scheme-2:

[0003] Scheme-3: substituents wherever necessary can be independently selected from ΝO2 and halogens such as F, CI, Br & I; the substitution can takes place at single or multiple positions on aryl group represents benzyl, C1-C6 straight chain or branched chain alkyl.

[0004] Scheme-4: the substituents wherever necessary can be independently selected from ΝO2 and halogens such as F, CI, Br & I; the substitution can takes place at single or multiple positions on aryl group benzyl, C1-C6straight chain or branched chain alkyl. . . Scheme-5: R4is selected . Examples: Example-1: Preparation of Resin bound protected Tirzepatide Step-1: Fmoc-Ser(tBu)-Resin Rink Amide AM Resin (50 gm) was swelled in DCM (500 ml) at 25-30°C and stirred for 1 hr at the same temperature. Drained out the solvent from the peptide flask and washed the Resin with DCM at 25-30°C. 15% Piperidine solution (75 ml of piperidine in 425 ml of DMF) was added lot wise to remove Fmoc from the Resin at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF. A solution of Fmoc-Ser(tBu)-OH (18.4 gm), HOBt (6.48 gm) and DIC (7.47 ml) in DMF (250 ml) at 25-30°C were added to the reaction mixture at 25-30°C and stirred for 4 hr at the same temperature. Drained out the solvent from the peptide flask and washed the reaction mixture with DMF. Further the unreacted resin was capped with mixture of acetic anhydride (15.12 ml), pyridine (12.9 ml) and dichloromethane (250 ml) at 25-30°C and stirred for 2 hr at the same temperature. Drained out the solvent from the peptide flask and washed the reaction mixture with DMF followed by methanol to get the title compound. Step-2: Fmoc deprotection of Fmoc-Ser(tBu)-Resin Resin was swelled in DCM (400 ml) at 25-30°C. 15% Piperidine solution (75 ml of piperidine in 425 ml of DMF) was added lot wise to Fmoc-Ser(tBu)-Resin obtained in step-1 at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the compound with DMF to get H-Ser(tBu)-Resin. Step-3: Preparation of Resin bound protected Tirzepatide including side chain Fmoc-Pro-OH (15.4 gm) was dissolved in DMF (250 ml) at 25-30°C. HOBt (6.18 gm) and DIC (7.12 ml) were added to the reaction mixture at 25-30°C and stirred for 5 min at the same temperature. The resulting solution was added to H-Ser(tBu)-Resin obtained in step-2 at 25-30°C and stirred for 3 hr 10 min at the same temperature. Drained out the solvent from the peptide flask and washed with DMF to get Fmoc-Pro-Ser(tBu)-Resin. 15% Piperidine solution (75 ml of piperidine in 425 ml of DMF) was added lot wise to Fmoc-Pro-Ser(tBu)- Resin at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF to get H-Pro- Ser(tBu)-Resin. Repeated the above amino acids coupling and Fmoc deprotection step with remaining amino acids as per the amino acid sequence of Tirzepatide by using Fmoc-Pro-OH (15.4 gm), Fmoc-Pro-OH (15.4 gm), Fmoc-Ala-OH (14.24 gm), Fmoc-Gly-OH (13.60 gm), Fmoc-Ser(tBu)-OH (17.54 gm), Fmoc-Ser(tBu)-OH (17.54 gm), Fmoc-Pro-OH (15.43 gm), Fmoc-Gly-OH (13.60 gm), Fmoc-Gly-OH (13.60 gm), Fmoc-Ala-OH (14.24 gm), Fmoc-Ile- OH (16.16 gm), Fmoc-Leu-OH (21.55 gm), Fmoc-Trp(Boc)-OH (32.12 gm), Fmoc-Gln(Trt)- OH (52.1 gm), Fmoc-Val-OH (20.70 gm), Fmoc-Phe-OH (23.63 gm), Fmoc-Ala-OH (18.9 gm), Fmoc-Lys(Alloc)-OH (48.3 gm), Fmoc-Gln(Trt)-OH (55.87 gm), Fmoc-Ala-OH (18.9 gm), Fmoc-Ile-OH (23.65 gm), Fmoc-Lys(Boc)-OH (28.6 gm), Fmoc-Asp(OtBu)-OH (25.10 gm), Fmoc-Leu-OH (21.5 gm), Fmoc-Aib-OH (19.84 gm), Fmoc-Ile-OH (21.55 gm), Fmoc- Ser(tBu)-OH (23.38 gm), Fmoc-Tyr(tBu)-OH (42.03 gm), Fmoc-Asp(OtBu)-OH (31.37 gm), Fmoc-Ser(tBu)-OH (29.2 gm), Fmoc-Thr(tBu)-OH (36.3), Fmoc-Phe-OH (29.5 gm), Fmoc- Thr(tBu)-OH (30.3 gm), Fmoc-Gly-OH (22.67 gm), Fmoc-Glu(tBu)-OH (32.4 gm) coupled to H-Pro-Ser(tBu)-Resin to get Fmoc-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)- Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Fmoc 3-39 resin bound protected backbone of Tirzepatide). 3 gm of the material was taken from the obtained compound and swelled in DCM (35 ml) and washed with DMF. 15% Piperidine solution (4.5 ml of piperidine in 25.5 ml of DMF) was added lot wise to above obtained compound at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF to get H-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)- Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (3-39 resin bound protected backbone of Tirzepatide). Fmoc-Aib-OH (1.19 gm) was dissolved in DMF (6 ml) and NMP (9 ml) at 25-30°C. HOBt (0.49 gm) and DIC (0.57 ml) were added to reaction mixture at 25-30°C and stirred for 5 min. The resulting solution was added to the above obtained 3-39 resin bound protected backbone of Tirzepatide (Approximately 3 gm was taken) at 25-30°C and stirred for 3 hr at the same temperature. Drained out the solvent from the peptide flask and washed with DMF to provide Fmoc-Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)- Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(Alloc)-Ala-Phe-Val- Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro- Ser(tBu)-Resin (Fmoc 2-39 resin bound protected backbone of Tirzepatide). 15% Piperidine solution (4.5 ml of piperidine in 25.5 ml of DMF) was added lot wise to above obtained compound at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF to get H- Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib- leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu- Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (2-39 resin bound protected backbone of Tirzepatide). Boc-Tyr(tBu)-OH (1.23 gm) dissolved in DMF (6 ml) and NMP (9 ml) at 25-30°C. HOBt (0.49 gm) and DIC (0.57 ml) were added to the reaction mixture at 25-30°C and stirred for 5 min. The resulting solution was added to the above obtained 2-39 resin bound protected backbone of Tirzepatide at 25-30°C and stirred for 3 hr at the same temperature. Drained out the solvent from the peptide flask and washed with DMF and followed by methanol and dried to provide Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly- Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)- Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly- Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected backbone of Tirzepatide). Step-4: Alloc deprotection of Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected backbone of Tirzepatide) The Resin bound protected backbone of Tirzepatide was swelled in DCM at 25-30°C. Drained out the solvent from the peptide flask. A mixture of Pd(PPh3)4 (1.26 gm), morpholine (0.32 gm) and dichloromethane (60 ml) was added lot wise to the resin bound protected backbone of Tirzepatide to remove Alloc protecting group and stirred for 40 min, further washed with DCM. Drained out the solvent from the peptide flask to get Boc- Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)- Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu- Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin. Step-5: Acylation of Resin bound protected backbone of Tirzepatide with compound of formula-2a. A solution of compound formula-2a (3.23 gm), DMF (15 ml) and DIPEA (0.96 ml) was stirred for 5 min at 25-30°C. The obtained solution was added to the compound obtained in step-4 at 25-30°C and stirred for 24 hr at the same temperature and washed with DMF followed by methanol. Drained out the solvent from the peptide flask and dried to get Resin bound protected Tirzepatide including side chain Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)- Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile- Ala-Gln(Trt)-Lys(AEEA-AEEA-γ-Glu-Eicosanedioicacid)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)- Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected Tirzepatide). Yield: 6.2 gm. Example-2: Alternate preparation of Resin bound protected Tirzepatide Step-1: Fmoc-Ser(tBu)-Resin Rink Amide AM Resin (50 gm) was swelled in DCM (400 ml) at 25-30°C and stirred for 1 hr at the same temperature. Drained out the solvent from the peptide flask and washed the Resin with DCM at 25-30°C. 15% Piperidine solution (90 ml of piperidine in 510 ml of DMF) was added lot wise to remove Fmoc from the Resin at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF and followed by DCM. A solution of Fmoc-Ser(tBu)-OH (19.55 gm), DMF (250 ml), HOBt (6.89 gm) and DIC (7.93 ml) at 25-30°C were added to the reaction mixture at 25-30°C and stirred for 4 hr at the same temperature. Drained out the solvent from the peptide flask and washed the reaction mixture with DMF and followed by DCM. Further the unreacted resin was capped with mixture of acetic anhydride (16.06 ml), pyridine (13.8 ml) and dichloromethane (250 ml) at 25-30°C and stirred for 2 hr at the same temperature. Drained out the solvent from the peptide flask and washed the reaction mixture with DMF to get the title compound. Step-2: Fmoc deprotection of Fmoc-Ser(tBu)-Resin 15% Piperidine solution (90 ml of piperidine in 510 ml of DMF) was added lot wise to Fmoc-Ser(tBu)-Resin obtained in step-1 at 25-30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF and followed by DCM to get H-Ser(tBu)-Resin. Step-3: Preparation of Resin bound protected Tirzepatide including side chain Fmoc-Pro-OH (15.6 gm) was dissolved in DMF (250 ml) at 25-30°C. HOBt (6.2 gm) and DIC (7.2 ml) were added to the reaction mixture at 25-30°C and stirred for 5 min at the same temperature. The resulting solution was added to H-Ser(tBu)-Resin obtained in step-2 at 25- 30°C and stirred for 4 hr at the same temperature. Drained out the solvent from the peptide flask and washed with DMF to get Fmoc-Pro-Ser(tBu)-Resin. 15% Piperidine solution (90 ml of piperidine in 510 ml of DMF) was added lot wise to Fmoc-Pro-Ser(tBu)-Resin at 25- 30°C and stirred the reaction mixture at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF and followed by DCM to get H-Pro-Ser(tBu)-Resin. Repeated the above amino acids coupling and Fmoc deprotection step with remaining amino acids as per the amino acid sequence of Tirzepatide by using Fmoc- Pro-OH (15.6 gm), Fmoc-Pro-OH (15.6 gm), Fmoc-Gly-Ala-OH (17.1 gm), Fmoc-Ser(tBu)- OH (17.8 gm), Fmoc-Ser(tBu)-OH (17.8 gm), Fmoc-Pro-OH (15.6 gm), Fmoc-Gly-Gly-OH (16.4 gm), Fmoc-Ala-OH (14.4 gm), Fmoc-Ile-OH (16.4 gm), Fmoc-Leu-OH (16.4 gm), Fmoc-Trp(Boc)-OH (24.4 gm), Fmoc-Gln(Trt)-OH (37.7 gm), Fmoc-Val-OH (15.7 gm), Fmoc-Phe-OH (18 gm), Fmoc-Ala-OH (14.4 gm), Fmoc-Lys(Dde)-OH (32.96 gm), Fmoc- Gln(Trt)-OH (37.7 gm), Fmoc-Ala-OH (14.4 gm), Fmoc-Ile-OH (21.9 gm), Fmoc-Lys(Boc)- OH (28.9 gm), Fmoc-Asp(OtBu)-OH (25.5 gm), Fmoc-Leu-OH (21.9 gm), Fmoc-Ile-Aib- OH (33.7 gm), Fmoc-Ser(tBu)-OH (23.7 gm), Fmoc-Tyr(tBu)-OH (28.4 gm), Fmoc- Asp(OtBu)-OH (25.5 gm), Fmoc-Ser(tBu)-OH (23.7 gm), Fmoc-Thr(tBu)-OH (24.6), Fmoc- Phe-OH (24 gm), Fmoc-Thr(tBu)-OH (24.6 gm), Fmoc-Gly-OH (18.4 gm), Fmoc-Glu(tBu)- OH (26.2 gm), Boc-Tyr(tBu)-Aib-OH (32.6 gm) coupled to H-Pro-Ser(tBu)-Resin and finally washed with DMF to get Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(Dde)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected backbone of Tirzepatide). Step-4: Dde deprotection of Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(Dde)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected backbone of Tirzepatide) Mixture of Hydrazine hydrate (30 ml) and DMF (1500 ml) was added lot wise to Resin bound protected backbone of Tirzepatide (compound obtained in step-2) at 25-30°C and stirred for 45 min at the same temperature. Drained out the solvent from the peptide flask and washed the obtained compound with DMF to get Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)- Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile- Ala-Gln(Trt)-Lys-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected backbone of Tirzepatide). Step-5: Acylation of Resin bound protected backbone of Tirzepatide with compound of formula-7a A solution of compound of formula-7a (40.6 gm), HOBt (6.1 gm), DIC (7.1 ml) in DMF (250 ml) was stirred for 16 hr at 25-30°C and washed with DMF followed by methanol. Drained out the solvent from the peptide flask and dried to get Resin bound protected Tirzepatide including side chain Boc-Tyr(tBu)-Aib-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(AEEA-AEEA-γ-Glu-Eicosanedioicacid)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala- Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin (Resin bound protected Tirzepatide). Yield: 152 gm. Example-3: Preparation of crude Tirzepatide Resin bound protected Tirzepatide (6 gm) was added to pre-cooled cocktail mixture TFA(39.84ml):TIS(2.4ml):Phenol(4.8ml):Water(0.96ml) at 10-15°C and stirred the reaction mixture for 10 min at the same temperature. Raised the reaction mixture temperature to 25- 30°C and stirred for 3 hr at the same temperature. Filtered the reaction mixture and washed with TFA. The obtained filtrate was slowly added to pre-cooled MTBE (180 ml) at 10-15°C and stirred for 20 min at the same temperature. Raised the reaction mixture temperature to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and washed with MTBE. MTBE (120 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with MTBE. Further MTBE (60 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with MTBE and dried to get crude Tirzepatide. Yield: 2.8 gm; Purity by HPLC: 17.88%. Example-4: Alternate preparation of crude Tirzepatide Resin bound protected Tirzepatide (50 gm) was added to pre-cooled cocktail mixture TFA (356 ml), TIS (20 ml), DTT (4 gm), water (20 ml) at 10-15°C and stirred the reaction mixture for 10 min at the same temperature. Raised the reaction mixture temperature to 20-25°C and stirred for 3 hr at the same temperature. Filtered the reaction mixture and washed with TFA. The obtained filtrate was slowly added to pre-cooled MTBE (1500 ml) at 10-15°C and stirred for 15 min at the same temperature. Raised the reaction mixture temperature to 25-30°C and stirred for 2 hr 30 min at the same temperature. Filtered the precipitated solid and washed with MTBE. MTBE (1000 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with MTBE. Further MTBE (500 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with MTBE and dried to get crude Tirzepatide. Yield: 23 gm; Purity by HPLC: 42.35%. Example-5: Purification of Tirzepatide by RP-HPLC Step-1: Crude Tirzepatide (2 gm) was dissolved in 1% ammonia in water. The solution was filtered through 0.45 micron filter paper. The C18 column was equilibrated with Mobile phase A [0.025M Ammonium acetate in water]. The crude solution was loaded onto the column. The C18 column was stabilized with Mobile phase A. A purification cycle was performed by using the following conditions: Mobile phase A: Mobile phase B [Acetonitrile:Methanol:Isopropanol (8:1:1)]. Elution: Gradient. Desired fractions were collected and distilled under reduced pressure. Purity by HPLC of the desired fractions: 93.49%. Another lot of crude Tirzepatide purified by same manner as exemplified in step-1. Desired fractions were collected and distilled under reduced pressure. Purity by HPLC of the desired fractions: 89.49%. Step-2: The C18 column was equilibrated with Mobile phase A [0.025M Ammonium acetate and 0.1% acetic acid in water]. The above obtained fractions combined and loaded onto the column. The C18 column was stabilized with Mobile phase A. A purification cycle was performed by using the following conditions: Mobile phase A: Mobile phase B [Acetonitrile:Methanol (9:1) and 0.05% acetic acid]. Elution: Gradient. Desired fractions were collected and distilled under reduced pressure. The obtained solution was subjected to lyophilization to get pure Tirzepatide. Yield: 0.38 gm; Purity by HPLC: 99.34%. Example-6: Alternate purification of Tirzepatide by RP-HPLC Step-1: Crude Tirzepatide (9 gm) was dissolved in ammonia in water. The solution was filtered through 0.45 micron filter paper. The C18 column was equilibrated with Mobile phase A [0.005M Ammonium Formate and pH adjusted to 3-4 with TFA in water]. The crude solution was loaded onto the column. The C18 column was stabilized with Mobile phase A. A purification cycle was performed by using the following conditions: Mobile phase A: Mobile phase B [Acetonitrile:Methanol:Water]. Elution: Gradient. Desired fractions were collected and distilled under reduced pressure. Purity by HPLC of the desired fractions: 97%. Step-2: The C18 column was equilibrated with Mobile phase A [0.025M Ammonium acetate in water]. The above obtained fractions were combined and loaded onto the column. The C18 column was stabilized with Mobile phase A. A purification cycle was performed by using the following conditions: Mobile phase A: Mobile phase B [Acetonitrile:Methanol:Isopropanol]. Elution: Gradient. Desired fractions were collected and distilled under reduced pressure. The obtained solution was subjected to lyophilization to get pure Tirzepatide. Yield: 0.515 gm; Purity by HPLC: 99.14%. Example-7: Preparation of compound of formula-2a Step-1: Preparation of compound of formula-5a Dichloromethane (250 ml) was added to compound of formula-3a (50 gm) at 25-30°C. A solution of N-hydroxysuccinimide (21.65 gm), HOBt (1.69 gm) was added to reaction mixture at 25-30°C and stirred for 10 min at the same temperature. DCC (51.74 gm) in dichloromethane (250 ml) was added to reaction mixture at 25-30°C and stirred for 10 min at the same temperature. DIPEA (43.68 ml) was added to reaction mixture at 25-30°C and stirred for 3 hr 30 min at the same temperature. DMF (50 ml) was added to reaction mixture at 25-30°C and stirred for 1 hr 40 min at the same temperature. Filtered the reaction mixture and washed with dichloromethane. Distilled the filtrate under reduced pressure and further cooled to 25-30°C. Co-distilled with acetonitrile (50 ml) under reduced pressure and further cooled to 25-30°C. Acetonitrile (150 ml) was added to reaction mixture at 25-30°C. Further cooled to 5-10°C and stirred for 1 hr 20 min at the same temperature. Filtered the solid and washed with n-heptane to get compound of formula-9a. IPA (250 ml) was added to compound of formula-4a (25.49 gm) at 25-30°C and stirred for 5 min at the same temperature. DIPEA (26.2 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. The obtained compound of formula-9a was added to reaction mixture at 25-30°C and stirred for 2 hr 30 min at the same temperature. Distilled the reaction mixture under reduced pressure and further cooled to 25-30°C. Ethyl acetate (250 ml) was added to reaction mixture at 25-30°C. Sodium bisulfate monohydrate solution (Sodium bisulfate monohydrate (12.5 gm) in water (250 ml)) was added to reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Filtered the reaction mixture with hy flow bed and washed with ethyl acetate. Both the organic and aqueous layers were separated from the filtrate. Sodium bisulfate monohydrate solution (Sodium bisulfate monohydrate (25 gm) in water (500 ml)) was added lot wise to the organic layer at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated. Distilled off the solvent from the organic layer under reduced pressure. Cooled to 25-30°C and co-distilled with n-heptane (50 ml) under reduced pressure. Cooled to 25-30°C. n-Heptane (500 ml) was added to reaction mixture at 25-30°C. Heated the reaction mixture temperature to 40-45°C and stirred for 15 min at the same temperature. Cooled to 5-10°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with n-heptane. Acetonitrile (250 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture temperature to 40-45°C and stirred for 1 hr at the same temperature. Cooled to 25- 30°C. Filtered the solid and washed with acetonitrile and dried to get the title compound. Yield: 39.5 gm; Purity by HPLC: 99.57%. Step-2: Preparation of compound of formula-7a Acetonitrile (150 ml) was added to compound of formula-5a (30 gm) at 25-30°C. TSTU (18.56 gm) was added to reaction mixture at 25-30°C and stirred for 5 min at the same temperature. DIPEA (13.42 ml) was added to reaction mixture at 25-30°C and stirred for 1 hr 10 min at the same temperature. Water (300 ml) was added to the reaction mixture at 25- 30°C and stirred for 1 hr 10 min at the same temperature. Filtered the solid and washed with water to get formula-10a. IPA (150 ml) was added to compound of formula-6 (19 gm) at 25- 30°C and stirred for 5 min at the same temperature. DIPEA (11.60 ml) was added to reaction mixture at 25-30°C. The obtained compound of formula-10a was added to reaction mixture at 25-30°C and stirred for 2 hr at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure and cooled to 25-30°C. Acetonitrile (150 ml) was added to the reaction mixture at 25-30°C and further reaction mixture pH was adjusted to 9- 11 with sodium carbonate solution at 25-30°C. Ethyl acetate (300 ml) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Mixture of acetonitrile (150 ml) and ethyl acetate (300 ml) was added to the aqueous layer at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated. Ethyl acetate (300 ml) was added to the aqueous layer at 25-30°C and further reaction mixture pH was adjusted to 2-4 with sodium bisulfate monohydrate solution at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Sodium bisulfate monohydrate solution was added lot wise to the organic layer at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated. Hy flow was added to organic layer at 25-30°C and stirred for 1 hr 10 min at the same temperature. Filtered the mixture and washed with ethyl acetate. Distilled off the solvent from the filtrate under reduced pressure, co-distilled with dichloromethane and dried to get the title compound. Yield: 36 gm; Purity by HPLC: 95.82%. Step-3: Preparation of compound of formula-2a DCM (50 ml) was added to compound of formula-7a (10 gm) at 25-30°C and stirred 5 min at the same temperature. p-Nitrophenol (1.91 gm) and HOBt (0.15 gm) were added to the reaction mixture at 25-30°C. DIPEA (3 ml) was added to the reaction mixture at 25-30°C. DCC (3.54 gm) in DCM (50 ml) was added to the reaction mixture at 25-30°C and stirred for 3 hr at the same temperature. Filtered the reaction mixture and washed with DCM. Water (100 ml) was added to the obtained filtrate at 25-30°C. The reaction mixture pH was adjusted to 5-6 with dilute HCl solution (2 ml of HCl in 10 ml of water) at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Water (100 ml) was added to the organic layer at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and dried the organic layer with sodium sulfate. TFA (50 ml) was added to the organic layer at 25-30°C and stirred for 2 hr at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure and co-distilled with toluene followed by MTBE. MTBE (200 ml) was added to the obtained compound at 25-30°C and stirred for 2 hr at the same temperature. Filtered the solid and washed with MTBE and dried to get the title compound. Yield: 7.6 gm. Example-8 Preparation of compound of formula-6 Step 1: Preparation of compound of formula-13 DMF (200 ml) was added to compound of formula-11 (100 gm) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Compound of formula-12a (82.08 gm) was added to the reaction mixture at 25-30°C and stirred for 5 min at the same temperature. Sodium carbonate (53.73 gm) followed by potassium iodide (8.4 gm) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 120-125°C and stirred for 6 hr 30 min at the same temperature. Cooled the reaction mixture to 20-25°C. Filtered the reaction mixture and washed with DMF. Water (800 ml) was added to the filtrate at 20-25°C. Reaction mixture pH was adjusted to 2-4 with HCl solution at same temperature. MTBE (300 ml) was added to reaction mixture at 20-25°C and stirred for 10 min at same temperature. Both the organic and aqueous layers were separated. MTBE (300 ml) was added to aqueous layer at 20-25°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Aqueous layer pH was adjusted to 8-10 with ammonia solution at 20-25°C. Toluene (250 ml) was added to reaction mixture at 20-25°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Toluene (250 ml) was added to the aqueous layer at 20-25°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated. Combined the organic layers, water (500 ml) was added to it at 20-25°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Charcoal (50 gm) was added to the organic layer at 20-25°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hy flow bed and washed with toluene. Distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 144.2 gm. Step 2: Preparation of compound of formula-15 THF (500 ml) was added to the compound obtained in step-1 at 25-30°C and cooled the mixture to 10-15°C. Potassium tert-butoxide (KOBt; 85.29 gm) was added lot wise to the reaction mixture at 10-15°C and stirred for 2 hr at the same temperature. Compound of formula-14a; Sodium monochloroacetate (66.42 gm) was added lot wise to the reaction mixture at 10-15°C and stirred for 1 hr 30 min at the same temperature. Another lot of sodium monochloroacetate (22.14 gm) was added to the reaction mixture at 10-15°C. Raised the reaction mixture temperature to 25-30°C and stirred for 8 hr at the same temperature. Cooled the reaction mixture to 20-25°C and water (1000 ml) was added to it. MTBE (500 ml) was added to the reaction mixture at 20-25°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated. MTBE (500 ml) was added to the aqueous layer at 20-25°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated. Aqueous HCl solution was added to the aqueous layer. DCM (500 ml) was added to reaction mixture at 20-25°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with DCM. Again both the organic and aqueous layers were separated and extracted the aqueous layer with DCM. Combined the organic layers and acidic carbon (10 gm) was added to it at 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hy flow bed and washed with DCM. Distilled off the solvent from the organic layer under reduced pressure to get the title compound. Yield: 143 gm. Step 3: Preparation of compound of formula-16a THF (250 ml) was added to the compound obtained in step-2 at 25-30°C. TSTU (183.12 gm), THF (250 ml) were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. DIPEA (132.45 ml) was slowly added to the reaction mixture at 25- 30°C and stirred for 2 hr at the same temperature to get the title compound. Step 4: Preparation of compound of formula-18 A solution of water (500 ml) and sodium bicarbonate (51.09 gm) was added to compound of formula-17 (99.25 gm) at 25-30°C and stirred for 10 min at the same temperature. Compound obtained in step-3 was slowly added to reaction mixture at 25-30°C and stirred for 3 hr at the same temperature. Cooled the reaction mixture to 15-20°C and then water (500 ml) was added to it at 15-20°C and stirred for 15 min at the same temperature. MTBE (500 ml) was added to the reaction mixture at 15-20°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated. MTBE (500 ml) was added to aqueous layer at 20-25°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated. Sodium chloride solution was added to the aqueous layer at 20-25°C and stirred for 3 hr at the same temperature. Cooled the reaction mixture to 10- 15°C and pH was adjusted to 2-3 with HCl solution at same temperature. DCM (500 ml) was added to reaction mixture at 10-15°C. Raised the reaction mixture temperature to 20-25°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with DCM. Combined the organic layers, triethylamine was added to it at 25-30°C. Charcoal (10 gm) was added to the reaction mixture at 20-25°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hy flow bed and washed with DCM. Distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 228 gm. Step 5: Preparation of compound of formula-19 IPA (250 ml) was added to the compound obtained in step-4 at 25-30°C. 5% Pd-C solution (10 gm Pd-C in 250 ml of IPA) was added to the reaction mixture at 25-30°C. Hydrogen gas pressure was applied to the reaction mixture at 25-30°C. Heated the reaction mixture to 55- 60°C and stirred for 18 hr at the same temperature. Cooled the reaction mixture to 25-30°C to get the title compound. Step 6: Preparation of compound of formula-6 5% Pd-C (10 gm of Pd-C in 100 ml of IPA) was added to the reaction mixture obtained in step 5 at 25-30°C. Hydrogen gas pressure was applied to the reaction mixture. Heated the reaction mixture to 55-60°C and stirred for 16 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Methanol (500 ml) was added to the reaction mixture at 25- 30°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture through hy flow bed and washed with methanol. Distilled off the solvent from the filtrate under reduced pressure and co-distilled with acetonitrile under reduced pressure. Cooled the reaction mixture to 25-30°C. Acetonitrile (300 ml) was added to the obtained compound at 25-30°C. Triethylamine was added to the reaction mixture at 25-30°C and stirred for 6 hr at the same temperature. Cooled the reaction mixture 5-10°C and stirred for 5 hr 20 min at the same temperature. Filtered the reaction mixture and washed with acetonitrile. MTBE (500 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr 30 min at the same temperature. Filtered solid and washed with MTBE. A mixture of IPA (200 ml) and methanol (20 ml) was added to the obtained compound at 25-30°C and stirred for 10 min at the same temperature. Raised the temperature of the reaction mixture to 65-70°C and stirred for 2 hr at the same temperature. Filtered the solid, washed with IPA and dried. Acetonitrile (300 ml) was added to the obtained compound at 25-30°C. Methanol (20 ml) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 1 hr 20 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr 30 min at the same temperature. Filtered the solid, washed with acetonitrile and dried to get the title compound. Yield: 48 gm; Purity by HPLC: 95.14%. *****

Claims

We Claim:

1. An improved process for the preparation of Tirzepatide, comprising; a) coupling Fmoc-Ser(tBu)-OH with Resin, b) capping the Resin, c) selectively deprotecting the Fmoc group, d) repeating steps-a) & c) to couple remaining amino acids which are optionally protected as per the desired peptide sequence of the Tirzepatide to the compound obtained in step c) in presence of a coupling agent optionally in presence of a solvent to provide Resin bound Tirzepatide backbone, e) converting the compound obtained in step-d) to Tirzepatide or its salt, f) purifying Tirzepatide or its salt to provide pure Tirzepatide or its salt.

2. The process as claimed in claim 1, wherein in the process of step-d) various amino acids of Tirzepatide backbone are optionally protected with different protecting groups which include but not limited to alkyloxy carbonyl such as methoxy carbonyl, ethoxy carbonyl, tert.butoxycarbonyl (Boc) and the like; benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), allyloxy carbonyl (Alloc), tert.butyl (tBu), 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf), p- methoxy benzyloxycarbonyl (Moz), p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), formyl (CHO), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 1-adamantyloxycarbonyl (Adoc), 2-(p-biphenyl)isopropyloxycarbonyl (Bpoc), triphenylmethyl (Trityl or Trt), methoxymethyl (MOM), allyl, N-benzyloxymethyl (Bom), Tosyl (Tos), monomethoxytrityl (Mmt), methyltrityl (Mtt), 2,4-dimethylpent-3-yloxycarbonyl (Doc), tert-butoxymethyl (Bum), 2-(4-nitrophenyl) ethoxycarbonyl (Npeoc), 2,2,2- trichloroethoxycarbonyl (Troc), N-dithiasuccinoyl (Dts), benzothiazol-2-sulfonyl (Betsyl), 1,1-dimethyl-2,2,2-trichloroethoxy carbonyl (TcBoc), N-(diphenyl-4-pyridyl)methyl (Dppm), Dde, IVDde and the like.

3. The process as claimed in claim 1, wherein the Resin is selected from Rink Amide Resin, Rink Amide AM Resin, Rink Amide MBHA Resin, PAL Resin, Sieber Amide Resin and step b) is carried out in a solvent optionally in presence of a base; 1the solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, water and the like or mixtures thereof; the base is selected from diisopropylethyl amine (DIPEA), diisopropylamine, pyridine, triethylamine, N-methylmorpholine or combination thereof; the coupling agent is selected from N,N'-dicyclohexylcarbodiimide, N,N‟- diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), N,N‟-carbonyl diimidazole (CDI), 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-(1Hbenzotriazol- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1H-benzo triazolium 1-[bis(dimethylamino)methylene]-5-chloro-hexafluorophosphate(1)-3-oxide (HCTU), (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluoro phosphate 15 (BOP), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxy-7-azatriazole (HOAt), 1-hydroxy benzotriazole (HOBt),1-hydroxy- 1H-1,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N- hydroxysulfosuccinimide (Sulfo-NHS), N-Hydroxyphthalimide (NHPI), ethyl cyanohydroxyiminoacetate (Oxyma), 7-Azabenzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), N,N,N′,N′- TetramethylO-(N-succinimidyl)uronium tetrafluoroborate (TSTU) or mixtures thereof; the Fmoc deprotection can be carried out by using bases such as piperidine, piperazine, DBU optionally in presence of a solvent such as DMF, NMP, THF, 2-methyl THF and the like.

4. The process as claimed in claim 1, wherein the capping in step-b) is carried out by using acetic anhydride optionally in presence of a base and a solvent; wherein the base is selected from organic bases such as diisopropylethyl amine (DIPEA), diisopropylamine, pyridine, triethylamine, N-methylmorpholine and the solvent is selected from DCM, DMF, THF, methanol, ethanol and the like or mixtures thereof.

25. The process as claimed in claim 1, wherein in step-e) the conversion can be carried out by cleavage of the peptide chain from the Resin and deprotection of all the amino acids wherever applicable by using “cocktail mixture / cleaving reagent” and reacting the obtained compound with compound of formula-2 wherein 'R1' wherevernecessary can Br & I, ΝO2 and the substitution can take place at single or multiple positions on aryl group or R1 is in a solvent optionally in presence of a a coupling agent.

6. The process as claimed in claim 1, wherein in step-e) the conversion is carried out by deprotection of Lysine (if applicable), coupling of compound of formula-2 to the backbone at Lysine followed by deprotection of the amino acids and cleavage of the peptide chain from the Resin by using “cocktail mixture / cleaving reagent”.

7. The process as claimed in claim 1, wherein when the protection group on Lysine at position 20 is Alloc group, the conversion in step-e) is carried out by deprotecting the Alloc protecting group of Lysine by using Alloc deprotecting agent optionally in presence of a base and a solvent, coupling of compound of formula-2 wherein, 'R1'wherever necessary can be independently selected from halogens such as F, CI, Br & I, ΝO2 and the substitution can take place at single or multiple positions on aryl group or R1isto the back bone at Lysine in a solvent optionally in presence of a base and / or a coupling agent followed by deprotection of the amino acids and cleavage of the peptide chain from the Resin by using “cocktail mixture / cleaving reagent” to provide Tirzepatide.

8. The process as claimed in claim 7, wherein the “cocktail mixture / cleaving reagent” comprises HF, TFA (trifluoroacetic acid), TIS or TIPS (triisopropylsilane), Acetic acid, Hydrochloric acid, Phosphoric acid, Perchloric acid, Phenol, Anisole, Thioanisole, EDT (Ethane-1,2-dithiol), 1-dodecanethiol (DDT), Dithiothreitol (DTT), 3,6-dioxa-1,8- octanedithiol (DODT), methanesulfonic acid, water or mixtures thereof.

9. An improved process for the preparation of Tirzepatide, comprising; a) coupling Fmoc-Ser(tBu)-OH with Resin optionally in presence of a coupling agent and a solvent to provide Fmoc-Ser(tBu)-Resin, b) capping the Resin, c) Fmoc deprotection of Fmoc-Ser(tBu)-Resin by using a base optionally in presence of a solvent to provide H-Ser(tBu)-Resin, d) repeating the coupling and Fmoc deprotection steps with amino acids Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala- OH, Fmoc-Ile-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc- Aib-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc- Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Aib-OH and Boc-Tyr(tBu)-OH to the compound obtained in step c) to provide Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Resin, e) deprotecting the Alloc protecting group by using Alloc deprotecting agent optionally in presence of a base and a solvent, 4f) coupling compound of formula-2a with the compound obtained in step-e) in a solvent optionally in presence of a base to provide Resin bound protected Tirzepatide, g) treating to provideh) subjecting Tirzepatide to purification to provide pure Tirzepatide.

10. The process as claimed in claim 9, wherein, coupling step is carried out in presence of a coupling agent and / or a base in a solvent; Capping step is carried out by using an acetic anhydride, in presence of base and a solvent; Fmoc deprotection step is carried out by using base optionally in presence of a solvent; Alloc deprotection step is carried out by using Alloc deprotecting agent like tetrakis(triphenylphosphine)palladium(0) (Pd(pph3)4) optionally in presence of a base such as morpholine, N-methylmorpholine (NMM), DBU, piperidine, N- methylaniline and a solvent which is selected from dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), dichloromethane (DCM), dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and the like or mixtures thereof; 11. An improved process for the preparation of Tirzepatide, comprising; a) treating Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(Alloc)-Ala- Phe-Val-Gln(Trt)-Trp(Boc)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-Resin with Alloc deprotecting agent optionally in presence of a base and a solvent, 5b) coupling compound of formula-2a with the compound obtained in step-a) in a solvent optionally in presence of a base to provide Resin bound protected Tirzepatide, c) treating the to provideTirzepatide, d) subjecting Tirzepatide to purification to provide pure Tirzepatide.

12. A compound represented by the following structural formula-2 wherein 'R1'wherever necessary can be independently selected from halogens such as F, CI, Br & I, ΝO2and the substitution can take place at single or multiple positions on aryl group or R1 is 13. The compound as claimed in claim the novel intermediate compound isrepresented by the following structural formula-2a14. A process for6wherein, 'R1' represents substituted or unsubstituted aryl and the substituents wherever necessary can be independently selected from halogens such as F, CI, Br & I, ΝO2 and the substitution can take place at single or multiple positions on aryl group or R1is a) reacting compound of a solvent optionally in presence of a coupling agent and / or a base of formula-8,b) treating a agent presence of a solvent to provide compound of formula-2.

15. The process as claimed in claim 14, the deprotecting agent is selected from acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid (TFA), methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid; acetyl chloride in combination with alcohols and the like, hydrogenating agents such as Pd / C, Pd(OH)2 / C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh / C, Raney-Ni, Zn-acetic acid, tri(C1-C6)alkylsilanes, tri(C1-C6) alkylsilyl halides and the like.

16. A compound represented by the following structural formula-16,17. ed by the following structural formula-16a 18. A compound18 19. A process fora) treating a optionally in presence of a base to provide compound of formula-16, .8b) reacting compound of formula-16 with compound of formula-17 in a solvent optionally in presence of a base to provide compound of formula-18, c) in presence ofa solvent to provide compound of formula-6, d) optionally purifying the compound of formula-6 with a solvent to provide pure compound of formula-6.

20. The process as claimed in claim 19, wherein, the solvent in step-a) to step-d) wherever necessary is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, water and the like or mixtures thereof; the base in step-a) and step-b) is selected from inorganic bases, organic bases or mixtures thereof; The debenzylating agent in step-c) is selected from Pd / C, Raney-Ni, Pd(OH)2 / C, palladium acetate, platinum oxide, Rhodium and the like. ***** 9

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